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N Ratnaraj

Publications and source records attributed to N Ratnaraj.

At least 19 recordsLinked to original sources
PubMed2006

The pharmacokinetics of vigabatrin in rat blood and cerebrospinal fluid.

PURPOSE: Data on the blood pharmacokinetics of vigabatrin, an antiepileptic drug with a unique and novel mechanism of action, in the rat are sparse. Additionally, little is known of the kinetics of vigabatrin in the central cerebrospinal fluid (CSF) compartment. We therefore investigated the rate of penetration into and the inter-relationship between serum and CSF compartments following systemic administration of vigabatrin in the rat. METHODS: Sprague-Dawley rats were implanted with a jugular vein catheter and a cisterna magna catheter for blood and CSF sampling, respectively. Vigabatrin was administered by intraperitonial injection at three different doses (250, 500 and 1000mg/kg) and blood and CSF collected at timed intervals up to 8h. Vigabatrin concentrations in sera and CSF were determined by high performance liquid chromatography. RESULTS: Vigabatrin concentrations in blood and CSF rose linearly and dose-dependently and the time to maximum concentration (Tmax) was 0.4 and 1.0h, respectively. Vigabatrin is not protein bound in serum and its elimination from serum (mean t1/2 values, 1.1-1.4 h) is rapid and dose-independent. The efflux of vigabatrin from CSF was significantly slower than that seen for serum (mean t1/2 values, 2.2-3.3h). CONCLUSIONS: The kinetics of vigabatrin are linear with rapid entry into CSF. However, although vigabatrin CSF kinetics parallel that seen in serum, CSF vigabatrin concentrations represent only 2% of concentrations seen in serum and do not reflect free drug concentrations in serum.

Animals↗
PubMed2006

Free phenytoin concentration measurement in brain extracellular fluid: a pilot study.

This article investigates the relationship between brain extracellular fluid free phenytoin concentration and plasma free phenytoin concentration in adults with acute brain injury. Daily cerebral microdialysate free phenytoin concentration was measured in eight adults with acute brain injury and compared with simultaneous measurement of plasma free phenytoin concentration. The group data revealed no significant correlation between microdialysate and plasma free phenytoin concentration (r = 0.34, p = 0.41). However, in two patients, with a sufficient number of samples for intra-individual analysis, there was a significant correlation between microdialysate and plasma free phenytoin concentration (r = 0.92, p < 0.001 and r = 0.88, p < 0.01). In vitro microdialysis relative recovery for phenytoin was 2.1%. In the context of acute brain injury, measurement of free plasma phenytoin concentration may not provide an accurate reflection of regional brain extracellular fluid free phenytoin concentration and may have limitations with respect to achieving reproducible brain extracellular fluid free phenytoin concentrations. This has implications for dosing regimens relying on plasma phenytoin levels.

Adolescent↗
PubMed2005

Caffeine has no effect on measures of cortical excitability.

OBJECTIVE: To assess the effect of caffeine on motor thresholds, short interval intra-cortical inhibition (SICI), intra-cortical facilitation (ICF) and cortical silent periods in a placebo controlled double-blinded trial. METHODS: In eleven healthy non-smoking subjects the following parameters were measured using transcranial magnetic stimulation (TMS): motor thresholds (rest, RMT and active, AMT), SICI and ICF at different conditioning stimulus intensities (60, 70, 80, 90% AMT), cortical silent periods at 130, 150 and 175% AMT, and size of motor evoked potential at rest at 110, 125 and 150% RMT. Measurements were repeated after one cup of decaffeinated coffee. On another day, measurements were obtained before and after one cup of decaffeinated coffee that contained caffeine (3 mg/kg bodyweight). Caffeine concentrations were measured in serum before and after experiments. Experiments were conducted and data were evaluated blinded to the experimental condition. RESULTS: The results of repeated measurements of all parameters were similar comparing experiments on each day, or when comparing the caffeine arm of the study with the placebo arm. CONCLUSIONS: Caffeine in a concentration similar to that in a strong cup of coffee does not have a major effect on TMS measures of motor cortex excitability. SIGNIFICANCE: In healthy controls, the design of TMS experiments that investigate the parameters assessed in this TMS study does not need to control for caffeine.

Adult↗
PubMed2004

Effect of felbamate and its combinations with conventional antiepileptics in amygdala-kindled rats.

We investigated the effect of felbamate, administered singly and in combination with carbamazepine, phenobarbital, phenytoin or clonazepam, on various behavioral and electrographic correlates of seizures in amygdala-kindled rats. Felbamate (5 or 10 mg/kg) significantly increased afterdischarge threshold, shortened seizure and afterdischarge durations but remained without effect on seizure severity. Furthermore, the combination of felbamate (2.5 mg/kg) with carbamazepine (7.5 mg/kg; both drugs at their subeffective doses), was associated with the reduction in seizure severity and afterdischarge duration. In relation to the afterdischarge duration, the antiseizure potency of felbamate and carbamazepine, in combination, was comparable with that of carbamazepine (10 mg/kg) administered alone. Neither carbamazepine (7.5 and 10 mg/kg) nor felbamate (2.5-10 mg/kg) affected seizure severity, whereas the combined administration of felbamate (2.5 mg/kg) with carbamazepine (7.5 mg/kg) led to significant reduction in seizure severity from the fifth to the third stage of Racine's scale. Among the conventional antiepileptic drugs evaluated in this study, only valproate (100 mg/kg) and clonazepam (0.1 mg/kg) exerted similar action on seizure severity. However, the combinations of felbamate (2.5 mg/kg), with subeffective doses of valproate, phenobarbital, phenytoin or clonazepam, were not associated with any protective action. As blood and brain felbamate and carbamazepine concentrations were unaffected, a pharmacokinetic interaction can be excluded and a pharmacodynamic interaction concluded. These data suggest that felbamate and carbamazepine, administered in combination, may be useful in patients with drug-resistant partial epilepsy.

Amygdala↗
PubMed2004

Mucuna pruriens in Parkinson's disease: a double blind clinical and pharmacological study.

BACKGROUND: The seed powder of the leguminous plant, Mucuna pruriens has long been used in traditional Ayurvedic Indian medicine for diseases including parkinsonism. We have assessed the clinical effects and levodopa (L-dopa) pharmacokinetics following two different doses of mucuna preparation and compared them with standard L-dopa/carbidopa (LD/CD). METHODS: Eight Parkinson's disease patients with a short duration L-dopa response and on period dyskinesias completed a randomised, controlled, double blind crossover trial. Patients were challenged with single doses of 200/50 mg LD/CD, and 15 and 30 g of mucuna preparation in randomised order at weekly intervals. L-dopa pharmacokinetics were determined, and Unified Parkinson's Disease Rating Scale and tapping speed were obtained at baseline and repeatedly during the 4 h following drug ingestion. Dyskinesias were assessed using modified AIMS and Goetz scales. RESULTS: Compared with standard LD/CD, the 30 g mucuna preparation led to a considerably faster onset of effect (34.6 v 68.5 min; p = 0.021), reflected in shorter latencies to peak L-dopa plasma concentrations. Mean on time was 21.9% (37 min) longer with 30 g mucuna than with LD/CD (p = 0.021); peak L-dopa plasma concentrations were 110% higher and the area under the plasma concentration v time curve (area under curve) was 165.3% larger (p = 0.012). No significant differences in dyskinesias or tolerability occurred. CONCLUSIONS: The rapid onset of action and longer on time without concomitant increase in dyskinesias on mucuna seed powder formulation suggest that this natural source of L-dopa might possess advantages over conventional L-dopa preparations in the long term management of PD. Assessment of long term efficacy and tolerability in a randomised, controlled study is warranted.

Administration, Oral↗
PubMed2001

Visual field constriction: accumulation of vigabatrin but not tiagabine in the retina.

BACKGROUND: The antiepileptic drug (AED) vigabatrin (VGB) causes concentric visual field constriction. Anecdotal reports involving tiagabine (TGB) have implied that this may be a class effect of all AEDs with gamma-aminobutyric acid (GABA)-related actions. We investigated the pharmacokinetic and pharmacodynamic profiles of VGB and TGB in rat brain and eye. METHODS: Adult male rats (n = 8) were administered 0.9% saline (control), VGB (500 or 1,000 mg/kg), or TGB (5, 10, or 20 mg/kg). At 1 (TGB) and 4 hours (VGB) postdosing, the animals were killed, a blood sample was obtained, their brains were dissected into five anatomic regions, and the retina and vitreous humor were isolated from each eye. Samples were analyzed for GABA concentrations and the activity of the enzyme GABA-transaminase (GABA-T). Plasma and tissue drug concentrations were also determined. RESULTS: VGB treatment produced a decrease in the activity of GABA-T and a rise in GABA concentrations in all tissues investigated. This effect was most pronounced in the retina. VGB concentrations were as much as fivefold higher in the retina than in the brain. TGB was without effect on GABA concentrations and activity of GABA-T. TGB concentrations were notably lower in the retina than in the brain. CONCLUSIONS: Accumulation of VGB in the retina, with or without an increase in GABA, may be responsible for the visual field constriction reported clinically. In contrast, TGB had no effect on GABA concentrations and did not accumulate in the retina. These results suggest that TGB is unlikely to cause visual field defects in humans.

Animals↗
PubMed2001

Intravenous apomorphine therapy in Parkinson's disease: clinical and pharmacokinetic observations.

Six patients with Parkinson's disease and refractory motor fluctuations, with severe subcutaneous (s.c.) nodule formation as a result of long-term s.c. apomorphine infusions, were switched to intravenous (i.v.) therapy via a long-term in-dwelling venous catheter. Five patients were followed-up for a mean of 7 months (range 0.5-18 months). All patients had plasma apomorphine concentrations measured at baseline during s.c. infusions and three had follow-up measurements when stabilized on i.v. therapy, to test the hypothesis that motor fluctuations in these patients are largely due to impaired absorption of apomorphine. The mean i.v. rate of 9.0 mg/h (range 5-14 mg) and 24-h dose of 256.7 mg (range 90-456 mg) of apomorphine were not significantly reduced compared with the s.c. route (9.24 mg/h and 243.4 mg). However, additional oral anti-parkinsonian medication was reduced by a mean of 59%, and 'off' time was virtually eliminated (mean reduction from 5.4 to 0.5 h per day, P< 0.05). There was also a significant reduction in dyskinesias and markedly improved quality of life. Pharmacokinetic analysis demonstrated more reliable and smoother delivery of apomorphine via the i.v. route, although 'off' periods were not always explained by low plasma apomorphine concentrations. Complication rates were high and included three unforeseen hazardous intravascular thrombotic complications, secondary to apomorphine crystal accumulation, necessitating cardiothoracic surgery. We conclude that i.v. apomorphine therapy holds promise as a more effective way of controlling motor fluctuations than the s.c. route. However, further preclinical research is required before i.v. Britaject apomorphine can be recommended for routine clinical practice. Even when stable plasma apomorphine concentrations were achieved, motor fluctuations could not be totally eradicated, suggesting that postsynaptic receptor changes may also play a role in the refractory 'off' periods in these patients.

Aged↗
PubMed1999

Blood and cerebrospinal fluid pharmacokinetics of the novel anticonvulsant levetiracetam (ucb L059) in the rat.

The temporal pharmacokinetic interrelationship of levetiracetam in blood and cerebrospinal fluid (CSF) was studied after acute intraperitoneal administration of levetiracetam (20, 40 and 80 mg/kg), using an animal model that permits concurrent blood and CSF sampling in freely moving rats. After administration, levetiracetam rapidly appeared in both serum (time to maximum concentration (Tmax) mean range 0.25 0.50 h) and CSF (Tmax mean range 1.33-1.92 h), suggesting ready penetration of the blood brain barrier. Both serum and CSF levetiracetam concentrations rose essentially linearly and dose-dependently, suggesting that transport across the blood-brain barrier is not rate limiting over the levetiracetam concentration range observed in the present study. However, while apparent elimination half-life (t1/2) values for both serum and CSF were dose-independent (mean value range 1.8-2.8 and 4.4-4.9 h, respectively), t1/2 values for CSF were significantly larger. As the serum free/total serum levetiracetam concentration ratio (free fraction) was 1.01+/-0.02 (mean+/-S.E.M.), it can be concluded that levetiracetam is not protein bound. Furthermore, the free fraction was indistinguishable from that of the CSF/serum levetiracetam concentration ratio at equilibrium. It can be concluded that the kinetics of levetiracetam, in the rat, is simple and, thus, dosing strategies in studies designed to elucidate its mechanism of action should be straightforward.

Animals↗
PubMed1998

A high-performance liquid chromatography micromethod for the simultaneous determination of vigabatrin and gabapentin in serum.

A gradient high-performance liquid chromatography micromethod is described for the simultaneous quantitation of vigabatrin and gabapentin in human serum. Chromatography was performed using a 125- x 3-mm ID Hypersil BDS C-18 column with a 3-microm mini-bore, eluted with a gradient system comprised of phosphate buffer (pH 6.5)-acetonitrile-methanol-water at a flow rate of 0.45 ml/minute. The column eluent was monitored on a fluorescence detector using excitation and emission wavelengths of 340 and 440 nm, respectively. The lower limit of quantitation for vigabatrin and for gabapentin was 5 micromol/l, and the within-batch and between-batch coefficients of variation were <5%. No interference from commonly prescribed antiepileptic drugs (carbamazepine and its metabolite carbamazepine epoxide, oxcarbazepine and its metabolite 10-hydroxycarbazepine, ethosuximide, lamotrigine, phenobarbitone, phenytoin, primidone, and valproic acid) was observed; thus, the method can be used to monitor vigabatrin and gabapentin in patients on polytherapy antiepileptic drug regimens.

Acetates↗
PubMed1996

A micromethod for the determination of the new antiepileptic drug levetiracetam (ucb LO59) in serum or plasma by high performance liquid chromatography.

An isocratic high performance liquid chromatographic micromethod is described for the quantitation of levetiracetam (ucb L059) in plasma or serum of patients. The chromatography is performed on a 250 x 4 mm I.D. LiChrospher 60 RP-select B, 5-micron column, eluted with an acetonitrile/50 mM phosphate buffer (15:85 vol/vol, pH 5.6) mobile phase, and levetiracetam detected using ultraviolet absorbance at 220 nm. The limit of quantitation was 5 mumol/L and the within-batch and between-batch coefficients of variation were < 7%. No interference from commonly prescribed antiepileptic drugs (carbamazepine and its metabolite carbamazepine epoxide, ethosuximide, gabapentin, lamotrigine, phenobarbitone, phenytoin, primidone, valproic acid, and vigabatrin) was observed, and thus the method can be used to monitor levetiracetam in patients on polytherapy antiepileptic drug regimens.

Anticonvulsants↗
PubMed1995

Prediction of free levels of phenytoin and carbamazepine in patients comedicated with valproic acid.

Serum samples from patients receiving phenytoin (PHT) or carbamazepine (CBZ) and sodium volproate (VPA) polytherapy were filtered at 37 degrees C and the free concentrations were measured by high-performance liquid chromatography. The mean apparent dissociation constants (KD) for the binding of PHT and CBZ to albumin were calculated. The mean KD values were used to predict free levels of PHT or CBZ in serum from patients also taking VPA, based on information about the total serum concentrations of the drugs and albumin. In the presence of VPA the values of the free fraction (alpha) for PHT and CBZ increased and the values for the apparent dissociation constants (KD) decreased compared with the situation of monotherapy. These decreases in the value of KD and increases in the value of alpha were statistically significant. The correlations between values for predicted and analysed free levels of PHT or CBZ were close, with r values of 0.999 and 0.998, respectively. The mean prediction error was small, 0.01 +/- 0.22 mumol/L for PHT and 0.03 +/- 0.42 mumol/L for CBZ. The percentage differences between predicted and observed free levels for PHT and CBZ were < 10%. We conclude that our method of prediction is sufficiently accurate and precise for clinical use.

Adult↗
PubMed1995

A comparison of the OPUS and TDx analysers for antiepileptic drug monitoring.

Therapeutic drug monitoring of a variety of antiepileptic drugs is used routinely as a guide to individualising the drug treatment of patients with epilepsy. Thin dry film multilayer immunoassays (OPUS) for carbamazepine, phenytoin, phenobarbitone, and valproic acid were evaluated and compared with fluorescence polarisation immunoassay (TDx), using commercially available control material and patient sera. For the OPUS, the within-batch coefficient of variation (CV) for the different drugs in the control material varied between 3.9% (phenobarbitone) and 8.1% (valproic acid). The between-batch CVs varied between 5.3% (valproic acid) and 18.3% (carbamazepine). The comparative between-batch CVs for the TDx varied between 2.0% (phenytoin) and 7.0% (valproic acid). Analysis of 209 patient samples containing carbamazepine, phenytoin, phenobarbitone, or valproic acid demonstrated significant correlation between the two analytical methods, with correlation coefficients of 0.9336, 0.9560, 0.9448, and 0.9618, with slopes of the regression lines of 0.9042, 0.8663, 1.1368, and 1.1244, respectively. It is concluded that both the TDx and OPUS instruments exhibit comparable performance for the analysis of carbamazepine, phenobarbitone, phenytoin, and valproic acid in patient samples. Moreover, the OPUS instrument, with its facilities of random assay access and statim analysis, may be useful in an outpatient setting in which a major consideration would be a rapid turnaround of patient assay results.

Anticonvulsants↗
PubMed1994

Antiepileptic drug pharmacokinetics and neuropharmacokinetics in individual rats by repetitive withdrawal of blood and cerebrospinal fluid: phenytoin.

The temporal pharmacokinetic (blood) and neuropharmacokinetic (cerebrospinal fluid, CSF) interrelationship of phenytoin was studied after acute and during chronic (up to 5 days) intraperitoneal administration of phenytoin (30, 50 or 100 mg/kg) using a new freely behaving rat model. After administration, phenytoin rapidly appeared in both serum (Tmax mean range 0.15-0.38 h) and CSF (Tmax mean range 0.9-1.4 h), suggesting ready penetration of the blood-brain barrier. However, transport across the blood-brain barrier may be rate limiting since whilst phenytoin concentrations rose dose dependently in serum, CSF concentrations did not. Further, the divergence between the blood and CSF compartments increased with chronic dosing. Cmax, AUC and t1/2 values for serum increased non-linearly, suggestive of accumulation kinetics. Based on these data, high initial phenytoin blood concentrations are essential if phenytoin entry into the brain is to be facilitated, and this may be important in studies of phenytoin in animal models of status epilepticus.

Animals↗
PubMed1991

Simple and rapid micro-analytical procedures for the estimation of milacemide and its metabolite glycinamide in rat plasma and cerebrospinal fluid by high-performance liquid chromatography.

A high-performance liquid chromatographic technique is described for the determination of milacemide and its primary metabolite glycinamide in rat plasma and cerebrospinal fluid. Milacemide and glycinamide are derivatized with fluorescamine to form a chromophore and a fluorophore and subsequent analysis using ultraviolet and fluorescence detectors, respectively. The extraction procedures are simple with a limit of detection 2 and 0.5 micrograms/ml for milacemide in plasma and cerebrospinal fluid, respectively, and 0.5 micrograms/ml for glycinamide in plasma or cerebrospinal fluid. The within-batch coefficients of variation for both analytes were less than 3%. Since only a small amount of sample is required, these techniques are well suited for the study of milacemide pharmacokinetics in the rat.

Acetamides↗
PubMed1990

Temperature effects on the estimation of free levels of phenytoin carbamazepine and phenobarbitone.

Serum samples from patients on phenytoin (PHT), carbamazepine (CBZ), or phenobarbitone (PB) monotherapy were filtered at 15, 25, and 37 degrees C and the free concentrations measured by high-performance liquid chromatography. The mean apparent dissociation constants at each temperature were calculated, and were used to predict free drug levels from a further series of patients' samples in which total drug and albumin concentrations only were known. The correlation coefficients (r) between these predicted free levels and experimental results obtained by analysis of the same samples for PHT, CBZ, or PB were 0.977, 0.968, and 0.998, respectively, at 25 degrees C; at 37 degrees C, the corresponding values of r were 0.975, 0.961, and 0.997, respectively. We then determined free fractions (alpha) of PHT, CBZ, and PB at 25 and 37 degrees C and used these values to derive theoretical target ranges for free levels for each of the three drugs. We discuss the implication of these results for patient care, with special reference to the need to specify temperature and quote the appropriate target range when analyses of free levels of AEDs are carried out.

Blood Proteins↗
PubMed1989

A micromethod for the estimation of free levels of anticonvulsant drugs in serum.

A micromethod for estimating free levels of phenobarbitone, phenytoin and carbamazepine in patients' sera is described. Serum samples are subjected to a process of ultrafiltration, the filtrates treated with acetonitrile and the drug concentration quantified using high performance liquid chromatography. The stability of free levels in specimens before and after storage is investigated. The method is reproducible and mean recovery exceeds 98.5% showing that there is no significant absorption of drug onto the filters used. There is no interference from other substances normally present in patients' sera and there is a good correlation between results obtained by this method and a fluorescence polarisation immunoassay with correlation coefficient between 0.975 and 0.999. Serum samples can be stored for a lengthy period before ultrafiltration without adverse effects. The relevance of the method to patient care is discussed.

Carbamazepine↗