Therapeutic drug monitoring of lamotrigine in patients suffering from resistant partial seizures

Sixty patients, all potential candidates for ongoing lamotrigine (LTG) treatment as add-on therapy for resistant partial seizures and receiving carbamazepine (CBZ) and/or valproate (VPA) treatment, were submitted to therapeutic drug monitoring (TDM). The aim was to evaluate the possible relation between serum levels and the clinical effect of LTG, to verify whether CNS toxicity has to be considered the result of a pharmacokinetic or a pharmacodynamic interaction with CBZ, and to investigate whether possible changes in the clinical response during long-term treatment are dependent on LTG serum level variations. Sixteen patients achieved complete control, 26 a >or=50% reduction in seizures, the remainder did not respond. Mean LTG serum concentrations were higher in responders than in nonresponders, the difference being statistically insignificant. The best results were observed in VPA-cotreated patients with the highest LTG blood levels. CNS toxicity occurred after giving LTG to subjects who subsequently developed the highest LTG concentrations, whereas CNS toxicity seemed unrelated to CBZ and CBZ-epoxide serum concentrations. No decrease in LTG, CBZ and VPA serum levels was observed even in patients showing a reduction in the response during long-term treatment.     

Effect of phenobarbital on carbamazepine and its major metabolites in serum, different brain areas, and urine after acute and chronic administration to rats

The influence of coadministration of phenobarbital (PB) on disposition of carbamazepine (CBZ) and carbamazepine-10,11-epoxide (CBZ-E) in serum and in discrete areas of rat brain, together with its effects on urinary excretion of CBZ, CBZ-E, and trans-10,11-dihydro-10,11-dihydroxycarbamazepine (CBZ-DIOL) were investigated after both acute and chronic administration. Acute coadministration of PB resulted in increased serum CBZ levels, whereas serum CBZ-E levels were initially lower and then higher. In daily urinary excretion, a reduction in both CBZ-E/CBZ ratio and CBZ-DIOL/CBZ ratio was observed. Chronic (30 day) coadministration of PB led to a decrease in serum CBZ levels after the first hour, whereas serum CBZ-E levels were initially higher and then lower. In daily urinary excretion, a decrease in CBZ-E/CBZ ratio and an increase in CBZ-DIOL/CBZ ratio were noted. These results are consistent with an inhibitory interaction and a metabolic induction on both CBZ epoxidation and CBZ-E metabolism in acute and chronic administration, respectively. However, effects on CBZ epoxidation were preferential. In the various brain areas, the effects observed were similar to those noted in serum. In addition, a relevant increase in brain/serum CBZ ratios was observed with chronic coadministration of PB.     

Effect of viloxazine on serum carbamazepine levels in epileptic patients

The present study describes the interaction between carbamazepine (CBZ) and viloxazine, a recently synthesized antidepressant agent. Seven epileptic patients on chronic anticonvulsant therapy showed a significant (p less than 0.005) increase in steady-state serum CBZ levels (from 8.1 +/- 2.5 SD to 12.1 +/- 2.5 SD micrograms/ml) when viloxazine (300 mg/day) was added to the therapy. The effect was associated with the appearance of mild CBZ intoxication. The symptoms of this intoxication (i.e., dizziness, ataxia, fatigue, drowsiness) disappeared rapidly, and serum CBZ levels decreased to the basal values, when viloxazine administration was stopped.     

Effects of Carbamazepine on the Hypothalamic-Pituitary-Gonadal Axis in Male Patients with Epilepsy: A Prospective Study

The effects of carbamazepine (CBZ) monotherapy on serum sex hormone levels and on pituitary responsiveness to various stimuli were evaluated in a prospective study with 21 male patients with epilepsy. The serum levels of testosterone (T), free testosterone (FT), sex hormone binding globulin (SHBG), estradiol (E2), luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin (PRL), and dehydroepiandrosterone sulfate (DHEAS) were assayed, and the free androgen index (FAI) values were calculated for each patient before and after 2-month CBZ treatment. The pituitary PRL, LH, and FSH responses to luteinizing hormone-releasing hormone (LH-RH), thyrotropin-releasing hormone (TRH), and metoclopramide (MC) were also measured before and after CBZ treatment. The baseline serum hormone and SHBG levels were measured and the FAI values calculated in 16 healthy male control subjects of similar age. The mean E2 level was higher in patients before CBZ treatment than in control subjects, and untreated patients had greater variances for FAI values, PRL levels, and LH levels than control subjects. No other significant differences were found between untreated patients and control subjects. The FAI values and DHEAS levels of patients decreased during 2-month treatment with CBZ. The PRL response to MC was higher after CBZ treatment than before. The baseline levels of other hormones and SHBG, as well as the LH and FSH responses to LH-RH, remained unaltered. The results indicate that during the first 2 months of CBZ treatment the androgen balance in male epileptic patients changes: Serum DHEAS levels and FAI values decrease, although FT levels remain unchanged. The clinical relevance of these hormonal changes is obscure.     

Tolerance of high dosage carbamazepine monotherapy in treatment of epilepsy

We examined whether high dose carbamazepine (CBZ) monotherapy (CBZ serum levels > 9 mg/l) is well tolerated. Forty-one patients with localisation-related epilepsy were enrolled. They received high dose monotherapy either from the time of recruitment (30/41), or their CBZ treatment was pushed into the high dose range (11/41) during the observation period (mean 145 days). CBZ and CBZ metabolite serum levels, full blood counts, liver function tests, electrolytes were measured in addition to clinical assessments. The mean daily CBZ dose was 1515 mg (median 1500, range 600-3600 mg). Mean CBZ serum level was 11.1 mg/l (median 11.1, range 5.3-16.4 mg/l). Eleven of 41 patients (26.8%) reported side effects (mean serum level 11.4, median 11.6, range 8.7-13.7 mg/l), but side effects were intolerable in only five patients so that the CBZ dose had to be reduced (mean CBZ serum level 11.4, median 11.6, range 8.7-13.7 mg/l). The total daily CBZ dose but not CBZ or CBZ metabolite levels were correlated with side effects. No treatment changes had to be undertaken because of abnormal laboratory parameters. High dose CBZ anticonvulsant monotherapy is well tolerated.     

Use of Saliva in Home Monitoring of Carbamazepine Levels

Summary: Total carbamazepine (CBZ) levels in serum of 61 epileptic children were compared with saliva levels. Both resting and stimulated saliva was analyzed. The salivary levels were 38.6% of serum CBZ levels. A highly significant correlation was noted ( r = 0.89, p < 0.001). Stimulation had no effect on saliva CBZ levels ( r = 0.97). Salivary and serum CBZ levels were not affected by storing the samples for 7 days at room temperature. The data indicate that salivary CBZ may provide a reliable alter-native monitoring method to Tegretol therapy, especially in children, in whom blood sampling is difficult. Further-more, the samples may be collected at home and delivered to the laboratory by mail.     

The pharmacology of chewable versus regular carbamazepine in chronically treated children with epilepsy.

We report the first comparison of Chewable and Regular Carbamazepine (CBZ) tablets in children with epilepsy. Forty-four children receiving chronic monotherapy CBZ participated. In month 1 children received regular CBZ; in month 2, the same dose of Chewable CBZ. Once per week fasting predose CBZ and CBZ epoxide serum levels were determined. In a subset of 15 children, at the end of each month serum levels were obtained every 2 hours for 12 hours beginning pre-dose. Standards for CBZ and CBZ epoxide were tested in each centre. Overall, weekly levels showed no consistent differences between the month on chewable CBZ and regular CBZ. Seizure control and rates of reported side effects were similar. In five patients chewable CBZ produced higher peak CBZ levels while five had higher peaks with regular CBZ. In conclusion, regular and chewable CBZ often have unpredictable differences in peak but not trough levels of CBZ suggesting that peak level side effects with one form of CBZ might be alleviated by changing to the other.     

Serum Steroid Hormones and Pituitary Function in Female Epileptic Patients During Carbamazepine Therapy

Ten regularly menstruating women with epilepsy were studied in a 12-month prospective follow-up study to evaluate the short-term effects of carbamazepine (CBZ) on serum sex hormone balance and pituitary function. Thirteen female epilepsy patients receiving long-term CBZ monotherapy (mean medication duration 5.3 years) were also studied. Controls were 17 regularly menstruating healthy volunteers. Untreated patients had higher free testosterone (FT) and luteinizing hormone (LH) serum concentrations than control subjects, whereas the other parameters did not differ between these two groups. However, serum sex hormone binding globulin (SHBG) levels increased and dehydroepiandrosterone sulfate (DHEAS) levels decreased during CBZ treatment. Although calculated free androgen index (FAI) decreased during CBZ therapy, the directly measured FT levels remained unaltered. These changes were found after 2 months and continued after 12 months of CBZ treatment. Moreover, patients with long-term CBZ also had high SHBG levels, low serum DHEAS levels, and low FAI values. Basal LH serum levels decreased during the first year of CBZ treatment and luteinizing hormone-releasing hormone (LH-RH)-stimulated LH concentrations were lower after 2 months of CBZ treatment. Although the serum basal follicle-stimulating hormone (FSH) and prolactin (PRL) levels were unaffected during the first year of CBZ therapy, the LH-RH-stimulated FSH concentrations and metoclopramide (MC)-stimulated PRL concentrations were lower after 12 months of CBZ treatment than before CBZ. Both basal and stimulated gonadotropin and PRL serum levels of long-term CBZ patients were unaffected. No changes were found in estradiol (E2), testosterone (T), or cortisol (C) serum concentrations during short or long-term CBZ treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Carbamazepine-Valnoctamide Interaction in Epileptic Patients: In Vitro/In Vivo Correlation

Six patients stabilized with carbamazepine (CBZ) therapy received an 8-day “add-on” supplement of valnoctamide (VCD), a tranquilizer available over the counter (OTC) in several European countries that exhibits promising anticonvulsant activity in animal models. During VCD intake, serum levels of the active CBZ metabolite, carbamazepine-10,ll-epoxide (CBZ-E), increased fivefold from 1.5 ± 0.7 μg/ml at baseline to 7.4 ± 4.4 μg/ml after 4 days of VCD therapy and 7.7 ± 3.1 ^g/ml after 7 days of VCD therapy (means ± SD, p < 0.01). In 4 patients, the increase in serum CBZ-E levels was associated with clinical signs of CBZ intoxication. CBZ-E levels returned to baseline after VCD therapy was discontinued. Serum CBZ levels remained stable throughout the study. The interaction observed in this study is similar to that described in patients treated with CBZ and valpromide (VPD, an isomer of VCD). In a mechanistic study, therapeutic concentrations of VCD inhibited hydrolysis of styrene oxide in human liver mi-crosome preparations. Thus, VCD is a potent inhibitor of microsomal epoxide hydrolase (IC₅₀ 15 μM). There was a striking similarity between in vitro and in vivo inhibition potencies. In this study, VCD clearance was higher in epileptic patients (treated with CBZ) than in healthy subjects.     

Evaluation of thyroid and parathyroid functions in children receiving long-term carbamazepine therapy

We studied serum calcium, phosphorus, alkaline phosphatase (ALP), thyroid hormones (total thyroxine [TT4], free thyroxine [FT4], thyroid-stimulating hormone [TSH]), parathyroid hormone (PH), and osteocalcine levels in children with epilepsy who had been receiving long-term carbamazepine (CBZ) therapy to determine whether there was any effect of CBZ therapy on these hormones. The study included 18 patients with epilepsy receiving CBZ and 16 healthy age-matched controls. The age ranged from 4-18 years (11.26 +/- 3.59 years) and 4.5-17 years (11.16 +/- 3.13 years) in the study and control group, respectively. The duration of CBZ use was between 10 months-5 years (3.12 +/- 1.09 years). When comparing the results we did not find any significant difference in serum calcium, phosphorus, ALP, osteocalcine and TSH and PH levels between the groups (p >.05). However, serum TT4 and FT4 levels were found to be significantly lower in the study group than those of control group (p <.05). However, we observed no clinical signs of hypothyroidism in all subjects. To these findings we suggest that serum thyroid hormone levels should be monitored in children receiving long-term CBZ therapy.     

Lamotrigine-induced carbamazepine toxicity: an interaction with carbamazepine-10,11-epoxide.

We report an interaction between lamotrigine (LTG), a new antiepileptic drug (AED), and carbamazepine (CBZ) and its primary metabolite CBZ-10,11-epoxide (CBZ-E) in 9 consecutive patients (5 male, 4 female, aged 19-31 years). After introduction of LTG (median daily dose 200 mg, range 100-300 mg) the mean serum CBZ-E concentration increased by 45% (P less than 0.01) and the CBZ-E/CBZ ratio increased by 19% (P less than 0.02). In 4 patients these changes were associated with clinical toxicity (dizziness, nausea, diplopia). The possibility of an increase in serum CBZ-E concentrations needs to be considered if toxicity symptoms develop when LTG is added to CBZ therapy.     

Chromatin-negative Klinefelter''s syndrome with focal megalencephaly

Interactions between analgesics and anti-epileptic drugs may sometimes present a serious clinical problem. The aim of the study was to investigate the influence of usually applied doses of dextropropoxyphene (DPX) on the steady state levels of carbamazepine (CBZ), phenytoin (DPH) and phenobarbital (PB).
Sixteen patients in monotherapy completed the trial, while four patients dropped out. In patients on CBZ serum levels increased (mean appr. 66 %) after 6 days on DPX. In three of the patients a further increase was seen after an additional week on DPX. One patient discontinued the DPX intake because of clinical signs of toxicity, but the remainder were clinically unaffected. CBZ-epoxide levels declined simultaneously. For DPH only a doubtful increase was observed after 1–2 weeks on DPX. For PB an average increase of 20 % in serum level was noted after 1 week. The protein binding of CBZ and DPH was not affected. It is concluded that patients on CBZ should be treated only with DPX if monitored properly. Patients on DPH or PB should be followed carefully until further evidence has been produced.     

Effects of Enteral Tube Feeding on the Absorption and Pharmacokinetic Profile of Carbamazepine Suspension

In a randomized, two-period crossover clinical study, eight normal male volunteers received two separate 500-mg doses of carbamazepine (CBZ) suspension 1 week apart. One dose was administered orally after an overnight fast, and the other was administered by nasogastric feeding tube during a continuous enteral feeding infusion. Serial serum CBZ concentrations were determined by high-performance liquid chromatography (HPLC) to assess the effects of the enteral feeding on CBZ absorption. Noncompartmental methods were used to estimate pharmacokinetic data. One volunteer experienced a mild hypersensitivity reaction after his first CBZ dose and was withdrawn from the study. The other subjects tolerated both doses very well, although most experienced mild drowsiness or lightheadedness. Serum CBZ concentrations were lower during enteral feeding administration, but the differences were statistically significant only at 8 h (p = 0.044). Changes in pharmacokinetic data were not significant, although the decrease in maximum serum concentration approached significance (p = 0.052). The relative bioavailability of CBZ suspension with enteral feeding administration was 90.1% of that during fasting. There was a strong correlation between CBZ dose (mg/kg) and Cmax after oral administration (r = 0.97, Y = 1.88X - 4.49, p less than 0.001) but not during enteral feeding administration. Although absorption of CBZ suspension was generally slower and slightly diminished during nasogastric feeding, this interaction may lessen unwanted side effects.     

Brief Communication: EVALUATION OF THYROID AND PARATHYROID FUNCTIONS IN CHILDREN RECEIVING LONG-TERM CARBAMAZEPINE THERAPY

We studied serum calcium, phosphorus, alkaline phosphatase (ALP), thyroid hormones (total thyroxine [TT4], free thyroxine [FT4], thyroid-stimulating hormone [TSH]), parathyroid hormone (PH), and osteocalcine levels in children with epilepsy who had been receiving long-term carbamazepine (CBZ) therapy to determine whether there was any effect of CBZ therapy on these hormones. The study included 18 patients with epilepsy receiving CBZ and 16 healthy age-matched controls. The age ranged from 4-18 years (11.26 &#45 3.59 years) and 4.5-17 years (11.16 &#45 3.13 years) in the study and control group, respectively. The duration of CBZ use was between 10 months-5 years (3.12 &#45 1.09 years). When comparing the results we did not find any significant difference in serum calcium, phosphorus, ALP, osteocalcine and TSH and PH levels between the groups (p >. 05). However, serum TT4 and FT4 levels were found to be significantly lower in the study group than those of control group (p <. 05). However, we observed no clinical signs of hypothyroidism in all subjects. To these findings we suggest that serum thyroid hormone levels should be monitored in children receiving long-term CBZ therapy.­­     

A prospective study of serum sex hormones during carbamazepine therapy.

This paper reports the results of a 12-month prospective follow-up study on the effects of carbamazepine (CBZ) medication on serum sex and pituitary hormone concentrations in 21 male patients with recently diagnosed epilepsy. The results of the present study indicate that a change occurs in the androgen balance during CBZ medication in male patients with epilepsy: a rise in serum sex hormone binding globulin levels results in decreased free androgen index values, and dehydroepiandrosterone sulfate serum levels decrease. Serum testosterone and free testosterone levels remain unchanged, but estradiol levels decrease. Serum basal prolactin (PRL) levels remain unchanged, but the PRL responses to thyrotropin-releasing hormone and metoclopramide increase slightly during the first year of CBZ medication. Basal and stimulated serum gonadotropin levels remain unchanged. The clinical consequences of these hormonal changes during CBZ medication call for further studies.     

Thyroid function in men taking carbamazepine, oxcarbazepine, or valproate for epilepsy

PURPOSE: Antiepileptic drugs (AEDs) may affect serum thyroid hormone concentrations. This study aimed to evaluate thyroid function in men taking carbamazepine (CBZ), oxcarbazepine (OCBZ), or valproate (VPA) for epilepsy. METHODS: Ninety men with epilepsy (40 taking CBZ, 29 taking OCBZ, and 21 taking VPA monotherapy) and 25 control subjects participated in the study. After clinical examination, a blood sample for hormone, gamma-glutamyl-transferase (GGT) and antibody (ab) assays was obtained. RESULTS: Serum thyroxine (T4) and free thyroxine (FT4) concentrations were low in men taking CBZ or OCBZ. Forty-five percent of men taking CBZ and 24% of men taking OCBZ had serum T4 and/or FT4 levels below the reference range. However, no correlations were found between T4 or FT4 and GGT concentrations in men taking CBZ or OCBZ. Thirteen percent of men taking CBZ, 17% of men taking OCBZ, and 6% of control men had increased levels of thyroid peroxidase (TPO)-ab and/or thyroglobulin (TG)-ab, but these were not associated with altered serum thyroid hormone concentrations. Serum triiodothyronine and thyrotropin levels in men taking CBZ or OCBZ were normal. In men taking VPA, the concentrations of thyroid hormones, thyrotropin, and antithyroid ab were normal. CONCLUSIONS: Serum thyroid hormone concentrations are low in CBZ- or OCBZ-treated men. However, these low levels do not seem to be due to liver enzyme induction or activation of immunologic mechanisms. Therefore, interference with hypothalamic regulation of thyroid function by CBZ and OCBZ seems possible. VPA does not have any significant effects on thyroid function.     

Lack of Interaction of Gabapentin with Carbamazepine or Valproate

Summary: Gabapentin (GBP) studies were conducted in patients with epilepsy receiving carbamazepine (CBZ, n= 12) or valproate (VPA, n = 14) monotherapy. The effects of GBP coadministration on steady-state CBZ or VPA concentrations and of these antiepileptic drugs (AEDs) on GBP pharmacokinetics were investigated. GBP (400 mg) was coadministered every 8 h for 3% days with CBZ or for 5 1/3 days with VPA. GBP was well tolerated. Mean steady-state plasma CBZ/CBZ-10, ll-epoxide (CBZ-E) and serum VPA concentrations before, during, and after GBP administration were not significantly different. Mean steady-state GBP pharmacokinetic parameters during CBZ or VPA coadministration were similar to steady-state parameters reported in healthy subjects. Thus, no pharmacokinetic interaction exists between CBZ or VPA and GBP. No dosage adjustment is necessary when GBP and CBZ or VPA are coadministered.     

Effects of Carbamazepine Therapy on Serum Sex Hormone Levels in Male Patients with Epilepsy

The effects of carbamazepine (CBZ) therapy and epilepsy on sex hormone plasma levels in male patients with epilepsy were evaluated by measuring the levels of testosterone (T), free testosterone (FT), sex hormone binding globulin (SHBG), estradiol (E2), luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin (PRL), and dehydroepiandrosterone sulfate (DHEAS) and by calculating the free androgen index (FAI) in 23 male patients with epilepsy receiving CBZ medication, in 18 untreated male patients with epilepsy, and in 19 healthy age-matched control subjects. No significant differences in the mean T or FT levels were found between the three groups, but the CBZ-treated patients had significantly higher SHBG levels and their FAI values and DHEAS concentrations were lower. The LH, FSH, PRL, or E2 levels in CBZ-treated and untreated male patients with epilepsy did not differ from the controls. CBZ monotherapy does not significantly change the serum balance of sex hormones; however, CBZ clearly affects the serum levels of SHBG and DHEAS.     

Acute hepatitis in a patient treated with carbamazepine

Summary A case of serious acute hepatic damage probably induced by carbamazepine (CBZ) is described. A 4-year-old patient with generalized tonic-clonic seizures was started on CBZ after various ineffective therapies. On the 10th day of CBZ therapy, he was readmitted to the hospital because of reappearance of fits, and went into hepatic coma. On the hypothesis that he was suffering an acute toxic reaction to CBZ, the drug was withdrawn (the serum level was not toxic) and the patient was subjected to peritoneal dialysis. The patient was discharged after 15 days in general conditions similar to those preceding the comatose state. The type of hepatic damage revealed by the laboratory tests and the early appearance of the clinical symptoms with non-toxic serum CBZ levels support the hypothesis of an idiosyncratic reaction to CBZ.     

Brain distribution and efficacy of carbamazepine in kainic acid induced seizure in rats

To investigate the relationships between carbamazepine (CBZ) concentrations in serum and the brain, and the anticonvulsive efficacy in kainic acid (KA) induced seizures in rats, adult Wistar rats (n=25) were intraperitoneally given 40 mg/kg CBZ, followed by 15 mg/kg KA (n=20) or saline (control, n=5). At 90 min after the injection, CBZ concentrations in 5 rats without seizures (CBZ effective group), 5 rats with seizures (CBZ no-effective group) and five control rats were measured. Serum and brain tissues from six areas (cortex, brain stem, cerebellum, thalamus, hippocampus and striatum) were used for CBZ assay. CBZ was measured using a EMIT immunoassay kit. In blood, CBZ was higher in rats treated with CBZ+KA than in a control group (CBZ+saline). In the brain, the effective group demonstrated significantly high CBZ concentration in the hippocampus. KA appeared to raise serum CBZ level when it was given in combination with CBZ. This was probably caused by the accelerated absorption of CBZ from local site as the results of an increased metabolic rate and the more demands for blood supply after KA treatment. The positive correlation between efficacy of CBZ and the concentration in the hippocampus suggests that CBZ levels in the hippocampus is closely correlated with the efficacy of CBZ against KA induced seizures.