A static magnetic field modulates severity of audiogenic seizures and anticonvulsant effects of phenytoin in DBA/2 mice.

RATIONALE: In a search for potential supplements or alternatives to the pharmacological treatment of epilepsy, we examined the effects of static magnetic fields on audiogenic seizures of DBA/2 mice. METHODS: Two strains of DBA/2 mice were subjected to auditory stimulation that resulted sequentially in wild running, loss of righting, clonus, tonic hindlimb extension, and death in 80-95% of animals in different experiments. The incidence of seizure stages in groups of animals pretreated with a static magnetic field, phenytoin (PHT) or both was compared to the incidence in sham-exposed control mice. RESULTS: Depending on magnetic flux density and duration of exposure to the field, seizure severity decreased significantly, but not completely, in both strains. However, incidence of five seizure stages was reduced in one strain, with about half of the mice seizure free. Two seizure stages (tonic hindlimb extension and death) were reduced significantly in the other. Magnetic field pretreatment potentiated the effect of PHT. Clonic seizures refractory to PHT or magnetic field pretreatment in DBA/2J mice responded to pretreatment with a combination of PHT and the magnetic field. CONCLUSIONS: A static magnetic field had some anticonvulsant effects when employed alone. More robust effects were seen in combination with PHT. Further testing of magnetic fields for anticonvulsant effects and elucidation of mechanisms of action seem to be warranted.

The arithmetic mean of ratio-normalized experiments overestimates the true E/C ratio.

Biological assays often suffer from large systematic variation between sets of experiments. This variation is sometimes countered by normalizing the results of an "exposed" (E) experiment to that of a simultaneously performed "control" (C). We demonstrate that the arithmetic mean of such ratios overestimates the "true" E/C ratio. Fortunately, the overestimation may be calculated from experimentally accessible information, and it is generally possible to correct for this factor using formulas presented in this paper. We have studied the impact of this effect on a set of studies in the bioelectromagnetics literature and find that, although most results are weakened by the correction, few are significantly altered. Some of the papers used for our literature study are controversial; we believe that the present study may strengthen the quoted results by removing doubts about the statistical treatment of E/C ratios. Both false positives and negatives are possible if the proper correction is not made to the arithmetic mean of a set of E/C data. Realistic examples of erroneous statistical conclusions demonstrate that this is a real concern for E/C data which are marginal in both magnitude (mean < 2) and variance (standard deviation > 0.5).

Triglyceride-based microemulsion for intravenous administration of sparingly soluble substances.

A pharmaceutically acceptable microemulsion system composed of a medium-chain triglyceride (MCT), soybean phosphatidylcholine and poly(ethylene glycol)(660)-12-hydroxystearate (12-HSA-EO15) as amphiphiles, and poly(ethylene glycol) 400 (PEG 400) and ethanol as cosolvents is presented and characterized in terms of phase behavior, microstructure, solubilization capacity and in vivo effects after intravenous administration to conscious rats. At a total concentration of 11.9 wt % of soybean phosphatidylcholine and 12-HSA-EO15, a microemulsion region was formed over a wide range of alpha, where alpha is the weight fraction of MCT/(MCT + water + PEG 400 + ethanol). The microstructure of the microemulsion was of a bicontinuous nature even at high oil concentrations. The mean droplet diameter of the oil-in-water emulsion formed after dilution of microemulsions prepared at different alpha within the one-phase region was between 60 and 200 nm. It was concluded that it is possible to administer up to 0.5 mL/kg of the microemulsion (alpha = 0.5) without producing any significant effect on acid-base balance, blood gases, plasma electrolytes, mean arterial blood pressure (MAP), heart rate (HR), and PQ time (the time between depolarization of atrium and chamber). At a dose of 1.5 mL/kg, a temporary increase in MAP, a decrease in HR, and a prolongation of the PQ time were observed.

Drug compatibility with the sponge phases formed in monoolein, water, and propylene glycol or poly(ethylene glycol).

The liquid sponge phase, a bicontinuous lipid-water system, formed in solvent-monoolein-water systems was investigated with respect to drug compatibility. The solvents propylene glycol and poly(ethylene glycol) swell the bicontinuous cubic phase of the monoolein-water system and form the sponge phase at constant water contents, 40 and 30% w/w, respectively. Amphiphilic drugs such as lidocaine participate in the bilayer and act on the interfacial curvature according to the amphiphilic packing concept. The interfacial curvatures increase/decrease depending on the salt/base forms of the molecules. The quantity of lidocaine that can be incorporated into the sponge phase depends not only on the form of lidocaine but also on the lipid content and the solvent used in the sponge phase. Addition of the water-insoluble gramicidin S to the sponge phase resulted in a stiff isotropic phase, possibly a cubic phase, indicating interaction of gramicidin S with the lipid bilayer. The in vitro release of lidocaine was significantly faster from the sponge phase in the propylene glycol system than from the corresponding cubic phase without solvent.

Dynamic properties of Lednev's parametric resonance mechanism.

This paper presents a further development of the mechanism for the detection of weak magnetic fields proposed by [Lednev (1991): Bioelectromagnetics 12:71-75]. The fraction of excited oscillator states of an unhydrated ion is studied in a dynamic model driven by the predicted (time-varying) transition probability in the presence of thermal noise and an unspecified excitation mechanism. The main results of Lednev are confirmed. In addition, I conclude that ultraharmonic and ultrasubharmonic resonances may also be observed, provided that the response time of the dynamic system is similar to the period of the oscillating magnetic field. I discuss the time scales involved in the mechanism and present theoretical constraints on these parameters. The crucial requirement for the theory's applicability is that the lifetime of the excited states of the affected ion oscillator exceeds the period of the applied magnetic field. Numerical solutions of the dynamic system are given and are shown to correspond well to theoretical expectations. The main discrepancy between the theories of Lednev and of Blanchard and Blackman [Blanchard and Blackman (1994): Bioelectromagnetics 15:217-238] appears to be due to an inconsistency in the latter paper. The general problem of robust analysis of experimental data is discussed, and I suggest a test of compliance with the Lednev model that is independent of all parameters except for the ratio of oscillating and static field strength (B1/B0) for many resonance conditions and experimental models.

Formulation of a drug delivery system based on a mixture of monoglycerides and triglycerides for use in the treatment of periodontal disease.

This paper describes the development of a stable, controlled-release formulation of metronidazole for use in the treatment of periodontal disease. It is formulated as a suspension, which undergoes transformation to a release-controlling, semi-solid on contact with gingival fluid. The system is based on the ability of mixtures of monoglycerides and triglycerides to form liquid crystals, i.e., reversed hexagonals, in contact with water. The reversed hexagonal form was found to have the most favourable sustained release properties, compared with those from the cubic form. The source of metronidazole is the prodrug, metronidazole benzoate, which further helps to slow down the release rate. Product characteristics are assessed by differential scanning calorimetry and viscometry. The release data derive from the results of in vitro dissolution tests. X-ray diffraction, phase diagrams, and polarized light microscopy were used to elucidate the structure of the liquid crystalline phases.