Neuronal MDR-1 gene expression and persistent low levels of anticonvulsants in a child with refractory epilepsy

SUMMARY: It is estimated that 20-25% of epileptic patients fail to achieve good control with antiepileptic drug (AED) treatment; thus, refractory epilepsy (RE) has been described in patients who have adequate therapeutic levels of AEDs without control of seizures. Multidrug resistance genes have been reported to be highly expressed in brain of patients with RE. Persistent low plasma levels of AEDs and high brain expression of the multidrug resistance product P-glycoprotein (P-gp) have been previously communicated in a case report of RE secondary to tuberous sclerosis. Here, the authors report a case of an 8-year-old boy diagnosed with partial RE with focal seizures who was admitted to hospital for a severe episode of subintrant crisis. The patient received polytherapy with carbamazepine (CBZ), phenytoin (PHT), and valproic acid (VA); however, habitual doses of these AEDs failed to control the patient's symptoms. AED blood levels were monitored for 25 consecutive days and showed low values in 8/25 (33%) for CBZ, 10/25 (40%) for PHT, and 25/25 (100%) for VA of samples studied. Because the patient developed focal status epilepticus, surgical treatment by callosotomy was done, resulting in a significant improvement in epileptic symptoms. The immunostaining of brain specimens showed significantly increased expression of P-gp not only in vascular endothelial cells and related astrocytes but also in neurons. Overexpression of P-gp in the brain does not explain the low blood levels of AEDs described in these cases. Different mechanisms such as drug-drug interactions and drug transporters can be involved in the results observed. The P-gp overexpression and/or its pharmacologic induction should be considered as a potential mechanism responsible for drug resistance to epilepsy treatment and highly suspected in patients with persistent subtherapeutic AEDs plasma levels.     

Long-term effects of rivastigmine treatment on neuropsychiatric and behavioral disturbances in nursing home residents with moderate to severe Alzheimer's disease: results of a 52-week open-label study

OBJECTIVES: To evaluate the safety and efficacy of long-term treatment with rivastigmine (3-12 mg/day) and its effects on neuropsychiatric and behavioral disturbances in nursing home patients with moderate to severe probable Alzheimer's disease (AD). METHODS: A prospective, multicenter 26-week open-label extension to a 26-week open-label study (52 week results) of rivastigmine treatment in patients with Mini-Mental State Examination (MMSE) scores of 6-15 inclusive, residing in nursing homes at 13 centers in the US. Effects of treatment with rivastigmine for up to 52 weeks on neuropsychiatric and behavioral symptoms were examined using the Neuropsychiatric Inventory-Nursing Home (NPI-NH) scale. Cognitive function was assessed by the MMSE, and the Naming Objects and Fingers Test (NOFT) subset of the Alzheimer's Disease Assessment Scale -- Cognitive subscale (ADAS-Cog). Global functioning was assessed using the simplified Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus). RESULTS: Rivastigmine (3-12 mg/day) significantly improved neuropsychiatric and behavioral symptoms compared to baseline (in patients with specific behavioral disturbances at baseline) in observed cases (OC) and last observation carried forward (LOCF) analyses. Over 52 weeks, treatment with rivastigmine significantly improved 10 of 12 individual NPI-NH domains from baseline in LOCF patients with symptoms present at baseline. Cognitive function was stable, indicated by the lack of decline in MMSE and the NOFT. Global function was stabilized or improved in greater than half of the patients as indicated by the simplified CIBIC-Plus scores. CONCLUSION: Rivastigmine showed potential benefit in the long-term treatment of behavioral symptoms as well as cognitive and global functioning in nursing home residents with moderate to severe AD with concurrent behavioral symptoms present at baseline. Although these results suggest that treatment with rivastigmine may have beneficial behavioral effects and cognitive benefits on patients with moderate to severe AD, they are subject to the limitations of an open-label study.     

Effect of magnesium on mechanical properties of pressurized mesenteric small arteries from old and adult rats

The purpose of the present study was to determine the effects of magnesium (Mg) on the mechanical properties of resistance arteries in adult and old rats. Studies were performed in adult (17 weeks) and old (104 weeks) male Wistar rats. The vasodilatory response and the passive mechanical properties of the wall of isolated perfused and pressurized arterial segments of mesenteric small arteries were investigated after Mg and verapamil application, both known for their calcium antagonistic properties. Mesenteric resistance arteries from old rats exhibited an outward hypertrophic remodelling, with enlargment of the lumen, thickening of the media and enlarged media cross-sectional area. The vasodilatory response induced by the application of increasing extracellular concentrations of Mg and verapamil was significantly smaller in preconstricted mesenteric arteries of old rats than in those of adult rats. Incremental distensibility in response to increasing intravascular pressures did not change. However, the stress-strain curve was shifted to the left in pressurized mesenteric arteries from old rats, indicating arterial wall stiffness. Verapamil (3 micro mol/L) did not modify the stress-strain curves in either adult or aged rats. However, Mg (4.8 mmol/L) significantly shifted the curve to the right in mesenteric arteries from adult rats and, to a greater degree, in those from old rats. Although Mg-induced vasodilatation is impaired in aged rats, increased Mg concentration improved the mechanics of pressurized mesenteric resistance arteries. The fact that Mg decreases arterial stiffness in arteries from old rats suggests that Mg has a beneficial effect on age-related changes to the vascular wall.     

Acute human self-poisoning with the N-phenylpyrazole insecticide fipronil--a GABAA-gated chloride channel blocker

OBJECTIVE: Fipronil, a broad spectrum N-phenylpyrazole insecticide that inhibits GABAA-gated chloride channels, has been in use since the mid-1990s. A high affinity for insect compared to mammalian GABA receptors results in lower animal toxicity than other insecticides blocking this channel. To date, only two accidental cases of fipronil poisoning in humans have been published. CASE SERIES: We report seven patients with fipronil self-poisoning seen prospectively in Sri Lanka together with pharmacokinetics for four patients. Non-sustained generalized tonic-clonic seizures were seen in two patients (peak measured plasma fipronil concentrations 1600 and 3744 microg/L); both were managed with diazepam without complications. A patient with a peak measured plasma concentration of 1040 microg/L was asymptomatic throughout his stay. Plasma concentration was still high at discharge 3-4 days post-ingestion when the patients were well. Retrospective review of >1000 pesticide poisoning deaths since 1995 found only one death from fipronil-based products. In contrast to the good outcome of the above cases, this patient required intubation and ventilation and had continuous fits despite therapy with barbiturates and benzodiazepines. CONCLUSIONS: Our experience with prospectively observed patients suggests that fipronil poisoning is characterized by vomiting, agitation, and seizures, and normally has a favorable outcome. Management should concentrate on supportive care and early treatment of seizures. However, further experience is needed to determine whether increased susceptibility to fipronil or larger doses can produce status epilepticus.     

Fast-flow EPR spectroscopic observation of the isoniazid, iproniazid, and phenylhydrazine hydrazyl radicals

Hydrazyl radical intermediates have been suggested as important intermediates in the biochemistry of hydrazides and hydrazines. Although spin-trapping studies have intercepted those species previously, there has been no report of the direct observation of the unstable hydrazyl radicals of isoniazid and iproniazid. We have employed the fast-flow technique in electron paramagnetic resonance (EPR) spectroscopy to measure spectra for the short-lived hydrazyl radicals of a family of hydrazides, including the pharmacologically important compounds isoniazid and iproniazid, as well as for a series of phenylhydrazines. Our investigations of the phenylhydrazine radical and the related chloro-substituted analogues have allowed definitive assignments of the hyperfine coupling constants of that toxicologically important free radical. Theoretical values of hyperfine coupling constants, calculated by density functional formalism, provided a guide to assignments for the hydrazyl species and confirmed the experimentally based assignments for phenylhydrazyl radical.     

Immunomodulation of human natural killer cell cytotoxic function by organochlorine pesticides

Organochlorine pesticides are used worldwide. To our knowledge there have been no studies dealing with the effects of these agents under in vitro conditions on human natural killer (NK) cell cytotoxic function. NK cells play a central role in immune defense against tumor development and viral infections. Thus, any agent that interferes with the ability of NK cells to lyse their targets could increase the risk of tumor incidence and/or viral infections. In this study, we examined the effects of organochlorine pesticides and some of their breakdown products on the ability of human NK cells to lyse tumor cells. A total of 11 compounds were tested. The compounds were tested in both purified NK cells as well as a cell preparation that contained other mononuclear cells (predominantly T cells) and NK lymphocytes (referred to as T/NK cells). Lymphocytes were exposed to the compounds for periods of time ranging from 1 hour to 6 days. Exposure of highly purified NK cells to 5 microM alpha-chlordane, gamma-chlordane, 4,4'-DDT, heptachlor, oxychlordane, or pentachlorophenol (PCP) inhibited their ability to destroy K562 tumor-cells by 88+/-5, 92+/-8, 61+/-13%, 64+/-10%, 69+/-11%, 76+/-12%, respectively, after a 24 h exposure. The loss of cytotoxic function seen with alpha-and gamma-chlordane remained essentially constant out to 6 days, while that seen with 4,4'-DDT, oxychordane and PCP increased with longer exposures (6 d). PCP was the most effective of the compounds tested at decreasing NK function. Of the compounds that caused decreased lytic function when tested in purified NK cells, only PCP and oxychordane decreased the lytic function of the T/NK cell preparation after any exposure. The results provide evidence of relative toxic potential for the 11 compounds and their immunomodulatory effects on other mononuclear cells (such as T-cells, B-cells, and monocytes) as well as NK lymphocyte function.     

Effects of pirenzepine on pupil size and accommodation in rhesus monkeys

PURPOSE: Pirenzepine is suggested to be a relatively selective muscarinic (M(1)) antagonist and is currently under investigation for the treatment of myopia. Atropine, a nonselective M-type antagonist, is used in the treatment of myopia, but has undesired ocular and systemic side effects. An M(1)-specific antagonist may decrease side effects and remain effective at reducing the progression of myopia. In the current study, the effects of pirenzepine on pupil diameter, resting refraction, and accommodation were studied in rhesus monkeys. METHODS: The time course and extent of mydriasis from subconjunctival injection of 2% pirenzepine were determined in five normal rhesus monkeys, and the effects on static and dynamic accommodation were determined in four rhesus monkeys with permanent indwelling electrodes in the Edinger-Westphal (EW) nucleus of the midbrain. Subconjunctival injections of 0.0002% to 0.2% pirenzepine in log unit dilutions were tested in three monkeys to determine the effects on static EW-stimulated accommodation. At 40 to 50 minutes after pirenzepine injection, accommodation was stimulated pharmacologically in both eyes, and the response was measured for 30 minutes. RESULTS: After 2% pirenzepine injection, pupil size increased 2.02 +/- 0.41 mm, there was a hyperopic shift in resting refraction of 1.07 +/- 0.23 D, and nearly complete cycloplegia occurred. Maximum EW-stimulated accommodation was significantly decreased 20 to 40 minutes after 0.02% or greater pirenzepine. Carbachol-stimulated accommodation was significantly decreased after 0.2% or greater pirenzepine. CONCLUSIONS: Subconjunctival injections of 0.02% or greater pirenzepine result in a significant decrease in accommodation and are probably acting through nonselective muscarinic antagonism. Subconjunctival injections of 0.002% or less pirenzepine do not decrease EW-stimulated accommodation.