Oral Lamotrigine Research Articles

Population Pharmacokinetics of Lamotrigine and Its N2-Glucuronide Metabolite in Chinese Patients With Epilepsy.

Lamotrigine is a new antiepileptic drug with substantial interindividual variability in its pharmacokinetics and therapeutic responses. This study aimed to develop population pharmacokinetic (PPK) models of lamotrigine and its N2-glucuronide metabolites for model-informed individualized therapy. A total of 353 plasma concentrations from Chinese patients with epilepsy receiving oral lamotrigine were used to develop a population PPK model using a nonlinear mixed effects modeling method. One- and two-compartment models were applied to the nonmetabolite and metabolite model, respectively. Forward addition and backward elimination were used to establish the final model. Model validation was performed using standard goodness-of-fit, bootstrap, visual predictive checks, and normalized prediction distribution errors. Finally, simulations were performed to propose lamotrigine dosages in different situations to achieve trough concentrations within the reference interval (2.5-15 mg/L). For both final population PPK models, coadministration with valproic acid (VPA) or enzyme inducer, and body weight significantly affected lamotrigine clearance. The final models for lamotrigine clearance were and for nonmetabolite and metabolite models, respectively. The precision of the PPK parameters was acceptable, and the models exhibited good predictability. Monte Carlo simulations revealed that the lamotrigine dosage administered to patients combined with an enzyme inducer must be tripled that administered with VPA to reach the target trough concentration. Variability in the pharmacokinetics of lamotrigine is large. Coadministration of VPA or an enzyme inducer and body weight are the most important factors in lamotrigine clearance in Chinese patients with epilepsy. The developed population PPK models might support further optimization of lamotrigine dosing regimens.

Investigating Hematological and Renal Effects of Levetiracetam Versus Lamotrigine in Children With Epilepsy: A Randomized Clinical Trial

Objectives: Alterations in hematological and renal parameters have been reported with antiepileptic drugs. This study evaluates the effects of lamotrigine (LTG) and levetiracetam (LEV) on these parameters in children with epilepsy. Methods: This randomized clinical trial included children with a first-time diagnosis of epilepsy referred to Bandar Abbas Children’s Hospital, Bandar Abbas, Iran, from 2017 to 2018. The participants’ age, gender, and family history of epilepsy were recorded. The patients in the LTG group received 0.6 mg/kg oral LTG in two divided doses for two weeks which continued with 1.2 mg/kg for another two weeks and then with a maintenance dose of 5-15 mg/kg daily. The patients in the LEV group received 10 mg/kg oral LEV twice a day. When necessary, the dosage is increased to a maximum of 30 mg/kg twice a day. The treatment continued until seizures were controlled. Hematological and renal parameters were measured at baseline and 3 months after treatment. The total duration of treatment with each drug was also noted. Results: From the 66 children evaluated in this study with a mean age of 8.51±2.11 years, 31 (47%) were male. Age, gender, family history of epilepsy, treatment duration, and baseline hematological and renal parameters did not differ between the LTG group (n=26) and the LEV group (n=40). The patients in both groups were comparable in terms of all the parameters after treatment. Also, no significant change was observed after treatment compared to baseline in either group. Discussion: LTG and LEV have no significant effect on the hematological and renal parameters of children with epilepsy.

Formulation design of oral lamotrigine suspension for the treatment of epilepsy

Aim: Lamotrigine is a broad-spectrum anticonvulsant drug widely used as mono- or adjunct therapy in adults and children. The aim of this study was to develop a liquid formulation of lamotrigine to fulfil the unmet needs of children and geriatric epileptic patients. Materials and Methods: Suspension formulation was prepared using Carbopol 974P as a suspending agent. It was evaluated for its sedimentation and re-dispersibility, solubility, morphology, particle-size distribution, rheological properties, pH measurement, uniformity of dosage unit, in vitro drug release behaviour and results were compared with marketed formulation Lamictal tablets. Results: The release profile of marketed product Lamictal tablets and developed lamotrigine oral suspension shows a complete release profile throughout physiological pH in all three media (0.1N hydrochloric acid, 4.5 pH acetate buffer and 6.8 pH phosphate buffer) and shows similar release as a marketed product. Microscopic observation clearly indicates the stability of the suspension (no aggregation of suspended particles) during the storage period of 12 months. The content uniformity of suspension was found well within the specified limits. Conclusion: Lamotrigine oral suspension was developed successfully and found a suitable alternative for a commercially available tablet for the treatment of epilepsy in children and geriatric patients.

Pharmacokinetics, Safety, and Tolerability of Lamotrigine Chewable/Dispersible Tablet Following Repeat‐Dose Administration in Healthy Chinese Volunteers

In this open-label, single-center study, the pharmacokinetics, safety, and tolerability of lamotrigine chewable/dispersible tablets were assessed in healthy Chinese volunteers. Each volunteer (N=16) received repeat doses of oral lamotrigine titrated from 25mg to 50mg to 100mg over 42days and was followed up for 10-17days. Safety and tolerability were assessed throughout the study. Lamotrigine pharmacokinetic parameters were estimated using noncompartmental analysis. Overall, 15 (94%) volunteers completed the study. Lamotrigine serum concentrations peaked 2.5hours postdose, with a mean terminal half-life of 36.8hours. The apparent lamotrigine oral clearance was 1577.88mL/h. The accumulation ratios (day14 vs day1) were 2.53 and 2.58 for area under the curve and peak concentration, respectively. Lamotrigine 25to 100mg once daily exhibited dose-proportional pharmacokinetics (based on area under the curve and peak concentration), following repeat dosing. Nine volunteers reported adverse events, 2 experienced oropharyngeal pain, each receiving 25mg and 50mg. One volunteer withdrew due to an increase in liver enzymes. No deaths, serious adverse effects, or skin rashes were reported during the study. No new safety concerns were observed. Overall, the pharmacokinetic profiles after repeat doses of lamotrigine chewable/dispersible tablets once daily in a Chinese population were similar to those observed in Western populations.

Lamotrigine loaded poly-ɛ-(d,l-lactide-co-caprolactone) nanoparticles as brain delivery system

Management of epilepsy requires brain delivery therapy, therefore, this study was aimed to prepare lamotrigine loaded poly-ɛ-(d,l-lactide-co-caprolactone) (PLCL) nanoparticles using spontaneous emulsification solvent diffusion method. Nanoparticles for brain delivery required to have a particle size <200 nm, polydispesity index <0.2 and a sustained drug release properties. For such aim different factors were considered in preparing the nanoparticles as PLCL monomers' ratio, type of organic solvent used to prepare the nanoparticles, amount of PLCL and Pluronic®F127 in the nanoparticles. Prepared nanoparticles were characterized for their shape, particle size, polydispersity index, zeta potential, encapsulation efficiency, drug loading capacity, process yield and in-vitro drug release pattern. The in-vivo investigation for brain delivery of selected nanoparticles delivered by intravenous route was investigated in rats and compared to that for oral tablet. The obtained nanoparticles were spherical in shape. The amount of surfactant and PLCL affected the properties of the obtained nanoparticles. Using a mixture of organic solvent in preparing the nanoparticles improved its properties. The nanoparticles prepared using PLCL with monomers' ratio of 25:75, had particle size value of 125 nm, polydispersity index value of 0.184, zeta potential value of −39 mV and encapsulation efficiency value of 99%, was selected to study their efficacy to deliver the drug to the brain. The tested nanoparticles showed higher values of Tmax, Cmax, AUC, and MRT in homogenized rat brain, compared to oral lamotrigine tablet, while the bioavailability of the oral tablet was higher in rat plasma compared to that for the nanoparticles. This reflects that brain was the main distribution site for tested nanoparticles, and plasma was the main distribution site for oral tablets. This confirms the goal of the selected formulation as brain delivery nanoparticles.

The antimyotonic effect of lamotrigine in non-dystrophic myotonias: a double-blind randomized study.

Mexiletine is the only drug with proven effect for treatment of non-dystrophic myotonia, but mexiletine is expensive, has limited availability and several side effects. There is therefore a need to identify other pharmacological compounds that can alleviate myotonia in non-dystrophic myotonias. Like mexiletine, lamotrigine is a sodium channel blocker, but unlike mexiletine, lamotrigine is available, inexpensive, and well tolerated. We investigated the potential of using lamotrigine for treatment of myotonia in patients with non-dystrophic myotonias. In this, randomized double-blind, placebo-controlled, two-period cross-over study, we included adult outpatients recruited from all of Denmark with clinical myotonia and genetically confirmed myotonia congenita and paramyotonia congenita for investigation at the Copenhagen Neuromuscular Center. A pharmacy produced the medication and placebo, and randomized patients in blocks of 10. Participants and investigators were all blinded to treatment until the end of the trial. In two 8-week periods, oral lamotrigine or placebo capsules were provided once daily, with increasing doses (from 25 mg, 50 mg, 150 mg to 300 mg) every second week. The primary outcome was a severity score of myotonia, the Myotonic Behaviour Scale ranging from asymptomatic (score 1) to invalidating myotonia (score 6), reported by the participants during Weeks 0 and 8 in each treatment period. Clinical myotonia was also measured and side effects were monitored. The study was registered at ClinicalTrials.gov (NCT02159963) and EudraCT (2013-003309-24). We included 26 patients (10 females, 16 males, age: 19-74 years) from 13 November 2013 to 6 July 2015. Twenty-two completed the entire study. One patient withdrew due to an allergic reaction to lamotrigine. Three patients withdrew for reasons not related to the trial intervention. The Myotonic Behaviour Scale at baseline was 3.2 ± 1.1, which changed after treatment with lamotrigine by 1.3 ± 0.2 scores (P < 0.001), but not with placebo (0.2 ± 0.1 scores, P = 0.4). The estimated effect size was 1.0 ± 0.2 (95% confidence interval = 0.5-1.5, P < 0.001, n = 22). The standardized effect size of lamotrigine was 1.5 (confidence interval: 1.2-1.8). Number needed to treat was 2.6 (P = 0.006, n = 26). No adverse or unsuspected event occurred. Common side effects occurred in both treatment groups; number needed to harm was 5.2 (P = 0.11, n = 26). Lamotrigine effectively reduced myotonia, emphasized by consistency between effects on patient-related outcomes and objective outcomes. The frequency of side effects was acceptable. Considering this and the high availability and low cost of the drug, we suggest that lamotrigine should be used as the first line of treatment for myotonia in treatment-naive patients with non-dystrophic myotonias.

Prefrontal Connectivity and Glutamate Transmission: Relevance to Depression Pathophysiology and Ketamine Treatment

BackgroundPrefrontal global brain connectivity with global signal regression (GBCr) was proposed as a robust biomarker of depression and was associated with ketamine’s mechanism of action. Here, we investigated prefrontal GBCr in treatment-resistant depression (TRD) at baseline and following treatment. Then, we conducted a set of pharmacological challenges in healthy subjects to investigate the glutamate neurotransmission correlates of GBCr. MethodsIn the cohort A study, we used functional magnetic resonance imaging to compare GBCr between 22 patients with TRD and 29 healthy control subjects. Then, we examined the effects of ketamine and midazolam on GBCr in patients with TRD 24 hours posttreatment. In the cohort B study, we acquired repeated functional magnetic resonance imaging in 18 healthy subjects to determine the effects of lamotrigine (a glutamate release inhibitor), ketamine, and lamotrigine-by-ketamine interaction. ResultsIn the cohort A study, patients with TRD showed significant reduction in dorsomedial and dorsolateral prefrontal GBCr compared with healthy control subjects. In patients with TRD, GBCr in the altered clusters significantly increased 24 hours following ketamine (effect size = 1.0, confidence interval = 0.3 to 1.8) but not following midazolam (effect size = 0.5, confidence interval = −0.6 to 1.3). In the cohort B study, oral lamotrigine reduced GBCr 2 hours postadministration, while ketamine increased medial prefrontal GBCr during infusion. Lamotrigine significantly reduced the ketamine-induced GBCr surge. Exploratory analyses showed elevated ventral prefrontal GBCr in TRD and significant reduction of ventral prefrontal GBCr during ketamine infusion in healthy subjects. ConclusionsThis study provides the first replication of the ability of ketamine to normalize depression-related prefrontal dysconnectivity. It also provides indirect evidence that these effects may be triggered by the capacity of ketamine to enhance glutamate neurotransmission.

Pregabalin and lamotrigine in central poststroke pain: A pilot study.

Comparative study of Class I drugs in central poststroke pain (CPSP) is lacking. To evaluate the safety and efficacy of pregabalin and lamotrigine in patients with CPSP. Tertiary care teaching referral hospital. We included consecutive patients with CPSP having ≥50 mm score on Visual Analog Scale (VAS) and randomized them to receive either oral pregabalin or oral lamotrigine. Their clinical findings, serum chemistry, and cranial magnetic resonance imaging findings were noted. The severity of CPSP was assessed by VAS while the allodynia was assessed on a 0-10 scale. The hospital anxiety and depression (HAD) score was also recorded. The primary outcome was> 50% reduction in the VAS score while the secondary outcome was> 50% reduction in the severity of allodynia and improvement in HAD score at 3 months. Adverse reactions were noted in both the groups. There were 30 patients with CPSP with a median age of 54.5 years (Male:Female = 36:4). While both pregabalin (P < 0.0001) and lamotrigine (P < 0.0001) resulted in significant improvement in the VAS score (63.3% vs. 53.3%), allodynia (66.7% vs. 75%), and HAD score (80% vs. 81.8%) compared to the baseline, the was no significant intergroup difference. Lamotrigine had to be withdrawn in three patients due to skin rash. Both pregabalin and lamotrigine are equally effective in CPSP, but significant side effects leading to drug withdrawal occured with lamotrigine administration.

A STUDY ON EVALUATION OF THE EFFICACY OF LAMOTRIGINE AS ADD-ON TREATMENT IN RESISTANT TYPE OF PRIMARILY GENERALIZED TONIC-CLONIC EPILEPSY IN BURDWAN MEDICAL COLLEGE, WEST BENGAL, INDIA

Background: Treatment of resistant type of Primarily Generalized Tonic-Clonic (PGTC) Epilepsy is a difficult area. In different parts of the world lots of studies conducted on this area with varying results. In this perspective, there was need of this study, especially in this part of the country, Burdwan Medical College, West Bengal, India, where previously there was no such study. Objective: The objective of my study was to evaluate the efficacy of Lamotrigine as Add-On Treatment in Primarily Generalized Tonic-Clonic Epilepsy. Materials and Methods: 46 resistant type of Primarily Generalized Tonic-Clonic Epileptic patients were randomly recruited from the Out Patient Department (OPD), Burdwan Medical College& Hospital, West Bengal. The patients were taking either Valproic acid or Carbamazepine or combination of Valproic acid & Carbamazepine. All were placed on oral Lamotrigine in addition to their exiting antiepileptic drugs. Efficacy was measured subsequently by efficacy measuring scale. Results: After add-on Lamotrigine 50% responder rate was 39.129%. 5 patients (10.869%) rendered seizure free. The reduction of mean seizure frequency was 47.129% and response ratio was -0.32 ± 0.249 (mean ± SD). Add-on lamotrigine cause significant reduction (p < 0.05) of seizure frequency from the baseline value and desirable effects were seen irrespective of patients whether taking valproic acid or carbamazepine or combination of valproic acid& carbamazepine. CONCLUSION: Add-on lamotrigine was efficacious in resistant type of Primarily Generalized Tonic- Clonic Epilepsy, in this tertiary care teaching hospital. Key Words: Epilepsy, Primarily, Generalized, Tonic-Clonic, Resistant

Population pharmacokinetics of lamotrigine in Indian epileptic patients

The aim of this analysis was to describe the pharmacokinetics of oral lamotrigine (LTG) in Indian epileptic patients using a population pharmacokinetic (PPK) modeling approach to confirm that the PK is similar to that of the Caucasian population, and to evaluate and confirm the impact of covariates predictive of inter-individual variability using a simulation platform. Blood samples were obtained from 95 patients, and LTG plasma concentrations were determined. Population PK modeling was performed using NONMEM. A one-compartment PK model with first-order absorption and elimination was used to describe the LTG PK. Log-likelihood profiling and normalized prediction distribution errors (NPDE) were used for model evaluation. A simulation study was performed to investigate dose regimens. Clearance (CL) was estimated to be 2.27L/h with inter-individual variability (IIV) of 29 CV%. Volume of distribution (V) was estimated to be 53.6L (31 CV% IIV). Body weight and concurrent use of carbamazepine and valproate were identified as significant covariates on clearance. Log-likelihood profiling indicated that parameters could be estimated with adequate precision, and NPDE indicated that the model adequately described the data observed. The simulation study illustrated the impact of carbamazepine and valproate on LTG PK, and negligible differences in PK between Indian and Caucasian patients. This is the first PK analysis of LTG in Indian patients. The population PK model developed adequately described the data observed. Comparison of identified PK parameters with previous PK analyses in Caucasian patients indicates that CL of LTG is similar, while V is somewhat lower compared with Caucasian patients, but this is not expected to lead to relevant differences in PK profiles during steady state.

Efficacy and safety of pregabalin versus lamotrigine in patients with newly diagnosed partial seizures: a phase 3, double-blind, randomised, parallel-group trial

Efficacious and safe monotherapy options are needed for adult patients with newly diagnosed epilepsy. As an adjunctive treatment for partial seizures, pregabalin compares favourably with lamotrigine and is an effective, approved treatment. We studied the efficacy and safety of pregabalin as monotherapy, using a design that complied with European regulatory requirements and International League Against Epilepsy guidelines. This phase 3, double-blind, randomised, non-inferiority study compared the efficacy and tolerability of pregabalin and lamotrigine monotherapy in patients with newly diagnosed partial seizures at 105 centres, mostly in Europe and Asia. Randomisation to treatment groups (1:1 ratio) was by a computer-generated pseudorandom code (random permuted blocks), with patients sequentially assigned numbers by telephone. Investigators, site staff, and patients were masked to the assigned treatment. After randomisation, patients were titrated to either 75 mg oral pregabalin or 50 mg oral lamotrigine twice daily during a 4-week dose-escalation phase, followed by a 52-week efficacy assessment phase during which the daily dose could be increased as needed to a maximum of 600 mg and 500 mg, respectively. The primary efficacy endpoint was the proportion of patients who remained seizure-free for 6 or more continuous months during the efficacy assessment phase; analysis included all patients who were randomly assigned to treatment groups and received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT00280059. 660 patients were randomly assigned to treatment groups (330 pregabalin, 330 lamotrigine), of whom 622 entered the efficacy assessment phase (314 pregabalin, 308 lamotrigine). Fewer patients in the pregabalin group than in the lamotrigine group became seizure-free for 6 or more continuous months (162 [52%] vs 209 [68%]; difference in proportion, -0·16, 95% CI -0·24 to -0·09). The overall incidence of adverse events was similar between the groups and consistent with that in previous studies; dizziness (55 [17%] vs 45 [14%] patients), somnolence (29 [9%] vs 14 [4%]), fatigue (27 [8%] vs 19 [6%]), and weight increase (21 [6%] vs 7 [2%]) were numerically more common in the pregabalin group than in the lamotrigine group. Pregabalin has similar tolerability but seems to have inferior efficacy to lamotrigine for the treatment of newly diagnosed partial seizures in adults. Inferior efficacy of pregabalin might have been attributable to limitations in the study design, as treatment doses might have not been optimised adequately or early enough. Pfizer Inc.

P19.7 Temporal dissociations between serum drug levels and transcranial magnetic stimulation motor thresholds after oral lamotrigine

P19.7 Temporal dissociations between serum drug levels and transcranial magnetic stimulation motor thresholds after oral lamotrigine

Comparison of the efficacy of carbamazepine, gabapentin and lamotrigine for neuropathic pain in rats

Background:Neuropathic pain in cancer patients remain a treatment challenge. Many of the anticancer drugs have to be abandoned because patients develop neuropathic pain. Several antiepileptic drugs like carbamazepine, phenytoin, lamotrigine, felbamate are effective in neuropathic pain and trigeminal neuralgia. However, their efficacy varies.Aim:The aim of this study is to compare the efficacy of antiepileptic drugs in neuropathic pain induced by anticancer drugs.Materials and Methods:Neuropathic pain was induced in rats by injecting 4 doses of paclitaxel. The rats were divided into four groups of six animals each. Group I was treated with oral carbamazepine (cbz) 100 mg/kg, group II received oral gabapentin (gbp) 60 mg/kg, and group III was treated with oral lamotrigine (lam) 40 mg/kg and group IV was the control group. Behavioural testing for thermal hyperalgesia and mechanical hyperalgesia was assessed from 26th day of paclitaxel administration to next five days by hot plate method and Randall Siletto test, respectively, in all the four groups. One way analysis of variance followed by Scheffe's post hoc test was used for statistical analysis.Results:In thermal hyperalgesia lam treated group was found to be significantly (P < 0.001) superior to cbz and gbp treated group. In mechanical hyperalgesia, lam group showed significant response (P < 0.05) as compared to gbp group. However, the gbp treated group showed a significant (P < 0.01) improvement after three days of treatment.Conclusions:In paclitaxel induced neuropathic pain, lamotrigine appears to be a promising drug. The difference in responses shown by different antiepileptics’ depends on the etiology of the underlying mechanisms in neuropathic pain.

Pharmacokinetic Modelling of Lamotrigine from Plasma Concentrations in Healthy Volunteers

T he phar macokinetics of the antiepileptic a gent lamotrigine (CAS 84057-84-1) was investigated after single oral doses in 14 healthy volunteers. After t he ad- ministration of single oral doses of 2x100 mg lamot rigine chewable/soluble tablets to healthy volunteers, blo od samples were collected for the next 96 h. The pharm aco- kinetic modelling of lamotrigine showed that the dr ug exhibited two compartment open model with regard to the goodness of fits, Residual Sum of Squares (RSS), Ak aike’s Information Criteria (AIC), Schwartz Criteria (SC), stan- dard deviation of the regression (Sr), and determin ation coefficient (r 2 ). The time-concentration curves showed a mean time to reach peak plasma concentration, C max (t max ) of 2.0 h. The pharmacokinetic parameters were calcu lated based on the plasma curves. Area under the curve of con- centration versus time from zero to infinity ( 0 AUC → ∞ ), sys- temic clearance (Cl), apparent volume of distributi on (V darea ), apparent volume of distribution at steady state (V dss ), apparent volume of distribution for I.V. (V dext ), and mean residence time (MRT) were found to be 128±31 μ g.h/ mL, 1.63±0.39 L/h, 88.5±28.6 L, 83.2±23.6 L, 93.2±3 5.6 L, and 62.6±13.7 h (mean±SD), respectively. Compart - mental analysis demonstrated that oral lamotrigine tab- lets obey two compartment open model with rapid abs orp- tion and a relatively long half life.

The Effect of Atazanavir and Atazanavir/Ritonavir on UDP-Glucuronosyltransferase Using Lamotrigine as a Phenotypic Probe

Atazanavir (ATV) is known to inhibit UGT1A1-mediated glucuronidation. Here we report the effect of ATV and ATV/ritonavir (RTV) on another UGT1A isoenzyme, UGT1A4. Twenty-one healthy volunteers received a single dose of 100 mg of oral lamotrigine on days 1, 13, and 27; on each occasion blood was sampled before the dose was administered and through 120 h after ingestion of the drug. On days 8-17 the subjects received oral ATV 400 mg q.d. On days 18-30 the subjects received oral ATV 300 mg plus oral RTV 100 mg q.d. Seventeen subjects were evaluable for pharmacokinetic analysis. Geometric mean ratios (+90% confidence intervals (CIs)) of lamotrigine area under the plasma concentration-time curve (AUC)(0-inf) and peak plasma concentration (C(max)) for ATV + lamotrigine and for lamotrigine alone were 0.88 (0.86-0.91) and 0.99 (0.95-1.02), respectively; the corresponding ratios for ATV/RTV and for lamotrigine were 0.68 (0.65-0.70) and 0.94 (0.90-0.97), respectively. The mean ratio of lamotrigine-2N-glucuronide to lamotrigine AUC(0-inf) increased from 0.45 for lamotrigine to 0.71 for ATV/RTV + lamotrigine. ATV alone does not significantly influence glucuronidation of lamotrigine. In contrast, ATV/RTV results in moderately decreased exposure to lamotrigine.

Neuroprotective Effects of Oral Lamotrigine Administration on Rabbit Retinas After Pars Plana Vitrectomy and Silicone Oil Injection

To investigate potential retinal neuroprotective effects of oral lamotrigine in rabbits after pars plana vitrectomy (PPV) and intravitreal silicone oil injection (SOI). Twelve New Zealand rabbits (weight, 2.0-2.5 kg) underwent PPV with SOI on the right eye. For 30 days postoperatively, 6 rabbits received a daily oral dose of lamotrigine (25 mg/kg), and 6 rabbits received a daily oral dose of water. The animals were killed 30 days after surgery. All retinas were processed histologically, immunostained using glial fibrillary acidic protein (GFAP), and analyzed by fluorescence microscopy. Retina sections from all groups were analyzed by TUNEL for the presence of apoptosis and stained with hematoxylin-eosin for morphologic analysis and retina cell density measurements in each layer using a Zeiss Axiophot microscope and KS 400 software. Retinas from water-operated eyes showed a significant decrease in cell density associated with cell death compared with retinas from water-control eyes; cell density was reduced by 56% in the outer nuclear layer (ONL), 49% in the inner nuclear layer (INL), and 64% in the ganglion cell layer (GCL). Lamotrigine-operated retinas showed a reduction in cell death when compared with water-operated retinas; cell death was reduced by 52% in the ONL, 25% in the INL, and 56% in the GCL. Water-operated retinas showed TUNEL-positive cells and GFAP immunofluorescence throughout Müller cell processes; lamotrigine-operated retinas showed no TUNEL-positive cells and decreased GFAP staining when compared with water-operated retinas. PPV with SOI was associated with apoptosis of retinal cells and activation of glial cells in rabbit eyes. Oral lamotrigine administration provided protection against these effects.

Lack of effect of two oral sodium channel antagonists, lamotrigine and 4030W92, on intradermal capsaicin-induced hyperalgesia model

Preclinical studies have emphasized that persistent small afferent input will induce a state of central facilitation, which can be regulated by systemically administered sodium channel blockers. We have extended these preclinical studies to the human volunteers by examining the effects of lamotrigine and 4030W92, two structurally related voltage-sensitive sodium channel antagonists, on acute sensory thresholds and facilitated processing induced by intradermal capsaicin. Fifteen healthy subjects received 4030W92, lamotrigine, and placebo in a randomized order using double-blinded crossover design methodology in three sessions each separated by a 7-day washout period. In each session, baseline neurosensory testing was performed on the volar aspect of the subject's left forearm. Subjects were then dosed with either lamotrigine (300 mg), 4030W92 (100 mg), or placebo, followed 2 h later by capsaicin (100 μg) injected intradermally on the volar aspect of the left forearm. Pain scores, blood pressure, heart rate, and respiratory rate were measured at the time of injection and every 5 min for 15 min. Fifteen minutes after the capsaicin injection, the hyperalgesic area was determined by von Frey hair, stroking, and heat; the flare response was outlined; and neurosensory testing again was performed halfway between the edge of the hyperalgesic area and the capsaicin injection site. While capsaicin significantly decreased the hot pain and VF pain thresholds, oral lamotrigine and 4030W92 failed to alter this response to capsaicin, relative to placebo treatment. Similarly, oral lamotrigine or 4030W92 did not alter the pain scores reported from mechanical pain stimuli at any time postcapsaicin. This study showed a lack of effect of two structurally similar sodium channel antagonists on a human experimental pain model using intradermal capsaicin, which is consistent with other studies on the effects of sodium channel antagonists of capsaicin-induced pain and hyperalgesia. This lack of effect stands in contrast to reported effects of sodium channel antagonists on preclinical models of cutaneous hyperalgesia or effects of lamotrigine on clinical neuropathic pain.

Lack of effect of two oral sodium channel antagonists, lamotrigine and 4030W92, on intradermal capsaicin-induced hyperalgesia model

Preclinical studies have emphasized that persistent small afferent input will induce a state of central facilitation, which can be regulated by systemically administered sodium channel blockers. We have extended these preclinical studies to the human volunteers by examining the effects of lamotrigine and 4030W92, two structurally related voltage-sensitive sodium channel antagonists, on acute sensory thresholds and facilitated processing induced by intradermal capsaicin. Fifteen healthy subjects received 4030W92, lamotrigine, and placebo in a randomized order using double-blinded crossover design methodology in three sessions each separated by a 7-day washout period. In each session, baseline neurosensory testing was performed on the volar aspect of the subject's left forearm. Subjects were then dosed with either lamotrigine (300 mg), 4030W92 (100 mg), or placebo, followed 2 h later by capsaicin (100 μg) injected intradermally on the volar aspect of the left forearm. Pain scores, blood pressure, heart rate, and respiratory rate were measured at the time of injection and every 5 min for 15 min. Fifteen minutes after the capsaicin injection, the hyperalgesic area was determined by von Frey hair, stroking, and heat; the flare response was outlined; and neurosensory testing again was performed halfway between the edge of the hyperalgesic area and the capsaicin injection site. While capsaicin significantly decreased the hot pain and VF pain thresholds, oral lamotrigine and 4030W92 failed to alter this response to capsaicin, relative to placebo treatment. Similarly, oral lamotrigine or 4030W92 did not alter the pain scores reported from mechanical pain stimuli at any time postcapsaicin. This study showed a lack of effect of two structurally similar sodium channel antagonists on a human experimental pain model using intradermal capsaicin, which is consistent with other studies on the effects of sodium channel antagonists of capsaicin-induced pain and hyperalgesia. This lack of effect stands in contrast to reported effects of sodium channel antagonists on preclinical models of cutaneous hyperalgesia or effects of lamotrigine on clinical neuropathic pain.

A randomized study of the effect of oral lamotrigine and hydromorphone on pain and hyperalgesia following heat/capsaicin sensitization

In this randomized double-blind placebo-controlled study, the analgesic effect of oral lamotrigine (400 mg) on cutaneous sensitization induced with the heat/capsaicin sensitization model was compared with the effect of oral hydromorphone (8 mg) in healthy volunteers. In a separate session, intravenous remifentanil (0.10 μg · kg −1 · min −1) and placebo were administered. This session was used as an additional reference comparator. Outcome measures were the areas of secondary hyperalgesia to brush and von Frey hair stimulation and the painfulness of noxious thermal stimulation in nonsensitized skin. Compared with placebo, both intravenous remifentanil and oral hydromorphone significantly suppressed secondary hyperalgesia and acute thermal nociception. Oral lamotrigine did not reduce secondary hyperalgesia or acute thermal nociception but produced side effects of severity comparable with that of oral hydromorphone. Although lamotrigine is efficacious in the management of some types of chronic neuropathic pain, the lack of effect of this agent on human experimental pain suggests that its analgesic effects depend on nerve injury–associated abnormalities, which cannot be simulated in healthy human volunteers.

Population pharmacokinetics of lamotrigine.

The present study estimated the population pharmacokinetics of lamotrigine in patients receiving oral lamotrigine therapy with drug concentration monitoring, and determined intersubject and intrasubject variability. A total of 129 patients were analyzed from two clinical sites. Of these, 124 patients provided sparse data (198 concentration-time points); nine patients (four from a previous group plus five from the current group) provided rich data (431 points). The population analysis was conducted using P-PHARM (SIMED Scientific Software, Cedex, France), a nonlinear mixed-effect modeling program. A single exponential elimination model (first-order absorption) with heteroscedastic weighting was used. Apparent clearance (CL/F) and volume of distribution (V/F) were the pharmacokinetic parameters estimated. Covariate analysis was performed to determine which factors explained any of the variability associated with lamotrigine clearance. Population estimates of CL/F and V/F for lamotrigine generated in the final model were 2.14 +/- 0.81 L/h and 78.1 +/- 5.1 L/kg. Intersubject and intrasubject variability for clearance was 38% and 38%, respectively. The covariates of concomitant valproate and phenytoin therapy accounted for 42% of the intersubject variability of clearance. Age, gender, clinic site, and other concomitant antiepileptic drugs did not influence clearance. This study of the population pharmacokinetics of lamotrigine in patients using the drug clinically provides useful data and should lead to better dosage individualization for lamotrigine.