Disease relevance of Rilutek

• Riluzole in amyotrophic lateral sclerosis [1].
• Adverse reactions to riluzole included asthenia, spasticity, and mild elevations in aminotransferase levels [2].
• Methemoglobinemia due to riluzole [3].
• Icteric toxic hepatitis associated with riluzole [4].
• The neuroprotective effects of riluzole, a novel antiglutamate, has been demonstrated in a model of ischemia induced in female Mongolian gerbils by transient bilateral carotid occlusion [5].

Psychiatry related information on Rilutek

• This memory deficit was completely reversed in animals treated with riluzole [5].
• Open-label trial of riluzole in generalized anxiety disorder [6].
• Intoxication with riluzole in Huntington's disease [7].
• Riluzole augmentation in treatment-resistant obsessive-compulsive disorder: an open-label trial [8].
• CONCLUSIONS: Although preliminary, these results suggest that riluzole might indeed have antidepressant efficacy in subjects with bipolar depression [9].

High impact information on Rilutek

• A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group [2].
• Thus, a purely electrical alteration is sufficient to cause cerebellar ataxia, and SK openers such as the neuroprotective agent riluzole may reduce neuronal hyperexcitability and have therapeutic value [10].
• TRAAK channels are stimulated by the neuroprotective drug riluzole [11].
• Furthermore, cell culture studies revealed that 2-amino-4,7-dimethyl-benzothiazol-6-ol, a chemical compound similar to riluzole, significantly inhibits HD exon 1 aggregation in vivo [12].
• The neuronal degeneration of CA1 pyramidal cells in the hippocampus observed in the ischemic group was not seen in the riluzole-treated animals, which resembled the control group [5].

Chemical compound and disease context of Rilutek

• This region was shown to contribute to the high sensitivity and specificity of the induction mediated by riluzole in the C6 glioma cell line at pharmacologically relevant concentrations [13].
• Evaluation of the benzothiazole aggregation inhibitors riluzole and PGL-135 as therapeutics for Huntington's disease [14].
• The neuroprotective effects of Riluzole, a compound with several mechanisms of action including the inhibition of sodium channel activity and glutamate release, were evaluated in a rat model of parasagittal fluid-percussion (FP) brain injury [15].
• The neuroprotective drug riluzole blocked sodium channels and high-voltage-activated calcium channels, thereby preventing excess stimulation of N-methyl-D-aspartate receptors and massive influx of calcium, thereby retarding spread of infarction in the brain [16].
• The protective effect of riluzole in the MPTP model of Parkinson's disease in mice is not due to a decrease in MPP(+) accumulation [17].

Biological context of Rilutek

• Inactivation of dEAAT1 by RNA interference led to characteristic behavior deficits that were significantly rescued by expression of the human glutamate transporter hEAAT2 or the administration in food of riluzole, an anti-excitotoxic agent used in the clinic for human ALS patients [18].
• CONCLUSION: The pharmacokinetics of riluzole has been characterized in patients during long-term therapy [19].
• Decrement of the thenar compound muscle action potentials (CMAP), after repetitive nerve stimulation (RNS) of the median nerve at 3 Hz, was evaluated in patients with ALS before riluzole therapy [20].
• Mutants of TREK-1 lacking the Ser residue where the kinase A phosphorylation takes place are activated in a sustained manner by riluzole [21].
• These results show that the riluzole binding site is on the alpha subunit of the sodium channel, and they suggest that stabilization of the inactivated state may underlie the neuroprotective properties of riluzole [22].

Anatomical context of Rilutek

• (i) When the oocytes were held at strongly hyperpolarized potentials to close the sodium channels and riluzole was added to the external solution, the current elicited by test depolarizing pulses was reduced within a few minutes and recovered upon washout of the riluzole [22].
• In the Cox multivariate model, age, progression rate of respiratory, bulbar, and lower limb symptoms, EEDC classification, percutaneous endoscopic gastrostomy, and treatment with riluzole were significantly related to outcome [23].
• Rapid calpain I activation and cytoskeletal protein degradation following traumatic spinal cord injury: attenuation with riluzole pretreatment [24].
• DESIGN: Subjects with homozygous deletions of the survival motor neuron gene were recruited from pediatric neuromuscular clinics and randomized in a 2:1 ratio, 2 riluzole to 1 placebo [25].
• However, in the same cell systems, riluzole induced neuronal and glial cell death with concentrations higher than those needed for maximal protective effects (> or =100 microM:) [26].

Associations of Rilutek with other chemical compounds

• As with TREK1, TREK2 is activated by the volatile general anesthetics chloroform, halothane, and isoflurane and by the neuroprotective agent riluzole [27].
• Protection against excitotoxicity could be achieved with a combination of pharmacologic agents having neuroprotective activity, such as antiglutamate agents (e.g., riluzole), N-methyl-D-aspartate (NMDA) and non-NMDA antagonists, free-radical scavengers, calcium-channel blockers, and neurotrophic factors [28].
• Pharmacological blocking agents applied during whole-cell recordings in current-clamp mode demonstrated that the medium AHP conductance (apamin), BK-type Ca2+ -dependent K+ channels (iberiotoxin), voltage-activated Ca2+ channels (CdCl2), M-current (linopirdine) and persistent Na+ currents (riluzole) are all unnecessary for SFA [29].
• The metabotropic glutamate receptor subtype 5 antagonist MPEP and the Na+ channel blocker riluzole show different neuroprotective profiles in reversing behavioral deficits induced by excitotoxic prefrontal cortex lesions [30].
• In the second protocol, consisting of 3 injections of MPTP (15 mg/kg i.p.), riluzole, administered 4 times at the dose of 5 mg/kg p.o., had no effect on MPP(+) levels [17].
• Phosphorylation of GluR1 at the PKA (cAMP-dependent protein kinase) site (S845) was enhanced in both lamotrigine- and riluzole-treated hippocampal neurons, but reduced in valproate-treated neurons [31].

Gene context of Rilutek

• Thus, riluzole is predominantly metabolized by CYP1A2 in human hepatic microsomes to N-hydroxyriluzole; extrahepatic CYP1A1 can also be responsible for the formation of several other metabolites [32].
• Also, nNOS activity was significantly decreased in riluzole-anesthetized rats (40 mg kg(-1) i.p., -32+/-6% from controls, P<0.05) [33].
• Furthermore, riluzole markedly increased the striatal GFAP-positive astrocytes 3 days after MPTP treatments [34].
• Our immunohistochemical study with TH and MAP 2 staining showed that riluzole can protect against MPTP-induced neuronal damage in the substantia nigra [34].
• We investigated the effects of the neuroprotective drug, riluzole, on the GDNF gene expression in glial cells [13].
• In the hGRM1-positive cell lines C8161 and UACC903, riluzole enhanced the lethal effects of ionizing radiation; no difference was seen in the hGRM1-negative UACC930 cell line [35].

Analytical, diagnostic and therapeutic context of Rilutek

• FINDINGS: At the end of the study, after median follow-up of 18 months, 122 (50.4%) placebo-treated patients and 134 (56.8%) of those who received 100 mg/day riluzole were alive without tracheostomy (unadjusted risk 0.79, p = 0.076; adjusted risk 0.65, p = 0.002) [36].
• Using transcranial magnetic stimulation, the effect of riluzole (RLZ) on cortical excitability was studied in patients with amyotrophic lateral sclerosis (ALS) [37].
• One early attempt to define disease stages consisted of post-hoc analysis of the international, placebo-controlled, clinical trials of riluzole [38].
• Riluzole plasma levels were determined by HPLC, and the data were analyzed by nonlinear mixed-effect modeling (NONMEM program) with use of a one-compartment structural model [19].
• METHODS: Thirteen patients aged between 18 and 65 years with a primary diagnosis of OCD that had proven resistant to standard treatment were treated with the addition of riluzole to their existing pharmacotherapy [8].

References