Synthesis, characterization, in-silico, and pharmacological evaluation of new 2-amino-6­trifluoromethoxy benzothiazole derivatives.

Alzheimer's disease (AD), a relentless neurodegenerative disorder, is still waiting for safer profile drugs, risk factors affecting AD's pathogenesis include aß accumulation, tau protein hyperphosphorylation, and neuroinflammation. This research aimed to synthesize 2-amino-6­trifluoromethoxy benzothiazole schiff bases. Synthesis was straightforward, combining the riluzole skeleton with compounds containing the azomethine group. Schiff bases synthesized were characterized spectroscopically using proton NMR (1H NMR), and FTIR. In-vivo biological evaluation against scopolamine-induced neuronal damage revealed that these newly synthesized schiff bases were effective in protecting neurons against neuroinflammatory mediators. In-vitro results revealed that these compounds had remarkable potential in improving the anti-oxidant levels. It downregulated glutathione (GSH), glutathione S-transferase (GST), catalase levels, and upregulated lipid peroxidation (LPO) levels. Immunohistochemical studies revealed that groups treated with the newly synthesized schiff bases had reduced expression of inflammatory mediators such as cyclooxygenase 2 (COX-2), JNK, tumor necrosis factor (TNF-α), nuclear factor kappa B (NF-kB) in contrast to the disease group. Moreover, molecular docking studies on these compounds also showed that they possessed a better binding affinity for above mentioned inflammatory mediators. The results of these studies showed that 2-amino-6-trifluoromethoxy benzothiazole schiff bases are remarkably effective against oxidative stress-mediated neuroinflammation.

Longitudinal Impact of Acute Spinal Cord Injury on Clinical Pharmacokinetics of Riluzole, a Potential Neuroprotective Agent.

Riluzole, a benzothiazole sodium channel blocker that received US Food and Drug Administration approval to attenuate neurodegeneration in amyotrophic lateral sclerosis in 1995, was found to be safe and potentially efficacious in a spinal cord injury (SCI) population, as evident in a phase I clinical trial. The acute and progressive nature of traumatic SCI and the complexity of secondary injury processes can alter the pharmacokinetics of therapeutics. A 1-compartment with first-order elimination population pharmacokinetic model for riluzole incorporating time-dependent clearance and volume of distribution was developed from combined data of the phase 1 and the ongoing phase 2/3 trials. This change in therapeutic exposure may lead to a biased estimate of the exposure-response relationship when evaluating therapeutic effects. With the developed model, a rational, optimal dosing scheme can be designed with time-dependent modification that preserves the required therapeutic exposure of riluzole.

Riluzole-loaded nanoparticles to alleviate the symptoms of neurological disorders by attenuating oxidative stress.

Purpose: The objective of the research undertaken was to develop the Riluzole (RIZ) nanoparticles drug delivery system using Transferrin (Tf) as a ligand in the brain.Method: RIZ-loaded chitosan nanoparticles and RIZ-Tf chitosan (CS) nanoparticles (RIZ CSNPs and RIZ-Tf CSNPs) were formulated and compared for particles size, size distribution, encapsulation efficiency, and surface morphology, respectively. The in vitro drug release, permeation, pharmacokinetic, biochemical, and pharmacodynamic experiments were done to assess the improvement in in vivo fate and efficacy of RIZ.Results: The size of optimized RIZ CSNPs was found to be 173.6 ± 2.23 nm and polydispersity index (PDI) of 0.264 ± 0.002 while that of RIZ-Tf CSNPs was 207 ± 2.49 nm and 0.406 ± 0.002. In vitro release was found to be 86.15 ± 7.316% and 91.1 ± 5.836%, respectively, while permeability coefficient was found to be 4 × 10-2 and 4.2 × 10-2 cm/s for RIZ CSNPs and RIZ-Tf CSNPs. The biochemical analysis studies revealed that oxidative stress was significantly decreased in case of RIZ CSNPs and RIZ-Tf CSNPs (p < 0.01) treated groups. The antianxiety effect and the memory restoration were evident in pharmacodynamic studies (p < 0.05) of the prepared formulations.Conclusion: The results of pharmacokinetic studies demonstrated the remarkable brain delivery of RIZ-Tf CSNPs through intranasal route as compared to the RIZ solution.

A Pharmacokinetic Bioequivalence Study Comparing Sublingual Riluzole (BHV-0223) and Oral Tablet Formulation of Riluzole in Healthy Volunteers.

Orally administered riluzole extends survival in patients with amyotrophic lateral sclerosis, although it has significant shortcomings (eg, adverse events, dysphagic patients) that limit its utility. BHV-0223 is a Zydis-based orally disintegrating formulation of riluzole designed for sublingual administration that addresses the limitations of conventional tablets. This study assessed the bioequivalence between 40-mg BHV-0223 and standard 50-mg oral riluzole tablets, and the food effect on BHV-0223 pharmacokinetics in healthy volunteers. Overall, 133 healthy subjects received BHV-0223 and riluzole tablets under fasted conditions. Geometric mean ratios for the area under the plasma concentration-time curve (AUC) from time zero to time of last nonzero concentration (AUC0-t ) (89.9%; confidence interval [CI], 87.3%-92.5%), AUC from time zero to infinity (AUC0-∞ ) (89.8%; CI, 87.3%-92.4%), and maximum observed concentration (112.7%; CI, 105.5%-120.4%) all met bioequivalence criteria (80%-125%). Subsequently, 67 subjects received BHV-0223 under fed conditions. The geometric mean ratios of AUC0-t (91.2%; CI, 88.1-94.3%), and AUC0-∞ (92.0%; CI, 89.0-95.1%) were similar, but maximum observed concentration ratios were not within bioequivalence criteria. BHV-0223 was well tolerated. This study demonstrated that 40-mg sublingual BHV-0223 is bioequivalent to 50-mg oral riluzole tablets.

Riluzole Oral Suspension: Bioavailability Following Percutaneous Gastrostomy Tube-modeled Administration Versus Direct Oral Administration.

PURPOSE: During amyotrophic lateral sclerosis progression, up to 85% of patients develop dysphagia. Riluzole oral suspension 50 mg/10 mL is bioequivalent to riluzole 50-mg film-coated tablets administered orally under fasting conditions. Here, we compare the bioavailability of a single 50-mg dose of riluzole oral suspension via intragastric tube, a proxy for percutaneous endoscopic gastrostomy administration, with that of oral administration in healthy volunteers under fasting conditions. Secondary objectives included the plasma pharmacokinetic and safety profiles of each administration route. METHODS: This was a single-center, single-dose, open-label, randomized, 2-period, 2-sequence, crossover bioequivalence/bioavailability study. Healthy volunteers were randomized to riluzole oral suspension 50 mg/10 mL either via nasogastric tube or orally, with a 5-day washout before crossover. FINDINGS: A total of 32 subjects were randomized (safety population); 30 were eligible for pharmacokinetic analysis. The ratios (nasogastric tube/oral) of the geometric least squares means and the geometric 90% CIs of AUC0-t, AUC0-inf, and Cmax were calculated to be 90.60% (85.66%-95.82%), 90.43% (85.47%-95.67%), and 96.99% (89.40%-105.23%), respectively, indicating bioequivalence. No significant differences in Cmax, Tmax, Kel, and t1/2el between treatments were found. Overall, riluzole oral suspension was well tolerated. No deaths or other serious adverse events were reported. IMPLICATIONS: In this study, riluzole oral suspension was bioequivalent when administered intragastrically and orally in healthy subjects under fasting conditions. Both administration methods were well tolerated. These results show that intragastric administration of riluzole oral suspension may provide an important formulation option in people with amyotrophic lateral sclerosis who have a percutaneous endoscopic gastrostomy tube.

Chalcogen OCF3 Isosteres Modulate Drug Properties without Introducing Inherent Liabilities.

The synthesis of SCF3 as well as SeCF3 isosteres of two OCF3 -containing drugs was achieved through visible light and copper-catalyzed processes. Herein, we show that chalcogen replacement modulates physicochemical and ADME properties without introducing intrinsic liabilities. The SCF3 and SeCF3 groups are more lipophilic than their oxygen counterpart; however, microsomal stability is unchanged, indicating that these molecular changes may be beneficial for in vivo half-life. Enabled by modern synthetic methods, we present the chalcogen-CF3 groups as potential key players for future fluorinated pharmaceuticals.

Efficacy of riluzole in the treatment of spinal cord injury: a systematic review of the literature.

OBJECTIVERiluzole is a glutamatergic modulator that has recently shown potential for neuroprotection after spinal cord injury (SCI). While the effects of riluzole are extensively documented in animal models of SCI, there remains heterogeneity in findings. Moreover, there is a paucity of data on the pharmacology of riluzole and its effects in humans. For the present study, the authors systematically reviewed the literature to provide a comprehensive understanding of the effects of riluzole in SCI.METHODSThe PubMed database was queried from 1996 to September 2018 to identify animal studies and clinical trials involving riluzole administration for SCI. Once articles were identified, they were processed for year of publication, study design, subject type, injury model, number of subjects in experimental and control groups, dose, timing/route of administration, and outcomes.RESULTSA total of 37 studies were included in this study. Three placebo-controlled clinical trials were included with a total of 73 patients with a mean age of 39.1 years (range 18-70 years). For the clinical trials included within this study, the American Spinal Injury Association Impairment Scale distributions for SCI were 42.6% grade A, 25% grade B, 26.6% grade C, and 6.2% grade D. Key findings from studies in humans included decreased nociception, improved motor function, and attenuated spastic reflexes. Twenty-six animal studies (24 in vivo, 1 in vitro, and 1 including both in vivo and in vitro) were included. A total of 520 animals/in vitro specimens were exposed to riluzole and 515 animals/in vitro specimens underwent other treatment for comparison. The average dose of riluzole for intraperitoneal, in vivo studies was 6.5 mg/kg (range 1-10 mg/kg). Key findings from animal studies included behavioral improvement, histopathological tissue sparing, and modified electrophysiology after SCI. Eight studies examined the pharmacology of riluzole in SCI. Key findings from pharmacological studies included riluzole dose-dependent effects on glutamate uptake and its modified bioavailability after SCI in both animal and clinical models.CONCLUSIONSSCI has many negative sequelae requiring neuroprotective intervention. While still relatively new in its applications for SCI, both animal and human studies demonstrate riluzole to be a promising pharmacological intervention to attenuate the devastating effects of this condition.

Pharmacokinetics of Riluzole in Beagle Dogs.

BACKGROUND: Riluzole is a benzothiazole anticonvulsant used in the treatment of patients with amyotrophic lateral sclerosis and it is being investigated for clinical use in patients with spinal cord injury. The present study evaluated the pharmacokinetics of riluzole in beagle dogs after oral dose administration. METHODS: The oral doses (1.5, 5, 15 and 50 mg/kg) of riluzole were administered to beagle dogs and blood samples were collected from 0 h to 24 h post drug administration. Riluzole was quantified by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). RESULTS: The method was sensitive, precise, accurate and selective to riluzole quantification in plasma of beagle dogs. The pharmacokinetics following oral administration was linear from 1.5 to 15 mg/kg and the t1/2 was 2.16, 1.5, 1.8 and 3.0 h after oral administration of 1.5, 5.0, 15 and 50 mg/kg riluzole. CONCLUSION: The riluzole pharmacokinetics was linear up to 15 mg/kg and had a significantlyshorter t1/2 in beagle dogs than in humans.

Rational design and development of a stable liquid formulation of riluzole and its pharmacokinetic evaluation after oral and IV administrations in rats.

Enterally administered riluzole is currently being investigated in a Phase II/III clinical trial for the treatment of acute spinal cord injury (SCI). Many SCI patients suffer from severe motor dysfunction and exhibit swallowing difficulties and cannot swallow riluzole tablets. The purpose of the present study was to develop a liquid solution formulation of riluzole, which can be administered more easily to this patient population with the capability to adjust the dose if needed. Riluzole was solubilized using water miscible organic solvents, namely, polyethylene glycol 400, propylene glycol and glycerin. A Central Composite Design (CCD) approach was used to develop an optimum co-solvent composition that can solubilize the entire 50 mg dose of riluzole in 5 ml. A three-factor five-level design was employed to investigate the effects of composition of co-solvents on riluzole solubility. The selected optimum formulation consists of 15% v/v PEG 400, 20% v/v propylene glycol and 10% v/v glycerin, with riluzole concentration of 10 mg/ml. The optimum composition was assessed for stability at different temperatures. Satisfactory stability was obtained at room temperature and 4 °C (t90 of 17 and 35 months, respectively). The optimum formulation of riluzole was suitable for both oral and intravenous administrations. Single dose pharmacokinetic studies of the optimum formulation by oral and IV routes were evaluated in rats, using commercially available Rilutek® tablets as a reference. The co-solvent formulation was well tolerated both orally and intravenously. In comparison to the commercial tablet, the co-solvent formulation had a faster rate of absorption and more sustained plasma levels with a significantly longer elimination half-life. Higher concentrations of riluzole in brain and spinal cord were achieved from co-solvent formulation as compared to tablet. The riluzole solution formulation is stable and offers advantages of ease of administration, consistent dosing, rapid onset and longer duration of action, better availability at site of action which can be extremely beneficial for the therapy in SCI patients.

Acute Effects of Riluzole and Retigabine on Axonal Excitability in Patients With Amyotrophic Lateral Sclerosis: A Randomized, Double-Blind, Placebo-Controlled, Crossover Trial.

Increased excitability of motor neurons in patients with amyotrophic lateral sclerosis (ALS) may be a relevant factor leading to motor neuron damage. This randomized, double-blind, three-way crossover, placebo-controlled study evaluated peripheral motor nerve excitability testing as a biomarker of hyperexcitability and assessed the effects of riluzole and retigabine in 18 patients with ALS. We performed excitability testing at baseline, and twice after participants had received a single dose of either 100 mg riluzole, 300 mg retigabine, or placebo. Between- and within-day repeatability was at least acceptable for 14 out of 18 recorded excitability variables. No effects of riluzole on excitability testing were observed, but retigabine significantly decreased strength-duration time-constant (9.2%) and refractoriness at 2 ms (10.2) compared to placebo. Excitability testing was shown to be a reliable biomarker in patients with ALS, and the acute reversal of previously abnormal variables by retigabine justifies long-term studies evaluating the impact on disease progression and survival.

Two Decades-Long Journey from Riluzole to Edaravone: Revisiting the Clinical Pharmacokinetics of the Only Two Amyotrophic Lateral Sclerosis Therapeutics.

The recent approval of edaravone has provided an intravenous option to treat amyotrophic lateral sclerosis (ALS) in addition to the existing oral agent, riluzole. The present work was primarily undertaken to provide a comprehensive clinical pharmacokinetic summary of the two approved ALS therapeutics. The key objectives of the review were to (i) tabulate the clinical pharmacokinetics of riluzole and edaravone with emphasis on absorption, distribution, metabolism and excretion (ADME) properties; (ii) provide a comparative scenario of the pharmacokinetics of the two drugs wherever possible; and (iii) provide perspectives and introspection on the gathered clinical pharmacokinetic data of the two drugs with appropriate conjectures to quench scientific curiosity. Based on this review, the following key highlights were deduced: (i) as a result of both presystemic metabolism and polymorphic hepatic cytochrome P450 (CYP) metabolism, the oral drug riluzole exhibited more inter-subject variability than that of intravenous edaravone; (ii) using various parameters for comparison, including the published intravenous data for riluzole, it was apparent that edaravone was achieving the desired systemic concentrations to possibly drive the local brain concentrations for its efficacy in ALS patients with lesser variability than riluzole; (iii) using scientific conjectures, it was deduced that the availability of intravenous riluzole may not be beneficial in therapy due to its fast systemic clearance; (iv) on the contrary, however, there appeared to be an opportunity for the development of an oral dosage form of edaravone, which may potentially benefit the therapy option for ALS patients by avoiding hospitalization costs; and (v) because of the existence of pharmaco-resistance for the brain entry in ALS patients, it appeared prudent to consider combination strategies of edaravone and/or riluzole with suitable P-glycoprotein efflux-blocking drugs to gain more favorable outcomes in ALS patients.

A validated UHPLC-MS/MS method for the measurement of riluzole in plasma and myocardial tissue samples.

Through blocking the cardiac persistent sodium current, riluzole has the potential to prevent myocardial damage post cardiac bypass surgery. A sensitive UHPLC-MS/MS method was developed and validated for quantitation of riluzole and 5-methoxypsoralen in human plasma and myocardial tissue homogenate using a liquid-liquid extraction with dichloromethane. The chromatographic separation was achieved using Shimadzu Shim-pack XR-ODS III, 2.0 × 50 mm, 1.6 µm column with a gradient mobile phase comprising methanol and ammonium acetate buffer pH 3.6 in purified water. The analyte and internal standard were separated within 3.5 min. Riluzole quantitation was achieved using the mass transitions of 235-138 for riluzole and 217-156 for 5-methoxypsoralen. The method was linear for riluzole plasma concentrations from 0.2 to 500 ng/mL and myocardial tissue homogenate concentrations from 0.2 to 100 ng/mL. The method developed was successfully applied to a clinical study for patients receiving riluzole while undergoing cardiac bypass surgery.

Riluzole 5 mg/mL oral suspension: for optimized drug delivery in amyotrophic lateral sclerosis.

The aim of the present work is to extensively evaluate the pharmaceutical attributes of currently available riluzole presentations. The article describes the limitations and risks associated with the administration of crushed tablets, including the potential for inaccurate dosing and reduced rate of absorption when riluzole is administered with high-fat foods, and the advantages that a recently approved innovative oral liquid form of riluzole confers on amyotrophic lateral sclerosis (ALS) patients. The article further evaluates the patented and innovative controlled flocculation technology used in the pseudoplastic suspension formulation to reduce the oral anesthesia seen with crushed tablets, resulting in optimized drug delivery for riluzole. Riluzole is the only drug licensed for treating ALS, which is the most common form of motor neurone disease and a highly devastating neurodegenerative condition. The licensed indication is to extend life or the time to mechanical ventilation. Until recently, riluzole was only available as an oral tablet dosage form in the UK; however, an innovative oral liquid form, Teglutik® 5 mg/mL oral suspension, is now available. An oral liquid formulation provides an important therapeutic option for patients with ALS, >80% of who may become unable to swallow solid oral dosage forms due to disease-related dysphagia. Prior to the launch of riluzole oral suspension, the only way for many patients to continue to take riluzole as their disease progressed was through crushed tablets. A novel suspension formulation enables more accurate dosing and consistent ongoing administration of riluzole. There are clear and important advantages such as enhanced patient compliance compared with crushed tablets administered with food or via an enteral feeding tube and the potential for an improved therapeutic outcome and enhanced quality of life for ALS patients.

Nanoemulsions for Intranasal Delivery of Riluzole to Improve Brain Bioavailability: Formulation Development and Pharmacokinetic Studies.

BACKGROUND: Amyotrophic Lateral Sclerosis (ALS), a motor neuron disease (MND), is a progressive neurodegenerative disorder characterized by the deterioration of both upper and lower motor neurons. Only one drug (riluzole) has been approved for the treatment of ALS. Riluzole is a BCS class II drug having 60% absolute bioavailability. It is a substrate of P-glycoprotein and BBB restricts its entry in brain. OBJECTIVE: This investigation was aimed to develop O/W nanoemulsion system of riluzole to improve its brain bioavailability. METHODS: Riluzole loaded nanoemulsion was prepared by phase titration method. It was consisting of 3% w/w Sefsol 218, 28.3% w/w Tween 80:Carbitol (1:1) and 68.7% w/w water. It was characterized for drop size, drop size distribution, transmittance, viscosity, pH, zeta potential, conductivity and nasal ciliotoxicity study. Thermodynamic stability and room temperature stability of prepared nanoemulsion formulation were evaluated. Pharmacokinetic and brain uptake study was carried out using albino rats (wistar) post intranasal and oral administration. RESULTS: Riluzole loaded nanoemulsion was having a drop size of 23.92±0.52 nm. It was free from nasal ciliotoxicity and stable for three months. Brain uptake of riluzole post intranasal administration of riluzole loaded nanoemulsion was significantly (P <4.10 × 10-6) higher when it was compared with oral administration of riluzole loaded nanoemulsion. CONCLUSION: This study indicates that nanoemulsion of riluzole for intranasal administration could be a promising approach for the treatment of ALS to minimize the dose of riluzole in order to avoid dose related adverse events.

A prospective, multicenter, phase I matched-comparison group trial of safety, pharmacokinetics, and preliminary efficacy of riluzole in patients with traumatic spinal cord injury.

A prospective, multicenter phase I trial was undertaken by the North American Clinical Trials Network (NACTN) to investigate the pharmacokinetics and safety of, as well as obtain pilot data on, the effects of riluzole on neurological outcome in acute spinal cord injury (SCI). Thirty-six patients, with ASIA impairment grades A-C (28 cervical and 8 thoracic) were enrolled at 6 NACTN sites between April 2010 and June 2011. Patients received 50 mg of riluzole PO/NG twice-daily, within 12 h of SCI, for 14 days. Peak and trough plasma concentrations were quantified on days 3 and 14. Peak plasma concentration (Cmax) and systemic exposure to riluzole varied significantly between patients. On the same dose basis, Cmax did not reach levels comparable to those in patients with amyotrophic lateral sclerosis. Riluzole plasma levels were significantly higher on day 3 than on day 14, resulting from a lower clearance and a smaller volume of distribution on day 3. Rates of medical complications, adverse events, and progression of neurological status were evaluated by comparison with matched patients in the NACTN SCI Registry. Medical complications in riluzole-treated patients occurred with incidences similar to those in patients in the comparison group. Mild-to-moderate increase in liver enzyme and bilirubin levels were found in 14-70% of patients for different enzymes. Three patients had borderline severe elevations of enzymes. No patient had elevated bilirubin on day 14 of administration of riluzole. There were no serious adverse events related to riluzole and no deaths. The mean motor score of 24 cervical injury riluzole-treated patients gained 31.2 points from admission to 90 days, compared to 15.7 points for 26 registry patients, a 15.5-point difference (p=0.021). Patients with cervical injuries treated with riluzole had more-robust conversions of impairment grades to higher grades than the comparison group.

Effect of ciprofloxacin and grapefruit juice on oral pharmacokinetics of riluzole in Wistar rats.

OBJECTIVES: The objective of this study was to explore potential drug-drug/food interactions of ciprofloxacin and grapefruit juice, known hepatic cytochrome P450 (CYP) 1A2 inhibitors, on single-dose oral pharmacokinetics of riluzole, a substrate of CYP 1A2 enzymes. METHODS: Pharmacokinetic parameters of riluzole were determined in Wistar rats after single-dose co-administration with ciprofloxacin and grapefruit juice. In-vitro metabolic inhibition studies using rat and human liver microsomes and intestinal absorption studies of riluzole in a rat everted gut-sac model were conducted to elucidate the mechanism of interaction. A validated HPLC method was employed to quantify riluzole in the samples obtained in various studies. KEY FINDINGS: Co-administration of ciprofloxacin with riluzole caused significant increase in systemic exposure of riluzole (area under the curve, maximum plasma concentration and mean residence time were found to increase). Co-administration of grapefruit juice with riluzole did not cause any significant difference in the pharmacokinetic parameters of riluzole. In-vitro metabolism studies demonstrated significant inhibition of riluzole metabolism when it was co-incubated with ciprofloxacin or grapefruit juice. No significant change was observed in apparent permeability of riluzole. CONCLUSIONS: Co-administration of ciprofloxacin with riluzole increases the systemic levels of riluzole and thereby the oral pharmacokinetic properties of riluzole while co-administration of grapefruit juice with riluzole has no significant effect.

Pharmacology of riluzole in acute spinal cord injury.

OBJECT: The aim of this paper was to characterize individual and population pharmacokinetics of enterally administered riluzole in a Phase 1 clinical trial of riluzole as a neuroprotective agent in adults 18-70 years old with acute spinal cord injury (SCI). METHODS: Thirty-five individuals with acute SCI, American Spinal Injury Association Impairment Scale Grades A-C, neurological levels from C-4 to T-12, who were enrolled in the Phase 1 clinical trial sponsored by the North American Clinical Trials Network for Treatment of Spinal Cord Injury, received 50 mg riluzole twice daily for 28 doses. The first dose was administered at a mean of 8.7 ± 2.2 hours postinjury. Trough plasma samples were collected within 1 hour predose, and peak plasma samples were collected 2 hours postdose on Days 3 and 14 of treatment. Riluzole concentrations were quantified by high-performance liquid chromatography assay. The data were analyzed for individual and population pharmacokinetics using basic structural and covariate models. The pharmacokinetic measures studied were the peak concentration (C(max)), trough concentration (C(min)), systemic exposure (AUC(0-12)), clearance (CL/F), and volume of distribution (V_F) normalized by the bioavailability (F). RESULTS: The C(max) and AUC(0-12) achieved in SCI patients were lower than those in ALS patients on the same dose basis, due to a higher CL and larger V. The pharmacokinetics of riluzole (C(max), C(min), AUC(0-12), CL, and V) changed during the acute and subacute phases of SCI during the 14 days of therapy. It was consistently observed in patients at all clinical sites that C(max), C(min), and AUC(0-12) (128.9 ng/ml, 45.6 ng/ml, and 982.0 ng × hr/ml, respectively) were significantly higher on Day 3 than on Day 14 (76.5 ng/ml, 19.1 ng/ml, and 521.0 ng × hr/ml, respectively). These changes resulted from lower CL (49.5 vs 106.2 L/hour) and smaller V (557.1 vs 1297.9/L) on Day 3. No fluid imbalance or cytochrome P 1A2 induction due to concomitant medications was identified during the treatment course to account for such increases in V and CL, respectively. Possible mechanisms underlying these changes are discussed. CONCLUSIONS: This is the first report of clinical pharmacokinetics of riluzole in patients with SCI. The C(max) and AUC(0-12) achieved in SCI patients were lower than those in ALS patients on the same dose basis, due to a higher clearance and larger volume of distribution in SCI patients. The finding in SCI patients of an increase in the clearance and distribution of riluzole between the 3rd and 14th days after SCI, with a lower plasma concentration of riluzole on the 14th day, stresses the importance of monitoring changes in drug metabolism after SCI in interpreting the safety and efficacy of therapeutic drugs that are used in clinical trials in SCI. Clinical trial registration no.: NCT00876889.

Quantitative estimation of riluzole in human plasma by LC-ESI-MS/MS and its application to a bioequivalence study.

A novel simple, sensitive, selective, and rapid high-performance liquid chromatography coupled with tandem mass spectrometry method was developed and validated for quantification of riluzole in human plasma. The chromatography was performed by using a Zorbax-SB-C18 (4.6 x 75 mm, 3.5 microm) column , isocratic mobile phase 0.1% formic acid/acetonitrile (10:90 v/v), and an isotope-labeled internal standard (IS), [(13)C,(15)N(2)]riluzole. The extraction of drug and internal standard was performed by liquid-liquid extraction and analyzed by MS in the multiple reaction monitoring (MRM) mode using the respective [M+H](+) ions, m/z 235.0/165.9 for riluzole and m/z 238.1/169.0 for the IS. The calibration curve was linear over the concentration range 0.5-500.0 ng/ml for riluzole in human plasma. The limit of quantification (LOQ) was demonstrated at 0.5 ng/ml. The within-batch and between-batch precision were 0.6-2.3% and 1.4-5.7%, and accuracy was 97.1-101.1% and 98.8-101.2% for riluzole respectively. Drug and IS were eluted within 3.0 min. The validated method was successfully applied in a bioequivalence study of riluzole in human plasma.

Riluzole, neuroprotection and amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a universally fatal neurodegenerative disease of the human motor system. Aetiological mechanisms implicated in the development of ALS have been linked to the glutamatergic neurotransmitter system, with destruction of motor neurons triggered through excessive activation of glutamate receptors at the synaptic cleft. This 'excitotoxicity' theory of ALS gave rise to the development of therapeutic approaches and ultimately clinical trials involving riluzole, initially thought to act solely as an inhibitor of glutamate release. Subsequent effects of riluzole have been postulated to include indirect antagonism of glutamate receptors, in addition to inactivation of neuronal voltage-gated Na+ channels. Riluzole remains the only disease-modifying therapy available to patients with ALS. Despite having been clinically available since the mid-1990 s, the in vivo pharmacological targets of riluzole have been poorly defined. An improved understanding concerning the potential neuroprotective mechanisms of riluzole may unearth pathophysiological processes that mediate neurodegeneration in ALS. The present review summarises the known chemical and pharmacological properties of riluzole. The failure of other putative neuroprotective therapies to demonstrate positive treatment outcomes in this intractable disease will be reviewed. Finally, the hypothesis that Na+ conductances may be involved in the processes of neuronal and axonal degeneration in ALS will be explored.

Evidences for pharmacokinetic interaction of riluzole and topiramate with pilocarpine in pilocarpine-induced seizures in rats.

In this study we investigated the effectiveness of two antiepileptic drugs: riluzole and topiramate against pilocarpine-induced seizures, which are considered to be a model of intractable epilepsy commonly used to investigate the antiepileptic effect of drugs and mechanisms of epileptogenesis. Seizures and status epilepticus were induced by pilocarpine in adult male Wistar rats. Riluzole (1-4mg/kg) administered intraperitoneally before pilocarpine dose-dependently protected rats against seizures with the anticonvulsant ED(50) value (50% effective anticonvulsant dose) of 1.8 (1.3-2.6)mg/kg. In contrast, riluzole at 8 and 12mg/kg administered after the onset of pilocarpine-induced seizures affected neither status epilepticus nor mortality of rats. Topiramate significantly enhanced convulsive action of pilocarpine, lowering the convulsant CD(50) value (50% effective convulsant dose) of pilocarpine from 350.8 (329.2-373.8) to 246.4 (218.6-278.2)mg/kg. Riluzole (4mg/kg) lowered plasma and brain concentration of pilocarpine administered at a dose of 400mg/kg from 168.0+/-8.6 to 75.3+/-19.9microg/ml and from 193.7+/-6.6 to 97.0+/-26.1microg/g, respectively. Topiramate (200mg/kg) increased plasma and brain concentration of pilocarpine administered at a dose of 300mg/kg from 78.1+/-2.9 to 106.0+/-6.8microg/ml and from 138.4+/-5.0 to 155.2+/-5.1microg/g, respectively. It seems that both anticonvulsant effect exerted by riluzole and proconvulsant effect exerted by topiramate in pilocarpine model of seizures are due to a pharmacokinetic interaction. Therefore, we postulate that the concentration of pilocarpine should be measured routinely whenever the anticonvulsant effect of drugs is determined in the pilocarpine model of seizures.