Concentrations and Effects of Oral Midazolam are Greatly Reduced in Patients Treated with Carbamazepine or Phenytoin

Midazolam is a short-acting benzodiazepine which is used as an oral hypnotic agent in several countries. We studied the pharmacokinetic and pharmacody-namic aspects of an oral 15–mg dose of midazolam in 6 patients with epilepsy who are also taking carbamazepine (CBZ) or phenytoin (PHT). We compared results with those obtained in 7 noninduced control subjects. Plasma concentrations and effects of midazolam were measured for 10 h. In patients with epilepsy, the area under the plasma concentration-time curve (AUC) of midazolam (mean 2 SEM) was only 5.7% (0.60 ± 0.16 vs. 10.5 ± 0.6 μg - min/ml), and the peak midazolam concentration was 7.4% (5.2 ± 1.2 vs. 70.4 ± 9.0 μg/ml) of its value in control subjects (p < 0.001). The elimination half-life (t1/2) of midazolam was 1.3 ± 0.2 h in patients and 3.1 ± 0.1 h in controls (p < 0.001). The low plasma midazolam concentrations in the patient group were associated with reduced pharmacodynamic effects as compared with control subjects [e.g., the Critical Flicker Fusion Test (CFFT), p < 0.05]. Induction of CYP3A (cytochrome P-450IIIA) enzymes by CBZ and PHT is the most likely explanation of the great difference in the pharmacokinetic and pharmacodynamic profiles of oral midazolam in the two groups.     

Effect of topiramate or carbamazepine on the pharmacokinetics of an oral contraceptive containing norethindrone and ethinyl estradiol in healthy obese and nonobese female subjects

PURPOSE: To study the pharmacokinetics of a combination oral contraceptive (OC) containing norethindrone and ethinyl estradiol during OC monotherapy, concomitant OC and topiramate (TPM) therapy, and concomitant OC and carbamazepine (CBZ) therapy in order to comparatively evaluate the pharmacokinetic interaction, which may cause contraceptive failure. METHODS: This randomized, open-label, five-group study included two 28-day cycles. Five groups of female subjects received oral doses of ORTHO-NOVUM 1/35 alone (cycle 1) and then concomitant with TPM or CBZ (cycle 2). The treatment groups were group 1, TPM, 50 mg/day; group 2, TPM, 100 mg/day; group 3, TPM, 200 mg/day; group 4, TPM, 200 mg/day (obese women); and group 5, CBZ, 600 mg/day. Group 4 comprised obese women whose body mass index (BMI) was between 30 and 35 kg/m(2). The BMI of the remaining four groups was < or =27 kg/m2. RESULTS: Coadministration of TPM at daily doses of 50, 100, and 200 mg (nonobese) and 200 mg (obese) nonsignificantly (p > 0.05) changed the mean area under the curve (AUC) of ethinyl estradiol by -12%, +5%, -11%, and -9%, respectively, compared with OC monotherapy. A similar nonsignificant difference was observed with the plasma levels and AUC values of norethindrone (p > 0.05). CBZ (600 mg/day) significantly (p < 0.05) decreased the AUC values of norethindrone and ethinyl estradiol by 58% and 42%, respectively, and increased their respective oral clearance by 69% and 127% (p < 0.05). Because CBZ induces CYP 3A-mediated and glucuronide conjugation metabolic pathways, the significant increase in the oral clearance of ethinyl estradiol and norethindrone was anticipated. CONCLUSIONS: TPM, at daily doses of 50-200 mg, does not interact with an OC containing norethindrone and ethinyl estradiol. The lack of the TPM-OC interaction is notable when it is compared with the CBZ-OC interaction.     

Effect of Topiramate on the Pharmacokinetics of an Oral Contraceptive Containing Norethindrone and Ethinyl Estradiol in Patients with Epilepsy

Summary: Purpose: Because enzyme-inducing antiepileptic drugs (AEDs) can affect pharmacokinetics of oral contraceptives and thereby cause contraceptive failure, the potential effect of topiramate, a new AED, on the pharmacokinetics of the combination oral contraceptive norethindrone/ethinyl estradiol was evaluated. Methods: Twelve women receiving stable valproic acid (VPA) monotherapy for epilepsy received a combination norethindrone 1.0 mg/ethinyl estradiol 35-μg tablet daily for 21 days followed by seven daily doses of inert tablets for four 28-day cycles. After a baseline cycle (cycle 1), topiramate 100, 200f and 400 mg every 12 h was administered in cycles 2 through 4, respectively. Serial blood samples were obtained on day 20 of each cycle and were analyzed for norethindrone, ethinyl estradiol, and progesterone by using validated radioimmunoassay methods. Results: Compared with cycle 1, none of the norethindrone pharmacokinetic parameters changed significantly in the presence of topiramate, 100–400 mg every 12 h. Individual patient serum progesterone concentrations measured during each cycle were at or close to the limit of quantification with no apparent differences among cycles. However, mean area under the concentration-versus-time curve over the 24-h period (AUC_0–24) values for ethinyl estradiol were 18–30% lower in cycles 2 through 4 compared with cycle 1 (p 0.05 for all pairs), whereas mean oral serum clearance (CL/F) values were 14.7–33.0% higher (p 0.05 for cycles 2 and 4 vs. cycle 1). Mean time of peak concentration (T_max values determined during topiramate therapy were not significantly different from those at baseline. Conclusions: When prescribing an oral contraceptive for patients receiving topiramate, clinicians should consider initial therapy with an agent containing 235 μg of ethinyl estradiol.     

Levetiracetam does not alter the pharmacokinetics of an oral contraceptive in healthy women

PURPOSE: This study was designed to evaluate whether levetiracetam, a novel antiepileptic drug (AED), influences the pharmacokinetics of steroid oral contraceptives. METHODS: During a run-in phase, 18 healthy female patients received an oral contraceptive containing ethinyl estradiol, 0.03 mg, and levonorgestrel, 0.15 mg, for the first 21 days of two consecutive menstrual cycles. In a subsequent double-blind, randomized, two-way crossover treatment phase, subjects received either levetiracetam, 500 mg, or placebo twice daily concomitant with the oral contraceptive. Plasma concentrations of ethinyl estradiol and levonorgestrel were measured on days 14 and 15 of the two treatment periods for the evaluation of the 24-h kinetic parameters, and an additional sample was collected on day 21 to determine the trough plasma concentrations. Serum progesterone and luteinizing hormone (LH) levels were determined on days 13, 14, 15, and 21 of each cycle of the treatment phase. RESULTS: The plasma concentration-time curves and pharmacokinetic parameters of ethinyl estradiol and levonorgestrel were not statistically different during concomitant treatment with either levetiracetam or placebo. The ratios of the log-transformed geometric mean areas under the plasma concentration-time curves (AUCs), maximal (Cmax) and minimal (Cmin) plasma concentrations, and trough concentrations on day 21 (C21) ranged from 99.12 to 99.96% for ethinyl estradiol and from 97.13 to 99.41% for levonorgestrel. The 90% confidence intervals of these ratios were well within the 80 to 125% acceptance range for lack of interaction. Serum progesterone and LH concentrations were fairly constant during the run-in and treatment phases and remained markedly below their respective physiologic levels. Safety and menstrual-bleeding patterns were comparable during levetiracetam and placebo administration. CONCLUSIONS: Levetiracetam does not affect the pharmacokinetics of an oral contraceptive containing ethinyl estradiol and levonorgestrel, and on the basis of serum progesterone and LH levels, it does not affect the contraceptive efficacy.     

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.     

Carbamazepine coadministration with an oral contraceptive: effects on steroid pharmacokinetics, ovulation, and bleeding

Purpose: Antiepileptic drugs (AEDs) are widely used in reproductive‐age women. The AED carbamazepine (CBZ) induces the hepatic cytochrome P450 system, thereby accelerating hormone metabolism. We sought to assess the pharmacodynamic effects of CBZ on breakthrough bleeding and ovulation during oral contraceptive (OC) use. Methods: A double‐blind, randomized, crossover study of healthy women ages 18–35 years. Participants took an OC containing 20 μg ethinyl estradiol (EE) and 100 μg levonorgestrel (LNG) for 4 months. Concurrently, participants took 600 mg CBZ or a matching placebo for 2 months each, administered in random order. During the second month of CBZ or placebo, we measured EE and LNG levels 12 times over 24 h, ovarian follicular diameters with eight biweekly vaginal ultrasounds, weekly progesterone levels, and bleeding (using a diary). Key Findings: We enrolled 25 women; 10 completed the study. Five women discontinued because of reversible CBZ side effects. Mean area under the curve (AUC) measurements were lower during CBZ use compared to placebo for EE (1,778 vs. 986 pg*h/ml, p < 0.001) and LNG (24.8 vs. 13.8 pg*h/ml, p = 0.04). Ovulation occurred in 5 of 10 CBZ cycles compared to 1 of 10 placebo cycles (p = 0.06). Three or more days of breakthrough bleeding occurred during 8 of the 10 CBZ cycles compared to 2 of the 10 placebo cycles (p = 0.07). Significance: A commonly used dose of CBZ decreased levels of contraceptive steroids, increased breakthrough bleeding, and permitted ovulation during use of a low‐dose OC. Women treated with CBZ are not adequately protected from pregnancy by low‐dose OCs.     

No Effect of Long-Term Vigabatrin Treatment on Central Nervous System Conduction in Patients with Refractory Epilepsy: Results of a Multicenter Study of Somatosensory and Visual Evoked Potentials

Summary: Purpose: In dogs, vigabatrin (VGB) has been associated with intramyelinic edema producing delayed central conduction in somatosensory and visual evoked potentials (SEP, VEP). No such effects have been reported in humans. We assessed whether abnormalities of central conduction could be detected prospectively in patients with epilepsy treated with VGB as long-term add-on medication. Methods: Two hundred one patients with refractory partial epilepsy were enrolled and monitored for as long as 2 years. VGB was added to the treatment at an average dose of 2–3g/ day. Conduction in somatosensory and visual pathways was assessed by median nerve SEP and pattern VEP recordings performed at inclusion and once every 6 months. The upper limit and test-retest variability of EP latencies were evaluated at time of enrollment in the patient group. Prolonged N13-N20 or P14-N20 SEP intervals and P100 VEP latency >2.5 SD above the baseline mean, observed on repeated runs in the same session and exceeding the test-retest variability at enrollment were considered to indicate central conduction slowing. Results: One hundred nine patients completed the 2-year study period, and 92 discontinued VGB, of whom 37 were monitored with regard to EP until the end of the study. No consistent change in SEP or VEP was observed in the entire group during VGB treatment. The number of occasional EP values outside the baseline range in patients treated with VGB similar to that in patients whose VGB treatment had been discontinued. Conclusions: We detected no evidence of changes in SEP and VEP attributable to altered neuronal conduction in the CNS during long-term VGB treatment.     

Dose Frequency and Dose Interval Compliance with Multiple Antiepileptic Medications During a Controlled Clinical Trial

Summary: Compliance with medication regimens and clinical trial schedules was evaluated during a study of vigabatrin (VGB), an antiepileptic drug (AED). Medication Event Monitors (MEMS, Aprex Corp., Fremont, CA, U.S.A.) were provided to monitor use of VGB and other AEDs administered to 111 patients at 10 sites. MEMS reports showed the number of doses administered daily, times of doses, and intervals between doses. The 66 patients whose data were evaluable took VGB as prescribed (twice daily, b.i.d.) on 89 ± 7% of days in the clinical trial (mean 189 ± 63 days). However, only 66 ± 24% of doses were taken within the 9-15-h dose interval window for twice-daily dosing, a lower rate than that for dose frequency compliance (p < 0.001). Concomitant medications prescribed b.i.d. (n = 66) (86 ± 11% dose frequency compliance) were taken at lower rates than VGB (p < 0.02). Interval compliance also was lower for concomitant b.i.d. medications (59 ± 26%) than for VGB (p < 0.01). Dose frequency compliance for thrice-daily (t.i.d.) medications (n = 36) was 80 ± 18 and 40 ± 19% for interval compliance (6–10 h) (both p < 0.0001 vs. VGB). Dose frequency compliance for four times daily (q.i.d.) medications (n = 23) was 80 ± 23 and 33 ± 18% for interval compliance (4–8 h) (both p < 0.0001 vs. VGB). Patients at eight sites did not use MEMS properly, often for practical reasons, voiding including of data for 93 medications (32%) because of noncompliance with the study design to monitor compliance. Medication monitoring showed differences in dose frequency compliance and dose interval compliance between investigational and concomitant medications, as well as study protocol noncompliance, by outpatients in a long-term clinical trial.     

Vigabatrin in the treatment of infantile spasms

Infantile spasms (IS) have been conventionally treated with adrenocorticotropic hormone (ACTH), which is often associated with significant side effects. This study assessed the efficacy of vigabatrin (VGB) as an alternative in the treatment of IS and compared the efficacy of VGB in symptomatic vs cryptogenic patients. The study retrospectively reviewed 25 infants with IS (19 symptomatic, six cryptogenic) who were treated with VGB. Of the symptomatic group, 13 (68.4%) of 19 had clinical improvement, and 15 (78.9%) had electroencephalographic improvement. Three (50%) of six in the cryptogenic group had clinical improvement, and two (33%) had electroencephalographic improvement. Overall, three patients demonstrated clinical spasm control but electroencephalographic deterioration or persistence of hypsarrhythmia coupled with further cognitive decline. Four of the six partial clinical responders had deterioration of spasms with additional VGB dosage increases. VGB is comparable with ACTH in effectiveness for treatment of symptomatic IS. Higher doses of VGB may sometimes cause deterioration rather than further improvement, and therefore an optimum dosage of VGB needs to be titrated for every patient. Persistent electroencephalographic abnormalities and even electroencephalographic deterioration despite clinical control have been observed with VGB treatment; electroencephalographic monitoring during VGB treatment is recommended.     

Vigabatrin as Initial Therapy for Infantile Spasms: A European Retrospective Survey

Purpose: The efficacy and tolerability of vigabatrin (VGB) as an add-on therapy in the treatment of infantile spasm (IS) prompted physicians to explore its use as the first drug in this seizure type. Methods: Our retrospective study included 250 infants diagnosed with IS; the data obtained were subjected to peer-group review. Of this infant population, 192 infants were considered to have classic IS and had received VGB as their first treatment for the spasms. There was a slight preponderance of boys (57%) in this population. Mean age of IS onset was 5.8 months; 60% had typical hypsarrhythmia. Results: Initial suppression of spasms was obtained in 68% of infants with a median time to response of 4 days at an average VGB dose of 99 mg/kg/day. The best response was seen in those infants with tuberous sclerosis (96% response) and in those younger than 3 months at onset of spasms (90% response). Of these infants, 43 (22%) of 192 subsequently had other types of seizures, and a recurrence of infantile spasms occurred in 28 (21%) of 131 responders. At the end of this study, 96 of 192 infants who could be evaluated were seizure free with VGB monotherapy. Treatment appeared to be well tolerated, with only 33 (13%) infants with adverse events, of which the most common were somnolence (15 patients) and hyper-kinesia (eight patients). In only two cases did adverse events require VGB withdrawal. Conclusion: This study supports the opinion that VGB may be considered an initial treatment for IS regardless of cause.     

Effects of the CYP2C19 genotype and cigarette smoking on the single oral dose pharmacokinetics and pharmacodynamics of estazolam

The effects of the cytochrome P450 (CYP)2C19 genotype and cigarette smoking on the single oral dose pharmacokinetics and pharmacodynamics of estazolam were studied in 16 healthy male volunteers. The two mutated alleles (CYP2C19*2 and CYP2C19*3) causing absent CYP2C19 activity were identified by PCR-based restriction enzyme analysis. Five subjects had no mutated allele, five had one mutated allele, and six had two mutated alleles. Seven subjects were smokers, and nine were nonsmokers. The subjects received a single oral 4-mg dose of estazolam, and blood samplings and evaluation of psychomotor function were conducted up to 72 h after dosing. There was no significant difference among the groups with no, one, and two mutated alleles for the peak plasma concentration (145.2+/-36.5 vs. 142.1+/-33.6 vs. 113.2+/-29.7 ng/ml), area under the plasma concentration-time curve (0- infinity ) (4916.0+/-1276.4 vs. 4389.6+/-736.1 vs. 4047.3+/-613.8 ng x h/ml), apparent oral clearance (0.22+/-0.05 vs. 0.25+/-0.03 vs. 0.25+/-0.03 ml/min/kg), and elimination half-life (24.4+/-4.6 vs. 29.6+/-8.5 vs. 30.7+/-3.9 h). Similarly, none of the pharmacokinetic parameters was significantly different between the nonsmoker and smoker groups. Neither the number of mutated allele nor cigarette smoking affected the psychomotor function parameters significantly. The present study suggests that neither the CYP2C19 genotype nor cigarette smoking affects the single oral dose pharmacokinetics and pharmacodynamics of estazolam.     

A 5-Day Estradiol Therapy, in Amounts Reproducing Concentrations of the Early-Mid Follicular Phase, Prevents the Activation of the Hypothalamo-Pituitary-Adrenal Axis by Interleukin-1α in the Ovariectomized Rhesus Monkey

In a previous report, we have shown that intracerebroventricular (icv) administration of the cytokine interleukin-1a (IL-1α) in the ovariectomized (OVX) rhesus monkey results in the acute activation of the hypothalamo-pituitary-adrenal (HPA) axis and the inhibition of LH and FSH secretion. Here, we compare the cortisol response to IL-1α administration in OVX monkeys and in OVX animals replaced with estradiol (E) to reproduce E concentrations typical of the early-mid follicular phase. Cortisol, LH and FSH were measured after an icv infusion of physiological saline or IL-1α (2.1 or 4.2 μg/30 min) in both groups. E-containing capsules were implanted sc 5 days prior to the experiment. In OVX, E concentrations were <5 pg/ml. Cortisol concentrations decreased throughout the afternoon after saline infusion (to 49.7 ± 5.1% of baseline at 5 h; n = 7), but increased significantly after IL-1α to 158.3 ± 13.8% (n = 7). In OVXE, cortisol also declined after saline (to 76.4 ± 16.2%; n = 5). There were 2 types of response to IL-1α: in grp 1 (mean E 18.0 ± 0.7 pg/ml), the cortisol response was similar to that in OVX (160.8 ± 17.0%; n = 5), while in grp 2 (E: 30.7 ± 3.1 pg/ml), the cortisol response was absent (66.6 ± 7.2% of baseline at 5 h; NS vs saline in OVXE; n = 7). The cortisol response to IL-1α was restored in 2 monkeys when E was increased to >100 pg/ml, confirming our previous observations. While saline infusion did not affect LH (102.3 ± 10.2% of baseline at 5 h) or FSH (102.5 ± 4.4%) secretion in OVX monkeys, there was a significant decrease in both hormones after IL-1α (LH: 33.3±3.7%, FSH: 66.2 ± 6.5%; P<0.05 vs saline). This effect was lessened in OVXE animals: By 5 h, areas under the LH curve were 62.8 ± 10.9% of baseline in grp 1 and 85.3 ± 7.9% in grp 2 (NS vs saline), while those under the FSH curve were 84.0 ± 6.5% in grp 1 and 77.7 ± 4.3% in grp 2 (NS vs saline). The data demonstrate a striking effect of a 5-day estradiol treatment in preventing the HPA axis response to the cytokine IL-1α in the OVX monkey. This action, however, occurs only within restricted estradiol concentrations that reproduce E levels typical of the early-mid follicular phase of the menstrual cycle. While the precise mechanism through which estradiol exerts this action remains to be investigated, the results may have clinical relevance to the issue of estrogen replacement therapy in physiology and pathology.     

Vancomycin Pharmacokinetic Parameters in Patients with Hemorrhagic Stroke

Background

Infections are a common medical complication in hemorrhagic stroke patients, with vancomycin commonly used as empiric therapy. The purpose of this study was to evaluate the pharmacokinetic parameters of vancomycin in hemorrhagic stroke patients.

Methods

This was a retrospective study of adult patients with aneurysmal subarachnoid hemorrhage (aSAH) or intracerebral hemorrhage (ICH) admitted between May 2010 and February 2015 who received vancomycin. Predicted pharmacokinetic parameters based on population data were compared with calculated pharmacokinetic parameters based on serum trough concentrations.

Results

Eighty aSAH patients and 66 ICH patients met inclusion criteria. In the aSAH group, the mean dosing regimen was 17.6 ± 4 mg/kg every 12 (8–12) h. The mean measured trough concentration was lower than the predicted trough concentration (9.9 ± 4.1 vs. 19 ± 8.7 μg/mL; p < 0.001). The mean calculated elimination rate constant was higher than the predicted value (0.135 ± 0.04 vs. 0.092 ± 0.03 h^?1; p < 0.001), and the mean calculated half-life was lower than predicted (5.7 ± 1.8 vs. 8.3 ± 2.9 h; p < 0.001). In the ICH group, the mean dosing regimen was 15.9 ± 4.3 mg/kg every 12 (8–12) h. Similarly, the mean measured trough concentration was lower than the predicted trough concentration (10.7 ± 4.6 vs. 17.5 ± 8.5 μg/mL; p < 0.001). The mean calculated elimination rate constant was higher than the predicted value (0.106 ± 0.03 vs. 0.079 ± 0.02 h^?1; p < 0.001), and the mean calculated half-life was lower than predicted (7.2 ± 2.3 vs. 9.6 ± 3.2 h; p < 0.001).

Conclusions

Patients with hemorrhagic stroke exhibited pharmacokinetic alterations favoring increased elimination of vancomycin when compared to predicted pharmacokinetic parameters based on population data. This may result in underexposure to vancomycin, leading to treatment failure and other medical complications.

     

Clinical analysis of the effectiveness and safety of vigabatrin

The efficacy and safety of vigabatrin (VGB) has been extensively evaluated in preclinical and clinical studies but level of effectiveness in different type of seizures has yet to be established. The aim of our study is the prospective evaluation of anticonvulsant efficacy and toxicity of VGB. This long-term observation mainly focusing on efficacy of VGB in partial vs. secondarily generalized seizures were considered separately. In our study the criterion of drug resistance is occurrence per month of at least 1 tonic-clonic seizure or at least 2 complex partial seizures in 3 following months. The studies are based on 73 patients (39 F and 34 M), with average age of 26 years. After two weeks of treatment with sabril the drug was withdrawn in 5 patients because of side effects. The period of observation was 12 months. In group I--from total of 73 patients with partial seizures (including secondarily generalized)--31 (42%) of patients suffered only from partial seizures. Complex partial seizures occurred in 18 of patients; in this group were also 13 patients with simple partial seizures. Group II consisted of 42 patients (58%) who suffered from secondarily generalized tonic-clonic seizures. Number of seizures in group of patients with tonic-clonic seizures was from 1 to 16 per month (average 3.4) and in group of patients with complex partial seizures was from 1 to 70 per month (average 13.29). After titration period, Vigabatrin was given in doses of 500 to 3500 mg daily. Mean monthly fit frequency was calculated for over 3 months prior to the addition of vigabatrin and 12 months of therapy at the patient's maximum dose. Monthly fit frequency expressed as mean +/- standard error of the mean, and this statistical significance was determined using MANOVA for repeated measurement. Average monthly fit frequency of partial seizures has been reduced from 13.29 to 6.96 (p < 0.0001) and of generalized seizures from 3.38 to 1.38 (p < 0.0001). The percentage of patients achieving an increase of at least 75%--(Ratio < -0.6)--of seizures was greater in generalized seizures (27.3) than in partial ones (21.3). VGB is effective and well tolerated in refractory patients requiring add-on antiepileptic treatment and it has shown efficacy both in therapy of refractory partial seizures as well of secondarily generalized ones.     

Adjuvant Vigabatrin in Refractory Epilepsy: A Ceiling to Effective Dosage in Individual Patients?

A double-blind, randomized, cross-over study of additional vigabatrin (γ-vinyl-GABA, VGB, 1.0 g twice daily for 6 weeks, followed by 1.5 g twice daily for 6 weeks) and matched placebo was undertaken in 24 patients with refractory epilepsy. Nineteen completed the trial satisfactorily. Fewer seizure days were reported during VGB treatment [placebo 41, VGB 23, p < 0.05, 95% confidence interval (CI) ?1.5 to ?14]. An overall reduction in median seizure numbers failed to reach statistical significance (n = 19; placebo 52, VGB 32, NS, 95% CI ?18 to + 24). Subgroup analysis, however, showed a significant reduction in partial seizures (n = 17) with 2 g VGB daily (placebo 22, VGB 13, p < 0.05, 95% CI ?0.5 to ?16.5), but not with higher dosage (placebo 28, VGB 22, NS, 95% CI ? 18 to + 11). A deterioration in control of partial seizures as compared with the equivalent placebo phase was observed when patients were changed from 2 to 3 g/day VGB (2 g VGB 13, 3 g VGB 22, p = 0.05, 95% CI 0 to +20). Loss of efficacy was noted in 3 patients, and seizure control worsened slightly in 5 others. One previously resistant patient developed a therapeutic response, and 2 other patients reported an additional useful reduction in seizures. In the remaining 8 patients, seizure frequency did not change. VGB did not appear to benefit tonic-clonic seizures. Serum VGB concentrations were higher during treatment with 3 g (15.5 ± 8.9 mg/L) daily than with 2 g (13.5 ± 11.2 mg/L). No important alterations were noted in the concentrations of concomitantly administered antiepileptic drugs (AEDs) throughout the trial. VGB is useful adjuvant therapy for treatment of partial seizures. There may be a ceiling to effective dosage. This demands individual dose titration for each patient.     

Treatment with Vigabatrin May Mimic α-Aminoadipic Aciduria

Summary: Purpose : We describe a secondary effect of treatment with vigabatrin (VGB). A significant increase in α-aminoadipic acid (AAA) occurred in plasma and urine of VGB-treated children, thus mimicking a known rare metabolic disease, α-aminoadipic aciduria (AAAuria).
Methods : We studied eight children, aged from 3 months to 5 years, who were receiving VGB for drug-resistant partial epilepsies. Plasma and urine amino acids were assayed with ninhydrin detection on an automated Beckman 6300 analyzer.
Results : In eight out of eight children, there was a significant increase of AAA in plasma and in urine. Plasma values ranged from 7 to 18 μ M (control values, < 5) and urinary values from 67 to 274 mmol/mol creatinine (control values, < 25).
Conclusions : The concentrations of AAA in these VGB-treated children were as high as the concentrations found in the inherited metabolic disease, AAAuria. This could lead to incorrect diagnosis and to inappropriate genetic counseling. Thus whenever a genetic metabolic disease is suspected, amino acid chromatography testing should be performed before initiation of treatment with VGB.     

Time Course of the GABAergic Effects of Vigabatrin: Is the Time Course-of Brain GABA Related to Platelet GABA-Transaminase Inhibition?

PURPOSE: To analyze the time course of the effects of vigabatrin (VGB) on brain gamma-aminobutyric acid (GABA), and its relation with 4-aminobutyrate-2-ketoglutarate amino-transferase (GABA-T) in brain and platelets. METHODS: Blood and brain samples were collected at 4, 24, 48, and 72 h after a single dose and after 3 and 8 days of treatment with 200 mg/kg of VGB in rats. RESULTS: Time courses of the GABAergic effects of VGB were different after single and multiple doses: with multiple doses, the inhibition of brain GABA-T was quicker and longer, the inhibition of platelet GABA-T was greater and longer, the increase in brain GABA was greater, and recovery began earlier. After pooling the data obtained at 4, 24, 48, and 72 h, we observed a power correlation between the increase in brain GABA in individual rats as percentage of the control and both the inhibition of brain GABA-T after a single dose of VGB (r = -0.40; p < 0.05), and the inhibition of platelet GABA-T after 3 days (r = -0.48; p < 0.01) and 8 days of treatment (r = -0.53; p < 0.01). When all data after single and multiple doses were pooled, the increase in brain GABA correlated better with the inhibition of GABA-T in platelets (r = -0.62; p < 0.001) than in brain (r = -0.38; p < 0.001). Platelet GABA-T correlated with brain GABA at 4 h (r = -0.64; p < 0.001) and 24 h (r = -0.66; p < 0.001) but not at 48 and 72 h. CONCLUSIONS: Platelet GABA-T reflects the time course of the increase in brain GABA better than does brain GABA-T after multiple doses of VGB in rats.     

Comparison of two distinct needle tip positions in pulsed radiofrequency for herpes zoster-related pain

Background

Herpes zoster (HZ)-related pain, characterized by chronic and persistent pain with a dermatomal distribution, is a relatively common complication of HZ. Pulsed radiofrequency (PRF) can effectively relieve HZ-related pain. There is no study on the effect of the needle tip position in patients with HZ for PRF treatment. This prospective study was conducted to compare two distinct needle tip positions in PRF for HZ-related pain.

Methods

Seventy-one patients suffering from HZ-related pain were enrolled in this study. According to the dorsal root ganglion (DRG) position and needle tip position, patients were randomly allocated to the IP group (group inside of the pedicle, n = 36) and OP group (group outside of the pedicle, n = 35). Quality of life and pain control were evaluated with the visual analog scale (VAS) and activities of daily living questionnaires (including 7 items: general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life), which were administered before therapy and at intervals of 1, 7, 30, and 90 days after therapy.

Results

Before therapy, the mean pain score was found to be 6.03 ± 0.45 in the IP group and 6.00 ± 0.65 in the OP group (p = 0.555). No significant differences were found when the two groups were compared at 1 and 7 days after therapy (p > 0.05). But, the pain score was significantly lower in the IP group at 30 days (1.78 ± 1.31 vs. 2.77 ± 1.31, p = 0.006) and 90 days of follow-up (1.29 ± 1.19 vs. 2.15 ± 1.74, p = 0.041). Significant differences between the two groups in terms of general activity (2.39 ± 0.87 vs. 2.86 ± 0.77, p = 0.035), mood (1.97 ± 1.65 vs. 2.86 ± 1.50, p = 0.021), relations with other people (1.94 ± 0.92 vs. 2.51 ± 1.22, p = 0.037), sleep (1.64 ± 1.44 vs. 2.97 ± 1.44, p < 0.001), and enjoyment of life (1.58 ± 1.11 vs. 2.43 ± 1.33, p = 0.004) were detected after the 30-day follow-up. In addition, scores for the activities of daily living were significantly lower in the IP group than that in the OP group at 90 days after therapy (p < 0.05).

Conclusion

The needle tip position had an influence on the PRF treatment in patients with HZ-related pain. Positioning the needle tip in the area between the medial and lateral edges of adjacent pedicles offered good pain relief and improved quality of life in HZ patients.     

Pre- rather than co-application of vigabatrin increases the efficacy of tiagabine in hippocampal slices

PURPOSE: The antiepileptic drug vigabatrin (VGB) increases intracellular availability of the inhibitory transmitter gamma-aminobutyric acid (GABA) by inhibition of GABA-transaminase. A blockade of the GABA uptake is the main mechanism of action of tiagabine (TGB). Based on this, the two antiepileptic drugs (AEDs) can be speculated to act synergistically so that their combined antiepileptic efficacy is supraadditive. METHODS: To test this, experiments were performed on hippocampal slices of guinea-pigs. As an epilepsy model, epileptiform field potentials (EFPs) were induced by omission of Mg2+ from the bath solution and recorded in stratum pyramidale of the CA3 region. VGB (7.5 microM) and TGB (0.75 microM) were added to the superfusate. RESULTS: VGB, given alone, failed to decrease the repetition rate of EFPs. Similarly, TGB applied alone only transiently led to a nonsignificant reduction of the EFP frequency. Combining VGB and TGB, their suppressive efficacy increased, yielding a significant reduction of EFP frequency, which, however, again did not persist. Pretreatment of the preparations with VGB for 2 h, followed by additional application of TGB, or TGB alone, drastically and persistently potentiated the effects. CONCLUSIONS: These results demonstrate that VGB and TGB show favorable pharmacodynamic interactions, provided VGB is allowed to block intracellular GABA degradation before GABA uptake block by TGB.     

Reduction of Plasma Alanine Aminotransferase During Vigabatrin Treatment

Summary: In 9 drug-resistant patients with partial seizures treated with vigabatrin, Γ-vinyl GABA (VGB), alanine aminotransaminase (ALAT) activity in plasma was significantly reduced. Comparison of in vitro with in vivo measurements led us to conclude that this reduction is mainly an in vivo phenomenon, perhaps due to crossenzyme inhibition. The assessment of two biological variables linked with ALAT, glucose and alanine levels under fasting conditions, failed to show any significant metabolic alterations. VGB is an effective drug for partial epilepsy. Our observations do not suggest that reduced ALAT activity'is of clinical concern.