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.

Two configurations of static magnetic fields for treating rheumatoid arthritis of the knee: a double-blind clinical trial.

OBJECTIVE: To assess the efficacy of a nonpharmacologic, noninvasive static magnetic device as adjunctive therapy for knee pain in patients with rheumatoid arthritis (RA). DESIGN: Randomized, double-blind, controlled, multisite clinical trial. SETTING: An American and a Japanese academic medical center as well as 4 community rheumatology and orthopedics practices. PATIENTS: Cohort of 64 patients over age 18 years with rheumatoid arthritis and persistent knee pain, rated greater than 40/100mm, despite appropriate use of medications. INTERVENTION: Four blinded MagnaBloc (with 4 steep field gradients) or control devices (with 1 steep field gradient) were taped to a knee of each subject for 1 week. MAIN OUTCOME MEASURES: The American College of Rheumatology recommended core set of disease activity measures for RA clinical trials and subjects' assessment of treatment outcome. RESULTS: Subjects randomly assigned to the MagnaBloc (n = 38) and control treatment groups (n = 26) reported baseline pain levels of 63/100mm and 61/100mm, respectively. A greater reduction in reported pain in the MagnaBloc group was sustained through the 1-week follow-up (40.4% vs 25.9%) and corroborated by twice daily pain diary results (p < .0001 for each vs baseline). However, comparison between the 2 groups demonstrated a statistically insignificant difference (p < .23). Subjects in the MagnaBloc group reported an average decrease in their global assessment of disease activity of 33% over 1 week, as compared with a 2% decline in the control group (p < .01). After 1 week, 68% of the MagnaBloc treatment group reported feeling better or much better, compared with 27% of the control group, and 29% and 65%, respectively, reported feeling the same as before treatment (p < .01). CONCLUSIONS: Both devices demonstrated statistically significant pain reduction in comparison to baseline, with concordance across multiple indices. However, a significant difference was not observed between the 2 treatment groups (p < .23). In future studies, the MagnaBloc treatment should be compared with a nonmagnetic placebo treatment to characterize further its therapeutic potential for treating RA. This study did elucidate methods for conducting clinical trials with magnetic devices.

Static magnetic field therapy for pain in the abdomen and genitals.

Two adolescents with debilitating, medication-resistant, chronic pain of the low back and abdomen with intermittent pain of the genitalia were diagnosed with intervertebral disk disease at spinal cord levels that correlated with their signs. Both patients had undergone multiple evaluations by physicians of different specialties and both underwent appendectomy without relief of their pain. The history of the onset of pain was important in determining the affected levels. The pain of both individuals was mimicked and localized by percussion of the vertebral spines at the level of disk protrusion. This maneuver and careful review of the history were important in making the correct diagnosis in each case. In both patients, treatment with novel magnetic devices provided rapid relief that was sustained for more than 2 years. These cases highlight the need for careful evaluation and correct diagnosis of abdominal and genital pain in young patients to avoid costly and unnecessary medical intervention and the stigma of painful debility.

Safety and tolerability of gabapentin as adjunctive therapy in a large, multicenter study.

PURPOSE: To evaluate the tolerability and safety of gabapentin (GBP) as add-on therapy for seizure control. METHODS: Conducted in an outpatient setting and reflecting usual practice, this study compared tolerability of GBP dosages < or = 1,800 versus >1,800 mg/day, when these doses were required to achieve the most effective seizure control. Two analyses of adverse events are presented: tolerability and safety. In the tolerability analysis, each patient served as his or her own control to compare the occurrence of adverse events at GBP < or =1,800 versus >1,800 mg/day. The safety analysis required patients to receive at least one dose of GBP and have a follow-up contact. RESULTS: A total of 2,216 patients enrolled in this open-label, 16-week study and were evaluable for safety. Of these, 74.0% completed the 16-week study, and 281 met the tolerability criteria. Within these 281 patients, two mutually exclusive groups were compared (a) those reporting adverse events at only < or =1,800 mg/day (low dose); and (b) those reporting adverse events at only >1,800 mg/day (high dose). Three adverse events (asthenia, headache, and dizziness) were observed in a statistically significantly larger number of patients at only the low dose than in the group reporting these same adverse events at only the high dose, suggesting that patients who tolerated GBP at < or = 1,800 mg/day did not experience a significant increase in adverse events with dosages >1,800 mg/day. Overall, 10.6% of the 2,216 patients in the safety population prematurely withdrew because of adverse events, and 3.5% discontinued because of lack of efficacy. Safety and tolerability of GBP was rated as excellent or good for 78.5% of all patients. CONCLUSIONS: Gabapentin doses >1,800 mg/day were as well tolerated as doses < or =1,800 mg/day and were not associated with more adverse events.

Fatal familial insomnia: clinical and pathologic heterogeneity in genetic half brothers.

We describe clinical and pathologic features of a patient with fatal familial insomnia (FFI) whose prion (PrP) genotype is D178N coupled with methionine at codon 129 on his mutant allele and valine at codon 129 on his normal allele. A cousin (genetic half brother) with identical PrP genotypes exhibited strikingly different clinical and pathologic changes. Comparison of these cousins shows the phenotypic heterogeneity of FFI and suggests that the phenotypic expression of D178N is influenced by multiple factors.

Oxcarbazepine: preclinical anticonvulsant profile and putative mechanisms of action.

Oxcarbazepine (OCBZ, Trileptal) and its main human monohydroxy metabolite (MHD) protected mice and rats against generalized tonic-clonic seizures induced by electroshock with ED50 values between 13.5 and 20.5 mg/kg p.o. No tolerance toward this anticonvulsant effect was observed when rats were treated with OCBZ or MHD daily for 4 weeks. The therapeutic indices were 4 (OCBZ) and > 6 (MHD) for sedation (observation test, mice and rats) and 8 (MHD) or 10 (OCBZ) for motor impairment (rotorod test, mice). Both compounds were less potent in suppressing chemically induced seizures and did not significantly influence rat kindling development. At doses of 50 mg/kg p.o. and 20 mg/kg i.m. and higher, OCBZ and, to a lesser extent, MHD protected Rhesus monkeys from aluminum-induced chronically recurring partial seizures. In vitro, OCBZ and MHD suppressed sustained high-frequency repetitive firing of sodium-dependent action potentials in mouse neurons in cell culture with equal potency (medium effective concentration 5 x 10(-8) M/L). This effect is probably due in part to a direct effect on sodium channels. Patch-clamp studies on rat dorsal root ganglia cells revealed that up to a concentration of 3 x 10(-4) M, MHD did not significantly interact with L-type calcium currents, whereas OCBZ diminished them by about 30% at the concentration of 3 x 10(-4) M. In biochemical investigations, no brain neurotransmitter or modulator receptor site responsible for the anticonvulsant mechanism of action of OCBZ and MHD was identified.(ABSTRACT TRUNCATED AT 250 WORDS)

Phenytoin blocks N-methyl-D-aspartate responses of mouse central neurons.

Intracellularly recorded depolarizing responses of mouse spinal cord neurons in cell culture to N-methyl-D-aspartate (NMDA) applied by pressure ejection at 37 degrees C had a reversal potential of about -13 mV. Amplitude increased when [Mg++]o was less than 1.0 mM or glycine was added to the buffer. Desensitization was complete within 30 pressure applications of NMDA (P30) at 2-s inter-response intervals (IRI; timed from return of one response to resting potential until next application) in bicarbonate buffer and was glycine-sensitive. Desensitization was insignificant in phosphate buffer. In both buffers, 8 x 10(-6) M phenytoin (PT) blocked responses reversibly by P10 of 10(-5) M NMDA at 0.2 Hz (overlapping responses) and at short 2-s IRI (responses not overlapping). At frequencies < or = 0.1 Hz or IRI > or = 5 s, desensitization and block were less prominent or inapparent. Block by PT was observed 1) in single isolated neurons; 2) in 7 mM [Mg++]o-, 150 mM [K+]o-, or tetrodotoxin (TTX)-containing buffer to suppress spontaneous synaptic activity and action potentials and 3) when voltage-dependent Mg++ block was removed by depolarization or in 0.1 mM Mg++, with or without glycine supplementation. The block was not competitive. The PT metabolite, 5-(4-hydroxyphenyl)-5-phenylhydantoin (80 microM), did not block responses to NMDA. Use- and frequency-dependent block of NMDA responses may contribute to clinical effects of PT, e.g., during sustained rapid activity along pathways excited by NMDA-preferring glutamate receptors.