Alterations in Pharmacokinetics of Orally Administered Carbamazepine in Rats Treated with Sodium alginate: Possible Interaction between Therapeutic Drugs and Semi-solid Enteral Nutrients.

OBJECTIVE: The use of enteral nutrients plays an extremely important role in accurate nutrition management. Sodium alginate (SA) is frequently used for the semi-solidification of enteral nutrients. In the present study, we investigated whether the pharmacokinetic profile of orally administered carbamazepine (CBZ) is altered by a treatment with SA immediately before and after dosing of the drug. Furthermore, the adsorption effects of SA on CBZ were examined using an in vitro analysis. METHOD: SA was orally administered to rats just before and immediately after CBZ dosing. The CBZ concentration profile following its oral administration was analyzed by a non-compartmental method. The adsorption of CBZ onto SA was evaluated after centrifugation using an ultrafiltration device. FINDINGS: The serum concentration of orally administered CBZ at each sampling point was reduced by the treatment with SA, and the extent of the decrease observed in the concentration of CBZ was larger when SA was ingested immediately after administration of the drug, which was consistent with the alteration observed in the value of the area under the curve (AUC). No significant differences were noted in the elimination rate at the terminal phase (ke) among the groups. In the in vitro assay, CBZ was adsorbed by SA in the solution used to reflect fluid in the intestinal tract. CONCLUSIONS: The pharmacological efficacies of CBZ might be reduced by SA through the pharmacokinetic interactions, and that the careful attention should be paid to the timing of administration of CBZ and semi-solid enteral nutrients.

Iron supplements in nursing home patients associated with reduced carbamazepine absorption.

Persons in nursing homes receive a number of medications that may interfere with the pharmacokinetics of carbamazepine (CBZ). The aim of our study was to determine factors that may affect the pharmacokinetics of CBZ in elderly nursing home patients. METHODS: CBZ concentration data collected from 60 nursing homes across the US were evaluated. Inclusion criteria included residency in a nursing home for at least 2 months, age 65 years or older, a stable dosing regimen of CBZ for at least 4 weeks (considered steady state), available CBZ concentration, and complete information regarding all co-medications. Using a nonlinear mixed-effects model, the data were adequately described by a one-compartment model with first-order absorption and elimination. Goodness-of-fit plots, plausibility of parameter estimates, visual predictive check and nonparametric bootstrap were used to evaluate the models. MAIN FINDINGS: The final data set consisted of 345 CBZ concentrations from 99 subjects (38 males, 61 females). The population estimate of apparent clearance (CL/F) for a 70-kg person was 3.69 L/hr (RSE 6.9%). Residents were receiving either immediate (93.9%) or extended release (6.1%) formulation of CBZ and the Ka of each formulation was fixed to literature values. Age, sex, and co-medications had no effect on CL/F and apparent volume of distribution. Iron supplementation, which was taken by 16% of the residents, resulted in a 33% decrease in bioavailability (p < 0.001). No other medications were found to have an effect. CONCLUSIONS: Results from this pharmacokinetic study indicate that use of iron supplementation is associated with a reduction in absorption of CBZ and may need to be considered when dosing CBZ in patients taking iron supplementation.

Effect of Sophora flavescens on the pharmacokinetics of carbamazepine in rats.

Carbamazepine (CBZ), an antiepileptic with narrow therapeutic window, is a substrate of CYP 3A4 which metabolizes CBZ to carbamazepine-10,11-epoxide (CBZE). CBZE is an active and toxicity metabolite, and it is a substrate of MRP-2. Using CBZ for a long time can cause hepatic injury. Sophora flavescens (SF) is a medicinal herb used for the protected hepatic injury. This study investigated the acute and chronic effects of SF on the pharmacokinetics of CBZ in rats. The concentrations of CBZ and CBZE in plasma and tissues were determined by HPLC method. The results showed that SF which significantly decreased the AUC0-t of CBZ, increased CBZE conversely. Tissue analysis showed that the concentrations of CBZ and CBZE in brain and liver were decreased by SF. In addition, the distribution of CBZE in kidney was reduced significantly, which influenced the CBZE excretion and increased the drug toxic potentially. Results in the current study suggest that patients using CBZ might be cautioned in the use of SF extract or Sophora-derived products. Meanwhile, patients receiving drugs which are substrates of CYP 3A4 and/or MRP-2 should be advised of the potential herb-drug interaction to reduce the risk of therapeutic failure or increased toxicity of conventional drug therapy.

Interaction profile of Zizyphus jujuba with phenytoin, phenobarbitone, and carbamazepine in maximal electroshock-induced seizures in rats.

The antiepileptic effect of hydroalcoholic extract of Zizyphus jujuba (HEZJ) in experimental seizures was demonstrated earlier. The present study aimed to evaluate the pharmacokinetic and pharmacodynamic interactions of HEZJ with phenytoin (PHT), phenobarbitone (PB), and carbamazepine (CBZ) in maximal electroshock (MES)-induced seizures in male Wistar rats. Maximal electroshock (70 mA, 9 ms pulse width, 0.2 s) was used to induce seizures. Blood samples were collected at two time points for estimation of serum PHT, PB, and CBZ levels using high-pressure liquid chromatography (HPLC). Co-administration of HEZJ with the sub-therapeutic doses of PHT, PB, and CBZ exhibited 66.7, 66.7, and 50.0% protection against tonic hind limb extension as compared to 33.3, 33.3, and 50% protection respectively, in the groups treated with PHT, PB, and CBZ alone in their sub-therapeutic doses. Co-administration of HEZJ with the sub-therapeutic doses of these antiepileptic drugs (AEDs) showed significant improvement in cognitive functions as compared to MES group as well as these AEDs alone. A significant increase in glutathione levels and decrease in malondialdehyde levels were observed with pretreatment of HEZJ with the sub-therapeutic doses of these AEDs. Co-administration of HEZJ with PHT, PB, and CBZ did not cause any significant changes in the serum concentrations of these AEDs. The results of the present study indicate that the co-administration of HEZJ with sub-therapeutic doses of PHT and PB potentiated the antiepileptic effect of PHT and PB in MES-induced seizures with no change found in the antiepileptic effect of CBZ.

The effect of combination therapy on the plasma concentrations of traditional antiepileptics: a retrospective study.

The present study aimed at determining the differences in plasma concentrations of traditional antiepileptics such as phenytoin, carbamazepine, and valproic acid in patients receiving monotherapy and combination therapy. In addition, the effect of gender and age on plasma drug concentration was evaluated in these patients. For this purpose, plasma trough concentrations obtained during routine therapeutic monitoring of these drugs were assessed retrospectively. The average plasma concentrations reached the apparent therapeutic ranges, except for the average plasma concentration of phenytoin, which was below the therapeutic range in patients who received only phenytoin or in combination with the other agents. Phenytoin when combined with carbamazepine or valproic acid significantly decreased the average plasma concentrations of these drugs to subtherapeutic concentrations. The results showed that plasma carbamazepine concentrations were higher in men than in women, whereas plasma concentrations of valproic acid and phenytoin were higher in women than in men. The difference in this regard between men and women was found to be statistically significant for phenytoin. The difference between the average plasma concentrations of carbamazepine, phenytoin, and valproic acid among age groups was not significant. In conclusion, our study measured the average plasma antiepileptic drug concentrations in patients with epilepsy who were receiving monotherapy and combination therapy and were routinely monitored, and has thus shown the importance of drug monitoring in the evaluation of the effectiveness of these drugs.

In vitro and in vivo evaluation of ordered mesoporous silica as a novel adsorbent in liquisolid formulation.

BACKGROUND: A liquisolid technique has been reported to be a new approach to improve the release of poorly water-soluble drugs for oral administration. However, an apparent limitation of this technique is the formulation of a high dose because a large amount of liquid vehicle is needed, which finally results in a low-dose liquisolid formulation. Silica as an absorbent has been used extensively in liquisolid formulations. Although nanoparticle silica can be prepared and used to improve liquid adsorption capacity, loading a high dose of drug into a liquisolid is still a challenge. With the aim of improving adsorption capacity and accordingly achieving high drug loading, ordered mesoporous silica with a high surface area and narrow pore size distribution was synthesized and used in a liquisolid formulation. METHODS: Ordered mesoporous silica was synthesized and its particle size and morphology were tailored by controlling the concentration of cetyltrimethyl ammonium bromide. The ordered mesoporous silica synthesized was characterized by transmission electron microscopy, scanning electron microscopy, Fourier transform infrared spectroscopy, small-angle x-ray diffraction, wide angle x-ray diffraction, and nitrogen adsorption-desorption measurements. The liquid adsorption capacity of ordered mesoporous silica was subsequently compared with that of conventional silica materials using PEG400 as the model liquid. Carbamazepine was chosen as a model drug to prepare the liquisolid formulation, with ordered mesoporous silica as the adsorbent material. The preparation was evaluated and compared with commercially available fast-release carbamazepine tablets in vitro and in vivo. RESULTS: Characterization of the ordered mesoporous silica synthesized in this study indicated a huge Brunauer-Emmett-Teller surface area (1030 m(2)/g), an ordered mesoporous structure with a pore size of 2.8 nm, and high adsorption capacity for liquid compared with conventional silica. Compared with fast-release commercial carbamazepine tablets, drug release from the liquisolid capsules was greatly improved, and the bioavailability of the liquisolid preparation was enhanced by 182.7%. CONCLUSION: Ordered mesoporous silica is a potentially attractive adsorbent which may lead to a new approach for development of liquisolid products.

Therapeutic effects of ciprofloxacin on the pharmacokinetics of carbamazepine in healthy adult male volunteers.

Carbamazepine is a (CYP1A2 and CYP3A4 enzyme inducer) medicine which is used by epileptic patients for a long time. During the course of therapy, patients are generally caught by other diseases like urinary tract infections, upper respiratory tract infection, skin and soft tissue infection etc. To cure them, physicians commonly prescribe fluoroquinolones like Ciprofloxacin (CYP1A2 inhibitor) along with Carbamazepine (CBZ). Interactions may result without recognition which may lead to unforeseen toxicity, untoward effects or even therapeutic failure. Therefore, studies were conducted to investigate the effect of Ciprofloxacin on the pharmacokinetics of carbamazepine in healthy adult male volunteers. The main objective of this study was to generate new knowledge regarding CBZ and ciprofloxacin interaction for physicians and research workers dealing with these medicines. Eight healthy adult male volunteers were selected to assess the effect of ciprofloxacin on the pharmacokinetics of carbamazepine. After overnight fast the selected male volunteers were given CBZ orally. Blood samples were drawn at different time intervals after medication. Then the same volunteers were given CBZ along with ciprofloxacin. Blood samples were again drawn at the same time intervals as done previously. Plasma was separated from the blood samples. Concentration of CBZ in the plasma samples was determined by using HPLC technique. Results of the present study indicated that ciprofloxacin significantly increased the plasma concentration of CBZ when given concurrently to the healthy adult male volunteers. Ciprofloxacin increased Cmax, AUC and t½ while it decreased the CL and Vd of CBZ when administered concurrently to the adult volunteers. Change in pharmacokinetic parameters was due to slow metabolism or elimination of CBZ when given concurrently with ciprofloxacin to the adult volunteers. This is probably due to the inhibition of CYP3A4 isoenzyme by ciprofloxacin which is responsible for metabolism of CBZ. Ciprofloxacin increased the plasma concentration of CBZ so dose adjustment as well as drug monitoring of CBZ is required when both the drugs are given concurrently. The knowledge regarding interaction between ciprofloxacin and CBZ would be helpful for the pharmaceutical industries, physicians and a blessing for the patients.

Effect of soybean administration on the pharmacokinetics of carbamazepine and omeprazole in rats.

Influence of soybean administration on the bioavailability of carbamazepine and omeprazole was studied after single dose administration of soybean (10 g/kg p.o.) or after chronic administration of soybean (50% w/w mixed with normal feed) for 15 days in rats. Carbamazepine was administered orally at a dose of 10 mg/kg and omeprazole at a dose of 20 mg/kg. Soybean decreased the bioavailability of carbamazepine after both single dose and chronic administration. It produced a significant decrease in C(max), T(max), AUC(0-t) of carbamazepine after single dose administration and increased the plasma clearance and V(d) along with decrease in C(max), T(max), AUC(0-t) and AUC(0-infinity) after chronic administration. On the contrary, soybean administration increased the bioavailability of omeprazole by producing an increase in C(max), AUC(0-t) and AUC(0-infinity) and a decrease in V(d) after single dose administration and a decrease in plasma clearance along with increase in C(max), AUC(0-t) and AUC(0-infinity) after chronic administration. The half-life of omeprazole was also increased after both acute and chronic administration of soybean. It was concluded that soybean decreases the bioavailability of carbamazepine and increases the bioavailability of omeprazole after both single dose and chronic administration.

Pharmacokinetic interaction of single dose of piperine with steady-state carbamazepine in epilepsy patients.

Piperine, the active principle of piper species, is commonly used as a spice and adjuvant in various traditional systems of medicine. It has been known as a bioavailability-enhancer. The present study aimed at evaluating the effect of piperine on the steady-state pharmacokinetics of a single dose of carbamazepine in poorly controlled epilepsy patients on carbamazepine monotherapy. Patients (n = 10 each) receiving either 300 mg or 500 mg dose of carbamazepine twice daily were selected. After administration of carbamazepine, venous blood samples were collected at 0, 0.5, 1, 2, 4, 6, 9, 12 h. Subsequently, piperine (20 mg p.o.) was administered along with carbamazepine and samples were collected similarly. The pharmacokinetic parameters were compared by Students t-test. Piperine significantly increased the mean plasma concentrations of carbamazepine at most of the time points in both dose groups. There was a significant increase in AUC(0-12hr) (p < 0.001), average C(ss) (p < 0.001), t(1\2el) (p < 0.05) and a decrease in K(el) (p < 0.05), in both the dose groups, whereas changes in K(a) and t(1\2a) were not significant. Cmax (p < 0.01) and t(max) (p < 0.01) were increased significantly following piperine administration in the 500 mg dose group; however, these parameters were not significant in the lower dose group. Piperine could significantly enhance the oral bioavailability of carbamazepine, possibly by decreasing the elimination and/or by increasing its absorption.

Enhanced clearance of highly protein-bound drugs by albumin-supplemented dialysate during modeled continuous hemodialysis.

BACKGROUND: In 2006, there were 16 796 toxic exposures attributed to valproic acid (VPA), carbamazepine (CBZ) and phenytoin (PHT) reported to the US Toxic Exposure Surveillance System. Of these, 30% (5046) were treated in a health care facility with 12 cases resulting in death. These drugs are highly protein bound and poorly dialyzable; however, it has been suggested that albumin-supplemented dialysate may enhance dialytic clearance. We investigated whether the addition of albumin to dialysate affects dialytic clearance of VPA, CBZ and PHT. METHODS: VPA, CBZ and PHT were added to a bovine blood-based in vitro continuous hemodialysis circuit, which included a polysulfone or an AN69 hemodialyzer. VPA, CBZ and PHT clearances were calculated from spent dialysate and pre-dialyzer plasma concentrations. VPA, CBZ and PHT clearances with control (albumin-free) dialysate were compared to clearances achieved with 2.5% or 5% human albumin-containing dialysate. The influences of blood flow (180 and 270 mL/min) and dialysate flow (1, 2 and 4 L/h) on dialysis clearance were also assessed. RESULTS: The addition of 2.5% albumin to dialysate significantly enhanced dialytic clearance of VPA and CBZ, but not PHT. Use of 5% albumin dialysate further increased VPA and CBZ clearance. Overall, drug clearance was related directly to dialysate flow but independent of blood flow. CONCLUSION: Continuous hemodialysis with albumin-supplemented dialysate significantly enhanced VPA and CBZ, but not PHT, clearance compared to control dialysate. Continuous hemodialysis with albumin-supplemented dialysate may be a promising therapy to enhance dialytic clearance of selected highly protein-bound drugs.

Drug monitoring: simultaneous analysis of lamotrigine, oxcarbazepine, 10-hydroxycarbazepine, and zonisamide by HPLC-UV and a rapid GC method using a nitrogen-phosphorus detector for levetiracetam.

A high-performance liquid chromatography (HPLC) assay using UV detection is described for the simultaneous measurement of the newer generation anti-epileptic medications lamotrigine, oxcarbazepine (parent drug and active metabolite 10- hydroxycarbazepine), and zonisamide. Detection of all four compounds can be done at 230 nm; however, there is a potential interference with zonisamide in patients on clonazepam therapy. Therefore, the method uses dual wavelength detection: 230 nm for oxcarbazepine and 10-hydroxycarbazepine and 270 nm for lamotrigine and zonisamide. In addition, a simple gas chromatography method using a nitrogen-phosphorus detector is described for the measurement of levetiracetam, another of the recently approved anti-epileptic medications. For both methods, limits of quantitation, linearities, accuracies, and imprecisions cover the therapeutic range for drug monitoring of patients. A wide variety of clinical drugs, including other anti-epileptic drugs, do not interfere with these assays. These procedures would be of special interest to clinical laboratories, particularly due to the limited availability of immunoassays for newer generation anti-epileptic medications and that therapeutic uses of these drugs are expanding beyond epilepsy to other neurologic and psychiatric disorders.

Chronotherapeutic dose schedule of phenytoin and carbamazepine in epileptic patients.

The objective of this study was to compare the efficacy and safety of a chronotherapeutic dosing schedule of phenytoin and carbamazepine versus a conventional dosing schedule for the treatment of tonic-clonic epileptic patients. Of 148 epileptic subjects found to have subtherapeutic trough drug levels (subtherapeutic group, STG), 103 subjects who completed the study were randomized to either STG I (n=51) for treatment by the conventional dosing schedule (tablet phenytoin 100-400 mg/day OD or BD, tablet carbamazepine 200-800 mg BD, or both, equally divided doses with no fixed time of drug intake), with a dose increment but no change in usual time of drug administration allowed; or to STG II (n=52), with no dose increment permitted but a shift in all or most (two-thirds or three-fourths) of the daily dose of one or both medications to 20:00 h. The 62 patients who experienced drug toxicity reactions (toxicity group, TG) and who had serum drug levels in the toxic range were assigned to TG I for dose reduction or TG II for dose reduction and drug administration at 20:00 h. Those 16 subjects in STG I and 47 subjects in STG II who initially evidenced subtherapeutic trough drug concentrations exhibited therapeutic drug levels by the end of four weeks of treatment (p<0.01). A significantly greater number of TG II, as compared to TG I, subjects who experienced toxic reactions showed improved drug tolerance. There were no poor responders and more good responders (control of epilepsy for one year) in STG II compared to STG I subjects. The findings of this study indicate that a chronotherapeutic dosing schedule of phenytoin and carbamazepine involving the administration of most or all the daily dose of medication(s) at 20:00 h can improve the response of diurnally active epileptic patients not responding to standard doses, achieve therapeutic drug levels, and reduce toxic manifestations in subjects having drug concentrations beyond the therapeutic range.

Systemic and presystemic conversion of carbamazepine to carbamazepine-10, 11-epoxide during long term treatment / Conversão da carbamazepina para 10, 11-epóxido-carbamazepina no tratamento prolongado

INTRODUCTION: Carbamazepine (CBZ) undergoes biotransformation, being CYP3A4 the major cytocrome P450 (CYP) enzyme catalyzing the carbamazepine-10,11-epoxide (EPOX) formation, which is quantitatively the most important pathway in CBZ metabolism. There is evidence of dose-dependent elimination of this drug due to its autoinduction capacity. Moreover, published data showed an incomplete bioavailability of CBZ since its absorption increases when grapefruit juice was administered. Both CYP3A4 and MRP2 (located in the enterocyte) are autoinduced during long term use of CBZ. As the other enzymes involved in CBZ metabolism are negligible in the gut, presystemic biotransformation through CYP3A4 could be responsible for the bioavailability of the drug as well as EPOX formation. OBJECTIVE: The purpose of our study was to assess the importance of presystemic formation of EPOX during the autoinduction of CBZ versus the daily administered dose. PATIENTS AND METHODS: 40 adults (average age: 28 years) and 29 children (average age: 9 years) receiving CBZ as monotherapy were included in the study. CBZ and EPOX plasma concentrations were analyzed by a previous validated HPLC method. RESULTS AND CONCLUSION: The results obtained confirmed the metabolic induction after chronic administration and provided new elements to suggest a strong contribution of dose-dependent bioavailability in the non linear kinetics of CBZ.

Thermally reversible in situ gelling carbamazepine liquid suppository.

Carbamazepine (CBZ), indicated for the control of epilepsy, undergoes extensive hepatic first-pass elimination after oral administration. A rectal dosage form of CBZ is not commercially available, although it is of particular interest when oral administration is impossible. Conventional suppositories can cause patient discomfort and may reach the end of the colon; consequently, the drug can undergo the first-pass effect. Mucoadhesive liquid suppositories of CBZ were prepared by adding carbopol to formulation of thermally gelling suppositories that contain 20% poloxamer 407 and either 15% poloxamer 188 or 1% methylcellulose. Gellan gum was also tried instead of 20% poloxamer. All formulations contained 10% CBZ. The characteristics of the suppositories differed depending on the formulation. The formula containing 20% poloxamer 407, 1% methylcellulose, and 0.5% carbopol showed reasonable gelation temperature, gel strength and bioadhesive force. The analysis of release mechanism showed that CBZ released from the suppositories by Fickian diffusion. In vivo evaluation of the same formulation showed higher peak plasma concentration of CBZ compared with the orally administered suspension containing the equivalent amount of drug. However, there was no statistical significant difference (p > 0.05) in extent of bioavailability between the liquid suppository and oral suspension as indicated by the values of AUC(0 - infinity), 17.9 and 18.8 micro g x h/ml, respectively. These results suggested that mucoadhesive in situ gelling liquid suppository could be an effective and convenient delivery system of carbamazepine.

Evaluation of in vitro-in vivo correlation and anticonvulsive effect of carbamazepine after cogrinding with microcrystalline cellulose.

PURPOSE: Carbamazepine is a poor water soluble drug and its bioavailability is limited by dissolution rate. Dissolution, serum concentration and anticonvulsive effect of the drug have been evaluated after cogrinding with microcrystalline cellulose. A cogrinding technique was used to increase the dissolution, serum concentrations and anticonvulsive effect of the drug. A novel deconvolution technique of in vitro in vivo correlation was evaluated. METHODS: The drug coground with microcrystalline cellulose, the corresponding physical mixture, unground and ground drug powder were subjected to dissolution measurement. Coground and unground drug serum concentrations were investigated in rabbits. Also the anticonvulsive effects of the latter preparations were assessed in mice. For elucidation of observed in vitro and in vivo differences FT-IR spectroscopy, X-ray diffraction patterns and DSC thermograms of the preparations were studied. RESULTS: The dissolution of the coground was the highest (percent dissolved in the first 20 minutes, %D20', was 97.5). The unground drug powder exhibited the lowest dissolution (%D20'=40). The difference was reflected in their corresponding area under the mean serum concentration curves between 0-16 hr (118.96 vs 54.17 microg x hr/ml) as well as protection abilities against strychnine and electrically induced seizures. The onset of tonic seizures induced by strychnine was increased between 40-140% in the case of the coground system depending on dose and time of carbamazepine administration. CONCLUSION: Cogrinding was an effective technique in increasing carbamazepine dissolution due to reduced crystallinity as seen in X-ray pattern, enhanced wettability and decreased particle size, which in turn resulted in increased serum concentrations and its anticonvulsive effect. A novel simple deconvolusion technique not requiring intravenous data denoted as the double reciprocal area method was used to establish correlation between in vitro and in vivo parameters.

Interactions between riluzole and conventional antiepileptic drugs -- a comparison of results obtained in the subthreshold method and isobolographic analysis.

The exact types of pharmacodynamic interactions between riluzole and conventional antiepileptic drugs were evaluated in two available ways, the subthreshold and isobolographic analysis. Maximal electroshock test in mice was used as an animal model for generalized tonic-clonic convulsions. In the first method, riluzole (1.25-2.5 mg/kg) significantly raised the electroconvulsive threshold in mice. The drug administered at its subprotective dose of 0.3125 mg/kg enhanced the antiseizure activity of carbamazepine and phenobarbital, while, when applied at the higher dose of 0.625 mg/kg, it potentiated also the action of valproate and diphenylhydantoin. Riluzole (0.625) alone and in combinations with antiepileptic drugs did not produced any motor or log-term memory deficit. Results obtained from isobolographic analysis determined pure additive interaction between riluzole and all used conventional antiepileptic drugs. Since riluzole did not change plasma concentrations of co-administered antiepileptics, pharmacokinetic interactions, at least in terms of their free plasma levels, do not seem probable. The results of the present study confirm significant antiseizure properties of riluzole in the model of generalized tonic-clonic epileptic attacks. Moreover, comparison of effects obtained from both methods evaluating drug interactions strongly indicates a crucial role of the isobolographic analysis in verification and supplementation data achieved from the subthreshold method.

Modulation of antiepileptic effect of phenytoin and carbamazepine by melatonin in mice.

The pharmacokinetic and pharmacodynamic interaction of phenytoin and carbamazepine with melatonin was studied in a maximal electroshock seizure (MES) model in mice. The anticonvulsant ED(20), ED(33), ED(50) and ED(100) of phenytoin and carbamazepine, and ED(50) of melatonin were determined. Thereafter, the subanticonvulsant doses of phenytoin and carbamazepine were combined with ED(50) dose of melatonin. In combination with melatonin, 100% protection against seizures was achieved with phenytoin and carbamazepine in doses as low as ED(50) and ED(33), respectively. Serum levels of phenytoin and carbamazepine in animals that received ED(50) dose of phenytoin and carbamazepine per se, were not significantly different to those of the groups that received melatonin also. The study suggests that the synergistic antiepileptic effect is most likely a pharmacodynamic interaction, and not due to pharmacokinetic changes. Melatonin, thus, can be a potential adjunct to antiepileptic drugs, achieving a therapeutic effect at lower concentrations, hence limiting their dose-related toxicities.

Allopurinol does not affect the anticonvulsant activity of carbamazepine and valproate in maximal electroshock-induced convulsions in mice.

Allopurinol, an inhibitor of xanthine oxidase, is indicated in the management of patients with elevated serum and urinary uric acid levels. It was also reported to be beneficial in patients with epilepsy when added to traditional antiepileptic drug. Here, we investigated the effect of allopurinol upon the electrical seizure threshold and its effect on the protective efficacy of common antiepileptic drugs, carbamazepine (CBZ) and valproate (VPA) against maximal electroshock (MES)-induced convulsions in mice. We found that allopurinol administered at doses of 5, 15 or 45 mg/kg, did not affect electrical seizure threshold. When administered acutely or for a prolonged period of time (5 times every 24 h), it did not affect anticonvulsant activity of CBZ and VPAin MES. Free plasma concentration of both anticonvulsants was not affected by allopurinol given at a dose of 45 mg/kg for 5 days. Thus, our results did not support suggestions that allopurinol can be beneficial as add-on drug in the management of epilepsy at least in patients treated with CBZ or VPA.

The effects of Cassia auriculata and Cardiospermum halicacabum teas on the steady state blood level and toxicity of carbamazepine.

A study was conducted using male Wistar rats as the experimental model, to compare the effects of concurrent administration of herbal tea prepared from dried flowers of Cassia auriculata or aerial parts of Cardiospermum halicacabum and carbamazepine, on (a). steady state serum levels of the prescription drug, and (b). changes in toxicity (as assessed by changes in general behaviour, haematological parameters, and liver and kidney function) that may occur due to drug interaction. Results demonstrate that in rats receiving the Cassia auriculata tea and carbamazepine, the blood levels of the prescription drug were significantly enhanced by 47.1% (P<0.04), when compared with the levels in animals receiving only carbamazepine for the same time period, with no apparent changes in toxicity. In animals receiving the Cardiospermum halicacabum tea, there were no significant changes in the blood levels of carbamazepine or drug-related toxicity. Cassia auriculata tea has therefore the potential to influence the bioavailability of carbamazepine, and hence its therapeutic actions. Concurrent ingestion of carbamazepine with herbal teas containing Cassia auriculata is therefore best avoided by patients under treatment for epilepsy.

Possible interaction of herbal tea and carbamazepine.

A study was conducted using Wistar rats to determine the effect of concurrent administration of a herbal tea prepared from dried flowers of Cassia auriculata and carbamazepine on (a) blood levels of the prescription drug and (b) changes in toxicity (as assessed by changes in hematological parameters, liver and kidney function, and histology of major body organs) that may occur due to drug interaction. Results demonstrate that in rats receiving the herbal tea and carbamazepine, the blood levels of the prescription drug were significantly enhanced by 47.1% (p <0.04) when compared with the levels in animals receiving only carbamazepine, with no apparent changes in toxicity. Concurrent ingestion of the herbal tea prepared from Cassia auriculata flowers with carbamazepine may therefore influence the bioavailability of the prescribed drug and hence its therapeutic potential.