Current Developments in Intraspinal Agents for Cancer and Noncancer Pain

Since the late 1980s, intrathecal (IT) analgesic therapy has improved, and implantable IT drug delivery devices have become increasingly sophisticated. Physicians and patients now have myriad more options for agents and their combination, as well as for refining their delivery. As recently as 2007, The Polyanalgesic Consensus Conference of expert panelists updated its algorithm for drug selection in IT polyanalgesia. We review this algorithm and the emerging therapy included. This article provides an update on newly approved as well as emerging IT agents and the advances in technology for their delivery

Comparative Analysis of Acid Sphingomyelinase Distribution in the CNS of Rats and Mice Following Intracerebroventricular Delivery

Niemann-Pick A (NPA) disease is a lysosomal storage disorder (LSD) caused by a deficiency in acid sphingomyelinase (ASM) activity. Previously, we reported that biochemical and functional abnormalities observed in ASM knockout (ASMKO) mice could be partially alleviated by intracerebroventricular (ICV) infusion of hASM. We now show that this route of delivery also results in widespread enzyme distribution throughout the rat brain and spinal cord. However, enzyme diffusion into CNS parenchyma did not occur in a linear dose-dependent fashion. Moreover, although the levels of hASM detected in the rat CNS were determined to be within the range shown to be therapeutic in ASMKO mice, the absolute amounts represented less than 1% of the total dose administered. Finally, our results also showed that similar levels of enzyme distribution are achieved across rodent species when the dose is normalized to CNS weight as opposed to whole body weight. Collectively, these data suggest that the efficacy observed following ICV delivery of hASM in ASMKO mice could be scaled to CNS of the rat

Limited P-glycoprotein mediated efflux for anti-epileptic drugs.

A variety of anti-epileptic drugs (AEDs) were tested for their ability to be transported by P-glycoprotein (P-gp) through Caco-2 monolayers using bi-directional (apical (Ap) to basolateral (Bas), and Bas to Ap) studies. Transport rates were equivalent in both directions for vigabatrin, gabapentin, phenobarbitone, lamotrigine and carbamazepine, being 0.7 × 10− 6, 0.1 × 10− 6, 34 × 10− 6, 36 × 10− 6 and 55 × 10− 6 cm/s, respectively. Phenytoin displayed a 20% increase in Ap to Bas transport, while topiramate and ethosuximide each had greater transport in the uptake direction, with both drugs showing no efflux. None of the transport rates for these drugs were affected by P-gp inhibitors. However, the efflux rate for acetazolamide was 3-fold higher than its uptake and this was significantly reduced by P-gp inhibitors. Thus, only one anti-epileptic, acetazolamide, was shown to be weak P-gp substrate, suggesting that P-gp efflux may not be a factor in relation to the development of resistance of epilepsy therapy