Publications by authors named "Maree T Smith"

115 Publications

Design, synthesis and evaluation of alpha lipoic acid derivatives to treat multiple sclerosis-associated central neuropathic pain.

Bioorg Med Chem 2022 09 20;69:116889. Epub 2022 Jun 20.

School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland 4072, Australia. Electronic address:

Multiple sclerosis-associated central neuropathic pain (MS-CNP) is difficult to alleviate with clinically used pain-killers and so there is a large unmet medical need for novel treatments for alleviating MS-CNP. Although (R)-alpha lipoic acid (ALA) evoked significant pain relief efficacy in a mouse model of multiple sclerosis-associated central neuropathic pain (MS-CNP), this dietary supplement has poor oral bioavailability due to low gastric stability. Eight ester prodrugs of the R enantiomer of ALA [(R)-ALA] were designed encompassing a range of biocompatible hydrophobic and hydrophilic features and synthesized in an effort to identify a prodrug candidate that was stable at gastric and upper gastrointestinal tract (GIT) pH, and that could be released (hydrolyzed by esterases) in the blood to (R)-ALA immediately after absorption into the portal vein (i.e., highly desirable features for pain relief development). These biocompatible hydrophobic and hydrophilic (R)-ALA pro-dugs underwent comprehensive preliminary screening to reveal PD-ALA4 HCl salt (10) as a promising candidate and PD-ALA 7 (8) could be a viable substitute, utilizing enzyme-free gastric and intestinal stability assessments, LogP evaluations, in vitro plasma stability and caco-2 cell monolayer permeability.
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http://dx.doi.org/10.1016/j.bmc.2022.116889DOI Listing
September 2022

Analgesic Opioid Ligand Discovery Based on Nonmorphinan Scaffolds Derived from Natural Sources.

J Med Chem 2022 02 7;65(3):1612-1661. Epub 2022 Jan 7.

Strong opioid analgesics, including morphine, are the mainstays for treating moderate to severe acute pain and alleviating chronic cancer pain. However, opioid-related adverse effects, including nausea or vomiting, sedation, respiratory depression, constipation, pruritus (itch), analgesic tolerance, and addiction and abuse liability, are problematic. In addition, the use of opioids to relieve chronic noncancer pain is controversial due to the "opioid crisis" characterized by opioid misuse or abuse and escalating unintentional death rates due to respiratory depression. Hence, considerable research internationally has been aimed at the "Holy Grail" of the opioid analgesic field, namely the discovery of novel and safer opioid analgesics with improved opioid-related adverse effects. In this Perspective, medicinal chemistry strategies are addressed, where structurally diverse nonmorphinan-based opioid ligands derived from natural sources were deployed as lead molecules. The current state of play, clinical or experimental status, and novel opioid ligand discovery approaches are elaborated in the context of retaining analgesia with improved safety and reduced adverse effects, especially addiction liability.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01915DOI Listing
February 2022

Sustained-release ketamine-loaded lipid-particulate system: in vivo assessment in mice.

Drug Deliv Transl Res 2021 Nov 20. Epub 2021 Nov 20.

Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia.

Ketamine is used as an analgesic adjuvant in patients with chronic cancer-related pain. However, ketamine's short half-life requires frequent dose administration. Our aim was to develop a sustained release formulation of ketamine with high loading and to evaluate the in vivo pharmacokinetics and biodistribution in mice. Here, ketamine hydrochloride sustained-release lipid particles (KSL) were developed using the thin-film hydration method. The mean (± SD) encapsulation efficiency (EE) and drug loading (DL) of KSL were 65.6 (± 1.7)% and 72.4 (± 0.5)% respectively, and the mean (± SD) size of the lipid particles and the polydispersity index were 738 (± 137) nm and 0.44 (± 0.02) respectively. The release period of KSL in pH 7.4 medium was 100% complete within 8 h in vitro but a sustained-release profile was observed for more than 5 days after intravenous injection in mice. Importantly, the KSL formulation resulted in a 27-fold increase in terminal half-life, a threefold increase in systemic exposure (AUC), and a threefold decrease in clearance compared with the corresponding pharmacokinetics for intravenous ketamine itself. Our findings demonstrate high encapsulation efficiency of ketamine in the sustained-release KSL formulation with prolonged release in mice after systemic dose administration despite 100% in vitro release within 8 h that requires future investigation.
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http://dx.doi.org/10.1007/s13346-021-01093-3DOI Listing
November 2021

Optimisation of a Microfluidic Method for the Delivery of a Small Peptide.

Pharmaceutics 2021 Sep 18;13(9). Epub 2021 Sep 18.

Faculty of Medicine, School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia.

Peptides hold promise as therapeutics, as they have high bioactivity and specificity, good aqueous solubility, and low toxicity. However, they typically suffer from short circulation half-lives in the body. To address this issue, here, we have developed a method for encapsulation of an innate-immune targeted hexapeptide into nanoparticles using safe non-toxic FDA-approved materials. Peptide-loaded nanoparticles were formulated using a two-stage microfluidic chip. Microfluidic-related factors (i.e., flow rate, organic solvent, theoretical drug loading, PLGA type, and concentration) that may potentially influence the nanoparticle properties were systematically investigated using dynamic light scattering and transmission electron microscopy. The pharmacokinetic (PK) profile and biodistribution of the optimised nanoparticles were assessed in mice. Peptide-loaded lipid shell-PLGA core nanoparticles with designated size (~400 nm) and a sustained in vitro release profile were further characterized in vivo. In the form of nanoparticles, the elimination half-life of the encapsulated peptide was extended significantly compared with the peptide alone and resulted in a much higher distribution into the lung. These novel nanoparticles with lipid shells have considerable potential for increasing the circulation half-life and improving the biodistribution of therapeutic peptides to improve their clinical utility, including peptides aimed at treating lung-related diseases.
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http://dx.doi.org/10.3390/pharmaceutics13091505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8468767PMC
September 2021

Pharmacological characterization of the chronic phase of the monoiodoacetate-induced rat model of osteoarthritis pain in the knee joint.

Clin Exp Pharmacol Physiol 2021 11 22;48(11):1515-1522. Epub 2021 Aug 22.

Faculty of Medicine, School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia.

For patients with osteoarthritis (OA) of the knee, pain is the most debilitating symptom. Although it has been proposed that the chronic phase of the monoiodoacetate (MIA)-induced rodent model of knee joint pain may be superior to other chronic or acute OA models for assessing the analgesic efficacy of novel molecules, relatively few pharmacological studies have been conducted in the chronic phase of this model. Hence, this study was designed to use pharmacological methods to characterize the chronic phase of the MIA-induced rat model of knee joint OA pain. Rats received a single intraarticular injection of MIA at 2.5 mg or vehicle (saline) into the left (ipsilateral) knee joint. Pain behaviour was assessed by measuring paw withdrawal thresholds (PWTs) in the hindpaws pre-MIA injection and twice-weekly until study completion on day 42. Mechanical allodynia was fully developed in the ipsilateral hindpaws (PWTs ≤6 g) from day 7 and it persisted until day 42. MIA-injected rats with PWTs ≤6 g in the ipsilateral hindpaws received single doses of one of four clinically available drugs that represent four distinct pharmacological classes, viz gabapentin, amitriptyline, meloxicam and morphine, according to a 'washout' protocol with at least 48 hours between successive doses. Gabapentin evoked dose-dependent anti-allodynia as did morphine whereas amitriptyline and meloxicam were inactive. Our findings are aligned with clinical data showing that gabapentin and morphine alleviated OA pain in the knee. The lack of efficacy of amitriptyline is consistent with the loss of descending diffuse noxious inhibitory controls reported by others in this model.
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http://dx.doi.org/10.1111/1440-1681.13551DOI Listing
November 2021

Assessment of the Anti-Allodynic and Anti-Hyperalgesic Efficacy of a Glycine Transporter 2 Inhibitor Relative to Pregabalin, Duloxetine and Indomethacin in a Rat Model of Cisplatin-Induced Peripheral Neuropathy.

Biomolecules 2021 06 24;11(7). Epub 2021 Jun 24.

Centre for Integrated Preclinical Drug Development, Faculty of Medicine, School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia.

Cisplatin, which is a chemotherapy drug listed on the World Health Organisation's List of Essential Medicines, commonly induces dose-limiting side effects including chemotherapy-induced peripheral neuropathy (CIPN) that has a major negative impact on quality of life in cancer survivors. Although adjuvant drugs including anticonvulsants and antidepressants are used for the relief of CIPN, analgesia is often unsatisfactory. Herein, we used a rat model of CIPN (cisplatin) to assess the effect of a glycine transporter 2 (GlyT2) inhibitor, relative to pregabalin, duloxetine, indomethacin and vehicle. Male Sprague-Dawley rats with cisplatin-induced mechanical allodynia and mechanical hyperalgesia in the bilateral hindpaws received oral bolus doses of the GlyT2 inhibitor (3-30 mg/kg), pregabalin (3-100 mg/kg), duloxetine (3-100 mg/kg), indomethacin (1-10 mg/kg) or vehicle. The GlyT2 inhibitor alleviated both mechanical allodynia and hyperalgesia in the bilateral hindpaws at a dose of 10 mg/kg, but not at higher or lower doses. Pregabalin and indomethacin induced dose-dependent relief of mechanical allodynia but duloxetine lacked efficacy. Pregabalin and duloxetine alleviated mechanical hyperalgesia in the bilateral hindpaws while indomethacin lacked efficacy. The mechanism underpinning pain relief induced by the GlyT2 inhibitor at 10 mg/kg is likely due to increased glycinergic inhibition in the lumbar spinal cord, although the bell-shaped dose-response curve warrants further translational considerations.
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http://dx.doi.org/10.3390/biom11070940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301897PMC
June 2021

Sustained release ketamine-loaded porous silicon-PLGA microparticles prepared by an optimized supercritical CO process.

Drug Deliv Transl Res 2022 03 28;12(3):676-694. Epub 2021 Apr 28.

School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.

Ketamine in sub-anaesthetic doses has analgesic properties and an opioid-sparing effect. Intrathecal (i.t.) delivery of analgesics bypasses systemic metabolism and delivers the analgesic agent adjacent to the target receptors in the spinal cord and so small doses are required to achieve effective pain relief. In order to relieve intractable cancer-related pain, sustained-release ketamine formulations are required in combination with a strong opioid because frequent i.t. injection is not practical. In this study, ketamine or ketamine-loaded porous silicon (pSi) were encapsulated into poly(lactic-co-glycolic acid) (PLGA) microparticles by a novel supercritical carbon dioxide (scCO) method, thereby avoiding the use of organic solvent. Multiple parameters including theoretical drug loading (DL), presence of pSi, size of scCO vessel, PLGA type, and use of co-solvent were investigated with a view to obtaining high DL and a sustained-release for an extended period. The most important finding was that the use of a large scCO vessel (60 mL) resulted in a much higher encapsulation efficiency (EE) compared with a small vessel (12 mL). In addition, pre-loading ketamine into pSi slightly improved the level of drug incorporation (i.e. EE and DL). Although the in vitro release was mainly affected by the drug payload, the use of the large scCO vessel reduced the burst release and extended the release period for PLGA microparticles with 10% or 20% ketamine loading. Together, our findings provide valuable information for optimization of drug delivery systems prepared with the aid of scCO.
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http://dx.doi.org/10.1007/s13346-021-00991-wDOI Listing
March 2022

Use of Microfluidics to Fabricate Bioerodable Lipid Hybrid Nanoparticles Containing Hydromorphone or Ketamine for the Relief of Intractable Pain.

Pharm Res 2020 Oct 2;37(10):211. Epub 2020 Oct 2.

Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia.

Purpose: For patients with intractable cancer-related pain, administration of strong opioid analgesics and adjuvant agents by the intrathecal (i.t.) route in close proximity to the target receptors/ion channels, may restore pain relief. Hence, the aim of this study was to use bioerodable polymers to encapsulate an opioid analgesic (hydromorphone) and an adjuvant drug (ketamine) to produce prolonged-release formulations for i.t. injection.

Methods: A two-stage microfluidic method was used to fabricate nanoparticles (NPs). The physical properties were characterised using dynamic light scattering and transmission electron microscopy. A pilot in vivo study was conducted in a rat model of peripheral neuropathic pain.

Results: The in vitro release of encapsulated payload from NPs produced with a polymer mixture (CPP-SA/PLGA 50:50) was sustained for 28 days. In a pilot in vivo study, analgesia was maintained over a three day period following i.t. injection of hydromorphone-loaded NPs at 50 μg. Co-administration of ketamine-loaded NPs at 340 μg did not increase the duration of analgesia significantly.

Conclusions: The two-stage microfluidic method allowed efficient production of analgesic/adjuvant drug-loaded NPs. Our proof-of-principle in vivo study shows prolonged hydromorphone analgesic for 78 h after single i.t. injection. At the i.t. dose administered, ketamine released from NPs was insufficient to augment hydromorphone analgesia.
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http://dx.doi.org/10.1007/s11095-020-02939-0DOI Listing
October 2020

Herbicides That Target Acetohydroxyacid Synthase Are Potent Inhibitors of the Growth of Drug-Resistant .

ACS Infect Dis 2020 11 22;6(11):2901-2912. Epub 2020 Oct 22.

School of Dentistry, São Paulo State University (UNESP), Araraquara, Rua Humaita, 1680, 14801-903 Araraquara, SP Brazil.

Acetohydroxyacid synthase (AHAS, EC 2.2.1.6), the first enzyme in the branched chain amino acid biosynthesis pathway, is the target for more than 50 commercially available herbicides, and is a promising target for antimicrobial drug discovery. Herein, we have expressed and purified AHAS from , a newly identified human invasive fungal pathogen. Thirteen AHAS inhibiting herbicides have values of <2 μM for this enzyme, with the most potent having values of <32 nM. Six of these compounds exhibited MIC values of <1 μM against (CBS10913 strain) grown in culture, with bensulfuron methyl (BSM) being fungicidal and the most potent (MIC of 0.090 μM) in defined minimal media. The MIC value increases to 0.90 μM in media enriched by the addition of branched-chain amino acids at the expected concentration in the blood serum. The sessile MIC for BSM is 0.6 μM. Thus, it is also an excellent inhibitor of the growth of biofilms. BSM is nontoxic in HEK-293 cells at concentrations >100 μM and thus possesses a therapeutic index of >100. These data suggest that targeting AHAS is a viable strategy for treating infections.
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http://dx.doi.org/10.1021/acsinfecdis.0c00229DOI Listing
November 2020

Characterisation of a rat model of mechanical low back pain at an advanced stage using immunohistochemical methods.

Clin Exp Pharmacol Physiol 2020 Sep 5. Epub 2020 Sep 5.

Faculty of Medicine, School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia.

Chronic low back pain (LBP) has high prevalence in the adult population which is associated with enormous disability. Hence, our aim was to further characterise our LBP rat model by using immunohistological and immunohistochemical methods at an advanced stage (day 49) of the model. Male Sprague-Dawley rats were anaesthetised and their lumbar L4/L5 and L5/L6 intervertebral discs (IVDs) were punctured (0.5 mm outer diameter, 2 mm-deep) 10 times per disc. Sham-rats underwent similar surgery, but no discs were punctured. For LBP- but not sham-rats, noxious pressure hyperalgesia was fully developed in the lumbar axial deep tissues on day 21 post-surgery, which was maintained until at least day 49. In the lumbar (L4-L6) dorsal root ganglia (DRGs), somatostatin (SRIF) and the somatostatin receptor type 4 (SST receptor) were co-localised with substance P and IB4, markers of small diameter unmyelinated peptidergic and non-peptidergic C-fibres respectively as well as with NF200, a marker of medium to large diameter neurons. On day 49, there was increased expression of SRIF but not the somatostatin receptor type 4 (SST receptor) in the lumbar DRGs and the spinal dorsal horns. There were increased DRG expression levels of the putative pro-nociceptive mediators: phosphorylated p38 (pp38) mitogen-activated protein kinase (MAPK) and phosphorylated p44/p42 MAPK (pp44/pp42 MAPK) as well as pp38 MAPK expression levels in the lumbar spinal cord. Taken together, the increased expression of SRIF in the lumbar DRGs and spinal cord and its co-localisation with nociceptive fibres in DRG sections suggest a potential role of SRIF in modulating chronic mechanical LBP.
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http://dx.doi.org/10.1111/1440-1681.13402DOI Listing
September 2020

Assessment of the anti-allodynic efficacy of a glycine transporter 2 inhibitor relative to pregabalin and duloxetine in a rat model of prostate cancer-induced bone pain.

Pharmacol Rep 2020 Oct 26;72(5):1418-1425. Epub 2020 Jul 26.

Centre for Integrated Preclinical Drug Development, School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.

Background: The pathobiology of prostate cancer-induced bone pain (PCIBP) is underpinned by both inflammatory and neuropathic components. Here, we used a rat model of PCIBP to assess the analgesic efficacy of a glycine transporter 2 (GlyT2) inhibitor (N-(6-((1,3-dihydroxypropan-2-yl)amino)-2-(dimethylamino)pyridin-3-yl)-3,5-dimethoxy-4-(4-(trifluoromethyl)phenoxy) benzamide) relative to two clinically available adjuvant drugs that are recommended for the relief of neuropathic pain, viz, pregabalin and duloxetine.

Methods: PCIBP was induced in male Wistar Han rats following intra-tibial injection (ITI) of rat prostate cancer (AT3B) cells into the left tibia. Sham-rats received an ITI of heat-killed AT3B cells. PCIBP rats with fully developed mechanical allodynia in the ipsilateral hindpaws as assessed using von Frey filaments, received single oral (p.o.) bolus doses of the GlyT2 inhibitor (3-30 mg/kg), pregabalin (3-100 mg/kg), duloxetine (3-100 mg/kg), or vehicle. Baseline paw withdrawal thresholds (PWTs) were determined in the ipsilateral (injured side) and contralateral hindpaws immediately prior to dosing and at scheduled times for 3 h post dosing in individual animals.

Results: Single oral bolus doses of the GlyT2 inhibitor (3-30 mg/kg) evoked partial pain relief at the doses tested in the ipsilateral hindpaws of PCIBP rats without any discernible behavioural side effects. By contrast, single oral bolus doses of pregabalin at 10-100 mg/kg evoked dose-dependent and complete alleviation of mechanical allodynia. By comparison, single oral bolus doses of duloxetine at doses up to 100 mg/kg lacked efficacy.

Conclusion: Oral administration of this GlyT2 inhibitor evoked partial pain relief in PCIBP rats and did not evoke central nervous system side effects in contrast to GlyT2 inhibitors reported by others.
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http://dx.doi.org/10.1007/s43440-020-00145-8DOI Listing
October 2020

Assessment of the anti-hyperalgesic efficacy of J-2156, relative to clinically available analgesic/adjuvant agents in a rat model of mild to moderate chronic mechanical low back pain (LBP).

Clin Exp Pharmacol Physiol 2020 12 4;47(12):1912-1922. Epub 2020 Aug 4.

Centre for Integrated Preclinical Drug Development, School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.

Chronic mechanical low back pain (cLBP) is a leading cause of disability and a major socio-economic burden internationally. The lifetime prevalence of non-specific LBP is approximately 84%, with the prevalence of cLBP at about 23%. Clinically available analgesic/adjuvant medications often provide inadequate pain relief in patients experiencing cLBP. Hence, the urgency for discovery of effective and better tolerated medications. Fourteen days after the induction of five shallow annular punctures (5X) in the lumbar intervertebral discs at L4/L5 and L5/L6 in male Sprague-Dawley rats, mechanical hyperalgesia was fully developed in the lumbar axial deep tissues at L4/L5 (primary) and L1 (secondary). Importantly, mechanical allodynia in the hindpaws was absent. From day 28, we assessed the face validity of our mild to moderate LBP-5X rat model using four clinically available analgesic/adjuvant drugs, namely gabapentin, morphine, meloxicam and amitriptyline relative to vehicle. Additionally, the anti-hyperalgesic effects of J-2156, a highly selective small molecule somatostatin type 4 receptor agonist was assessed. Single i.p. bolus doses of gabapentin and meloxicam at the highest doses tested (100 and 30 mg/kg, respectively) alleviated secondary hyperalgesia (L1) but not primary hyperalgesia (L4/5). Morphine at 1 mg/kg alleviated both primary and secondary hyperalgesia in these tissues, whereas amitriptyline at the doses tested, lacked efficacy. These findings attest to the face validity of our model. J-2156 at 10 and 30 mg/kg alleviated secondary hyperalgesia in the lumbar axial deep tissues at L1 with a non-significant trend for relief of primary hyperalgesia in the corresponding tissues at L4/L5 in these animals.
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http://dx.doi.org/10.1111/1440-1681.13383DOI Listing
December 2020

Comparative studies of glial fibrillary acidic protein and brain-derived neurotrophic factor expression in two transgenic mouse models of Alzheimer's disease.

Clin Exp Pharmacol Physiol 2020 10 17;47(10):1740-1750. Epub 2020 Jul 17.

School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.

In Alzheimer's disease (AD) glial fibrillary acidic protein (GFAP) is expressed by reactive astrocytes surrounding β-amyloid (Aβ) plaques, whereas brain-derived neurotrophic factor (BDNF) levels are typically reduced. We compared the expression of GFAP, BDNF, and its precursor proBDNF in the dorsal hippocampus of two transgenic AD mouse models. APPSwe YAC mice expressing the APPSwe transgene on a yeast artificial chromosome (YAC) were assessed at age 4 and 21 months, and APPSwe/PS1dE9 mice co-expressing mutant amyloid precursor protein (APPSwe) and presenilin-1 (PS1dE9) were assessed at age 4 and 9 months. Significantly increased (1.4-fold) GFAP expression was observed in APPSwe YAC c.f. wild-type (Wt) mice aged 21 months, when Aβ deposition was first evident in these mice. In APPSwe/PS1dE9 mice aged 4 and 9 months, GFAP expression was significantly increased (1.6- and 3.1-fold, respectively) c.f. Wt mice, and was associated with robust Aβ deposition at 9 months. BDNF expression was significantly lower in 4- and 21-month old APPSwe YAC mice (0.8- and 0.6-fold, respectively) c.f. age-matched Wt mice, whereas proBDNF expression was significantly higher (10-fold) in the APPSwe YAC c.f. Wt mice aged 21 months. In APPSwe/PS1dE9 mice aged 4 months, BDNF expression was significantly lower (0.4-fold) c.f. age-matched Wt mice and was equivalent to that in 9-month old mice of both genotypes; proBDNF expression mirrored that of BDNF in this strain. These findings support a role for reactive astrocytes and neuroinflammation, rather than BDNF, in the spatial memory deficits previously reported for APPSwe YAC and APPSwe/PS1dE9 mice.
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http://dx.doi.org/10.1111/1440-1681.13363DOI Listing
October 2020

Sustained-release ketamine-loaded nanoparticles fabricated by sequential nanoprecipitation.

Int J Pharm 2020 May 4;581:119291. Epub 2020 Apr 4.

School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, QLD, Australia.

Ketamine in sub-anaesthetic doses is an analgesic adjuvant with a morphine-sparing effect. Co-administration of a strong opioid with an analgesic adjuvant such as ketamine is a potential treatment option, especially for patients with cancer-related pain. A limitation of ketamine is its short in vivo elimination half-life. Hence, our aim was to develop biocompatible and biodegradable ketamine-loaded poly(ethylene glycol) (PEG)-block-poly(lactic-co-glycolic acid) (PLGA) nanoparticles for sustained release. Ketamine-encapsulated single polymer PEG-PLGA nanoparticles and double polymer PEG-PLGA/shellac (SH) nanoparticles with a high drug loading of 41.8% (drug weight/the total weight of drug-loaded nanoparticles) were prepared using a new sequential nanoprecipitation method. These drug-loaded nanoparticles exhibited a sustained-release profile for up to 21 days in vitro and for more than 5 days after intravenous injection in mice. Our study demonstrates that high drug loading and a sustained release profile can be achieved with ketamine-loaded PEG-PLGA nanoparticles prepared using this new nanoprecipitation method.
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http://dx.doi.org/10.1016/j.ijpharm.2020.119291DOI Listing
May 2020

Countering opioid-induced respiratory depression by non-opioids that are respiratory stimulants.

F1000Res 2020 7;9. Epub 2020 Feb 7.

School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.

Strong opioid analgesics are the mainstay of therapy for the relief of moderate to severe acute nociceptive pain that may occur post-operatively or following major trauma, as well as for the management of chronic cancer-related pain. Opioid-related adverse effects include nausea and vomiting, sedation, respiratory depression, constipation, tolerance, and addiction/abuse liability. Of these, respiratory depression is of the most concern to clinicians owing to the potential for fatal consequences. In the broader community, opioid overdose due to either prescription or illicit opioids or co-administration with central nervous system depressants may evoke respiratory depression. To address this problem, there is ongoing interest in the identification of non-opioid respiratory stimulants to reverse opioid-induced respiratory depression but without reversing opioid analgesia. Promising compound classes evaluated to date include those that act on a diverse array of receptors including 5-hydroxytryptamine, D -dopamine, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-D-aspartate (NMDA) receptor antagonists, and nicotinic acetylcholine as well as phosphodiesterase inhibitors and molecules that act on potassium channels on oxygen-sensing cells in the carotid body. The aim of this article is to review recent advances in the development potential of these compounds for countering opioid-induced respiratory depression.
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http://dx.doi.org/10.12688/f1000research.21738.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008602PMC
October 2020

Intracerebroventricular administration of CYX-6, a potent μ-opioid receptor agonist, a δ- and κ-opioid receptor antagonist and a biased ligand at μ, δ & κ-opioid receptors, evokes antinociception with minimal constipation and respiratory depression in rats in contrast to morphine.

Eur J Pharmacol 2020 Mar 17;871:172918. Epub 2020 Jan 17.

School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia. Electronic address:

Mu opioid receptor (MOPr) agonists are thought to produce analgesia via modulation of G-protein-coupled intracellular signalling pathways whereas the β-arrestin2 pathway is proposed to mediate opioid-related adverse effects. Here, we report the antinociception, constipation and respiratory depressant profile of CYX-6, a potent MOPr agonist that is also a delta and a kappa opioid receptor (DOPr/KOPr) antagonist and that lacks β-arrestin2 recruitment at each of the MOPr, DOPr and the KOPr. In anaesthetised male Sprague Dawley rats, an intracerebroventricular (i.c.v.) guide cannula was stereotaxically implanted. After 5-7 days post-surgical recovery, rats received a single i.c.v. bolus dose of CYX-6 (3-30 nmol), morphine (100 nmol) or vehicle. Antinociception was assessed using the warm water tail flick test (52.5 ± 0.5 °C). Constipation was assessed using the charcoal meal gut motility test and the castor oil-induced diarrhoea test. Respiratory depression was measured by whole-body plethysmography in awake, freely moving animals, upon exposure to a hypercapnic gas mixture (8% CO, 21% O and 71% N). The intrinsic pharmacology of CYX-6 given by the i.c.v. route in rats showed that it produced dose-dependent antinociception. It also produced respiratory stimulation rather than depression and it had a minimal effect on intestinal motility in contrast to the positive control, morphine. CYX-6 is an endomorphin-2 analogue that dissociates antinociception from constipation and respiratory depression in rats. Our findings provide useful insight to inform the discovery and development of novel opioid analgesics with a superior tolerability profile compared with morphine.
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http://dx.doi.org/10.1016/j.ejphar.2020.172918DOI Listing
March 2020

Transcriptomic characterisation of the optimised rat model of Walker 256 breast cancer cell-induced bone pain.

Clin Exp Pharmacol Physiol 2019 12 15;46(12):1201-1215. Epub 2019 Sep 15.

Faculty of Medicine, School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia.

In patients with breast cancer, metastases of cancer cells to the axial skeleton may cause excruciating pain, particularly in the advanced stages. The current drug treatments available to alleviate this debilitating pain condition often lack efficacy and/or produce undesirable side effects. Preclinical animal models of cancer-induced bone pain are key to studying the mechanisms that cause this pain and for the success of drug discovery programs. In a previous study conducted in our laboratory, we validated and characterised the rat model of Walker 256 cell-induced bone pain, which displayed several key resemblances to the human pain condition. However, gene level changes that occur in the pathophysiology of cancer-induced bone pain in this preclinical model are unknown. Hence, in this study, we performed the transcriptomic characterisation of the Walker 256 cell line cultured in vitro to predict the molecular genetic profile of this cell line. We also performed transcriptomic characterisation of the Walker 256 cell-induced bone pain model in rats using the lumbar spinal cord and lumbar dorsal root ganglia tissues. Here we show that the Walker 256 cell line resembles the basal-B molecular subtype of human breast cancer cell lines. We also identify several genes that may underpin the progression of pain hypersensitivities in this condition, however, this needs further confirmatory studies. These transcriptomic insights have the potential to direct future studies aimed at identifying various mechanisms underpinning pain hypersensitivities in this model that may also assist in discovery of novel pain therapeutics for breast cancer-induced bone pain.
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http://dx.doi.org/10.1111/1440-1681.13165DOI Listing
December 2019

The cubane paradigm in bioactive molecule discovery: further scope, limitations and the cyclooctatetraene complement.

Org Biomol Chem 2019 07;17(28):6790-6798

School of Chemistry and Molecular Biosciences, University of Queensland (UQ), Brisbane, 4072, Queensland (QLD), Australia.

The cubane phenyl ring bioisostere paradigm was further explored in an extensive study covering a wide range of pharmaceutical and agrochemical templates, which included antibiotics (cefaclor, penicillin G) and antihistamine (diphenhydramine), a smooth muscle relaxant (alverine), an anaesthetic (ketamine), an agrochemical instecticide (triflumuron), an antiparasitic (benznidazole) and an anticancer agent (tamibarotene). This investigation highlights the scope and limitations of incorporating cubane into bioactive molecule discovery, both in terms of synthetic compatibility and physical property matching. Cubane maintained bioisosterism in the case of the Chagas disease antiparasitic benznidazole, although it was less active in the case of the anticancer agent (tamibarotenne). Application of the cyclooctatetraene (COT) (bio)motif complement was found to optimize benznidazole relative to the benzene parent, and augmented anticancer activity relative to the cubane analogue in the case of tamibarotene. Like all bioisosteres, scaffolds and biomotifs, however, there are limitations (e.g. synthetic implementation), and these have been specifically highlighted herein using failed examples. A summary of all templates prepared to date by our group that were biologically evaluated strongly supports the concept that cubane is a valuable tool in bioactive molecule discovery and COT is a viable complement.
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http://dx.doi.org/10.1039/c9ob01238aDOI Listing
July 2019

J-2156, a somatostatin receptor type 4 agonist, alleviates mechanical hyperalgesia in a rat model of chronic low back pain.

Biomed Pharmacother 2019 Sep 7;117:109056. Epub 2019 Jun 7.

School of Biomedical Sciences, Faculty of Medicine, Level 3, Steele Building, St Lucia Campus, The University of Queensland, Brisbane, Australia. Electronic address:

Chronic low back pain (LBP) ranks among the most common reasons for patient visits to healthcare providers. Drug treatments often provide only partial pain relief and are associated with considerable side-effects. J-2156 [(1'S,2S)-4amino-N-(1'-carbamoyl-2'-phenylethyl)-2-(4"-methyl-1"-naphthalenesulfonylamino)butanamide] is an agonist that binds with nanomolar affinity to the rat and human somatostatin receptor type 4 (SST receptor). Hence, our aim was to assess the efficacy of J-2156 for relief of chronic mechanical LBP in a rat model. Male Sprague Dawley rats were anaesthetised and their lumbar L4/L5 and L5/L6 intervertebral discs (IVDs) were punctured (0.5 mm outer diameter, 2 mm-deep) 10 times per disc. Sham-rats underwent similar surgery, but without disc puncture. For LBP-rats, noxious pressure hyperalgesia developed in the lumbar axial deep tissues from day 7 to day 21 post-surgery, which was maintained until study completion. Importantly, mechanical hyperalgesia did not develop in the lumbar axial deep tissues of sham-rats. In LBP-rats, single intraperitoneal (i.p.) injection of J-2156 (3, 10, 30 mg kg) alleviated primary and secondary hyperalgesia in the lumbar axial deep tissues at L4/L5 and L1, respectively. This was accompanied by a reduction in the otherwise augmented lumbar (L4-L6) dorsal root ganglia expression levels of the pro-nociceptive mediators: phosphorylated p38 (pp38) mitogen-activated protein kinase (MAPK) and phosphorylated p44/p42 MAPK and a reduction in pp38 MAPK in the lumbar enlargement of the spinal cord. The SST receptor is worthy of further investigation as a target for discovery of novel analgesics for the relief of chronic LBP.
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http://dx.doi.org/10.1016/j.biopha.2019.109056DOI Listing
September 2019

Study Protocol for a Pilot, Open-Label, Prospective, and Observational Study to Evaluate the Pharmacokinetics of Drugs Administered to Patients during Extracorporeal Circulation; Potential of In Vivo Cytochrome P450 Phenotyping to Optimise Pharmacotherapy.

Methods Protoc 2019 May 13;2(2). Epub 2019 May 13.

Centre for Integrated Preclinical Drug Development, School of Biomedical Sciences, Faculty of Medicine, University of Queensland, 4072 Brisbane, Australia.

Pharmacokinetic alterations of medications administered during surgeries involving cardiopulmonary bypass (CPB) and extracorporeal membrane oxygenation (ECMO) have been reported. The impact of CPB on the cytochrome P450 (CYP) enzymes' activity is the key factor. The metabolic rates of caffeine, dextromethorphan, midazolam, omeprazole, and Losartan to the CYP-specific metabolites are validated measures of in vivo CYP 1A2, 2D6, 3A4, 2C19, and 2C9 activities, respectively. The study aim is to assess the activities of major CYPs in patients on extracorporeal circulation (EC). This is a pilot, prospective, open-label, observational study in patients undergoing surgery using EC and patients undergoing laparoscopic cholecystectomy as a control group. CYP activities will be measured on the day, and 1-2 days pre-surgery/3-4 days post-surgery (cardiac surgery and Laparoscopic cholecystectomy) and 1-2 days after starting ECMO, 1-2 weeks after starting ECMO, and 1-2 days after discontinuation from ECMO. Aforementioned CYP substrates will be administered to the patient and blood samples will be collected at 0, 1, 2, 4, and 6 h post-dose. Major CYP enzymes' activities will be compared in each participant on the day, and before/after surgery. The CYP activities will be compared in three study groups to investigate the impact of CYPs on EC.
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http://dx.doi.org/10.3390/mps2020038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6632166PMC
May 2019

Nitric oxide modulates μ-opioid receptor function in vitro.

Clin Exp Pharmacol Physiol 2019 07 14;46(7):676-685. Epub 2019 Apr 14.

School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.

Painful diabetic neuropathy (PDN) is a type of peripheral neuropathic pain that develops as a consequence of prolonged hyperglycaemia-induced injury to the long nerves. Apart from pain, PDN is also characterized by morphine hyposensitivity. Intriguingly, in streptozotocin (STZ)-induced diabetic rats exhibiting marked morphine hyposensitivity, dietary administration of the nitric oxide (NO) precursor, L-arginine at 1 g/d, progressively rescued morphine efficacy and potency over an 8-week treatment period. In earlier work, single bolus doses of the furoxan nitric oxide (NO) donor, PRG150 (3-methylfuroxan-4-carbaldehyde), evoked dose-dependent pain relief in STZ-diabetic rats but the efficacious doses were 3-4 orders of magnitude higher in advanced diabetes than that required in early STZ diabetes. Together, these findings suggested a role for NO in the modulation of μ-opioid (MOP) receptor signalling. Therefore, the present study was designed to assess a role for NO released from PRG150, in modulating MOP receptor function in vitro. Here, we show an absolute requirement for the MOP receptor, but not the δ-opioid (DOP) or the κ-opioid (KOP) receptor, to transduce the cellular effects of PRG150 on forskolin-stimulated cAMP responses in vitro. PRG150 did not interact with the classical naloxone-sensitive binding site of the MOP receptor, and its effects on cAMP responses in HEK-MOP cells were also naloxone-insensitive. Nevertheless, the inhibitory effects of PRG150 on forskolin-stimulated cAMP responses in HEK-MOP cells were dependent upon pertussis toxin (PTX)-sensitive G proteins as well as membrane lipid rafts and src kinase. Together, our findings implicate a role for NO in modulating MOP receptor function in vivo.
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http://dx.doi.org/10.1111/1440-1681.13091DOI Listing
July 2019

Bioerodable Ketamine-Loaded Microparticles Fabricated Using Dissolvable Hydrogel Template Technology.

J Pharm Sci 2019 03 26;108(3):1220-1226. Epub 2018 Oct 26.

School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia. Electronic address:

For severe cancer-related pain that is not relieved adequately by escalating doses of oral or parenterally administered strong opioid analgesics such as morphine, alone or in combination with an adjuvant drug such as ketamine, more invasive dosing routes may be warranted. One such approach involves surgical implantation of an intrathecal pump to deliver small doses of analgesic or adjuvant drugs in close proximity to the receptors that transduce their pain-relieving effects. However, the use of implanted devices is associated with a range of catheter-related problems. To address this, we have developed biodegradable microparticles loaded with the analgesic adjuvant drug, ketamine, for sustained release after a single bolus intrathecal injection. Drug-loaded poly(lactic-co-glycolic acid) (PLGA) microparticles were prepared using a dissolvable hydrogel template. Using PLGA with 3 different ratios of lactic acid to glycolic acid (L/G), relatively high ketamine loading and homogenous particle shape and size were achieved. Specifically, ketamine loading of PLGA5050, PLGA7525, and PLGA8515 in ester-terminated microparticles was 20.0%, 20.4%, and 18.9%, respectively. The microparticles were within the desired size range (20 μm diameter and 30 μm height) and in vitro release was sustained for ≥14 days with an acceptable initial burst release (∼10%-20%) achieved.
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http://dx.doi.org/10.1016/j.xphs.2018.10.029DOI Listing
March 2019

Cyclooctatetraene: A Bioactive Cubane Paradigm Complement.

Chemistry 2019 Feb 25;25(11):2729-2734. Epub 2019 Jan 25.

School of Chemistry and Molecular Biosciences, University of Queensland (UQ), Brisbane, 4072, Queensland (QLD, Australia.

Cubane was recently validated as a phenyl ring (bio)isostere, but highly strained caged carbocyclic systems lack π character, which is often critical for mediating key biological interactions. This electronic property restriction associated with cubane has been addressed herein with cyclooctatetraene (COT), using known pharmaceutical and agrochemical compounds as templates. COT either outperformed or matched cubane in multiple cases suggesting that versatile complementarity exists between the two systems for enhanced bioactive molecule discovery.
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http://dx.doi.org/10.1002/chem.201806277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436534PMC
February 2019

Establishment and characterisation of a stavudine (d4T)-induced rat model of antiretroviral toxic neuropathy (ATN) using behavioural and pharmacological methods.

Inflammopharmacology 2019 Apr 1;27(2):387-396. Epub 2019 Jan 1.

Centre for Integrated Preclinical Drug Development, School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia Campus, Brisbane, QLD, 4072, Australia.

Human immuno-deficiency virus (HIV) associated sensory neuropathy (SN) is a frequent complication of HIV infection. It is extremely difficult to alleviate and hence the quality of life of affected individuals is severely and adversely impacted. Stavudine (d4T) is an antiretroviral drug that was widely used globally prior to 2010 and that is still used today in resource-limited settings. Its low cost and relatively good efficacy when included in antiretroviral dosing regimens means that there is a large population of patients with d4T-induced antiretroviral toxic neuropathy (ATN). As there are no FDA approved drugs for alleviating ATN, it is important to establish rodent models to probe the pathobiology and to identify potentially efficacious new drug treatments. In the model establishment phase, d4T administered intravenously at a cumulative dose of 375 mg/kg in male Wistar Han rats evoked temporal development of sustained mechanical allodynia in the hindpaws from day 10 to day 30 after initiation of d4T treatment. As this d4T dosing regimen was also well tolerated, it was used for ATN model induction for subsequent pharmacological profiling. Both gabapentin at 30-100 mg/kg and morphine at 0.3-2 mg/kg given subcutaneously produced dose-dependent relief of mechanical allodynia with estimated ED's of 19 mg/kg and 0.4 mg/kg, respectively. In contrast, intraperitoneal administration of meloxicam or amitriptyline up to 30 mg/kg and 7 mg/kg, respectively, lacked efficacy. Our rat model of ATN is suitable for investigation of the pathophysiology of d4T-induced SN as well as for profiling novel molecules from analgesic drug discovery programs.
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http://dx.doi.org/10.1007/s10787-018-00551-8DOI Listing
April 2019

Formulation of Bioerodible Ketamine Microparticles as an Analgesic Adjuvant Treatment Produced by Supercritical Fluid Polymer Encapsulation.

Pharmaceutics 2018 Dec 6;10(4). Epub 2018 Dec 6.

School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane QLD 4072, Australia.

Pain is inadequately relieved by escalating doses of a strong opioid analgesic such as morphine in up to 25% of patients with cancer-related severe pain complicated by a neuropathic (nerve damage) component. Hence, there is an unmet medical need for research on novel painkiller strategies. In the present work, we used supercritical fluid polymer encapsulation to develop sustained-release poly(lactic--glycolic acid) (PLGA) biodegradable microparticles containing the analgesic adjuvant drug ketamine, for injection by the intrathecal route. Using this approach with a range of PLGA co-polymers, drug loading was in the range 10⁻60%, with encapsulation efficiency (EE) of 60⁻100%. Particles were mainly in the size range 20⁻45 µm and were produced in the absence of organic solvents and surfactants/emulsifiers. Investigation of the ketamine release profiles from these PLGA-based microparticles in vitro showed that release took place over varying periods in the range 0.5⁻4.0 weeks. Of the polymers assessed, the ester end-capped PLGA5050DLG-1.5E gave the best-controlled release profile with drug loading at 10%.
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http://dx.doi.org/10.3390/pharmaceutics10040264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321204PMC
December 2018

Sustained-Release Hydromorphone Microparticles Produced by Supercritical Fluid Polymer Encapsulation.

J Pharm Sci 2019 02 26;108(2):811-814. Epub 2018 Sep 26.

School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, QLD, Australia; School of Pharmacy, Faculty of Health and Behavioural Sciences, The University of Queensland Brisbane, QLD, Australia. Electronic address:

Chronic cancer pain remains prevalent and severe for many patients, particularly in those with advanced disease. The effectiveness of analgesic/adjuvant drug treatments in routine practice has changed little in the last 30 years. To address these issues herein, we have developed sustained-release poly(lactic-co-glycolic acid) microparticles of hydromorphone for intrathecal injection aimed at producing prolonged periods of satisfactory analgesia in patients, as a novel strategy for alleviation of intractable cancer-related pain. These hydromorphone-loaded microparticles were produced successfully using organic solvent-free supercritical fluid polymer encapsulation. Drug loading at 9.2% and encapsulation efficacy at 92% were achieved for particles in the desired size range (20-45 μm) with sustained release over a 5-week period in vitro.
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http://dx.doi.org/10.1016/j.xphs.2018.09.021DOI Listing
February 2019

An improved LC-MS/MS method for simultaneous evaluation of CYP2C9, CYP2C19, CYP2D6 and CYP3A4 activity.

Bioanalysis 2018 Oct 18;10(19):1577-1590. Epub 2018 Sep 18.

Centre for Integrated Preclinical Drug Development, School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.

Aim: To develop an LC-MS/MS assay to quantitate well-tolerated substrates; midazolam (CYP3A), omeprazole (CYP2C19), dextromethorphan (CYP2D6), losartan (CYP2C9) and their respective metabolites' concentrations in plasma samples.

Patients & Methods: A solid-phase extraction method was optimized to extract analytes of interest simultaneously from human plasma samples. The assay analyzed plasma samples collected from patients who received equal or lower than therapeutic doses of CYP substrates.

Results: This assay was validated based on the European Medicines Agency guideline for bioanalytical method validation and was sensitive, linear, accurate and precise with acceptable recovery and matrix effects.

Conclusion: Small sample volume and dose of cytochrome P450 substrates, short-run time, using stable isotope internal standards and being cost effective are the major advantages of the assay.
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http://dx.doi.org/10.4155/bio-2018-0102DOI Listing
October 2018

Synthesis and Biological Evaluation of Fentanyl Analogues Modified at Phenyl Groups with Alkyls.

ACS Chem Neurosci 2019 01 14;10(1):201-208. Epub 2018 Sep 14.

School of Pharmacy , Nanjing Medical University , Nanjing 211166 , China.

A series of fentanyl analogues modified at the phenyl group of the phenethyl with alkyl and/or hydroxyl and alkoxy, and the phenyl group in the anilido moiety replaced with benzyl or substituted benzyl, were synthesized. The in vitro opioid receptor functional activity of these compounds was evaluated by assessment of their ability to modulate forskolin-stimulated cAMP accumulation and by their ability to induce β-arrestin2 recruitment. Compound 12 is a potent μ-opioid (MOP) receptor agonist, a potent κ-opioid (KOP) receptor antagonist with weak β-arrestin2 recruitment activity. Compounds 10 and 11 are potent MOP receptor agonists with weak δ-opioid (DOP) receptor antagonist activity and moderate KOP receptor antagonist activity as well as weak β-arrestin2 recruitment activity at the MOP receptor. These compounds are promising leads for discovery of potent opioid analgesics with reduced side effects relative to clinically available strong opioid analgesics.
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http://dx.doi.org/10.1021/acschemneuro.8b00363DOI Listing
January 2019

Effects of long-term opioid analgesics on cognitive performance and plasma cytokine concentrations in patients with chronic low back pain: a cross-sectional pilot study.

Pain Rep 2018 Jul-Aug;3(4):e669. Epub 2018 Jul 16.

Occupational Therapy, School of Health and Rehabilitation Sciences, The University of Queensland, Brisbane, Australia.

Introduction: Cognitive performance and inflammation are altered in people with chronic low back pain (CLBP). Yet, the magnitude of these changes has been unclear because of the potential influence of opioid analgesics.

Objectives: This cross-sectional pilot study aimed to explore whether patients with CLBP receiving long-term opioid analgesics differed from patients not taking opioids on measures of cognitive performance and plasma cytokine concentrations.

Methods: Patients with CLBP who were either taking (N = 18) or not taking (N = 22) opioids daily for 3 or more months were recruited from a tertiary care private hospital and compared with healthy adults (N = 20). All groups were administered validated questionnaires to assess depression, anxiety, and stress; a cognitive test of memory, attention, and executive function; and a peripheral blood draw to measure proinflammatory (IL-1β, IL-2, IL-8, IL-12p70, TNF-α, and IFN-γ), anti-inflammatory (IL-4, IL-10, and IL-13), and pleiotropic (IL-6) cytokine concentrations. Patients also completed pain-specific questionnaires.

Results: Patients receiving opioid analgesics performed significantly ( < 0.05) worse in attention and had significantly ( < 0.05) lower pain self-efficacy beliefs than those patients not taking opioids. Patient groups did not differ in mean pain severity or pain interference scores, tests of memory and executive function, and mean plasma cytokine concentrations, despite long-term opioid analgesics.

Conclusion: Patients receiving long-term opioid analgesics for CLBP have minor differences when compared with patients not taking opioids. This has important clinical implications when considering long-term treatment for patients with CLBP.
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http://dx.doi.org/10.1097/PR9.0000000000000669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6085139PMC
July 2018
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