Flupirtine enhances the anti-hyperalgesic effects of morphine in a rat model of prostate bone metastasis

Objective Current treatments for cancer pain are often inadequate, particularly when metastasis to bone is involved. The addition to the treatment regimen of another drug that has a complementary analgesic effect may increase the overall analgesia without the necessity to increase doses, thus avoiding dose-related side effects. This project investigated the synergistic effect of the addition of the potassium channel (KCNQ2–3) modulator flupirtine to morphine treatment in a rat model of prostate cancer-induced bone pain. Design Syngeneic prostate cancer cells were injected into the right tibia of male Wistar rats under anesthesia. This led to expanding tumor within the bone in 2 weeks, together with the concurrent development of hyperalgesia to noxious heat. Paw withdrawal thresholds from noxious heat were measured before and after the maximum non-sedating doses of morphine and flupirtine given alone and in combinations. Dose-response curves for morphine (0.13–5.0 mg/kg ip) and flupirtine (1.25–10.0 mg/kg ip) given alone and in fixed-dose combinations were plotted and subjected to an isobolographic analysis. Results Both morphine (ED50 = 0.74 mg/kg) and flupirtine (ED50 = 3.32 mg/kg) caused dose-related anti-hyperalgesia at doses that did not cause sedation. Isobolographic analysis revealed that there was a synergistic interaction between flupirtine and morphine. Addition of flupirtine to morphine treatment improved morphine anti-hyperalgesia, and resulted in the reversal of cancer-induced heat hyperalgesia. Conclusions These results suggest that flupirtine in combination with morphine may be useful clinically to provide better analgesia at lower morphine doses in the management of pain caused by tumors growing in bone.

Intravenous injection of leconotide, an omega conotoxin : synergistic antihyperalgesic effects with morphine in a rat model of bone cancer pain

Objective.  Leconotide (CVID, AM336, CNSB004) is an omega conopeptide similar to ziconotide, which blocks voltage sensitive calcium channels. However, unlike ziconotide, which must be administered intrathecally, leconotide can be given intravenously because it is less toxic. This study investigated the antihyperalgesic potency of leconotide given intravenously alone and in combinations with morphine-administered intraperitoneally, in a rat model of bone cancer pain. Design.  Syngeneic rat prostate cancer cells AT3B-1 were injected into one tibia of male Wistar rats. The tumor expanded within the bone causing hyperalgesia to heat applied to the ipsilateral hind paw. Measurements were made of the maximum dose (MD) of morphine and leconotide given alone and in combinations that caused no effect in an open-field activity monitor, rotarod, and blood pressure and heart rate measurements. Paw withdrawal thresholds from noxious heat were measured. Dose response curves for morphine (0.312–5.0 mg/kg intraperitoneal) and leconotide (0.002–200 µg/kg intravenous) given alone were plotted and responses compared with those caused by morphine and leconotide in combinations. Results.  Leconotide caused minimal antihyperalgesic effects when administered alone. Morphine given alone intraperitoneally caused dose-related antihyperalgesic effects (ED50 = 2.40 ± 1.24 mg/kg), which were increased by coadministration of leconotide 20 µg/kg (morphine ED50 = 0.16 ± 1.30 mg/kg); 0.2 µg/kg (morphine ED50 = 0.39 ± 1.27 mg/kg); and 0.02 µg/kg (morphine ED50 = 1.24 ± 1.30 mg/kg). Conclusions.  Leconotide caused a significant increase in reversal by morphine of the bone cancer-induced hyperalgesia without increasing the side effect profile of either drug. Clinical Implication.  Translation into clinical practice of the method of analgesia described here will improve the quantity and quality of analgesia in patients with bone metastases. The use of an ordinary parenteral route for administration of the calcium channel blocker (leconotide) at low dose opens up the technique to large numbers of patients who could not have an intrathecal catheter for drug administration. Furthermore, the potentiating synergistic effect with morphine on hyperalgesia without increased side effects will lead to greater analgesia with improved quality of life.

The social foundations of risk

Ulrich Beck's argument about risk society emphasises, among other things, the pervasiveness of risk. As a feature of the human condition in the contemporary, globalised, world that distinguishes the present from the past, risk is widespread across society and affects all social strata. While Beck has gestured towards the irregular distribution of contemporary risks, nonetheless he has suggested that traditional structural entities – class and wealth – no longer provide the key interpretive frameworks for the calculation of susceptibility. In short, the tentacles of risk are long and almost no one is out of reach. Yet, while the risk society thesis has generated a large theoretical literature, there is very little in the way of research that marries theorising to original data collection. This paper represents an attempt to address this gap by using empirical data to investigate whether risk is more textured than Beck's account suggests. Focusing on health as a domain of risk, the paper uses data from a national sample survey of the Australian electorate to investigate the extent to which social divisions structure perceptions of risk within the general population. The findings suggest that various aspects of social stratification, such as income, occupation and education, do indeed play a role in shaping perceptions of risk.

Novel solutions for a model of wound healing angiogenesis

We prove the existence of novel, shock-fronted travelling wave solutions to a model of wound healing angiogenesis studied in Pettet et al (2000 IMA J. Math. App. Med. 17 395–413) assuming two conjectures hold. In the previous work, the authors showed that for certain parameter values, a heteroclinic orbit in the phase plane representing a smooth travelling wave solution exists. However, upon varying one of the parameters, the heteroclinic orbit was destroyed, or rather cut-off, by a wall of singularities in the phase plane. As a result, they concluded that under this parameter regime no travelling wave solutions existed. Using techniques from geometric singular perturbation theory and canard theory, we show that a travelling wave solution actually still exists for this parameter regime. We construct a heteroclinic orbit passing through the wall of singularities via a folded saddle canard point onto a repelling slow manifold. The orbit leaves this manifold via the fast dynamics and lands on the attracting slow manifold, finally connecting to its end state. This new travelling wave is no longer smooth but exhibits a sharp front or shock. Finally, we identify regions in parameter space where we expect that similar solutions exist. Moreover, we discuss the possibility of more exotic solutions.

System dynamics model of the knowledge management process

To effectively manage the challenges being faced by construction organisations in a fast changing business environment, many organisations are attempting to integrate knowledge management (KM) into their business operations. KM activities interact with each other and form a process which receives input from its internal business environment and produces outputs that should be justified by its business performance. This paper aims to provide further understanding on the dynamic nature of the KM process. Through a combination of path analysis and system dynamic simulation, this study found that: 1) an improved business performance enables active KM activities and provide feedback and guidance for formulating learning-based policies; and 2) effective human resource recruitment policies can enlarge the pool of individual knowledge, which lead to a more conducive internal business environment, as well as a higher KM activity level. Consequently, the desired business performance level can be reached within a shorter time frame.

Strange and stranger ruralities: Social constructions of rural crime in Australia

Rural crime has largely been understood through social disorganization theory. The dominance of this perspective has meant that most research into rural crime has tried to resolve perceived strains in communities, rather than analyze how social problems are constituted in rural places. Using Elias and Scotson's (1994) account of established-outsider relations, the paper examines how the organizational capacity of specific social groups is significant in determining the quality of crime-talk and responses to crime in isolated and rural settings. In particular social 'oldness' and notions of what constitutes 'community' are significant in determining what activities and individuals or groups are marked as features of crime-talk in these settings.

A computer generated model of adenosine receptors rationalising binding and selectivity of receptor ligands

Computer graphic analyses on a broad spectrum of adenosine receptor ligands has shown that both the A1 and A2 adenosine receptors have three binding sites. The spatial relationship of these three binding sites has been defined. Adenosine orientation at A1 and A2 is different.

The community and social impact of drink driving: Under the limit drink driving rehabilitation program

This video was prepared as a teaching resource for CARRS-Q's Under the Limit Drink Driving Rehabilitation Program

Multi-layered model of individual HIV infection progression and mechanisms of phenotypical expression

Cite as: Perrin, Dimitri (2008) Multi-layered model of individual HIV infection progression and mechanisms of phenotypical expression. PhD thesis, Dublin City University.