Safety and tolerability of zonisamide in elderly patients with epilepsy.

OBJECTIVES: To assess the safety/tolerability of zonisamide in elderly patients. MATERIALS & METHODS: A pooled analysis of clinical study data from elderly (≥65 years) patients receiving add-on/monotherapy zonisamide for partial seizures was compared with pooled adult (18-65 years) study data. Assessments included treatment-emergent adverse events (TEAEs), clinical laboratory parameters and weight change. RESULTS: Data were analyzed from 95 elderly and 1389 adult patients. Incidence of total TEAEs was similar (elderly, 78/95 [82%] vs adult, 1165/1389 [84%]); but lower in elderly versus adult patients for treatment-related TEAEs (53/95 [56%] vs 1010/1389 [73%]), severe TEAEs (11/95 [12%] vs 289/1389 [21%]), serious TEAEs (12/95 [13%] vs 230/1389 [17%]) and TEAEs leading to withdrawal (17/95 [18%] vs 312/1389 [23%]). Most TEAEs were of mild-to-moderate intensity. TEAEs reported more frequently by elderly versus adult patients included fatigue (11/95 [12%] vs 135/1389 [10%]), nasopharyngitis (8/95 [8%] vs 100/1389 [7%]), constipation (7/95 [7%] vs 67/1389 [5%]) and pruritus (6/95 [6%] vs 29/1389 [2%]). The only serious TEAEs reported by ≥2% of elderly patients were 'convulsions' (4/95 [4%] vs 49/1389 [4%]). Three elderly patients died; one death was considered treatment-related. TEAEs leading to discontinuation of ≥2% of elderly patients were dizziness (4/95 [4%]), headache (2/95 [2%]), somnolence (2/95 [2%]) and confusional state (2/95 [2%]). For elderly patients, there were minimal changes in clinical laboratory parameters, no reports of respiratory alkalosis or metabolic acidosis and no significant weight changes. CONCLUSIONS: Zonisamide demonstrated a favourable safety/tolerability profile in elderly patients. No new or unexpected safety findings were identified.

Nitric oxide-mediated regulation of dopamine release in the hippocampus in vivo.

Infusion of N-methyl-D-aspartate (NMDA) into the hippocampus of freely moving rats produced a concentration-dependent decrease in the extracellular levels of dopamine, an effect which was reversed by D-2-amino-5-phosphonovaleric acid (D-AP5). To determine the involvement of nitric oxide (NO) in this response, two nitric oxide synthase (NOS) inhibitors, N-nitro-L-arginine methyl ester (L-NAME) and 7-nitroindazole (7-NI), were examined for their ability to modify both basal and NMDA-inhibited dopamine release. When infused alone both NOS inhibitors elicited an increase in extracellular dopamine concentration, moreover, when administered prior to the application of NMDA, the agonist failed to elicit a decrease in dopamine levels. Infusion of the NO donor S-nitroso-N-acetylpenicillamine (SNAP) over a 30 min period caused either an increase or a decrease in dopamine release depending upon the concentration used. At the lower concentration (0.5 mM) SNAP promoted dopamine release whilst at the higher concentration (5 mM), the donor elicited a long lasting reduction in basal dopamine levels. The effect of the lower concentration of SNAP was reversed by the prior application of D-AP5, but that of the higher concentration was unaffected by the antagonist.

Repeated but not acute clomipramine decreases the effect of N-methyl-D-aspartate receptor activation on serotonergic transmission between the raphe nuclei and frontal cortex.

The effect of acute or repeated treatment with the antidepressant clomipramine (CIM) on N-methyl-D-aspartate (NMDA) evoked changes in extracellular 5-hydroxytryptamine (5-HT) in the raphe nuclei and frontal cortex of the same rat has been studied using microdialysis. Acute injection of CIM (10 or 20 mg/kg) caused an increase in raphe extracellular 5-HT but did not significantly alter extracellular 5-HT in the frontal cortex. Infusion of 25 microM NMDA into the raphe decreased extracellular 5-HT in this region and increased terminal extracellular 5-HT in the frontal cortex. In contrast, infusion of 100 microM NMDA into the raphe was followed by an increase in local dialysate 5-HT and a decrease in 5-HT release in the cortex. When NMDA infusion, at either 25 or 100 microM was preceded by one acute injection of CIM the effects of NMDA on 5-HT release in both brain structures were generally more marked than in vehicle injected controls. Repeated (15 day) treatment with CIM (10 or 20 mg/kg) caused a dose-dependent increase in basal extracellular 5-HT in both raphe and frontal cortex. In these animals, however, the effects of infusion of both 25 and 100 microM NMDA on 5-HT release in raphe and frontal cortex were greatly attenuated or abolished. This suggests that adaptive functional changes occur in NMDA receptor function during treatment with an antidepressant. The possible significance of this in the aetiology and treatment of depression is discussed.

N-methyl-d-aspartate receptors regulate 5-HT release in the raphe nuclei and frontal cortex of freely moving rats: differential role of 5-HT1A autoreceptors.

The effects of infusing N-methyl-d-aspartate (NMDA) into the raphe nuclei on release of 5-HT in this brain region and also the frontal cortex of the same animal were studied using in vivo microdialysis in freely moving rats. Infusion of 25 microM NMDA into the raphe led to a substantial decrease in dialysate 5-HT in this region and a prolonged increase in terminal 5-HT release in the frontal cortex. These effects were blocked by the specific NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (D-AP5; 100 microM). When 25 microM NMDA was co-infused into the raphe with the selective 5-HT1A receptor antagonist (N-¿2-¿4-(2-methoxyphenyl)-1-piperazinyl¿ethyl-N-(2-pyridinyl) cyclohexanecarboxamide) (WAY-100635; 1.0 microM) the effect of NMDA infusion was unaltered. WAY-100635 infused alone into the raphe did not alter local 5-HT or extracellular 5-HT in the cortex. Infusion of 100 microM NMDA into the raphe was followed by an increase in local dialysate 5-HT and a decrease in 5-HT release in the cortex. These changes were reversed by D-AP5. Following infusion of 100 microM NMDA with 1.0 microM WAY-100635 into the raphe local 5-HT release was still increased, however, the decrease in 5-HT observed in the frontal cortex was abolished. These data suggest that the degree of NMDA receptor activation leads to dramatically different outcomes with regard to serotonergic transmission to the frontal cortex. Furthermore, there appears to be a differential role of the 5-HT1A autoreceptor in regulating these effects. These data are discussed in relation to other studies on the regulation of serotonergic transmission in ascending pathways.

Chronic clomipramine administration reverses NMDA-evoked decreases in dopamine release in the raphe nuclei.

The effect of acute or chronic treatment with the antidepressant clomipramine (CIM) on basal and N-methyl-d-aspartate (NMDA) evoked release of dopamine (DA) in rat raphe has been studied using microdialysis. Acute injection of CIM (10 or 20 mg/kg) caused a decrease in raphe DA release, as did infusion of NMDA (25-100 microM) into this region. When NMDA infusion was preceded by a single acute injection of CIM no differences between NMDA and NMDA plus CIM treated groups was observed. Chronic (15 day) treatment with CIM caused a dose-dependent increase in basal extracellular DA. In addition the effect of infusing NMDA into the raphe on DA release was markedly reduced or abolished. This suggests that adaptive changes occur in NMDA receptor function during treatment with CIM.

Biphasic modulation of GABA release by nitric oxide in the hippocampus of freely moving rats in vivo.

The effect of altering hippocampal nitric oxide (NO) levels on basal and N-methyl-D-aspartate receptor-evoked release of GABA has been studied in freely moving rats. N-Methyl-D-aspartate (NMDA) increased extracellular GABA in a concentration-dependent manner. The nitric oxide synthase inhibitor L-nitro-arginine-methyl ester (L-NAME; 100 microM) increased basal GABA release, and also enhanced release of GABA evoked by NMDA (100 microM) compared with the same concentration of NMDA infused alone. 200 microM L-NAME increased basal dialysate GABA, but to a lesser extent than the 100 microM concentration of the drug, and the NMDA-induced release of GABA was decreased. 1.0 mM L-NAME significantly decreased basal extracellular GABA, while abolishing the NMDA-evoked release of the amino acid. The actions of L-NAME were not mimicked by its much less active isomer D-nitro-arginine-methyl ester. The NO donor S-nitroso-N-acetylpenicillamine decreased dialysate GABA at a 500 microM concentration but increased the extracellular level of the transmitter when infused at 1.0 and 2.0 mM concentrations. These data suggest that NO may mediate both excitatory and inhibitory functions in vivo.

Chronic but not acute clomipramine alters the effect of NMDA receptor regulation of dopamine release in rat frontal cortex.

The effect of acute or chronic treatment with the antidepressant clomipramine (CIM) on N-methyl-D-aspartate (NMDA) evoked release of dopamine (DA) in the frontal cortex of the rat has been studied using microdialysis. Acute injection of CIM (10 or 20 mg/kg) caused a decrease in dialysate DA in the frontal cortex. Infusion of 25-100 microM NMDA into the frontal cortex decreased DA release in this region. When NMDA infusion was preceded by a single injection of CIM no marked differences between NMDA and NMDA + CIM treated groups were observed. Chronic (15 day) treatment with CIM (10 or 20 mg/kg) caused a dose-dependent increase in basal extracellular DA. In these animals, however, the effects of infusion of NMDA on DA release in the cortex were greatly attenuated or abolished. This suggests that adaptive changes occur in NMDA receptor function during treatment with an antidepressant. The possible significance of this in the aetiology and treatment of depression is discussed.

Nitric oxide regulates excitatory amino acid release in a biphasic manner in freely moving rats.

The effect of altering hippocampal nitric oxide levels on basal and N-methyl-D-aspartate (NMDA) receptor-evoked release of glutamate and aspartate has been studied in freely moving rats. NMDA increased extracellular glutamate and aspartate in a concentration-dependent manner. The nitric oxide synthase inhibitor L-nitro-arginine-methyl ester (L-NAME; 100 microM) increased basal glutamate and aspartate release, and also enhanced release of these amino acids evoked by NMDA (100 microM) compared with the same concentration of NMDA infused alone. L-NAME at 200 microM increased basal dialysate glutamate, but not aspartate, to a lesser extent than the 100 microM concentration of the drug, and the NMDA-induced release of glutamate and aspartate was decreased. L-NAME at 1.0 mM did not significantly alter basal extracellular glutamate but significantly decreased dialysate aspartate, while abolishing the NMDA-evoked release of both amino acids. The actions of L-NAME were not mimicked by its much less active isomer D-nitro-arginine-methyl ester. The nitric oxide donor drug S-nitroso-N-penicillamine decreased dialysate glutamate and aspartate at a 500 microM concentration but increased the extracellular level of both amino acids when infused at 1.0 mM and 2.0 mM concentrations. These data suggest that nitric oxide may mediate both excitatory and inhibitory functions, according to the level of nitric oxide production in vivo.

Regulatory role of nitric oxide over hippocampal 5-HT release in vivo.

Previous work has shown that N-methyl-D-aspartate (NMDA) receptor activation decreases 5-hydroxytryptamine (5-HT) release in the hippocampus of freely moving rats. Given the association between NMDA receptor function and nitric oxide (NO) production with the regulation of 5-HT release in other brain regions, we have studied this in rat hippocampus. NMDA (100 microM) decreased hippocampal 5-HT release by approximately 70% and this was reversed by the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP5; 10 microM). The NO donor S-nitroso-N-acetylpenicillamine (SNAP) had an inverse concentration-dependent effect on 5-HT release. At 500 microM, SNAP elevated dialysate 5-HT by 55% over basal, while at 5 mM a 70% decrease was seen. The non-selective nitric oxide synthase (NOS) inhibitor N-nitro-L-arginine methyl ester (L-NAME) at 1 mM increased extracellular 5-HT, although a return to basal levels occurred despite the continued presence of the drug. At 1 mM L-NAME prevented the decrease in 5-HT elicited by NMDA (100 microM) infusion. 7-Nitroindazole (7-NI), a relatively selective neuronal NOS (nNOS) inhibitor, decreased extracellular 5-HT at 100 microM and 1 mM. When 100 microM 7-NI was infused for 60 min prior to NMDA, 5-HT levels were transiently increased above basal before returning to control levels. Following combined application of the two drugs, no decrease in dialysate 5-HT was seen. Our data support a role for NO in modulating both basal and NMDA-evoked changes in 5-HT release in the hippocampus, however, the association appears to be complex. It may be that the recorded changes in 5-HT release are secondary to changes in the release of amino acid transmitters which we have previously found to be dependent on the prevailing extracellular NO concentration.