Biphasic drug absorption from the epidural space of the dog may limit the utility of a slow release medium molecular weight hyaluronic acid-lidocaine ionic complex formulation.

Previous epidural studies conducted in rabbits have described a viscous lidocaine-hyaluronate formulation (L-HA) that prolonged the duration of sensory blockade twofold and decreased the rate of drug absorption fourfold relative to a solution formulation. As further evaluation of the L-HA formulation required studies in a larger animal that more closely reflected the characteristic absorption kinetics observed in humans, a conscious dog model was used to functionally and kinetically evaluate the viscous formulation relative to lidocaine solution. In terms of the measured pharmacodynamic end point (loss of weight-bearing ability in hind legs), epidural administration of the L-HA formulation did not prolong the duration of action relative to lidocaine solution in spite of a markedly altered pharmacokinetic profile. For example, administration of L-HA reduced the mean plasma lidocaine Cmax value approximately 50% and increased the Tmax value approximately fivefold relative to lidocaine solution. However, the viscous L-HA formulation did cause a significant prolongation in the latency of onset (P < 0.001) relative to lidocaine solution. The dog exhibited "flip-flop" pharmacokinetics and absorption was biphasic after epidural administration of lidocaine solution (apparent t1/2 of the fast and slow absorption phases were 4 min and 131 min, respectively). The L-HA formulation markedly altered the absorption kinetics such that a single, slow absorption phase was evident (apparent t1/2 of 56 min), although this rate was more rapid than the slow phase observed after lidocaine solution. It is possible that the inability of the hyaluronate-based formulation to further reduce the magnitude of the slow absorption phase resulted in the failure to prolong the duration of action. These data highlight the need to carefully consider the absorption kinetics and pharmacokinetic characteristics of the animal models chosen to evaluate new formulation of epidurally administered local anesthetics.

Prolongation of lidocaine-induced epidural anesthesia by medium molecular weight hyaluronic acid formulations: pharmacodynamic and pharmacokinetic studies in the rabbit.

We evaluated the utility of medium molecular weight hyaluronic acid for prolonging the local anesthetic activity of lidocaine in a rabbit model of epidural analgesia. Equiviscous formulations were prepared as either a physical mixture of lidocaine hydrochloride and sodium hyaluronate (where drug release occurred via diffusion) or as a lidocaine-hyaluronate complex (where drug release occurred via diffusional and electrostatic processes). The novel hyaluronic acid formulations were functionally evaluated, relative to lidocaine solution, in an intact, conscious rabbit model. The hyaluronate formulations were well tolerated. The duration of sensory block and loss of weight-bearing was prolonged twofold by the lidocaine-hyaluronate complex relative to the solution (P < 0.05). In terms of motor block, flaccid paresis occurred after administration of the solution formulation, whereas only partial motor block was evident after administration of the viscous formulations. Pharmacokinetic modeling of the lidocaine plasma concentration-time data indicated that the rate of drug absorption from the lidocaine-hyaluronate complex was decreased fourfold relative to the solution (P < 0.05). These observations indicate that ionic complexes of local anesthetics with medium molecular weight hyaluronic acid may offer advantages for the prolongation of epidural analgesia.

Preliminary studies on the inflammatory actions of the venoms of some Australian spiders.

Experiments were performed using an anaesthetised rat model to investigate the local inflammatory responses produced by intradermal injections of crude venom gland extracts from a number of Australian spiders, namely, Phonognatha graeffei, Delena cancerides, Isopeda montana, Badumna insignis, Lampona cylindrata, Steatoda grossa, S. capensis Hann. All of the venom gland extracts tested, with the exception of that from S. capensis, produced increases in vascular permeability consistent with acute inflammatory responses. The responses primarily involved the activation of 5-HT receptors, since they were markedly reduced by the nonselective 5-HT1/5-HT2-receptor antagonist methiothepin. Some of the venoms caused liberation of endogenous mediators of inflammation, and some had components that acted directly on the vasculature to increase vascular permeability. Histamine appeared to have little if any role in the observed increases in vascular permeability following intradermal injection of the spider venoms.

Opiate agonist and antagonist action on guinea-pig isolated ileum.

1. It is well known that morphine reduces acetylcholine output from the guinea-pig isolated ileum during transmural stimulation. However, the effect of morphine on tetanic responses of this preparation has not been examined. 2. The present study shows that responses elicited over the frequency range of 1-20 Hz were unaffected by a concentration of morphine which markedly reduced twitch responses. Similarly, the effect of naloxone on responses elicited in this preparation to transmural stimulation is not known. 3. We report here that naloxone (1 microM) had no effect on either twitches or tetanic responses elicited over the range of 1-20 Hz. 4. Therefore, it appears that morphine does not alter tetanic responses and endogenous opiates do not modulate neuroeffector transmission in this model.

Effects of the venom of the theridiid spider, Steatoda capensis Hann, on autonomic transmission in rat isolated atria and caudal artery.

The possibility of alpha-latrotoxin-like activity in the crude venom gland extract (VGE) of a related Theridiid spider, Steatoda capensis Hann, was investigated. The VGE from female S. capensis Hann spiders produced vasoconstriction in isolated segments of rat caudal artery but was without effect in artery segments obtained from rats that had been pretreated with reserpine (2.5 mg/kg) 24 hr prior to experimentation, indicating that the vasoconstriction was due to the release of noradrenaline from periarterial sympathetic nerves. Steatoda capensis Hann VGE also increased the rate of beating of rat isolated atrial preparations. The positive chronotropic action of the VGE was partly due to the release of noradrenaline from atrial sympathetic nerves since it was reduced by the beta-adrenoceptor antagonist propranolol, and smaller increases in rate were observed in atria taken from rats pretreated with reserpine. The positive chronotropic effect of the VGE was enhanced by atropine, suggesting that the VGE also releases acetylcholine from atrial parasympathetic nerves. The VGE evoked release of radioactivity from rat atria in which the transmitter stores of the atrial intramural noradrenergic nerves had been labelled with [3H]noradrenaline. There appeared to be two components of the release, one involving omega-conotoxin GVIA-sensitive Ca2+ channels, and the other independent of extracellular Ca2+.

Alpha- and beta-adrenoceptor agonist activity in the venom of the Australian huntsman spiders, Delena cancerides and Isopeda montana.

1. Crude venom gland extracts (VGE) were prepared from female Delena cancerides and Isopeda montana spiders. The VGE were tested in isolated rat atrial, caudal artery and pithed rat preparations for pharmacological activity. 2. In rat isolated atrial preparations, D. cancerides and I. montana VGE, each in a concentration of 2 glands/mL, produced increases in atrial rate which were abolished by propranolol (1 mumol/L) but not by ketanserin (0.1 mumol/L) or reserpine pretreatment (2.5 mg/kg s.c. 24 h prior to experimentation) indicating a direct action on atrial beta-adrenoceptors. 3. In rat caudal artery preparations each VGE produced an increase in perfusion pressure, which was taken as an index of vasoconstriction. Pressor responses to D. cancerides VGE (1 gland/mL) were abolished in the presence of prazosin (1 mol/L) but not by reserpine pretreatment, indicating an action of the VGE on vascular alpha 1-adrenoceptors. Neither prazosin nor reserpine pretreatment had any effect on pressor responses of rat caudal artery preparations to I. montana VGE. Ketanserin (6 nmol/L) produced a small reduction in the degree of vasoconstriction produced by the VGE. This demonstrates a lack of alpha 1-adrenoceptor agonist activity of the VGE. 4. Both VGE produced dose-dependent increases in mean arterial pressure and heart rate in pithed rat preparations. The use of relatively selective receptor antagonists indicated that the increases in mean arterial pressure (MAP) produced by both VGE were mediated by an action on alpha 2-adrenoceptors.