Efficacy and safety of gabapentin as an add-on therapy in refractory partial epileptic patients.

The study on the efficacy and safety of gabapentin as an add-on therapy trial was performed in 10 refractory partial seizure cases at Prasat Neurological Institute, Thailand from September 1996 to July 1998. This was an open-labeled titration dose of gabapentin starting at 600 mg/day add-on to the previously prescribed conventional antiepileptic drugs (AEDs). In cases that seizures could not be controlled, gabapentin dose was increased by 300 mg per day every two weeks until the total dose of 3,000 mg or until the side effects became intolerable. The result revealed that gabapentin reduced frequency, duration and severity of seizures and also improved the patients' activities of daily living (ADL) even at the minimum dose of 600 mg. The optimal dose of gabapentin was in the range of 600 to 1,200 mg per day. Seven patients were seizure free at the end of the study. There were some precipitating factors that interfered with the efficacy of gabapentin in some patients such as stress, menstruation, fever, and alcohol intake. Weight gain, somnolence, nystagmus, and dizziness were the major adverse events in these patients, whereas ataxia, tremor, and diplopia were found with gabapentin in a dose higher than 1,800 mg/day. These adverse events were mild and transient. No patients withdrew from the study due to adverse drug reactions. In addition, gabapentin did not alter conventional AED blood level and routine laboratory parameters. In conclusion, gabapentin was effective and well tolerated as an add-on therapy in refractory partial epileptic Thai patients.

The period prevalence of catamenial epilepsy at Prasat Neurological Institute, Bangkok.

The study was performed to assess the period prevalence of catamenial epilepsy in Thai female epileptic patients. Such a condition is defined as seizures related to menstruation which occur for at least 2 consecutive months within 1 patient during 4 days prior to and/or 6 days after the onset of menstruation. Patients with regular menstruation aged between 15-50 years attending the Out-Patient Department of Prasat Neurological Institute in Bangkok from 1 November, 1995 to 31 January, 1996 were recruited. Patients and/or their relatives were interviewed directly or by telephone using a questionnaire concerning menstrual history, seizures related to menstruation and they were requested to record these data for 2 further consecutive months. In cases where the interview could not be directly performed, a mailed questionnaire was used instead. All information was considered together with information reviewed from the OPD cards. Forty-six from 467 epileptic patients were considered to have catamenial epilepsy. The period prevalence thus was 98.5 in 1,000 women at risk and the mode of frequency of seizure occurrence was 2 days before menstruation. Generalized seizure was found more common in these patients than partial seizure. In particular, general tonic-clonic seizure and complex partial seizure were the most common for each type, respectively. About 70 per cent of the patients used more than 1 anti-convulsant drugs to control their seizures. Some have received other drug supplements to relieve seizure exacerbation but only mild improvement was observed. No change in body weights measured in 2 or 1 day before menstruation, on the first menstrual day and in 1 day after menstruation was demonstrated in all patients. The results suggest that catamenial epilepsy is one of the clinically significant problems of seizure control in Thai female epileptic patients and multifactors may be involved in this condition.

The prevalence and risk factors of refractory partial seizure Thai patients at Prasat Neurological Institute.

The prevalence of refractory partial seizure Thai patients at Prasat Neurological Institute was retrospectively from patient charts from January 1995-December 1996 and further prospectively analysed. All epileptic patients were screened by direct questions regarding the anti-epileptic drugs (AEDs) regimen, the frequency, nature of seizure attacks and risk factors of seizure. The criteria of clinical refractory partial seizure was defined as partial seizure which cannot be controlled by a combination of at least two AEDs for four weeks. The results were 3,018 cases of total epileptic patients out of 300,008 visits. These were classified as 2,802 cases of generalized seizures (92.8%), 184 cases of partial seizures (6.1%), and 32 cases of unclassified seizures (1.1%). In the partial seizures group, the number of clinical refractory partial seizures was found to be 48 cases (26.1% of partial seizure). We found that the major risk factor of refractory partial seizures was lack of therapeutic AEDs blood level monitoring (64.5% of cases) and the other risk factors were lack of compliance, loss of follow-up but continued medication, concomitant medication, and improper drug storage. AEDs dosage was adjusted until the blood levels were in the therapeutic range, and correction of other risk factors and patient counseling was given. The number of true refractory partial seizures was reduced to 10 cases (5.4% of partial seizure). This procedure revealed that AED blood level monitoring and correction of other risk factors were essential in controlling seizure frequency. Thus, the prevalence of true refractory partial seizure in our study was 3.3 cases of refractory partial seizure per 1,000 cases of the seizure population. We recommend that AEDs blood level monitoring and exclusion of other risk factors should be added to the criteria for the definition of refractory partial seizures. This criteria should be applied when considering the use of new AEDs as an add-on therapy in refractory Thai patients.

Bioavailability of phenytoin sodium capsules available in Thailand. Part II: In vivo study.

Four phenytoin brands, dilantin and three local brands (brand A, B and C) were selected for the bioavailability study. The study was carried out in 16 healthy male Thai volunteers with the average age of 21 years old. A single oral dose of 300 mg (three capsules of 100-mg) phenytoin sodium was given to subjects following an 8 hour-overnight fast. The tested drugs were given in a single-blind randomized crossover with at least 2 weeks of washout period. Venous blood samples of approximately 5 ml were drawn before medication and at 1, 2, 4, 6, 8, 10, 12, 24, 48 and 72 hours post dosing. Plasma phenytoin concentrations were determined by HPLC assay. The pharmacokinetic parameters were calculated from the plasma-concentration time curve of an innovator brand, dilantin, by PCNONLIN program. Elimination rate constant and half-life were 0.2 h-1 and 19 h, respectively. The maximum concentration (Cmax) and time to peak (Tmax) were 1.98 micrograms/ml and 9.6 h, respectively. Bioavailability study was determined by comparing the area under the plasma concentration time curve (AUC), maximum plasma concentration (Cmax) and time to reach maximum plasma concentration (Tmax) by using ANOVA. The result indicated that two local brands (brand A and brand C) were not bioequivalent to the innovator in terms of Cmax and AUC0-alpha, whereas Tmax was not significantly different among these 4 brands. Cmax and AUC of brand A and C were significantly higher than the innovator brand. In addition, the plasma concentration time profile of brand C was also different from other brands with the steep peak which yielded a Cmax value double that of the Cmax of the innovator. However, brand B (from Research and Development Institute, Government Pharmaceutical Organization) was bioequivalent to dilantin after 4 times of product formulation adjustment. This present study demonstrated that the local products (brand A and brand C) were not bioequivalent with the innovator. Thus, the interchange from one brand to another must be performed cautiously or should be avoided, otherwise phenytoin blood levels should be monitored closely together with the clinical signs and symptoms of the patients.

Bioavailability of phenytoin sodium capsules available in Thailand. Part I: In vitro study.

Phenytoin is commonly used as an antiepileptic drug worldwide. The unique properties of phenytoin such as poor water solubility and zero-order kinetics of its metabolism, together with difference in pharmaceutical formulations can result in dramatic changes in bioavailability of phenytoin capsule. The innovator (Dilantin, Parke Davis), three local brands (brand A, B and C) were investigated for pharmaceutical characteristics including drug content, content uniformity, and dissolution. All these tests were performed as described in the monograph of extended phenytoin sodium capsules in USP XXII with slight modification in HPLC analysis. It was found that all the products, except brand C, had drug content and content uniformity within the standard range. Brand A and brand C failed to meet the USP XXII specification for the dissolution test. Per cent dissolution of brand A was lower whereas per cent dissolution of brand C was much higher than the standard value. The qualities of innovator and brand B were within the pharmacopoeial specification. This result revealed that phenytoin capsules available in Thailand did not have homogeneous pharmaceutical equivalence which may lead to difference in plasma phenytoin levels (see part II: In vivo study). Thus, changing the brand of phenytoin in stable epileptic patients should be performed with caution.