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.

Effect of chute level on mill capacity

IN MANY FACTORIES, the feed chute of the first mill is operated with a high chute level for the purpose of maximising the cane rate through the mill. There is a trend towards trying to control chute level within a small control range near the top of a chute that can result in rapid changes in cane feeding rate to maintain the chute level set point. This paper reviews the theory that predicts higher cane rate with higher chute level and discusses the main weakness in the theory that it does not consider the beneficial effect on capacity of cane falling from the top of the chute to the top surface of the cane mat. An extension to the chute theory model is described that predicts higher capacity with lower chute level because of the effect of the falling cane. The original model and this extended model are believed to be the upper and lower limits to the true effect. The paper reports an experiment that measured the real effect of chute level on capacity and finds that increasing chute level does lead to higher capacity but that the trend is only about one-third as strong as the original theory predicted. The paper questions whether the benefits of slightly greater capacity outweigh the costs of operating with the small control range near the top of the chute.

An alternative approach to setting a mill

The conventional approach to setting a milling unit is essentially based on the desire to achieve a particular bagasse moisture content or fibre fill in each nip of the mill. This approach relies on the selection of the speed at which the mill will operate for the selected fibre rate. There is rarely any checking that the selected speed or the selected fibre fill is achieved and the same set of assumptions is generally carried over to use again in the next year. The conventional approach largely ignores the fact that the selection of mill settings actually determines the speed at which the mill will operate. Making an adjustment with the intent of changing the performance of the mill often also changes the speed of the mill as an unintended consequence. This paper presents an alternative approach to mill setting. The approach discussed makes use of mill feeding theory to define the relationship between fibre rate, mill speed and mill settings and uses that theory to provide an alternative means of determining the settings in some nips of the mill. Mill feeding theory shows that, as the feed work opening reduces, roll speed increases. The theory also shows that there is an optimal underfeed opening and Donnelly chute exit opening that will minimise roll speed and that the current South African guidelines appear to be well away from those optimal values.