Topiramate Rapidly Raises Brain GABA in Epilepsy Patients

PURPOSE: The short- and long-term pharmacodynamic effects of topiramate (TPM) on brain gammay-aminobutyric acid (GABA) metabolism were studied in patients with complex partial seizures. METHODS: In vivo measurements of GABA, homocarnosine, and pyrrolidinone were made of a 14-cc volume in the occipital cortex using 1H spectroscopy with a 2.1-Tesla magnetic resonance spectrometer and an 8-cm surface coil. Fifteen patients (four men) were studied serially after the first, oral dose (100 mg) of TPM. RESULTS: The first dose of TPM increased brain GABA within 1 h. Within 4 h, GABA was increased by 0.9 mM (95% CI, 0.7-1.1). Brain GABA remained elevated for > or =24 h. Pyrrolidinone and homocarnosine increased slowly during the first day. Daily TPM therapy (median, 300 mg; range, 200-500) increased GABA (0.3 mM; 95% CI, 0.1-0.5), homocarnosine (0.4 mM; 95% CI, 0.3-0.5), and pyrrolidinone (0.15 mM; 95% CI, 0.10-0.19), compared with levels before TPM. There was no dose response evident with daily TPM doses of 200-500 mg. CONCLUSIONS: TPM promptly elevates brain GABA and presumably offers partial protection against further seizures within hours of the first oral dose. Patients may expect to experience the effects of increased homocarnosine and pyrrolidinone within 24 h.     

Topiramate increases brain GABA, homocarnosine, and pyrrolidinone in patients with epilepsy

OBJECTIVE: To measure the effects of topiramate on brain gamma-aminobutyric acid (GABA) in patients with epilepsy. BACKGROUND: Topiramate is a new antiepileptic medication with multiple putative mechanisms of action. In a recent meta-analysis of the newer antiepileptic drugs, topiramate was the most potent. Homocarnosine and pyrrolidinone are important metabolites of GABA with antiepileptic actions. METHODS: In vivo measurements of GABA, homocarnosine, and pyrrolidinone were made of a 14-cm3 volume in the occipital cortex using 1H spectroscopy with a 2.1-Tesla magnetic resonance spectrometer and an 8-cm surface coil. Twelve patients (eight women) with refractory complex partial seizures were studied while using topiramate. Nine epilepsy-free, drug-free volunteers served as control subjects. RESULTS: Topiramate increased mean brain GABA, homocarnosine, and pyrrolidinone concentrations in all patients. In paired measurements, brain GABA increased by 0.7 micromol/g (SD 0.3, n 7, 95% CI 0.4 to 1.0, p < 0.01). Homocarnosine increased by 0.5 micromol/g (SD 0.2, n 7, 95% CI 0.3 to 0.7, p < 0.001). Pyrrolidinone increased by 0.21 micromol/g (SD 0.06, n 7, 95% CI 0.16 to 0.27, p < 0.01). In two additional patients, GABA, homocarnosine, and pyrrolidinone increased after they were switched from vigabatrin to topiramate. CONCLUSIONS: Topiramate increased brain GABA, homocarnosine, and pyrrolidinone to levels that could contribute to its potent antiepileptic action in patients with complex partial seizures.     

Acute Effects of Vigabatrin on Brain GABA and Homocarnosine in Patients with Complex Partial Seizures

PURPOSE: The acute, subacute, and chronic effects of vigabatrin (VGB) were studied in patients with refractory complex partial seizures. VGB increases human brain gamma-aminobutyric acid (GABA) and the related metabolites, homocarnosine and 2-pyrrolidinone. METHODS: In vivo measurements of GABA and homocarnosine were made of a 14-cc volume in the occipital cortex by using 1H spectroscopy with a 2.1-Tesla magnetic resonance spectrometer and an 8-cm surface coil. Six patients (three women) were studied serially during the initiation and maintenance of VGB as adjunct therapy. RESULTS: The first, 3 g dose of VGB increased brain GABA by 2.0 micromol/g within 81 min of oral administration. After 2 h, median edited GABA remained essentially the same for 2 days. The response to the second, 3-g dose of VGB given at 48 h was considerably less than that to the first dose, with a median increase of 0.5 micromol/g within 72 min. After 2-3 months, rechallenging patients taking 1.5-g VGB twice daily with 6 g increased GABA by 0.4 micromol/g within 87 min. Homocarnosine increased more gradually than GABA to above-normal levels after a week of VGB therapy. CONCLUSIONS: VGB promptly elevates brain GABA and presumably offers partial protection against further seizures within hours of the first oral dose. Once-a-day dosing is sufficient to increase GABA. Patients may be expected to experience the effects of increased homocarnosine within 1 week.     

Clinical science

Ognen A. C. Petroff , Fahmeed Hyder , Douglas L. Rothman , and Richard H. Mattson
Yale researchers in pioneering work have been able to study the effects of antiepileptic drugs (AEDs) on the brain chemistry of people with epilepsy in a safe and painless manner by using the principles of magnetic resonance imaging (MRI). Neurons in the human brain make homocarnosine from γ-aminobutyric acid (GABA; the brain's main inhibitory neurotransmitter) and histidine in larger amounts than the neurons of almost all other animals. Three of the newer AEDs, gabapentin (GBP; Neurontin), topiramate (TPM; Topamax), and vigabatrin (Sabril), increase human homocarnosine levels. We measured homocarnosine and GABA levels of 20 patients with complex partial seizures taking GBP and 17 patients taking TPM. Homocarnosine levels were higher in patients with better seizure control than in those whose seizure control was below the middle value (median) for the two groups. No differences were found in the GABA levels between the patients, who showed a better response to GBP or TPM, compared with those who did not. Higher homocarnosine levels (above the median) were associated with better seizure control in the patients taking GBP or TPM; higher brain GABA levels appeared to offer no additional protection. The current results are similar to our previously published findings, which showed higher brain homocarnosine levels in patients with juvenile myoclonic epilepsy with excellent seizure control, taking valproate (Depakote) or lamotrigine (Lamictal), than the levels of patients with more frequent seizures. The data support the hypothesis that increased homocarnosine and GABA levels contribute to the anticonvulsant properties of GBP and TPM, perhaps by limiting the spread of seizures from the areas where seizures start.     

Vigabatrin increases human brain homocarnosine and improves seizure control

Homocarnosine, a dipeptide of γ-aminobutyric acid (GABA) and histidine, is thought to be an inhibitory neuromodulator synthesized in subclasses of GABAergic neurons. Homocarnosine is present in human brain in greater amounts (0.4–1.0 μmol/g) than in other animals. The antiepileptic drug vigabatrin increases human cerebrospinal fluid homocarnosine linearly with daily dose. By using ¹H nuclear magnetic resonance spectroscopy, serial occipital lobe GABA and homocarnosine concentrations were measured in 11 patients started on vigabatrin. Daily low-dose (2 g) vigabatrin increased both homocarnosine and GABA. Larger doses of vigabatrin (4 g) further increased homocarnosine but changed GABA levels minimally. Seizure control improved with increasing homocarnosine and GABA concentrations. Patients whose seizure control improved with the addition of vigabatrin had higher mean homocarnosine, but the same mean GABA concentrations, than those whose seizure control did not improve. Increased homocarnosine may contribute to improved seizure control.     

Brain homocarnosine and seizure control of patients taking gabapentin or topiramate

PURPOSE: To assess the relation between seizure control and brain homocarnosine and gamma-aminobutyric acid (GABA) levels of patients with complex partial seizures taking gabapentin (GBP) or topiramate (TPM) as adjunctive therapy. METHODS: In vivo measurements of GABA and homocarnosine were made of a 14-cc volume in the occipital cortex by using (1)H spectroscopy with a 2.1-Tesla magnetic resonance spectrometer and an 8-cm surface coil. Poor seizure control was defined as more recent seizures than the median for the two groups of patients studied. RESULTS: Homocarnosine levels were higher in patients with better seizure control than in those with poor control. No differences were found in the intracellular GABA levels between the patients who responded to GBP or TPM compared with those who did not. CONCLUSIONS: In the visual neocortex, which is remote from the presumed seizure-onset zone, higher homocarnosine levels were associated with better seizure control in the patients taking GBP or TPM as adjunctive therapy; elevated intracellular GABA levels appeared to offer no additional protection.     

Homocarnosine and seizure control in juvenile myoclonic epilepsy and complex partial seizures

OBJECTIVE: To assess the relationship between seizure control and gamma-aminobutyric acid (GABA), homocarnosine, and pyrrolidinone levels in the visual cortex of patients with epilepsy taking valproate or lamotrigine. Previous studies suggested that poor seizure control was associated with low GABA and homocarnosine levels. METHODS: In vivo measurements of GABA, homocarnosine, and pyrrolidinone were made in a 14-cm(3) volume of the occipital cortex using (1)H spectroscopy with a 2.1-Tesla MR spectrometer and an 8-cm surface coil. Twenty-six adults (eight men) taking valproate or lamotrigine were recruited; 12 had complex partial seizures (CPS) and 14 had juvenile myoclonic epilepsy (JME). RESULTS: Median homocarnosine levels were normal for patients with JME and below normal for patients with CPS. Better seizure control was associated with higher homocarnosine levels for both groups. Median GABA was below normal for patients with JME, lower than for patients with CPS. Brain GABA was lowest in patients with JME even when seizure control was excellent. Pyrrolidinone levels were above normal in almost all patients with JME. CONCLUSIONS: Low GABA levels are associated with poor seizure control in patients with CPS, but not in JME. Higher homocarnosine levels are associated with better seizure control in both types of epilepsy.     

Effects of single doses of vigabatrin on CSF concentrations of GABA, homocarnosine, homovanillic acid and 5-hydroxyindoleacetic acid in patients with complex partial epilepsy

Vigabatrin, as a single oral dose of 50 mg/kg, was administered to 11 patients with drug-refractory complex partial epilepsy. Serial lumbar punctures were performed prior to and 5 times within the first week following treatment. Cerebrospinal fluid (CSF) concentrations of total GABA, free GABA, homocarnosine, homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and vigabatrin were determined as well as blood vigabatrin levels. CSF GABA, homocarnosine, HVA and 5-HIAA concentrations increased by 6 h after the single dose and remained elevated for up to 5-7 days. In contrast, CSF and blood vigabatrin levels were maximal within the first 24 h and were no longer detectable thereafter. Hence, these results are consistent with vigabatrin acting as an irreversible inhibitor of GABA-transaminase and suggest that it may also increase biogenic amine turnover.     

Effects of gabapentin and carbamazepine on the EEG and cognition in healthy volunteers

PURPOSE: Antiepileptic drug (AED) therapy can be associated with neurotoxic side effects including cognitive dysfunction. Objective methods for detection of neurotoxicity in individual patients would be useful. We studied the effects of gabapentin (GBP) and carbamazepine (CBZ) on neurophysiologic and cognitive/behavioral measures in healthy volunteers. METHODS: In a 12-week, randomized, double-blind, parallel-group study of CBZ and GBP in healthy volunteers, 23 subjects completed the protocol. All achieved the target dose of 1,200 mg CBZ or 3,600 mg GBP. A structured EEG for quantitative analysis and a cognitive test battery were administered before AED therapy and again after 12 weeks of therapy. Test-retest differences were compared with those of 72 untreated control subjects. RESULTS: Both CBZ and GBP significantly decreased the peak frequency of the posterior (alpha) rhythm, with CBZ exerting a greater effect. Ten CBZ and six GBP subjects exceeded the 95% confidence interval (CI) for an individual. Cognitive tests revealed AED vs. control group effects for two of seven measures (Digit Symbol, Stroop) and all subjective measures. However, few subjects exceeded the 95% CI for any objective test. Differences between CBZ and GBP were not significant. Greater EEG slowing was associated with greater subjective neurotoxicity and poorer test-retest performance on a cognitive test summary measure. CONCLUSIONS: Prolonged CBZ and GBP therapy induced EEG slowing that correlated with cognitive complaints and often exceeded the confidence interval for individual subjects. Quantitative EEG measures may be useful in the objective determination of AED-related neurotoxicity.     

Inhibitory and excitatory amino acids in CSF of patients suffering from complex partial seizures during chronic treatment with gamma-vinyl GABA (vigabatrin)

The effect of chronic administration of gamma-vinyl GABA (GVG; vigabatrin) on levels of neurotransmission-related amino compounds was studied in lumbar cerebrospinal fluid of 65 patients with complex partial epilepsy. The first sample of cerebrospinal fluid was taken before a 3-month period of treatment with 3 g gamma-vinyl GABA/day, and the second was taken afterwards. From patients who showed a greater than 50% reduction in seizures (responders) or marked improvement in global performance, a third sample was taken at the end of the next 3-month phase, during which 3 g or 1.5 g gamma-vinyl GABA had been administered daily. During treatment with 3 g gamma-vinyl GABA/day, 55% of the patients showed more than 50% reduction in complex partial seizures; and at the same time free GABA, total GABA, homocarnosine, and glycine concentrations in the cerebrospinal fluid increased by 104%, 151%, 194% and 16%, respectively. After reduction of the daily dose to 1.5 g, the levels of free GABA, total GABA and homocarnosine were still increased by 65%, 115% and 102%, respectively. gamma-Vinyl GABA correlated with the levels of free GABA (P less than 0.002) and glycine (P less than 0.001). Concentrations of homocarnosine at baseline and homocarnosine and total GABA during gamma-vinyl GABA treatment were lower (P less than 0.005) in the group of non-responders than in the responder group. Glutamic acid, glutamine, aspartic acid, asparagine, and taurine levels did not change during gamma-vinyl GABA treatment. In conclusion, administration of gamma-vinyl GABA reduces epileptic seizures and produces dosage-dependent increases in levels of free GABA, GABA-containing peptides and of glycine in cerebrospinal fluid, without concomitant change in levels of excitatory amino acids.     

Low-dose gabapentin combined with either lamotrigine or carbamazepine can be useful therapies for trigeminal neuralgia in multiple sclerosis

Paroxysmal symptoms occur frequently in multiple sclerosis (MS). Usually they are treated with carbamazepine (CBZ) and phenytoin, although these medications are often interrupted due to adverse effects. We report 11 MS patients with trigeminal neuralgia (TN): 6 intolerant to a therapeutic dosage of CBZ, showing serious adverse effects and subsequently treated with a combination of low-dose CBZ and gabapentin (GBP) (group 1); 5 treated with lamotrigine (LMT), showing adverse effects and subsequently treated with GBP (group 2). Subjective pain level and impairment in performing daily activities were rated utilizing a 3-point scale at time 0 and at optimal dosage time (T1). GBP was initiated at 300 mg daily and titrated, until pain control was achieved without new adverse effects, to a maximum dose of 1,200 mg daily. CBZ or LMT were reduced to a level which no longer produced adverse effects, although resulting in a lack of efficacy in relieving pain. Pain control was obtained in all patients but 1, with no side effects. The plasma level analysis, performed in 5 patients, resulted in normal values. The mean dosages at T1 were: group 1 CBZ 400 mg and GBP 850 mg daily; group 2 LMT 150 mg and GBP 780 mg daily. Combining drugs with complementary modes of action may provide a rational pharmacological approach to the management of TN in MS.     

Gabapentin and cognition: a double blind, dose ranging, placebo controlled study in refractory epilepsy.

OBJECTIVE: To assess the effect of different doses of gabapentin (GBP) on cognitive function in treated epileptic patients. METHODS: Twenty seven patients with refractory partial seizures commenced a double blind, dose ranging, placebo controlled, crossover study of adjuvant GBP. Each treatment phase lasted three months, during which the dose of GBP or matched placebo was increased stepwise at intervals of four weeks (1200 mg/day, 1800 mg/day, and 2400 mg/day in three daily doses). Psychomotor and memory testing was carried out at the end of each four week period, at which time the patient also completed subjective measures of cognition, fatigue, worry, temper, and dysphoria. A visual analogue scale was used to assess drowsiness and a questionnaire was employed to gauge the severity of side effects. RESULTS: In the 21 patients completing the study, GBP produced a significant reduction in median monthly seizure frequency from 7 to 4.3 (P = 0.02), the decrease being most pronounced for secondarily generalised seizures (from 1.0 to 0.3, P = 0.01). Forty three per cent of patients reported a reduction in seizure frequency of at least 50% throughout all GBP doses. Mean (SD) plasma concentrations of GBP at 1200, 1800, and 2400 mg/day were 4.7 (2.6), 6.8 (3.8), and 8.6 (3.3) mg/l respectively. The drug had no effect on composite psychomotor and memory scores; nor was there alteration in any self assessment subscore. The mean drowsiness (P = 0.03) score was higher during treatment with 2400 mg GBP daily compared with matched placebo. Composite psychomotor (r = -0.47, P < 0.01), tiredness (r = 0.42, P < 0.01), and side effect (r = 0.61, P < 0.001) scores correlated significantly with seizure frequency but not with GBP dose. CONCLUSION: GBP is a well tolerated and effective antiepileptic drug which had no measurable effect on cognition but did produce sedation at the highest dose. This study also supports the suggestion that seizures can cause cognitive impairment.     

Selected CSF biochemistry and gabapentin concentrations in the CSF and plasma in patients with partial seizures after a single oral dose of gabapentin.

Gabapentin (GBP) is a neutral amino acid and a GABA analog which in animal experimental models has shown a broad anticonvulsant spectrum. To evaluate the penetration of GBP into the CSF in humans as well as its possible effects on free and total GABA, homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA), a special investigation was performed as part of a placebo controlled add-on study of GBP in partial epilepsy. At the end of the 3-month double-blind period, 5 patients on placebo were given a single oral dose of GBP. Four patients received 600 mg and 1 patient 1200 mg GBP. CSF was collected immediately before and at 6, 24 and 72 h after the single dose. 5 ml of plasma was collected at 1, 2, 3, 6, 12, 24, 48 and 72 h. Plasma concentrations and plasma elimination half-life (4-6 h) of GBP were in agreement with the results of previous studies. The CSF/plasma concentration ratio of GBP 6 h after drug was 0.1. After 24 h, GBP could only be recovered in the CSF of the patient given 1200 mg. The CSF/plasma ratio at that time was 0.3. Free and total GABA concentrations did not change, but CSF 5-HIAA and HVA increased at 24 and 72 h post dose. The CSF/plasma ratio of gabapentin is similar to that of other amino acids.     

Conversion to High Dose Gabapentin Monotherapy in Patients with Medically Refractory Partial Epilepsy

Summary: Purpose: To evaluate the safety and efficacy of high dose gabapentin (GBP) monotherapy (3,0004,800 mg/ day) in patients with medically refractory partial epilepsy.
Methods: GBP monotherapy at daily doses up to 4,800 mg was attempted in patients participating in the open-label phase of a double-blind, dose-controlled, GBP monotherapy trial. For those who achieved monotherapy, the types and severity of adverse events were assessed and the average seizure frequency per 28 days while maintained on the highest daily GBP dose was compared to the seizure frequency during the baseline phase of the double blind trial. Correlation analysis between GBP serum level, total daily dose, and percentage of seizure change from baseline was performed.
Results: A total of 45 patients participated in the open-label phase of the trial and 23 (51%) were converted successfully to GBP monotherapy. In those patients, the average daily gabapentin dose was 3,900 mg and the mean length of follow-up was 252 days. Compared to baseline, there was a mean reduction of 54%, 43%, and 14% for simple partial, complex partial and secondarily generalized seizures respectively, while maintained on high-dose GBP monotherapy. A significant linear correlation between daily GBP dosage (2,4004,800 mg) and resultant mean serum levels was found (r = 0.51; p < 0.01). There was no significant correlation between seizure frequency and total daily GBP dose or with serum levels. High-dose GBP monotherapy was well tolerated; only one patient exited the trial because of adverse events. The most common adverse event was tiredness/sleepiness and was not dose-related.
Conclusions: GBP monotherapy is well tolerated in daily doses of up to 4,800 mg and is effective in a subgroup of patients with medically refractory partial epilepsy.     

Initial Observations on Effect of Vigabatrin on In Vivo 1H Spectroscopic Measurements of γ-Aminobutyric Acid, Glutamate, and Glutamine in Human Brain

Summary: Recent developments involving ¹H nuclear magnetic resonance (NMR) spectroscopic editing techniques have allowed noninvasive measurements of γ-aminobutyric acid (GABA) in human cerebrum. The additional information gained from GABA and macromolecule measurements permitted more precise glutamate (Glu) and glutamine (Gln) measurements. Occipital lobe GABA in 10 nonepileptic, healthy subjects was 1.0 μmol/g brain [95% confidence interval (CI) 0.9–1.1]. Vigabatrin (VGB) is a safe and effective antiepileptic drug (AED)that irreversibly inhibits neuronal and glial GABA transaminase. GABA levels were increased in all patients treated with VGB. With a standard dose of 3–6 g/day, GABA levels were 2.6 μmol/g (95% CI 2.3–2.8).Mean occipital GABA level measured in epileptic patients not receiving VGB was 0.9 μmol/g (95% CI 0.7–1.1). Gln was increased by 1.9 μmol/g and Glu was decreased by 0.8 μmol/g in patients receiving VGB as compared with patients receiving standard medications alone.     

Cerebrospinal fluid GABA and homocarnosine concentrations in patients with Friedreich's ataxia, Parkinson's disease, and Huntington's chorea

Free and total gamma-aminobutyric acid (GABA) and homocarnosine concentrations were measured in the lumbar cerebrospinal fluid (CSF) of patients with Friedreich's ataxia, Huntington's chorea, and Parkinson's disease (with and without levodopa treatment), and compared with those determined in control subjects. Values found in Friedreich's ataxia or Parkinson's disease were not significantly different from those in controls. Unexpectedly, in Huntington patients, known to have a characteristic decrease in GABA concentrations in specific brain areas, CSF concentrations of total GABA and homocarnosine were significantly higher, whereas free GABA was not different from controls. These findings indicate that the measurement of CSF GABA and homocarnosine in patients with CNS degenerative diseases should be interpreted cautiously.     

The absorption of gabapentin following high dose escalation.

Gabapentins (GBP) is structurally similar to GABA yet its mode of action remains uncertain. It is water-soluble and GI tract absorption occurs via the L-amino acid transport system in the proximal small bowel. It has been suggested that this transportation is capacity limited, thus decreasing GBP bioavailability at higher doses. GBP is not protein bound, therefore, salivary levels might be expected to be similar to those in serum; also the drug does not induce hepatic enzymes and is excreted unmetabolised by the kidney. Within the dose-range normally prescribed, it is devoid of pharmacokinetic (PK) drug interactions with all other anti-epileptic drugs. This study assesses two things in patients with epilepsy: (a) bioavailability of higher doses of GBP (1200-4800 mg per day), and (b) the influence of high dose GBP on between-dose serum concentrations of co-prescribed anti-epileptic drugs. After stabilising at each dosage, a sequence of serum and saliva samples were collected within the dosage interval; GBP and co-medication concentrations were determined and the results subjected to PK modelling. Meaned results from 10 patients indicate that GBP continues to be absorbed in a reasonably linear manner relative to dose up to 4800 mg per day. The study also shows that GBP is transported into saliva, however, salivary concentrations are only 5-10% of those in plasma. Furthermore, the results indicate that GBP, in higher than recommended doses, did not change plasma concentrations of lamotrigine, carbamazepine, carbamazepine-epoxide, vigabatrin, primidone, phenobarbitone or phenytoin when added to treatment.It is concluded that larger than recommended doses of GBP can be efficiently absorbed by some patients and also that GBP plasma levels do not fluctuate greatly between dosage intervals, therefore, twice daily dosage is a possibility.     

Gabapentin versus lamotrigine monotherapy: a double-blind comparison in newly diagnosed epilepsy

PURPOSE: This randomised, double-blind study compared the newer antiepileptic drugs (AEDs) gabapentin (GBP) and lamotrigine (LTG) as monotherapy in newly diagnosed epilepsy. METHODS: Patients with partial seizures with and/or without secondary generalization or primary generalized tonic-clonic seizures were randomized to either GBP or LTG. During 2- and 6-week titration periods, respectively, GBP dosage reached 1,800 mg/day, and LTG, 150 mg/day. In the subsequent 24-week maintenance phase, the dose could be adjusted based on seizure control or adverse events between 1,200 and 3,600 mg/day for GBP and 100 and 300 mg/day for LTG. The primary end point was time to exit, a composite of efficacy and tolerability. Evaluable patients were used for the primary efficacy analysis, whereas tolerability was examined on an intent-to-treat basis. RESULTS: A total of 309 patients was randomized, and 291 (148 GBP, 143 LTG) were included in the evaluable population. Nineteen patients in each group had an exit event. The median time to exit was 69 days for GBP and 48 days for LTG. The hazard ratio was estimated as 1.043 (90% confidence intervals, 0.602-1.809). Overall, 106 (71.6% of the evaluable population) GBP-treated and 96 (67.1%) LTG-treated patients completed the study. Of those, 80 (75.5%) patients taking GBP and 73 (76.0%) taking LTG remained seizure free during the final 12 weeks of treatment. Only 14 (8.9%) GBP-treated patients and 15 (9.9%) LTG-treated patients withdrew because of study drug-related adverse events. CONCLUSIONS: GBP and LTG monotherapy were similarly effective and well tolerated in patients with newly diagnosed epilepsy.     

A randomized, double-blind, placebo-controlled trial of safinamide as add-on therapy in early Parkinson's disease patients

Safinamide is an α-aminoamide with both dopaminergic and nondopaminergic mechanisms of action evaluated as an add-on to dopamine agonist (DA) therapy in early-stage PD. In this 24-week, double-blind study, patients with early PD receiving a stable dose of a single DA were randomized to once-daily safinamide 100 mg, safinamide 200 mg, or placebo. The primary efficacy variable was UPDRS part III (motor examination) total score. Analysis was hierarchical: 200 mg of safinamide versus placebo was tested first; the success of safinamide 100 mg versus placebo was contingent on this. Two hundred sixty-nine patients received safinamide 100 mg (n = 90), safinamide 200 mg (n = 89), or placebo (n = 90); 70, 81, and 81 patients, respectively, completed the study. Mean improvements from baseline to week 24 in UPDRS III total scores were -3.90 for safinamide 200 mg, -6.0 for safinamide 100 mg and -3.60 for placebo. The difference between safinamide 200 mg and placebo was not significant [point estimate: -0.4; 95% confidence interval (CI): -2.3-1.4; P = 0.6504]. Although the difference between 100 mg/day and placebo was significant (point estimate: -1.9; 95% CI: -3.7 to -0.1; P = 0.0419), these results are considered exploratory. No clinically meaningful differences from placebo were observed for any safety variables. This study did not demonstrate a significant improvement of the primary endpoint for safinamide 200 mg/day. Exploratory analysis of the primary endpoint for 100 mg/day demonstrated that the addition of safinamide to a stable dose of DA improves motor symptoms in early PD and warrants further investigation.     

Vigabatrin,but not gabapentin or topiramate,produces concentration-related effects on enzymes and intermediates of the GABA shunt in rat brain and retina

PURPOSE: The antiepileptic drug (AED) vigabatrin (VGB), which exerts its pharmacologic effects on the gamma-aminobutyric acid (GABA) system, causes concentric visual field constriction in >40% of exposed adults. This may be a class effect of all agents with GABA-related mechanisms of action. We compared the concentration-related effects of VGB in rat brain and eye with those of gabapentin (GBP) and topiramate (TPM), both of which have been reported to elevate brain GABA concentrations in humans. METHODS: Adult male rats (n = 10) were administered 0.9% saline (control), VGB (250, 500, 1,000 mg/kg), GBP (50, 100, 200 mg/kg), or TPM (12.5, 25, 50, 100 mg/kg). At 2 h after dosing, animals were killed, a blood sample obtained, the brain dissected into eight distinct regions, and the retina and vitreous humor isolated from each eye. Samples were analyzed for several GABA-related neurochemical parameters, and serum and tissue drug concentrations determined. RESULTS: VGB treatment produced a significant (p < 0.05) dose-related increase in GABA concentrations and decrease in GABA-transaminase activity in all tissues investigated. This effect was most pronounced in the retina, where VGB concentrations were 18.5-fold higher than those in brain. In contrast, GBP and TPM were without effect on any of the neurochemical parameters investigated and did not accumulate appreciably in the retina. CONCLUSIONS: These findings corroborate a previously reported accumulation of VGB in the retina, which may be responsible for the visual field constriction observed clinically. This phenomenon does not appear to extend to other GABAergic drugs, suggesting that these agents might not cause visual field defects.