Comprehensive molecular pharmacology screening reveals potential new receptor interactions for clinically relevant opioids

Most clinically used opioids are thought to induce analgesia through activation of the mu opioid receptor (MOR). However, disparities have been observed between the efficacy of opioids in activating the MOR in vitro and in inducing analgesia in vivo. In addition, some clinically used opioids do not produce cross-tolerance with each other, and desensitization produced in vitro does not match tolerance produced in vivo. These disparities suggest that some opioids could be acting through other targets in vivo, but this has not been comprehensively tested. We thus screened 9 clinically relevant opioids (buprenorphine, hydrocodone, hydromorphone, morphine, 0-desmethyl-tramadol, oxycodone, oxymorphone, tapentadol, tramadol) against 9 pain-related receptor targets (MOR, delta opioid receptor [DOR], kappa opioid receptor [KOR], nociceptin receptor [NOP], cannabinoid receptor type 1 [CB1], sigma-1 receptor [al R], and the monoamine transporters [NET/SERT/DAT]) expressed in cells using radioligand binding and functional activity assays. We found several novel interactions, including monoamine transporter activation by buprenorphine and al R binding by hydrocodone and tapentadol. Tail flick anti-nociception experiments with CD-1 mice demonstrated that the monoamine transporter inhibitor duloxetine selectively promoted buprenorphine anti-nociception while producing no effects by itself or in combination with the most MOR-selective drug oxymorphone, providing evidence that these novel interactions could be relevant in vivo. Our findings provide a comprehensive picture of the receptor interaction profiles of clinically relevant opioids, which has not previously been performed. Our findings also suggest novel receptor interactions for future investigation that could explain some of the disparities observed between opioid performance in vitro and in vivo.Depomed, Inc.; University of ArizonaOpen access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Turbulence, Cost Escalation and Capital Intensity Bias in Defense Contracting

The recent growth of defense expenditures has once more raised public concern about cost overruns on defense contractors. Economists have pointed out that cost overruns are not necessarily bad per se; instead, attention should be directed to the question as to whether the procurement policies of the Department of Defense (DoD) satisfy the criterion of economic efficiency (see Peck and Sherer (1962)). In connection with this, applications of the principal-agent model to defense contracting show that not only do cost plus fixed fee (CPFF) contracts create moral hazard problems, but that in fact so long as contractors are risk averse and perfect monitoring of their activities is not possible, inefficiencies will arise whatever the form of the contract employed in DoD procurement (see Ross (1973), Harris and Raviv (1979), and Weitzman (1980)). It has been suggested that improvements in efficiency might be achieved if contracts more closely resembling Arrow-Debreu contingent claims were employed (see Cummins (1977)), but this raises problems of manipulation of the probabilities of occurrence of the relevant states of the world. Looking at the problem of cost escalation from a completely different point of view, biases might be introduced into cost comparisons and into decision making with respect to risky projects simply because of the methodology by cost estimators (see Quirk and Terasawa (1983))

Turbulence, Cost Escalation and Capital Intensity Bias in Defense Contracting

The recent growth of defense expenditures has once more raised public concern about cost overruns on defense contractors. Economists have pointed out that cost overruns are not necessarily bad per se; instead, attention should be directed to the question as to whether the procurement policies of the Department of Defense (DoD) satisfy the criterion of economic efficiency (see Peck and Sherer (1962)). In connection with this, applications of the principal-agent model to defense contracting show that not only do cost plus fixed fee (CPFF) contracts create moral hazard problems, but that in fact so long as contractors are risk averse and perfect monitoring of their activities is not possible, inefficiencies will arise whatever the form of the contract employed in DoD procurement (see Ross (1973), Harris and Raviv (1979), and Weitzman (1980)). It has been suggested that improvements in efficiency might be achieved if contracts more closely resembling Arrow-Debreu contingent claims were employed (see Cummins (1977)), but this raises problems of manipulation of the probabilities of occurrence of the relevant states of the world. Looking at the problem of cost escalation from a completely different point of view, biases might be introduced into cost comparisons and into decision making with respect to risky projects simply because of the methodology by cost estimators (see Quirk and Terasawa (1983))