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Muralidharan A.,University of Queensland | Wyse B.D.,University of Queensland | Smith M.T.,Center for Integrated Preclinical Drug Development
Pharmacology Biochemistry and Behavior | Year: 2013

The major limitation of currently utilized rodent models of prostate cancer (PCa)-induced bone pain (PCIBP) involving intra-osseous injection of PCa cells, is their relatively short-term applicability due to progressive deterioration of animal health necessitating euthanasia. Here, we describe establishment of an optimized rat model of PCIBP where good animal health was maintained for at least 90-days following unilateral intra-tibial injection (ITI) of PCa cells. We have characterized this model using behavioral, pharmacological, radiological, histological and immunohistochemical methods. Our findings show that following unilateral ITI of 4 × 104 AT3B PCa cells (APCCs), there was temporal development of bilateral hindpaw hypersensitivity that was fully developed between days 14 and 21 post-ITI. Although there was apparent spontaneous reversal of bilateral hindpaw sensitivity that was maintained until at least day 90 post-ITI, administration of bolus doses of the opioid receptor antagonist, naloxone, rescued the pain phenotype in these animals. Hence, upregulation of endogenous opioid signaling mechanisms appears to underpin apparent spontaneous resolution of hindpaw hypersensitivity. Importantly, the histological and radiological assessments confirmed that tumor formation and development of osteosclerotic metastases was confined to the APCC-injected tibial bones. In our rat model of PCIBP, single bolus doses of morphine, gabapentin, meloxicam and amitriptyline produced dose-dependent relief of mechanical allodynia and thermal hyperalgesia in the bilateral hindpaws. The optimized rat model of PCIBP characterized herein has potential to provide new insights into the pathophysiological mechanisms associated with long-term (mal)adaptive pain due to advanced PCa-induced bony metastases and for screening novel compounds with potential for improved alleviation of this condition. © 2013 Elsevier Inc. All rights reserved.

Otto K.J.,University of Queensland | Wyse B.D.,University of Queensland | Wyse B.D.,Center for Integrated Preclinical Drug Development | Cabot P.J.,University of Queensland | And 2 more authors.
Pain Medicine | Year: 2011

Objective. As the Diabetes Control and Complications Trial showed that intensive glycemic control in patients with Type 1 diabetes decreased the risk of development of long-term microvascular complications including painful diabetic neuropathy by ∼60%, hyperglycemia was implicated as a causal factor in the etiology of this condition. Hence, the present study was designed as a 24-week longitudinal investigation of the extent to which the level of glycemic control in the streptozotocin (STZ)-diabetic rat model of Type 1 diabetes affects the development of mechanical allodynia and opioid hyposensitivity in these animals. Results. Diabetes was fully developed (blood glucose levels≥15mM) in adult male Wistar rats by 7 days after intravenous STZ (75mg/kg) administration. Mechanical allodynia developed in a temporal manner in the rat hindpaws, such that it was fully developed by 6 weeks and persisted for at least 24 weeks post-STZ administration. Morphine hyposensitivity also developed in a temporal manner in the same animals. By contrast, restoration and maintenance of euglycemia using insulin implants commencing at diabetes diagnosis on Day 7 post-streptozotocin administration, prevented development of both mechanical allodynia and opioid hyposensitivity in STZ-diabetic rats for the 24-week study duration. Conclusions. This study shows that long-term restoration of euglycemia over a 6-month period in STZ-diabetic rats prevents the hallmark symptoms of PDN including morphine hyposensitivity. Clinical Relevance. Our findings are consistent with epidemiological data showing that tight glycemic control in patients with Type 1 diabetes markedly reduces the prevalence of PDN, further implicating persistent hyperglycemia as a pathogenic factor. © 2011 Wiley Periodicals, Inc.

Zin C.S.,University of Queensland | Nissen L.M.,University of Queensland | O'Callaghan J.P.,Greenslopes Private Hospital | Duffull S.B.,University of Queensland | And 4 more authors.
Journal of Pain | Year: 2010

The aim of this randomized double-blind, placebo-controlled, parallel-group study was to evaluate the efficacy, safety, and tolerability of pregabalin in combination with oxycodone or placebo, in patients with either postherpetic neuralgia (PHN) or painful diabetic neuropathy (PDN). After a 7-day washout period, 62 patients were randomized to receive either oxycodone mixture 10 mg/day or placebo mixture for 1 week. Patients were then started on open-label pregabalin (75, 150, 300 and 600 mg/day) according to a forced titration dosing regimen, while continuing the same dosage of oxycodone or placebo for 4 weeks. The primary efficacy measure was a decrease in the pain-intensity score of at least 2cm and a pain score <4cm measured using a 10-cm visual analogue scale (VAS) following pregabalin dosage escalation and treatment for 4 weeks. Secondary efficacy measures included sleep interference and the Neuropathic Pain Scale. There were similar levels of overall efficacy between pregabalin/oxycodone and pregabalin/placebo groups in relieving PHN and PDN related pain. Perspective: Peripheral neuropathic pain presents commonly in clinical practice, and 2 of its most prevalent types are PHN and PDN. Currently available treatments provide some degree of pain relief in ∼40-60% of patients, leaving the remainder with unremitting pain. Although this study supports the effectiveness of pregabalin in the treatment of PHN or PDN, it also shows that the addition of a low dose of oxycodone at 10mg/day does not enhance the pain-relieving effects of pregabalin. © 2010 American Pain Society.

Chalmers B.A.,University of Queensland | Xing H.,University of Queensland | Houston S.,University of Queensland | Clark C.,Queensland Brain Institute | And 25 more authors.
Angewandte Chemie - International Edition | Year: 2016

Pharmaceutical and agrochemical discovery programs are under considerable pressure to meet increasing global demand and thus require constant innovation. Classical hydrocarbon scaffolds have long assisted in bringing new molecules to the market place, but an obvious omission is that of the Platonic solid cubane. Eaton, however, suggested that this molecule has the potential to act as a benzene bioisostere. Herein, we report the validation of Eaton's hypothesis with cubane derivatives of five molecules that are used clinically or as agrochemicals. Two cubane analogues showed increased bioactivity compared to their benzene counterparts whereas two further analogues displayed equal bioactivity, and the fifth one demonstrated only partial efficacy. Ramifications from this study are best realized by reflecting on the number of bioactive molecules that contain a benzene ring. Substitution with the cubane scaffold where possible could revitalize these systems, and thus expedite much needed lead candidate identification. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Smith M.T.,Center for Integrated Preclinical Drug Development | Smith M.T.,University of Queensland | Wyse B.D.,Center for Integrated Preclinical Drug Development | Wyse B.D.,University of Queensland | And 2 more authors.
Pain Medicine (United States) | Year: 2013

Objective: Neuropathic pain is an area of unmet clinical need. The objective of this study was to define the pharmacokinetics, oral bioavailability, and efficacy in rats of small molecule antagonists of the angiotensin II type 2 receptor (AT2R) for the relief of neuropathic pain. Design and Methods.: Adult male Sprague-Dawley (SD) rats received single intravenous (1-10mg/kg) or oral (5-10mg/kg) bolus doses of EMA200, EMA300, EMA400 or EMA401 (S-enantiomer of EMA400). Blood samples were collected immediately pre-dose and at specified times over a 12- to 24-hour post-dosing period. Liquid chromatography tandem mass spectrometry was used to measure plasma drug concentrations. Efficacy was assessed in adult male SD rats with a unilateral chronic constriction injury (CCI) of the sciatic nerve. Results.: After intravenous administration in rats, mean (±standard error of the mean) plasma clearance for EMA200, EMA300, EMA400, and EMA401 was 9.3, 6.1, 0.7, and 1.1L/hour/kg, respectively. After oral dosing, the dose-normalized systemic exposures of EMA400 and EMA401 were 20- to 30-fold and 50- to 60-fold higher than that for EMA300 and EMA200, respectively. The oral bioavailability of EMA400 and EMA401 was similar at ∼30%, whereas it was only 5.9% and 7.1% for EMA200 and EMA300, respectively. In CCI rats, single intraperitoneal bolus doses of EMA200, EMA300, and EMA400 evoked dose-dependent pain relief. The pain relief potency rank order in CCI rats was EMA400>EMA300>EMA200 in agreement with the dose-normalized systemic exposure rank order in SD rats. Conclusion.: The small molecule AT2R antagonist, EMA401, is in clinical development as a novel analgesic for the relief of neuropathic pain. Wiley Periodicals, Inc.

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