Advances in Reversal Strategies of Opioid-induced Respiratory Toxicity

Opioids may produce life-threatening respiratory depression and death from their actions at the opioid receptors within the brainstem respiratory neuronal network. Since there is an increasing number of conditions where the administration of the opioid receptor antagonist naloxone is inadequate or undesired, there is an increased interest in the development of novel reversal and prevention strategies aimed at providing efficacy close to that of the opioid receptor antagonist naloxone but with fewer of its drawbacks such as its short duration of action and lesser ability to reverse high-affinity opioids, such as carfentanil, or drug combinations. To give an overview of this highly relevant topic, the authors systematically discuss predominantly experimental pharmacotherapies, published in the last 5 yr, aimed at reversal of opioid-induced respiratory depression as alternatives to naloxone. The respiratory stimulants are discussed based on their characteristics and mechanism of action: nonopioid controlled substances (e.g., amphetamine, cannabinoids, ketamine), hormones (thyrotropin releasing hormone, oxytocin), nicotinic acetylcholine receptor agonists, ampakines, serotonin receptor agonists, antioxidants, miscellaneous peptides, potassium channel blockers acting at the carotid bodies (doxapram, ENA001), sequestration techniques (scrubber molecules, immunopharmacotherapy), and opioids (partial agonists/antagonists). The authors argue that none of these often still experimental therapies are sufficiently tested with respect to efficacy and safety, and many of the agents presented have a lesser efficacy at deeper levels of respiratory depression, i.e., inability to overcome apnea, or have ample side effects. The authors suggest development of reversal strategies that combine respiratory stimulants with naloxone. Furthermore, they encourage collaborations between research groups to expedite development of viable reversal strategies of potent synthetic opioid-induced respiratory depression.

Gut Microbiota and Serotonin - Biochemical Pathways in Age-Related Macular Disease

Age-related macular degeneration (AMD) is a multifactorial disease and is a major cause of blindness in the entire world. Current studies show a tight connection between gut microbiota and AMD. This literature review shows the positive role played by gut microbiota, which is essential in providing the optimal serotonin level in retina protection against the noxious action of various factors of the environment. Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter derived from tryptophan which is poorly expressed in the retina, but it may provide protection against retinal damage, such as light-induced retinopathy and age-related macular degeneration, due to the fact that certain serotonin receptor agonists and antagonists of those 7 classes and 17 subtypes of 5-HT receptors help prevent serum deprivation, anoxia and oxidative damage. Our study also shows the role played by other diet-related factors, which protect retina against oxidative stress and delay the onset of AMD.

Drug-Induced Serotonin Syndrome

Serotonin syndrome is a potentially fatal condition caused by drugs that affect serotonin metabolism or act as serotonin receptor agonists. Monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors are the medications most commonly associated with serotonin syndrome. Serotonin syndrome can be mild and of short duration, but a prolonged course, life-threatening complications, and death are possible. Detection of serotonin syndrome is not difficult if the diagnostic criteria are understood and properly used, but the syndrome has no confirmatory tests and other drug-induced syndromes can, to a degree, mimic serotonin syndrome. The treatment is symptomatic and supportive. Antidotal therapies are available, but the evidence for their effectiveness is limited. If serotonin syndrome is promptly identified and aggressively treated, the patient should fully recover.

ePrescribing: Reducing Costs through In-Class Therapeutic Interchange

SummaryIntroduction Spending on pharmaceuticals in the US reached $373.9 billion in 2014. Therapeutic interchange offers potential medication cost savings by replacing a prescribed drug for an equally efficacious therapeutic alternative.Methods Hard-stop therapeutic interchange recommendation alerts were developed for four medication classes (HMG-CoA reductase inhibitors, serotonin receptor agonists, intranasal steroid sprays, and proton-pump inhibitors) in an electronic prescription-writing tool for outpatient prescriptions. Using prescription data from January 2012 to June 2015, the Compliance Ratio (CR) was calculated by dividing the number of prescriptions with recommended therapeutic interchange medications by the number of prescriptions with non-recommended medications to measure effectiveness. To explore potential cost savings, prescription data and medication costs were analyzed for the 45,000 Vanderbilt Employee Health Plan members.Results for all medication classes, significant improvements were demonstrated – the CR improved (proton-pump inhibitors 2.8 to 5.32, nasal steroids 2.44 to 8.16, statins 2.06 to 5.51, and serotonin receptor agonists 0.8 to 1.52). Quarterly savings through the four therapeutic interchange interventions combined exceeded $200,000 with an estimated annual savings for the health plan of $800,000, or more than $17 per member.Conclusion A therapeutic interchange clinical decision support tool at the point of prescribing resulted in increased compliance with recommendations for outpatient prescriptions while producing substantial cost savings to the Vanderbilt Employee Health Plan – $17.77 per member per year.Therapeutic interchange rules require rational targeting, appropriate governance, and vigilant content updates.Citation: Stenner SP, Chakravarthy R, Johnson KB, Miller WL, Olson J, Wickizer M, Johnson NN, Ohmer R, Uskavitch DR, Bernard GR, Neal EB, Lehmann CU. eprescribing: reducing costs through in-class therapeutic interchange.

The role of triptans in the management of migraine

Migraine is one of the most prevalent disorders seen in clinical practice today and also a major cause of disability in the workplace. The prevalence of migraine is highest during the years of peak productivity, ie, between the ages of 25 and 55 years. The triptans are a group of selective 5-hydroxtriptamine (HT)1 serotonin receptor agonists that activate the 5-HT1B/1D receptor and possibly also the 5-HT1A dan 5-HT1F receptors. To date 7 subclasses of serotonin receptors have been identified, namely subclasses 5-HT1 to 5-HT7. Triptan causes cranial vasoconstriction, inhibits peripheral trigeminal activity and the trigeminal afferents. With its triple action, triptans can control acute attacks of migraine. Triptan is contraindicated in patients with previous ischemic or coronary artery disease, cerebral or peripheral vascular disease and other cardiovascular disorders. Triptans should be given immediately after an acute attack of migraine. The triptans are useful in the management of an acute migraine, but are not indicated for preventive therapy of migraine. Several new advances in migraine management have been made in regard to the recognition of the disease, the pathogenesis of migraine, and the phenomenon of central sensitization. More treatment options become available to patients and prescribers, the impact of such therapy on worker productivity will become more important in determining the value of such interventions.

Alterations of Hormone-Sensitive Adenylyl Cyclase System in the Tissues of Rats with Long-Term Streptozotocin Diabetes and the Influence of Intranasal Insulin

One of the causes of complications in type 1 diabetes mellitus (T1DM) is the changes in adenylyl cyclase (AC) signaling system, identified on the early stages of the disease. However, the most significant disturbances in this system occur on the later stages of T1DM, which ultimately leads to severe complications, but functional state of the AC system in late T1DM is poorly understood. The aim of this work was to study alterations in AC system sensitive to biogenic amines and polypeptide hormones in the heart, brain, and testes of male rats with long-term, 7-month, streptozotocin T1DM and to assess the influence on them of 135-day therapy with intranasal insulin. It was shown that AC effects of β-adrenergic agonists in the heart, serotonin receptor agonists and PACAP-38 in the brain, chorionic gonadotropin and PACAP-38 in the testes, and somatostatin in all investigated tissues in long-term T1DM were drastically decreased. The treatment with intranasal insulin (0.48 IU/day) significantly restored these effects. The results were obtained suggesting that long-term T1DM induces significant alterations in hormone-sensitive AC system in the heart, brain, and testes that are much more pronounced, compared with short-term T1DM, and include a large number of hormonal regulations.

Paracrine modulation of cholangiocyte serotonin synthesis orchestrates biliary remodeling in adults

Paracrine signaling between cholangiocytes and stromal cells regulates biliary remodeling. Cholangiocytes have neuroepithelial characteristics and serotonin receptor agonists inhibit their growth, but whether they are capable of serotonin biosynthesis is unknown. We hypothesized that cholangiocytes synthesize serotonin and that cross talk between liver myofibroblasts (MF) and cholangiocytes regulates this process to influence biliary remodeling. Transwell cultures of cholangiocytes ± MF, and tryptophan hydroxylase-2 knockin (TPH2KI) mice with an inactivating mutation of the neuronal tryptophan hydroxylase (TPH) isoform, TPH2, were evaluated. Results in the cell culture models confirm that cholangiocytes have serotonin receptors and demonstrate for the first time that these cells express TPH2 and produce serotonin, which autoinhibits their growth but stimulates MF production of TGF-β1. Increased TGF-β1, in turn, counteracts autocrine inhibition of cholangiocyte growth by repressing cholangiocyte TPH2 expression. Studies of TPH2KI mice confirm that TPH2-mediated production of serotonin plays an important role in remodeling damaged bile ducts because mice with decreased TPH2 function have reduced biliary serotonin levels and exhibit excessive cholangiocyte proliferation, accumulation of aberrant ductules and liver progenitors, and increased liver fibrosis after bile duct ligation. This new evidence that cholangiocytes express the so-called neuronal isoform of TPH, synthesize serotonin de novo, and deploy serotonin as an autocrine/paracrine signal to regulate regeneration of the biliary tree complements earlier work that revealed that passive release of serotonin from platelets stimulates hepatocyte proliferation. Given the prevalent use of serotonin-modulating drugs, these findings have potentially important implications for recovery from various types of liver damage.