From the Cover: Spatial mismatch between the Na+ flux and spike initiation in axon initial segment

It is widely believed that, in cortical pyramidal cells, action potentials (APs) initiate in the distal portion of axon initial segment (AIS) because that is where Na⁺ channel density is highest. To investigate the relationship between the density of Na⁺ channels and the spatiotemporal pattern of AP initiation, we simultaneously recorded Na⁺ flux and action currents along the proximal axonal length. We found that functional Na⁺ channel density is approximately four times lower in the AP trigger zone than in the middle of the AIS, where it is highest. Computational analysis of AP initiation revealed a paradoxical mismatch between the AP threshold and Na⁺ channel density, which could be explained by the lopsided capacitive load imposed on the proximal end of the AIS by the somatodendritic compartment. Favorable conditions for AP initiation are therefore achieved in the distal AIS portion, close to the edge of myelin, where the current source–load ratio is highest. Our findings suggest that cable properties play a central role in determining where the AP starts, such that small plastic changes in the local AIS Na⁺ channel density could have a large influence on neuronal excitability as a whole.     

Comparative study of taurine and tauropyrone: GABA receptor binding, mitochondrial processes and behaviour

Objectives Taurine, a sulfur‐containing amino acid, has high hydrophilicity and is poorly absorbed. Tauropyrone, a taurine‐containing 1,4‐dihydropyridine derivative, is suggested to have greater activity than taurine owing to improved physicochemical properties that facilitate delivery of the compound to target cells. The aim of this study was to determine whether the 1,4‐dihydropyridine moiety in tauropyrone improves the pharmacological efficacy of taurine in vitro and in vivo. Methods The effects of taurine and tauropyrone, as well as of the 1,4‐dihydropyridine moiety were compared in in‐vitro experiments to determine the binding to GABA receptors and influence on mitochondrial processes (isolated rat liver mitochondria), and in in‐vivo tests to assess the influence on behavioural effects caused by the GABA‐A receptor ligands, bicuculline, diazepam and ethanol. Key findings Unlike taurine, tauropyrone did not display binding activity for the GABA‐A receptor, and only taurine (but not tauropyrone) at low doses (0.1, 1.0 and 10 mg/kg) antagonised the bicuculline‐induced convulsion effect. Taurine and tauropyrone had no effect on diazepam myorelaxing action, and they both exerted a comparable ‘anti‐ethanol’ effect (shortening of the ethanol‐sleeping time). Taurine and tauropyrone did not influence processes of mitochondrial bioenergetics. Conclusions The action of tauropyrone at the level of the GABA‐A receptor differs qualitatively from that of taurine, probably because of its 1,4‐dihydropyridine moiety, which may hinder access to the GABA‐A receptor GABA site. Tauropyrone does not show improved pharmacological efficacy in in‐vitro and in‐vivo studies in comparison with taurine.     

In-situ phase transition from microemulsion to liquid crystal with the potential of prolonged parenteral drug delivery

This study is the first to investigate and demonstrate the potential of microemulsions (MEs) for sustained release parenteral drug delivery, due to phase transition behavior in aqueous environments. Phase diagrams were constructed with Miglyol 812N oil and a blend of (co)surfactants Solutol HS 15 and Span 80 with ethanol. Liquid crystal (LC) and coarse emulsion (CE) regions were found adjacent to the ME region in the water-rich corner of the phase diagram. Two formulations were selected, a LC-forming ME and a CE-forming ME and each were investigated with respect to their rheology, particle size, drug release profiles and particularly, the phase transition behavior. The spreadability in an aqueous environment was determined and release profiles from MEs were generated with gamma-scintigraphy. The CE-forming ME dispersed readily in an aqueous environment, whereas the LC-forming ME remained in a contracted region possibly due to the transition of ME to LC at the water/ME interface. Gamma-scintigraphy showed that the LC-forming ME had minimal spreadability and a slow release of (99m)Tc in the first-order manner, suggesting phase conversion at the interface. In conclusion, owing to the potential of phase transition, LC-forming MEs could be used as extravascular injectable drug delivery vehicles for prolonged drug release.     

Firing properties of frog tectal neurons in vitro

Whole-cell recordings from frog tectal slices revealed different types of neuronal firing patterns in response to prolonged current injection. The patterns included regular spiking without adaptation, accelerating firing, adapting spiking, repetitive bursting and phasic response with only one spike. The observed firing patterns are similar to those found in the mammalian superior colliculus. The frog tectum could be a useful preparation in elucidating the relationship between neuronal function and membrane properties.     

Extemporaneous compounding in New Zealand hospitals

Objective The skill to compound non‐sterile products is one of the seven competencies required of entry‐level pharmacists for registration with the New Zealand Pharmacy Council. The need for extemporaneous compounding skills has been questioned in other countries, as it is argued that the skill is not often required in modern pharmacy settings. The aim of the current study was to determine the scope and frequency of extemporaneous compounding in New Zealand hospitals Method Retrospective data were collected from eight large hospitals where extemporaneous compounded is regularly undertaken, for the period June 1, 2004 to December 31, 2004. Data were retrieved from compounding logbooks and batch sheets in hospital dispensaries. Data were collected from the north and south islands of the country. There are 32 hospitals of various sizes in New Zealand but extemporaneous compounding is not undertaken at all of them due to staff shortages or lack of demand. Key findings There were 2015 products compounded over the seven‐month period, with an average of 251.9 per month. Suspensions were the most frequently compounded oral dosage form. Omeprazole suspension was the most frequently compounded extemporaneous product. Nearly one‐third of the compounded products were for beta‐blockers. Creams, ointments and non‐oral solutions were the most common topical compounded products. Conclusion Pharmacists perform a broad range of extemporaneous compounding, and the skill of compounding is thus an essential competency for all hospital pharmacists.