Sensitive inexpensive HPLC determination of four antiepileptic drugs in human plasma: application to PK studies.

AIM: Recently, polytherapy regimen has been introduced for the treatment of epileptic patients for better seizure control with lesser side effects and better control of multiple seizure types. METHODOLOGY: A simple, sensitive and highly specific reversed-phase HPLC method was developed for simultaneous determination of four antiepileptic drugs (AEDs), levetiracetam, lamotrigine, oxcarbazepine and carbamazepine, in real human plasma without interference from endogenous components of plasma. CONCLUSION: The method was proved to be linear in the range of 0.5-50 µg/ml for all drugs. It was successfully applied for clinical PK study of the AEDs in healthy volunteers following single administration. Also, this method was applied for simultaneous determination of the studied drugs in volunteers' plasma receiving synergistic binary combinations from the four AEDs when used as add-on therapy. The good precision and selectivity of the developed method allow it to be used for routine therapeutic drug monitoring of such drugs as a useful tool in epilepsy management.

Comparison of equilibrium and non-equilibrium distribution coefficients for the human drug carbamazepine in soil.

The distribution coefficient (KD) for the human drug carbamazepine was measured using a non-equilibrium technique. Repacked soil columns were prepared using an Airport silt loam (Typic Natrustalf) with an average organic matter content of 2.45%. Carbamazepine solutions were then leached through the columns at 0.5, 1.0 and 1.5 mL min(-1) representing average linear velocities of 1.8, 3.5 and 5.3 cm h(-1) respectively. Each flow rate was replicated three times and three carbamazepine pulses were applied to each column resulting in a total of 9 columns with 27 total carbamazepine pulses. Breakthrough curves were used to determine KD using the parameter fitting software CXTFIT. Results indicate that as flow rate decreased from 5.3 to 1.8 cm h(-1), KD increased an average of 21%. Additionally, KD determined by column leaching (14.7-22.7 L kg(-1)) was greater than KD determined by a 2h batch equilibrium adsorption (12.6 L kg(-1)). Based on these KD's carbamazepine would be generally characterized as non-mobile in the soil investigated. However, repeated carbamazepine applications resulted in an average 22% decrease in KD between the first and third applications. Decreasing KD is attributed to differences in sorption site kinetics and carbamazepine residence time in contact with the soil. This would indicate that the repeated use of reclaimed wastewater at high application rates for long-term irrigation or groundwater recharge has the potential to lead to greater transport of carbamazepine than KD determined by batch equilibrium would predict.

Physico-mechanical and stability evaluation of carbamazepine cocrystal with nicotinamide.

The focus of this investigation was to prepare the cocrystal of carbamazepine (CBZ) using nicotinamide as a coformer and to compare its preformulation properties and stability profile with CBZ. The cocrystal was prepared by solution cooling crystallization, solvent evaporation, and melting and cryomilling methods. They were characterized for solubility, intrinsic dissolution rate, chemical identification by Fourier transform infrared spectroscopy, crystallinity by differential scanning calorimetry, powder X-ray diffraction, and morphology by scanning electron microscopy. Additionally, mechanical properties were evaluated by tensile strength and Heckel analysis of compacts. The cocrystal and CBZ were stored at 40°C/94% RH, 40°C/75% RH, 25°C/60% RH, and 60°C to determine their stability behavior. The cocrystals were fluffy, with a needle-shaped crystal, and were less dense than CBZ. The solubility profiles of the cocrystals were similar to CBZ, but its intrinsic dissolution rate was lower due to the high tensile strength of its compacts. Unlike CBZ, the cocrystals were resistant to hydrate transformation, as revealed by the stability studies. Plastic deformation started at a higher compression pressure in the cocrystals than CBZ, as indicated by the high yield pressure. In conclusion, the preformulation profile of the cocrystals was similar to CBZ, except that it had an advantageous resistance to hydrate transformation.

Effect of freezing and type of mucosa on ex vivo drug permeability parameters.

The porcine esophageal mucosa has been proposed as a substitute for the buccal mucosa barrier on ex vivo permeability studies mainly due to its large surface area as well as its easier preparation. Therefore, this study compared the ex vivo permeability parameters of two drugs (carmabazepine (CBZ) and triamcinolone acetonide (TAC)) with different permeabilities and physicochemical properties through buccal and esophageal mucosae using a Franz diffusion cell system and HPLC as detection method. The freezing effects on drug permeability parameters were also evaluated by comparing them when fresh and frozen tissues were used. The barrier properties were not affected by the freezing process since the obtained parameters for both drugs were similar in frozen and fresh tissues (buccal and esophageal mucosae). However, an increase of CBZ retention was shown in frozen tissues. Fresh and frozen esophageal mucosae provided higher permeation of TAC than on buccal mucosae while the obtained permeability parameters for CBZ were similar on both mucosae. According to our results, porcine esophageal mucosa could be used as a substitute for buccal mucosa on ex vivo studies involving CBZ but not TAC. Frozen tissues could be used as substitute for fresh tissues in both cases. However, any substitution should be done with care and only if previous tests were performed, because the results could differ depending on the tested drug.

A systematic review on acupuncture for trigeminal neuralgia.

BACKGROUND: Trigeminal neuralgia (TN) is a commonly seen pain condition with limited treatments available, and acupuncture is widely used for pain conditions, including TN. OBJECTIVES: To review the efficacy of acupuncture treatment for TN. METHODS: English and Chinese databases were searched extensively to identify randomized controlled studies of acupuncture treatment for TN. Selected studies were assessed for methodological quality. Odds ratios (OR) between treatment and control groups were used to assess efficacy. RESULTS: Twelve studies met the inclusion criteria with 506 people in the acupuncture arm and 414 people in the control arm, in which carbamazepine (CBZ) was used as the control treatment. They were all low-quality studies, hence precluding meta-analysis. Only four trials reported that acupuncture was superior to CBZ, and the remaining eight studies showed no difference between the treatment and control groups. Adverse effects of acupuncture, which were reported in three studies, were mild. CONCLUSION: The evidence reviewed previously suggests that acupuncture is of similar efficacy as CBZ but with fewer adverse effects in treatment of TN. However, the evidence is weak because of low methodological quality of the reviewed studies. Further studies with improved methodologies are recommended to support the use of acupuncture for TN.

Investigation of intrinsic dissolution behavior of different carbamazepine samples.

The aim of the present study was to investigate the effect of the variability of commercially available carbamazepine (CBZ) samples on the intrinsic dissolution behavior in order to recommend a strategy to maintain product quality by monitoring the variability of critical parameters of the bulk drug. Extensive physical characterization of nine anhydrous CBZ samples from three different sources and their respective dihydrates showed that the commercial anhydrous CBZ samples exhibited the same polymorphic form, but different morphology and particle size distribution which led to a variation in the kinetics of conversion from anhydrous to the dihydrate CBZ and therefore to variation in the kinetics of solubility. Disc intrinsic dissolution rate (DIDR) tests showed different intrinsic dissolution behavior of the samples, whereby the transition points of anhydrous to dihydrate conversion varied between 15 and 25 min. On the other hand, converting the anhydrous CBZ's to dihydrate eliminated the variation in intrinsic dissolution behavior. Tablets of the different CBZs and Ludipress were prepared by direct compression. The amount of CBZ dissolved after 15 min showed the same rank order as the rank order of the transition points determined by intrinsic dissolution test. Therefore, the intrinsic dissolution test with specific acceptance criteria can be a valuable and simple tool for monitoring, respectively reducing the variability of the CBZ bulk material.

Comparative in vitro study of six carbamazepine products.

The purpose of present study was to evaluate commercial preparations of carbamazepine tablets with respect to drug release through a defined sequence of experiments using Minitab software. The compliance of products with respect to United States Pharmacopeia (USP) dissolution test and comparison of the products with respect to drug release in different dissolution conditions is reported in the present paper. The different dissolution conditions studied include dissolution medium (1% SLS in purified water, 0.1 N HCl), volume (900 and 1,000 ml), rpm (50 rpm, 75 rpm). Studies indicated that all six products complied with USP dissolution criteria. However, the extent of influence of dissolution conditions on drug release was varied among the products. Distinct dissolution profiles were observed and there was no correlation with disintegration time in certain products. The in vitro dissolution experimentation helped in identifying the discriminatory dissolution conditions and also the formulations that were unaffected with change of dissolution variables. In summary, commercial preparations of carbamazepine vary widely in their dissolution behavior in multi dissolution run experimentation. Identifying this behavior of the products was essential as an in vitro tool for screening a good and a bad formulation.

Validation of a quick modeling program generating clearance estimates at steady state for routine therapeutic drug monitoring.

Therapeutic drug monitoring (TDM) of chronic treatments is justified for several reasons, including relative over- or underdosage due to variable individual elimination, pharmacokinetic interactions in drug combinations, and noncompliance. In all these circumstances, the prescribing physician is interested in having an estimation of the patient's clearance of the drug, even from one measurement. We compare a validated bayesian program, USC*Pack of Jelliffe, found difficult to use in daily routine, with a "home-made" program. The latter, which is capable of taking data from a clinical database, will generate a graphic simulation of daily plasma drug concentrations together with an estimation of steady-state clearance more rapidly than does USC*Pack. Both programs were run with only one measured plasma level. The patients were 83 children or young adults treated with phenobarbital (PB), carbamazepine (CBZ), and/or Valproic acid (VPA) who were resistant to monotherapy and who were to be sampled two to four times between doses. Drugs were routinely assayed by high-performance liquid chromatography (HPLC). Despite the rough character of Phacile (numeric integration and adjustment of only two of three parameters, without an acknowledged minimization algorithm), the results are comparable to those obtained with USC*Pack for estimating clearance and predicting plasma drug concentrations. Phacile algorithm, although simple, has proven of interest in routine TDM and as an introduction for medical students to the bayesian approach of population pharmacokinetics.

In vitro evaluation of carbamazepine 200 mg tablets.

A comparative in-vitro performance of carbamazepine 200mg tablet products available on the Kenyan market was evaluated. The products which include the innovator product, Tegretol, have similar quality consonant with pharmacopoeial specifications. A batch of one of the products had a carbamazepine content of 106.6% label claim which was outside the upper limits of 105%. One product packaged in multiple-unit containers of a 1000, had an unacceptable high friability of 6.82% loss in weight. All products had good dissolution profiles and released at least 70% of the dose within 45 minutes. Drug dissolution from tablets was found to vary between batches for one product. At each sampling time, most generics had wide variations in amount of dissolved drug. The effect of such variations on tablet efficacy cannot be ascertained in the absence of bioavailability data.