Levodopa and 3-OMD levels in Parkinson patients treated with Duodopa.

We studied 19 patients (14 men, 5 women, Hoehn and Yahr (H&Y)> or =3) with advanced Parkinson's disease (PD) attending the Parkinson Institute, Milan, whose motor fluctuations and dyskinesia were not controlled by oral medications. After all oral PD medications had been withdrawn, they received a duodenal levodopa infusions (Duodopa, Solvay Pharmaceuticals) for 14h/day through a transabdominal port; levodopa boluses were administered in the morning and during "off" periods. The patients were evaluated by means of the UPDRS in the morning ("off") and 60-120min after the infusion ("on") at baseline and for a mean follow-up of 13.5+/-12.5months (up to 36months in 10 patients:). Levodopa (l-DOPA) and its metabolites were determined by HPLC with electrochemical detection. l-DOPA concentrations tended to higher in the afternoon (2008+/-345 vs 1713+/-274ng/mL) and correlated with the daily dose. O-methyldopa (OMD) levels correlated with l-DOPA levels, and the OMD/l-DOPA ratios were stable over the day. There was a relationship between decreasing UPDRS III scores and decreasing OMD/l-DOPA ratios. Dyskinesia (UPDRS IV, items 32-34) showed a clear improvement over time but there was no clear relationship with l-DOPA and OMD levels, or the OMD/l-DOPA ratio. The l-DOPA/dose ratio was stable over time, whereas OMD levels and the OMD/l-DOPA ratio decreased. It is conceivable that continuous infusion decreases metabolism possibly due to a reduction in methyl donor availability, as demonstrated by the increase in total homocysteine levels. Our results do not support the development of tolerance even after several months of continuous infusion, and indicate that pharmacodynamic factors play a role in afternoon off periods.

Bimodal administration of entacapone in Parkinson's disease patients improves motor control.

Catechol-O-methyl transferase (COMT) inhibition by entacapone enhances levodopa absorption and reduces 'off' time in Parkinson's disease (PD). We hypothesized that the administration of entacapone in a bimodal fashion (two doses 1 h apart) would enhance levodopa absorption and improve the motor symptoms of PD. Patients with PD (n = 17) were given immediate (IR)- or controlled (CR)-release levodopa each with either one or two doses of entacapone. Bimodal entacapone produced a significant increase in IR and CR levodopa half-life, 'area under the curve' (AUC), and C(max) with levodopa CR. For both IR and CR levodopa, bimodal entacapone resulted in a significant improvement in the Unified Parkinson's Disease Rating Scale part III (motor). Bimodal entacapone increased COMT inhibition, improved the pharmacokinetics of levodopa and improved motor scores for 6 to 8 h. Bimodal use of entacapone may be useful in selected patients to improve motor control and implies that controlled release COMT inhibition would be beneficial in PD patients.

Determination of 5-chloro-7-iodo-8-quinolinol (clioquinol) in plasma and tissues of hamsters by high-performance liquid chromatography and electrochemical detection.

This paper describes a method of determining clioquinol levels in hamster plasma and tissue by means of HPLC and electrochemical detection. Clioquinol was separated on a Nucleosil C18 300 mm x 3.9 mm i.d. 7 microm column at 1 ml/min using a phosphate/citrate buffer 0.1M (400 ml) with 600 ml of a methanol:acetonitrile (1:1, v/v) mobile phase. The retention times of clioquinol and the IS were, respectively, 11.6 and 8.1 min; the quantitation limit (CV>8%) was 5 ng/ml in plasma and 10 ng/ml in tissues. The intra- and inter-assay accuracies of the method were more than 95%, with coefficients of variation between 3.0 and 7.7%, and plasma and tissue recovery rates of 72-77%. There was a linear response to clioquinol 5-2000 ng/ml in plasma, and 10-1000 ng/g in tissues. The method is highly sensitive and selective, makes it possible to study the pharmacokinetics of plasma clioquinol after oral administration and the distribution of clioquinol in tissues, and could be used to monitor plasma clioquinol levels in humans.

Pharmacokinetics and distribution of sodium 3,4-diaminonaphthalene-1-sulfonate, a Congo Red derivative active in inhibiting PrP(res) replication.

Sodium 3,4-diaminonaphthalene-1-sulfonate (CRA) is a compound, synthesised by our group from Congo Red (CR), that is active in preventing the pathological conversion of normal prion protein (PrP). As the precise mechanisms controlling the ways in which prions are distributed and infect the brain and other organs are not fully understood, studying the pharmacokinetics of drugs that are active against prions may clarify their targets and their means of inhibiting prion infection. This paper describes the pharmacokinetics of CRA in plasma, spleen and brain after single or repeated intraperitoneal or subcutaneous administration, as determined by means of specific and sensitive fluorimetric HPLC. A single intraperitoneal administration led to peak plasma CRA concentrations after 15 min, followed by biphasic decay with an apparent half-life of 4.3 h. After subcutaneous administration, T(max) was reached after 30 min, and was followed by a similar process of decay: Cmax and the AUC0-last were 25% those recorded after intraperitoneal administration. The mean peak concentrations and AUCs of CRA after a single intraperitoneal or subcutaneous administration in peripheral tissue (spleen) were similar to those observed in blood, whereas brain concentrations were about 2% those in plasma. After repeated intraperitoneal or subcutaneous doses, the Cmax values in plasma, brain and spleen were similar to those observed at the same times after a single dose. After repeated intraperitoneal doses, CRA was also found in the ventricular cerebrospinal fluid at concentrations of 1.8 +/- 0.2 microg(-1) mL, which is similar to, or slightly higher than, those found in brain. Brain concentrations may be sufficient to explain the activity of CRA on PrP reproduction in the CNS. However, peripheral involvement cannot be excluded because the effects of CRA are more pronounced after intraperitoneal than after intracerebral infection.

Neurochemical and behavioural modifications induced by scrapie infection in golden hamsters.

Scrapie-infected hamsters were tested for spontaneous motor activity and passive avoidance at various times after infection. After testing, some animals were killed and their whole brains assayed for norepinephrine, dopamine, serotonin and their metabolites. The apparent rate of turnover was estimated in terms of metabolite/amine concentrations. After 70 days, there was a decrease in passive avoidance and dopamine and serotonin. Passive avoidance correlated with the apparent rate of turnover of dopamine, whereas motor activity correlated with that of serotonin and dopamine.

Simultaneous determination of clomipramine and its desmethyl and hydroxy metabolites in plasma of patients by high-performance liquid chromatography after solid-phase extraction.

Clomipramine (CMI) is a typical tricyclic antidepressant with a wide clinical spectrum, being used in major depressive, panic and obsessive-compulsive disorders. The relationship between clinical response and plasma levels of clomipramine and its N-desmethylated (N-desmethylclomipramine, DMCMI) and hydroxy-metabolites remains unclear. In particular, limited information is available on the correlation with clinical response in patients with obsessive-compulsive disorder (OCD). This study describes a new sensitive method to simultaneously determine CMI and its major N-desmethylated and hydroxy-metabolites present in human plasma by HPLC with a UV detector. After a solid-phase extraction from plasma (Isolute C2 columns) the separation of the compounds was performed on a Lichrospher CN column (250 x 4 mm, 5 microm with a 2-cm pre-column) by an eluent consisting of 10 mM K(2)HPO(4)-acetonitrile-methanol (35:25:40 v/v/v) at a flow of 1.5 ml/min. UV detector was set at 214 nm. The lower limit of quantification for all the analytes was at least 5 ng/ml. The coefficients of variation ranged between 2.0 and 4.9% with recovery rates between 97.0 and 100.3%. Linear regression analyses showed correlation coefficients between 0.98 and 0.99. This method is simple, fast and reliable with good specificity and sensitivity. Solid phase extraction is efficient and rapid, allowing the extraction of several plasma samples on the same day and may therefore be usefully and realistically applied in the clinical context. We thus investigated the relevance of plasma levels of CMI and its metabolites as a predictor of clinical outcome in a group of 15 patients with OCD.

Determination of sodium 3,4-diaminonaphthalene-1-sulfonate, a Congo Red derivative, in plasma and brain of hamsters by high-performance liquid chromatography after solid-phase extraction and ultraviolet absorbance.

In the search for compounds with similar or greater activity than Congo Red (CR) in protecting normal prion protein from being converted into the pathological form, we have synthesized various compounds which derive from CR. One of these is the sodium 3,4-diaminonaphthalene-1-sulfonate (RCA) which has an activity similar to CR in preliminary experiments. This study describes a method to determine RCA in plasma and in brain tissue by high-performance liquid chromatography (HPLC), using a solid-phase extraction and UV detection. RCA is an amphoteric molecule difficult to separate from biological matrices. Extraction was achieved by solid-phase extraction (ENV+ columns) together with the use of a counter ion. The resulting solid-phase extraction is efficient and rapid. RCA was separated on a Symmetry C18 250 x 4.6 mm I.D. 5 lm column at 1 ml/min using a 50 mM NaSO4 in 5 mM tetra-n-butylammoniumiodide (TEBA) in water-methanol (82:18, v/v) mobile phase. Retention times of RCA and I.S. were 21 and 24 min. The UV detector was set at 210 nm. The limit of quantitation was 0.5 microg/ml. The method has intra-assay and inter-assay accuracies higher than 95%, coefficients of variation ranging between 2.8 and 8.6%, and recovery rates between 74.3 and 80.1% in plasma and in brain tissue. A linear response to quantities of RCA from 0.5 to 100 microg/ml or 10 microg/g in plasma or brain was obtained. The present method allows the study of the pharmacokinetics of RCA in plasma after i.p. administration, and the distribution of the compound into the brain at the peak time.

Effect of acute intravenous clomipramine and antiobsessional response to proserotonergic drugs: is gender a predictive variable?

BACKGROUND: Previous studies on serotonergic responsivity in obsessive-compulsive disorder (OCD) showed about 50% of patients experiencing an acute worsening of OC symptoms when administered meta-chlorophenylpiperazine or i.v. clomipramine. The aim of this study was to determine what variables influence the response to acute i.v. clomipramine. Could this response be predictive of the response to chronic treatment with two serotonergic drugs with differing selectivity profiles: clomipramine and fluvoxamine? METHODS: Fifty OC patients were consecutively recruited. All underwent a challenge with 25 mg i.v. clomipramine and placebo and were administered 10-week oral clomipramine or fluvoxamine according to a double-blind design. The efficacy of the antiobsessional treatment was evaluated by Yale-Brown Obsessive-Compulsive Scale and Clinical Global Impression scale scores. RESULTS: Obsessions worsened in 42% patients as rated by change values in 100-mm visual analogue scale scores for the clomipramine vs. placebo infusion. There was a significant difference in gender distribution between "worsened" and "unchanged" patients, since female subjects were more frequently "unchanged." Thirty-one patients completed the 10-week treatment. According to both qualitative and quantitative evaluations, female subjects showed a better antiobsessional response, and this difference was enhanced in the clomipramine-treated group. CONCLUSIONS: Results suggest a role for reproductive hormones in the pathophysiology or treatment of OC patients.

Pharmacodynamics and pharmacokinetics of pinacidil in normotensive volunteers after repeated doses of a new slow-release tablet formulation.

Pinacidil (CAS 85371-64-8) is an antihypertensive drug of the class of agents called "potassium channel openers". The pharmacokinetics of were studied after repeated oral administration of a new slow release tablet formulation (Pindac) as compared with the standard slow release capsule formulation in healthy volunteers. Eighteen healthy volunteers (3 males and 15 females), aged from 22 to 48 years, and 49 to 95 kg in weight, were given a 12.5 mg dose of each formulation every 12 h for 7 days on two occasions, in a randomized, cross-over trial with at least two weeks interval between trials. Blood samples were drawn immediately before drug administration on the morning of days 1, 2, 3, 4, 5, 6, and 7 and 0.5, 1, 2, 3, 4, 6, 8, 12, 24 and 36 h after the last drug administration. Blood pressure, heart rate, and respiratory function were assessed at admission and on the morning of day 0 (baseline), 2 and 7, before drug administration, and at 4, 24 and 36 h after the final administration. Pinacidil plasma levels were determined by an HPLC method. Both formulations elicited similar reductions of systolic and diastolic pressures from 4 h after administration, but did not change heart rate. The main model-independent pharmacokinetic parameters of pinacidil (Cmax, Tmax, AUC, MRT), as well as the absorption and elimination half-lives were similar with the two formulations. During the study there were no complaints of side-effects with either of the formulations. One advantage of the new formulation as compared to the capsules is that the tablets can be cut easily and the dosage adapted to a patient's needs.

Impairment of memory and plasma flunitrazepam levels.

Flunitrazepam was administered to volunteers in three different oral doses. The effects on psychomotor sedation, attention, working memory and explicit memory were then assessed at various intervals after dosing and compared with levels of the drug in the plasma. Three groups of 12 healthy males with similar levels of education were given placebo or flunitrazepam (1, 2 or 4 mg) in a double-blind, random-sequence study. Volunteers completed a battery of tests at night, 3.5 h after taking the drug and in the morning, 10 h afterward. Blood samples were collected for drug analysis before and after the nocturnal tests and before morning tests. At night, only the highest dose of flunitrazepam (4 mg) induced significant changes in psychomotor sedation, attention, working memory, and prose immediate recall. Doses of 2 and 4 mg flunitrazepam significantly reduced the mean scores of explicit memory (morning tests). Z-scores, calculated from differences between flunitrazepam and placebo, revealed that 2 mg flunitrazepam impaired memory but not alertness or attention. Linear regression analysis of the relationship between plasma levels of flunitrazepam and its effects (Z-scores) indicated that there was a significant positive correlation between peak levels of flunitrazepam at night and impairment of night attention and explicit memory, i.e. delayed recall of prose (r = 0.59, P < 0.01) and trigrams (r = 0.55, P < 0.01). However, memory and attention Z-scores as a function of plasma levels fitted with nonlinear regression analysis to the Emax model had higher correlation coefficients. To produce an effect equal to 50% of the maximum effect for memory impairment, concentrations (EC50) were 6.1 and 6.4 ng/ml for prose and trigrams delayed recall; but for attention they were much higher, at 13.2 ng/ml. The overall results indicate that higher concentrations were needed to impair attention than were required to impair memory.

Pharmacodynamics and pharmacokinetics of pinacidil after a single dose of a new slow release tablet in healthy volunteers.

Pinacidil (CAS 85371-64-8) is a recently developed antihypertensive drug of the class called "potassium channel openers". It produces vasodilatation and a fall of arterial blood pressure. The pharmacokinetics and the pharmacodynamics of pinacidil were studied after single oral administration of a new slow-release tablet formulation (Pindac) in comparison to the standard slow-release capsule formulation in healthy volunteers. Eighteen healthy subjects (3 men and 15 women), with a mean age of 31.1 years were given a single 12.5 mg dose of each formulation in an open, cross-over study, with randomised sequences and a 7-day wash-out period between doses. Blood samples were collected before and several times up to 36 h after drug administration. Blood pressure, heart rate and respiratory functions were assessed before and 1, 4, 24 and 36 h-after drug administration. Pinacidil plasma levels were determined by HPLC. Both formulations produced a similar significant reduction (10 +/- 4 mmHg) of systolic blood pressure 4 h after administration but no changes of diastolic pressure and heart rate. Both the maximal effect (Emax) and the area under the effect-time curve (AUE0-36) were similar for the two formulations. The main model-independent pharmacokinetic parameters of Pinacidil (Cmax, Tmax, AUC, MRT) as well as the absorption and the elimination half-lives were similar after the two formulations. The main advantage of the tablet formulation compared to the capsules is that tablets can be easily cut and therefore the dosage can be adapted to an individual patient's needs.

Skin and plasma levels of acetylsalicylic acid: a comparison between topical aspirin/diethyl ether mixture and oral aspirin in acute herpes zoster and postherpetic neuralgia.

OBJECTIVE: The aim of this investigation was to elucidate whether the analgesic effect was due to the local aspirin or to the systemic drug. This was done by comparing skin and plasma levels of acetylsalicylic acid (ASA) and salicylic acid (SA) after topically administered ASA/diethyl ether (ADE) mixture in acute herpetic neuralgia (AHN) and postherpetic neuralgia (PHN). The analgesia and the plasma and skin levels of ASA were also determined after oral administration of aspirin. METHODS: Nineteen patients, 11 (57.9%) with AHN and 8 (42.1 %) with PHN were given, on different days, a single 500-mg oral dose of ASA or a topical dose (750 mg) of (ADE) daubed onto the painful skin. The analgesic effect was assessed by means of a visual analogue scale (VAS). Overall pain relief was graded as: excellent, good, fair, or poor. AHN as well as PHN patients had severe pain at baseline (6.83 and 5.93). Levels of ASA and SA in plasma and in the stratum corneum after adhesive tape stripping of the treated area were determined by HPLC. RESULTS: After ADE application, the analgesic effect was very rapid and VAS scores were lower than at baseline. Pain significantly decreased by 82.6% after topical and 15.4% after oral ASA. After ADE, 95% of the patients had excellent or good pain relief, but after oral administration 79% of the patients had a poor response. Pain relief was similar in the two subgroups after ADE. Skin concentrations of ASA, but not of SA, after ADE were about 80- to 100-fold those after oral administration. Levels of ASA and SA in plasma after oral administration were similar to those previously found, but after ADE were undetectable or very low. Patients with excellent pain relief showed a trend towards higher ASA skin concentrations. CONCLUSIONS: The analgesic effect can be obtained only after topical administration, because by this route the skin levels of ASA are much higher than after oral administration. The mechanism is exclusively local; there are no active drugs in plasma after topical administration.

Determination of acetylsalicylic acid and salicylic acid in skin and plasma by high-performance liquid chromatography.

This study describes a HPLC method to determine the concentrations of acetylsalicylic acid (ASA) and salicylic acid (SA) in human stratum corneum and in plasma. The stratum corneum layers for ASA/SA analysis were removed from three patients with postherpetic hyperalgesia treated with topical and oral aspirin. Blood samples were also collected from the same patients. Tape strippings were placed in acetonitrile and sonicated for 15 min. After centrifuging, aliquots of the supernatant were injected into the chromatograph. ASA and SA from plasma samples were extracted on Isolute C8 columns. Due to interfering peaks in the tape samples, HPLC conditions were slightly different for tape and plasma samples. ASA and SA were separated on a LiChrospher 100 RP-18 column at 1 ml/min using a water-phosphate buffer (pH 2.5)-acetonitrile mobile phase (35:40:25, v/v/v). A linear response to quantities of ASA from 0.1 to 100 microg/cm2 and of SA from 0.1 to 5 microg/cm2 in tape and to quantities of ASA 0.1 to 2 microg/ml and 1 to 50 microg/ml was obtained and the recovery from tape and plasma samples was over 98%. The method is sensitive (0.1 microg/cm2) and specific enough to allow the determination of the drugs in the skin not only after topical but also after oral administration. A good sensitivity was also obtained in plasma (0.1 microg/ml) allowing study of the kinetics of ASA and SA in plasma after oral administration. Concentrations of ASA after topical administration were 100-200 times higher than after oral administration. Plasma levels of ASA and SA after oral administration were similar to those previously found. No ASA or SA were detected in plasma after topical ASA administration.

Absorption of oral lornoxicam in healthy volunteers using a granular formulation in comparison with standard tablets.

The bioavailability of lornoxicam (CAS 70374-39-9), a novel highly potent anti-inflammatory and analgesic agent, was studied in healthy volunteers after single doses of a new oral formulation (8 mg granules) in comparison to tablets (8 mg). Eighteen healthy volunteers (6 males and 12 females) with a mean age of 29.4 were given a single 8 mg dose of each formulation in an open, cross-over study, with randomised sequences. Lornoxicam plasma levels were determined by an HPLC method. Cmax, AUC0-infinity and t 1/2 beta values were similar for both the granules and tablets, but tmax and lag time values after lornoxicam granules were significantly shorter than after the tablets. During the study, no side-effects were noted with either of the formulations studied. Therefore this study showed that lornoxicam granular formulation had a faster absorption than tablets even though the two formulations can be considered bioequivalent.

Long-term pharmacotherapy of obsessive-compulsive disorder: a double-blind controlled study.

The aim of this study was to investigate whether obsessive-compulsive patients previously treated successfully with clomipramine or fluvoxamine could tolerate reduction of the daily dosage without worsening of the clinical condition. Thirty informed obsessive-compulsive patients, given a diagnosis according to DSM-III-R criteria, were recruited consecutively into the study. Patients were blindly assigned to one of the groups of treatment with different rates of reduction of the previously effective daily drug dosage: group 1 (control group, no reduction), group 2 (reduction of 33-40%), and group 3 (reduction of 60-66%). The entire study lasted 102 days. From baseline to the end of the study, the clinical condition was evaluated by the administration of standardized tests (Yale-Brown Obsessive-Compulsive Scale, Hamilton Rating Scale for Depression, Clinical Global Impression [CGI] scale), and blood samples were collected for plasma drug level determinations. The criterion for discontinuation of the study was the worsening of obsessive-compulsive symptoms, arbitrarily defined by an increase of > 5% from the baseline total Yale-Brown Obsessive-Compulsive Scale score, as measured in two successive assessments, and a worsening of global clinical condition as measured by the CGI scale. The main result of the study was borne out from the survival analysis. There were no significant differences in the cumulative proportion of patients from each group of treatment who did not worsen during the 102 days of observation. This preliminary result, which needs to be confirmed in larger samples, suggests that long-term maintenance therapy for obsessive-compulsive disorder might be provided with lower dosages of the antiobsessional drug, with clear advantages for tolerability and compliance.

Effects of liver disease on the pharmacokinetics of intravenous and oral chlordesmethyldiazepam.

We studied the pharmacokinetics of a single 0.5-mg i.v. dose of chlordesmethyldiazepam in 8 patients with liver disease and in 12 age-matched healthy controls. The kinetics were also studied of a single 1-mg oral dose in the patients with liver disease. After i.v. administration the kinetics of total chlordesmethyldiazepam in patients with liver disease differed from those in controls: elimination half-life was almost twice that in controls (395 and 204 h), as a consequence of a marked reduction in total clearance (0.13 and 0.25 ng.ml-1.h-1), whereas the apparent volume of distribution was similar in patients and controls (4.7 and 3.9 l/kg-1). The free fraction of the drug in patients was higher (5.5%) than in controls (2.9%). Correction for differences in protein binding revealed clearance in the patients was one-fifth (1.8 and 10.5 ng ml-1.kg-1) and volume of distribution one-half (65.0 and 118.4 l.kg-1) that in controls. The systemic availability of oral chlordesmethyldiazepam was high (110%) in spite of a relatively slow absorption rate. These results indicate a need for caution in the administration of chlordesmethyldiazepam to patients with liver disease.

Pharmacokinetics of zidovudine in HIV-positive patients with liver disease.

The pharmacokinetics of zidovudine (ZDV) have been studied in eight AIDS patients with normal liver function, and in four AIDS patients with liver disease. Patients who were previously untreated with ZDV were given 250 mg ZDV, and plasma levels of ZDV and its glucuronic metabolite, GZDV, were determined at 0.5, 1, 1.5, 2, 3, and 4 hours after the dose. In patients with liver disease, Cmax and AUC of ZDV were higher, the oral clearance was only one-eighth that of patients without liver disease, and the elimination half-life was longer. There was a trend for concentrations of the principal metabolite, GZDV, to be lower in patients, and, therefore, the ratio of the AUC for GZDV to that for ZDV was much lower in patients with liver disease. Therefore, HIV-seropositive patients with liver disease had the same markedly altered disposition of ZDV as seronegative patients with liver disease. Although this therapy was not clearly associated with a higher incidence of toxicity, some patients with liver disease had to discontinue therapy because of intolerance; therefore, plasma levels of these patients should be monitored when such therapy is undertaken.

Daily fluctuation of plasma levels with conventional and controlled-release carbamazepine: correlation with adverse effects.

The pharmacokinetics, tolerability, and efficacy of carbamazepine (CBZ) and the pharmacokinetics of carbamazepine-10, 11-epoxide (CBZE) were studied after chronic administration of a conventional tablet formation or of the controlled-release (CR) formulation of CBZ 400 mg (Tegretol 400) to 20 patients with epilepsy treated with carbamazepine and complaining of intermittent adverse effects. To compare the two formulations at the same doses and dose schedules, the study design had to be open, within-patient, with an initial 4 week period to individually adjust the dosage schedule with conventional CBZ followed by a 4 week period in which the CR formulation was substituted for conventional CBZ at the same daily dose and given by the same schedule. A further 4 week period was also studied to evaluate the same dosage of the CR formulation but given b.i.d. In this latter period six patients required an increase in dosage (200 mg/day). Before the beginning of the study and at the end of each period seizure frequency and tolerability were assessed. Tolerability was estimated with a specifically prepared scale that assesses the main items and with an overall rating scale. At the end of each treatment period, serum levels of CBZ and CBZE were determined at various times over a 10 h period. Peak plasma concentrations (Cmax) of CBZ and the fluctuation index (FI) were significantly lower for the CR CBZ, although minimal and mean plasma concentrations were the same in the three periods of the study.(ABSTRACT TRUNCATED AT 250 WORDS)