Pain market

Melnikova, Irena

doi:10.1038/nrd3226

Cited by 135 publications

(100 citation statements)

References 3 publications

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“…Opioid analgesics are the most efficacious drugs for the treatment of moderate to severe pain and represent the largest market share of prescription pain medications (Melnikova, 2010). Although opioids are effective pain relievers, they also produce a number of adverse side effects that can limit their clinical utility, including nausea and vomiting, constipation, and respiratory suppression.…”

Section: Introductionmentioning

confidence: 99%

Functional Selectivity at the μ-Opioid Receptor: Implications for Understanding Opioid Analgesia and Tolerance

et al. 2011

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Section: Introductionmentioning

confidence: 99%

Functional Selectivity at the μ-Opioid Receptor: Implications for Understanding Opioid Analgesia and Tolerance

et al. 2011

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“…This article focuses on CNS drug safety testing, the dynamics between development and Safety Pharmacology methods and strategic approaches that have been taken to garner marketing authorization of a new molecular entity (NME) under New Drug Applications (NDAs) or as new therapeutic biologic under a Biologics License Application (BLA). The aging population has benefited from a moderate but progressive increase in drug development efforts for neurological indications (Melnikova, 2010) and the CNS drug market is forecast to grow to $81.8 billion in 2015 (BCC Research, 2010).…”

Section: Introductionmentioning

confidence: 99%

Safety Pharmacology Investigations on the Nervous System: An Industry Survey

Authier

2017

Journal of Pharmacological and Toxicological Methods

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Abstract:The Safety Pharmacology Society (SPS) conducted an industry survey in 2015 to identify industry practices as they relate to central, peripheral and autonomic nervous system ("CNS") drug safety testing. One hundred fifty-eight (158) participants from Asia (16%), Europe (20%) and North America (56%) responded to the survey. 52% of participants were from pharmaceutical companies (>1,000 employees). Oncology (67%) and neurology/psychiatry (66%) were the most frequent target indications pursued by companies followed by inflammation (48%), cardiovascular (43%), metabolic (39%), infectious (37%), orphan (32%) and respiratory (29%) diseases. Seizures (67% of participants), gait abnormalities (67%), tremors (65%), emesis (56%), sedation (52%) and salivation (47%) were the most commonly encountered CNS issues in pre-clinical drug development while headache (65%), emesis/nausea (60%), fatigue (51%) and dizziness (49%) were the most frequent issues encountered in Phase I clinical trials. 54% of respondents reported that a standard battery of tests applied to screen drug candidates was the approach most commonly used to address nonclinical CNS safety testing. A minority (14% of all participants) reported using electroencephalography (EEG) screening prior to animal inclusion on toxicology studies. The most frequent group size was n=8 for functional observation battery (FOB), polysomnography and seizure liability studies. FOB evaluations were conducted in a dedicated room (78%) by blinded personnel (66%) with control for circadian cycle (55%) effects (e.g., dosing at a standardized time; balancing time of day across treatment groups). The rat was reported as the most common species used for seizure liability, nerve conduction and drug-abuse liability testing.

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“…Opioids targeting the m-opioid receptors (MOPs) are still the most powerful analgesics used for the treatment of moderate to severe pain conditions (Melnikova, 2010). However, the use of MOP agonists is often limited by the occurrence of adverse effects such as constipation and nausea (Cherny et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Label-Free Monitoring ofμ-Opioid Receptor–Mediated Signaling

et al. 2014

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In this study, we used a combination of traditional signaling investigation approaches, bioluminescence resonance energy transfer (BRET) biosensors, and the label-free approach surface plasmon resonance (SPR) spectroscopy to monitor the signaling cascades of the m-opioid receptor (MOP). In human embryonic kidney cells stably expressing a Flag-tagged version of human MOP, we compared the signals triggered by the noninternalizing and internalizing MOP agonists morphine and DAMGO (Tyr-DAla-Gly-N-methyl-Phe-Gly-ol), respectively. We studied three major and well described components of MOP signaling: receptor internalization, G protein coupling, and activation of extracellular signal-regulated kinase ERK1/ERK2. Our results show that morphine and DAMGO display different profiles of receptor internalization and a similar ability to trigger the phosphorylation of ERK1/ERK2. Our SPR analyses revealed that morphine and DAMGO evoke similar SPR signatures and that Ga i , cAMP-dependent pathways, and ERK1/ERK2 have key roles in morphine-and DAMGO-mediated signaling. Most interestingly, we found that the so-called MOP neutral antagonists CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH 2 ), naloxone, and naltrexone behave like partial agonists. Even more intriguing, BRET experiments indicate that CTAP (D-Phe-CysTyr-D-Trp-Arg-Thr-Pen-Thr-NH 2 ) induces similar conformational changes as naltrexone at the Ga i -bg interface, whereas it appears as an inverse agonist based on its SPR response thus indicating distinct signaling mechanisms for the two ligands. Taken together, our results support the usefulness of labelfree methods such as SPR to study whole-cell responses and signaling cascades triggered by G protein-coupled receptors and complement the conventional approaches by revealing cellular responses that would have been otherwise undetectable.

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Pain market

Cited by 135 publications

References 3 publications

Functional Selectivity at the μ-Opioid Receptor: Implications for Understanding Opioid Analgesia and Tolerance

Functional Selectivity at the μ-Opioid Receptor: Implications for Understanding Opioid Analgesia and Tolerance

Safety Pharmacology Investigations on the Nervous System: An Industry Survey

Label-Free Monitoring ofμ-Opioid Receptor–Mediated Signaling

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