Long-term use and remission of granulomatosis with polyangiitis with the oral C5a receptor inhibitor avacopan.

Granulomatosis with polyangiitis (GPA) is a rare antineutrophil cytoplasm antibody-associated vasculitis. Several therapeutic advances have occurred over the past two decades, but relapse rate remains high and refractory cases are not uncommon. Here, we present the case of a female patient diagnosed with GPA at the age of 9 years with a severe, multirelapsing disease course which failed to adequately respond to conventional therapies. Avacopan, a novel C5a receptor inhibitor, was started based on phase II studies that showed promise as a steroid-sparing adjunct. The patient was able to successfully reduce her glucocorticoid dose and reduce her immunosuppressive treatments without another flare. She has been on avacopan for 35 months, had no adverse events that required its discontinuation, and her disease is in sustained remission.

Pharmacokinetic optimitzation of CCG-203971: Novel inhibitors of the Rho/MRTF/SRF transcriptional pathway as potential antifibrotic therapeutics for systemic scleroderma.

We recently reported the development of a novel inhibitor of Rho-mediated gene transcription (1, CCG-203971) that is efficacious in multiple animal models of acute fibrosis, including scleroderma, when given intraperitoneally. The modest in vivo potency and poor pharmacokinetics (PK) of this lead, however, make it unsuitable for long term efficacy studies. We therefore undertook a systematic medicinal chemistry effort to improve both the metabolic stability and the solubility of 1, resulting in the identification of two analogs achieving over 10-fold increases in plasma exposures in mice. We subsequently showed that one of these analogs (8f, CCG-232601) could inhibit the development of bleomycin-induced dermal fibrosis in mice when administered orally at 50mg/kg, an effect that was comparable to what we had observed earlier with 1 at a 4-fold higher IP dose.

Inhibition of SRF/myocardin reduces aortic stiffness by targeting vascular smooth muscle cell stiffening in hypertension.

AIMS: Increased aortic stiffness is a fundamental manifestation of hypertension. However, the molecular mechanisms involved remain largely unknown. We tested the hypothesis that abnormal intrinsic vascular smooth muscle cell (VSMC) mechanical properties in large arteries, but not in distal arteries, contribute to the pathogenesis of aortic stiffening in hypertension, mediated by the serum response factor (SRF)/myocardin signalling pathway. METHODS AND RESULTS: Four month old male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were studied. Using atomic force microscopy, significant VSMC stiffening was observed in the large conducting aorta compared with the distal arteries in SHR (P < 0.001), however, this regional variation was not observed in WKY rats (P > 0.4). The increase of VSMC stiffness was accompanied by a parallel increase in the expression of SRF by 9.8-fold and of myocardin by 10.5-fold in thoracic aortic VSMCs from SHR vs. WKY rats, resulting in a significant increase of downstream stiffness-associated genes (all, P < 0.01 vs. WKY). Inhibition of SRF/myocardin expression selectively attenuated aortic VSMC stiffening, and normalized downstream targets in VSMCs isolated from SHR but not from WKY rats. In vivo, 2 weeks of treatment with SRF/myocardin inhibitor delivered by subcutaneous osmotic minipump significantly reduced aortic stiffness and then blood pressure in SHR but not in WKY rats, although concomitant changes in aortic wall remodelling were not detected during this time frame. CONCLUSIONS: SRF/myocardin pathway acts as a pivotal mediator of aortic VSMC mechanical properties and plays a central role in the pathological aortic stiffening in hypertension. Attenuation of aortic VSMC stiffening by pharmacological inhibition of SRF/myocardin signalling presents a novel therapeutic strategy for the treatment of hypertension by targeting the cellular contributors to aortic stiffness.

Inhibition of myocardin-related transcription factor/serum response factor signaling decreases lung fibrosis and promotes mesenchymal cell apoptosis.

Myofibroblasts are crucial to the pathogenesis of tissue fibrosis. Their formation of stress fibers results in the release of myocardin-related transcription factor (MRTF), a transcriptional coactivator of serum response factor (SRF). MRTF-A (Mkl1)-deficient mice are protected from lung fibrosis. We hypothesized that the SRF/MRTF pathway inhibitor CCG-203971 would modulate myofibroblast function in vitro and limit lung fibrosis in vivo. Normal and idiopathic pulmonary fibrosis lung fibroblasts were treated with/without CCG-203971 (N-[4-chlorophenyl]-1-[3-(2-furanyl)benzoyl]-3-piperidine carboxamide) and/or Fas-activating antibody in the presence/absence of transforming growth factor (TGF)-ß1, and apoptosis was assessed. In vivo studies examined the effect of therapeutically administered CCG-203971 on lung fibrosis in two distinct murine models of fibrosis induced by bleomycin or targeted type II alveolar epithelial injury. In vitro, CCG-203971 prevented nuclear localization of MRTF-A; increased the apoptotic susceptibility of normal and idiopathic pulmonary fibrosis fibroblasts; blocked TGF-ß1-induced myofibroblast differentiation; and inhibited TGF-ß1-induced expression of fibronectin, X-linked inhibitor of apoptosis, and plasminogen activator inhibitor-1. TGF-ß1 did not protect fibroblasts or myofibroblasts from apoptosis in the presence of CCG-203971. In vivo, CCG-203971 significantly reduced lung collagen content in both murine models while decreasing alveolar plasminogen activator inhibitor-1 and promoting myofibroblast apoptosis. These data support a central role of the SRF/MRTF pathway in the pathobiology of lung fibrosis and suggest that its inhibition can help resolve lung fibrosis by promoting fibroblast apoptosis.

Tiagabine improves hippocampal long-term depression in rat pups subjected to prenatal inflammation.

Maternal inflammation during pregnancy is associated with the later development of cognitive and behavioral impairment in the offspring, reminiscent of the traits of schizophrenia or autism spectrum disorders. Hippocampal long-term potentiation and long-term depression of glutamatergic synapses are respectively involved in memory formation and consolidation. In male rats, maternal inflammation with lipopolysaccharide (LPS) led to a premature loss of long-term depression, occurring between 12 and 25 postnatal days instead of after the first postnatal month, and aberrant occurrence of long-term potentiation. We hypothesized this would be related to GABAergic system impairment. Sprague Dawley rats received either LPS or isotonic saline ip on gestational day 19. Male offspring's hippocampus was studied between 12 and 25 postnatal days. Morphological and functional analyses demonstrated that prenatal LPS triggered a deficit of hippocampal GABAergic interneurons, associated with presynaptic GABAergic transmission deficiency in male offspring. Increasing ambient GABA by impairing GABA reuptake with tiagabine did not interact with the low frequency-induced long-term depression in control animals but fully prevented its impairment in male offspring of LPS-challenged dams. Tiagabine furthermore prevented the aberrant occurrence of paired-pulse triggered long-term potentiation in these rats. Deficiency in GABA seems to be central to the dysregulation of synaptic plasticity observed in juvenile in utero LPS-challenged rats. Modulating GABAergic tone may be a possible therapeutic strategy at this developmental stage.

Targeting the myofibroblast genetic switch: inhibitors of myocardin-related transcription factor/serum response factor-regulated gene transcription prevent fibrosis in a murine model of skin injury.

Systemic sclerosis (SSc), or scleroderma, similar to many fibrotic disorders, lacks effective therapies. Current trials focus on anti-inflammatory drugs or targeted approaches aimed at one of the many receptor mechanisms initiating fibrosis. In light of evidence that a myocardin-related transcription factor (MRTF)-and serum response factor (SRF)-regulated gene transcriptional program induced by Rho GTPases is essential for myofibroblast activation, we explored the hypothesis that inhibitors of this pathway may represent novel antifibrotics. MRTF/SRF-regulated genes show spontaneously increased expression in primary dermal fibroblasts from patients with diffuse cutaneous SSc. A novel small-molecule inhibitor of MRTF/SRF-regulated transcription (CCG-203971) inhibits expression of connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), and collagen 1 (COL1A2) in both SSc fibroblasts and in lysophosphatidic acid (LPA)-and transforming growth factor ß (TGFß)-stimulated fibroblasts. In vivo treatment with CCG-203971 also prevented bleomycin-induced skin thickening and collagen deposition. Thus, targeting the MRTF/SRF gene transcription pathway could provide an efficacious new approach to therapy for SSc and other fibrotic disorders.

GABA transporter-1 inhibitor NO-711 alters the EEG power spectra and enhances non-rapid eye movement sleep during the active phase in mice.

GABA transporter subtype 1 (GAT1) constructs high affinity reuptake sites for GABA in the CNS and regulates GABAergic transmission. Compounds that inhibit GAT1 are targets often used for the treatment of epilepsy; however sedation has been reported as a side effect of these agents, indicating potential sedative and/or hypnotic uses for these compounds. In the current study, we observed the sleep behaviors of mice treated with NO-711, a selective GAT1 inhibitor, in order to elucidate the role of GAT1 in sleep-wake regulation during the active phase. The data revealed that NO-711 at a high dose of 10 mg/kg caused a marked enhancement of EEG activity in the frequency ranges of 3-25 Hz during wakefulness as well as rapid eye movement (REM) sleep. During the non-REM (NREM) sleep, NO-711 (10 mg/kg) elevated EEG activity in the frequency ranges of 1.5-6.75 Hz. Similar changes were found in mice treated with a low dose of 3 mg/kg. NO-711 administered i.p. at a dose of 1, 3 or 10 mg/kg significantly shortened the sleep latency of NREM sleep, increased the amount of NREM sleep and the number of NREM sleep episodes. NO-711 did not affect the sleep latency and the amount of REM sleep. NO-711 dose-dependently increased c-Fos expression in sleep-promoting nucleus of the ventrolateral preoptic area and median preoptic area. However, c-Fos expression was decreased in the wake-promoting nuclei, tuberomammillary nucleus and lateral hypothalamus. These results indicate that NO-711 can increase NREM sleep in mice.

Elevating endogenous GABA levels with GAT-1 blockade modulates evoked but not induced responses in human visual cortex.

The electroencephalographic/magnetoencephalographic (EEG/MEG) signal is generated primarily by the summation of the postsynaptic currents of cortical principal cells. At a microcircuit level, these glutamatergic principal cells are reciprocally connected to GABAergic interneurons. Here we investigated the relative sensitivity of visual evoked and induced responses to altered levels of endogenous GABAergic inhibition. To do this, we pharmacologically manipulated the GABA system using tiagabine, which blocks the synaptic GABA transporter 1, and so increases endogenous GABA levels. In a single-blinded and placebo-controlled crossover study of 15 healthy participants, we administered either 15 mg of tiagabine or a placebo. We recorded whole-head MEG, while participants viewed a visual grating stimulus, before, 1, 3 and 5 h post tiagabine ingestion. Using beamformer source localization, we reconstructed responses from early visual cortices. Our results showed no change in either stimulus-induced gamma-band amplitude increases or stimulus-induced alpha amplitude decreases. However, the same data showed a 45% reduction in the evoked response component at ∼80 ms. These data demonstrate that, in early visual cortex the evoked response shows a greater sensitivity compared with induced oscillations to pharmacologically increased endogenous GABA levels. We suggest that previous studies correlating GABA concentrations as measured by magnetic resonance spectroscopy to gamma oscillation frequency may reflect underlying variations such as interneuron/inhibitory synapse density rather than functional synaptic GABA concentrations.

Blockade of ventral midbrain NMDA receptors enhances brain stimulation reward: a preferential role for GluN2A subunits.

Ventral midbrain (VM) neurons that project to limbic structures play a role in reward and incentive motivation. It has been suggested that a reward-related signal is transmitted when the firing rate of VM dopamine neurons shifts from a tonic to a phasic mode. Since glutamate is necessary for this transduction process, it is likely to play a role in reward signaling. This study was aimed at determining the effect of VM N-Methyl-D-Aspartate (NMDA) receptor blockade on reward induced by electrical brain stimulation. Experiments were performed on rats trained to self-administer an electrical stimulation in the medial posterior mesencephalon. Reward thresholds were measured with the curve-shift paradigm before and after bilateral VM injections of the following NMDA receptor antagonists: R-CPP, 3-(R-2-Carboxypiperazin-4-yl)-propyl-1 phosphonic acid, (0, 20.6, 41.2 and 82.5 pmol/0.5 µl/side), PPPA, (2R,4S)-4-(3-Phosphonopropyl)-2-piperidinecarboxylic acid, (0, 0.825 and 1.65 nmol/0.5 µl/side) orRo04-5595, 1-[2-(4-Chlorophenyl)ethyl]-1,2,3,4-tetrqahydro-6-methoxy-2-methyl-7-isoquinolinol hydrochloride (0, 0.825, 1.65 nmol/0.5 µl/side). R-CPP and PPPA produced a dose and time dependent decrease in reward threshold, an effect that was, at some doses and times after the injection, accompanied by an increase in maximum responses. These effects were not observed with Ro04-5595 over the range of doses tested. While previous studies suggest a role for glutamate in reward signaling, the present results show that VM glutamate exerts a tonic inhibition on the reward-relevant pathway. The selectivity of Ro04-5595 for NMDA receptors composed of GluN2B subunits and the higher affinity of R-CPP and PPPA for GluN2A suggest that the inhibition is mediated by receptors composed of GluN2A subunits.

Combinational spinal GAD65 gene delivery and systemic GABA-mimetic treatment for modulation of spasticity.

BACKGROUND: Loss of GABA-mediated pre-synaptic inhibition after spinal injury plays a key role in the progressive increase in spinal reflexes and the appearance of spasticity. Clinical studies show that the use of baclofen (GABA(B) receptor agonist), while effective in modulating spasticity is associated with major side effects such as general sedation and progressive tolerance development. The goal of the present study was to assess if a combined therapy composed of spinal segment-specific upregulation of GAD65 (glutamate decarboxylase) gene once combined with systemic treatment with tiagabine (GABA uptake inhibitor) will lead to an antispasticity effect and whether such an effect will only be present in GAD65 gene over-expressing spinal segments. METHODS/PRINCIPAL FINDINGS: Adult Sprague-Dawley (SD) rats were exposed to transient spinal ischemia (10 min) to induce muscle spasticity. Animals then received lumbar injection of HIV1-CMV-GAD65 lentivirus (LVs) targeting ventral α-motoneuronal pools. At 2-3 weeks after lentivirus delivery animals were treated systemically with tiagabine (4, 10, 20 or 40 mg/kg or vehicle) and the degree of spasticity response measured. In a separate experiment the expression of GAD65 gene after spinal parenchymal delivery of GAD65-lentivirus in naive minipigs was studied. Spastic SD rats receiving spinal injections of the GAD65 gene and treated with systemic tiagabine showed potent and tiagabine-dose-dependent alleviation of spasticity. Neither treatment alone (i.e., GAD65-LVs injection only or tiagabine treatment only) had any significant antispasticity effect nor had any detectable side effect. Measured antispasticity effect correlated with increase in spinal parenchymal GABA synthesis and was restricted to spinal segments overexpressing GAD65 gene. CONCLUSIONS/SIGNIFICANCE: These data show that treatment with orally bioavailable GABA-mimetic drugs if combined with spinal-segment-specific GAD65 gene overexpression can represent a novel and highly effective anti-spasticity treatment which is associated with minimal side effects and is restricted to GAD65-gene over-expressing spinal segments.

Chronic tiagabine administration and aggressive responding in individuals with a history of substance abuse and antisocial behavior.

Anticonvulsants, notably those which modulate GABA activity, have shown efficacy in reducing aggressive behavior. Previously, we found dose-related decreases in human aggressive responding following acute tiagabine administration. Here, we examined the effects of chronic tiagabine over a 5-week period. Twelve individuals at increased risk for aggressive and violent behavior (currently on parole/probation with personality and/or substance use disorders) were randomly assigned to placebo (n = 6) or an escalating dose sequence of placebo, 4 mg, 8 mg, 12 mg, placebo (n = 6). Data were analyzed using both frequentist and Bayesian mixed models, evaluating aggressive behavior as a function of time, dose condition, and their interaction. For aggressive responding, there was a significant interaction of drug condition and time. Aggression in the tiagabine condition decreased for each additional week in the study, while participants in the placebo condition failed to demonstrate similar change over time. For monetary-reinforced responding, no drug or drug by time interactions were observed, suggesting specificity of drug effects on aggression. The small number of subjects limits the generality of the findings, and previous studies with tiagabine are limited to acute dosing and case report investigations. However, the present data provide an indication that tiagabine merits further examination as an agent for management of impulsive aggression.

[Therapeutic drug monitoring of tiagabine]. / Suivi thérapeutique pharmacologique de la tiagabine.

Tiagabine, a second-generation anticonvulsant drug, is marketed in France since 1997. It is also prescribed outside marketing authorization in the treatment of anxiety. They are few studies allowing arguing a relation exposure efficiency or toxicity, but intra and inter individual important variations in serum concentrations are described. Hepatic insufficiency requires a dose adaptation. In patients treated with therapeutic dose, serum levels are between 20 and 100 microg/L (50-250 nmol/L). For this molecule, the level of proof of the interest of TDM was estimated in: remaining to estimate.

Gamma-vinyl GABA increases nonvesicular release of GABA and glutamate in the nucleus accumbens in rats via action on anion channels and GABA transporters.

RATIONALE: gamma-Amino butyric acid (GABA) is a well-characterized inhibitory neurotransmitter in the central nervous system, which may also stimulate nonvesicular release of other neurotransmitters under certain conditions. We have recently reported that gamma-vinyl GABA (GVG), an irreversible GABA transaminase inhibitor, elevates extracellular GABA but fails to alter dopamine release in the nucleus accumbens (NAc). OBJECTIVES: Here, we investigated the mechanism(s) by which GVG elevates extracellular GABA levels and whether GVG also alters glutamate release in the NAc. MATERIALS AND METHODS: In vivo microdialysis was used to simultaneously measure extracellular NAc GABA and glutamate before and after GVG administration in freely moving rats. RESULTS: Systemic administration of GVG or intra-NAc local perfusion of GVG significantly increased extracellular NAc GABA and glutamate. GVG-enhanced GABA was completely blocked by intra-NAc local perfusion of 5-nitro-2, 3-(phenylpropylamino)-benzoic acid (NPPB), a selective anion channel blocker and partially blocked by SKF89976A, a type 1 GABA transporter inhibitor. GVG-enhanced glutamate was completely blocked by NPPB or SKF89976A. Tetrodotoxin, a voltage-dependent Na(+)-channel blocker, failed to alter GVG-enhanced GABA and glutamate. CONCLUSIONS: These data suggest that GVG-enhanced extracellular GABA and glutamate are mediated predominantly by the opening of anion channels and partially by the reversal of GABA transporters. Enhanced extracellular glutamate may functionally attenuate the pharmacological action of GABA and prevent enhanced GABA-induced excess inhibition.

Long-term anxiolytic and antidepressant-like behavioural effects of tiagabine, a selective GABA transporter-1 (GAT-1) inhibitor, coincide with a decrease in HPA system activity in C57BL/6 mice.

Gamma-aminobutyric acid (GABA) system plays a pivotal role in the pathophysiology of anxiety and mood disorders. This study was aimed to assess the anxiolytic and antidepressant-like properties of tiagabine, an inhibitor of the GABA transporter-1 (GAT-1), after acute and chronic administration in C57BL/6JOlaHsD mice with paroxetine as a positive control. In first experiments, the acute administration of tiagabine (7.5 mg/kg, orally [PO]) and paroxetine (10 mg/kg PO) induced anxiolytic effects in the elevated plus maze test and the modified hole board test and an antidepressant-like effect in the forced swim test. Chronic application of tiagabine (7.5 mg/kg PO) and paroxetine (10 mg/kg PO) for 22 days revealed an anxiolytic and antidepressant-like efficacy of tiagabine only. In a further experiment, we analysed the impact of chronic tiagabine versus paroxetine treatment on the hypothalamic-pituitary-adrenocortical (HPA) system regulation. GAT-1 blockade induced a setpoint-shift of the stress hormone system toward lower levels as indicated by decreased plasma corticosterone concentrations and attenuated gene expression levels of corticotropin-releasing factor in the paraventricular nucleus of the hypothalamus and of hippocampal steroid receptors. This data indicate that both acute and long-term anxiolytic and antidepressant-like properties of brain GAT-1 inhibition coincide with a reduction in HPA system activity in mice.

Carnitine conjugate of nipecotic acid: a new example of dual prodrug.

As a novel example of improved entry of poorly delivered drugs into the brain by means of nutrient conjugates, L-carnitine was conjugated to nipecotic acid and the capacity to antagonize PTZ-induced convulsions of this novel entity was evaluated.

Thermal hyperalgesia via supraspinal mechanisms in mice lacking glutamate decarboxylase 65.

Gamma-aminobutyric acid, which is synthesized by two isoforms of glutamate decarboxylase (GAD), inhibits the transfer of nociceptive signals from primary afferent fibers to the central nervous system. However, the roles of a 65-kDa isoform of GAD (GAD65)-mediated GABA in nociceptive processing are less clear. This study tested whether partial reductions in GABAergic inhibitory tone by GAD65 gene knockout [GAD65(-/-)] would contribute to the regulation of pain threshold in mice. Experiments were performed on male wild-type (WT) mice and GAD65(-/-) mice. Acute nociception and inflammatory pain tests were compared between WT mice and GAD65(-/-) mice. GABA(A) receptor-mediated inhibitory postsynaptic currents were also examined by use of the whole-cell patch-clamp method in somatosensory cortical neurons in brain slices. In the hot plate test, which reflects supraspinal sensory integration, a significant reduction in the latency was observed for GAD65(-/-) mice. Intraperitoneal administration of the GABA transporter 1 inhibitor, 1-[2-[[(diphenylmethylene)imino]oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride (C(21)H(22)N(2)O(3).HCl; NO-711), dose-dependently prolonged the latency in both genotypes, suggesting that GABA concentration contributes to acute thermal nociception. However, there was no genotype difference in responses to the tail-immersion test or the von Frey test, indicating that spinal reflex and mechanical nociception are kept intact in GAD65(-/-) mice. There was no genotype difference in responses to chemical inflammatory nociception (formalin test and carrageenan test). Although properties of the phasic component of inhibitory postsynaptic currents were similar in both genotypes, tonic inhibition was significantly reduced in GAD65(-/-) mice. These results support the hypothesis that GAD65-mediated GABA synthesis plays relatively small but significant roles in nociceptive processing via supraspinal mechanisms.

Synergistic interaction of gabapentin with tiagabine in the hot-plate test in mice: an isobolographic analysis.

This study was aimed at determining the analgesic effect of gabapentin and tiagabine, two antiepileptic drugs that were administered alone and in combination at a fixed ratio of 1:1, in the acute thermal pain model (hot-plate test) in mice. Linear regression analysis was used to evaluate the dose-response relationships between logarithms of antiepileptic drug doses and their resultant maximum possible antinociceptive effects in the mouse hot-plate test. From linear equations, we calculated doses that increased the antinociceptive effect by 50% (ED(50) values) for gabapentin, tiagabine and their combination. The type of interaction between gabapentin and tiagabine was assessed using the isobolographic analysis. Results indicated that both antiepileptic drugs produced the definite antinociceptive effect, and the experimentally derived ED(50) values for gabapentin and tiagabine, when applied alone, were 504.4 mg/kg and 5.67 mg/kg, respectively. With isobolography, the experimentally derived ED(50 mix) value for the fixed ratio combination of 1:1 was 139.31 mg/kg and significantly differed from the theoretically calculated ED(50 add) value, which was 255.04 mg/kg (p < 0.05), indicating the synergistic interaction between gabapentin and tiagabine in the hot-plate test in mice. In conclusion, the combination of tiagabine with gabapentin at a fixed ratio of 1:1 exerted a synergistic interaction in the mouse model of nociceptive pain. If the results from this study could be extrapolated to clinical settings, the combination of tiagabine with gabapentin might be beneficial for pain relief in humans.

Interaction of tiagabine with valproate in the mouse pentylenetetrazole-induced seizure model: an isobolographic analysis for non-parallel dose-response relationship curves.

PURPOSE: To characterize the interaction between tiagabine (TGB) and valproate (VPA)--two antiepileptic drugs in the mouse pentylenetetrazole (PTZ)-induced clonic seizure model, type I isobolographic analysis for non-parallel dose-response relationship curves (DRRCs) was used. MATERIAL AND METHODS: Clonic seizures were evoked in albino Swiss mice by subcutaneous injection of PTZ at its CD97 (100 mg/ kg). To ascertain the nature of interaction between TGB and VPA administered in combination, total brain concentrations of TGB and VPA were estimated by using high-performance liquid chromatography (HPLC) and fluorescence polarization immunoassay (FPIA). RESULTS: TGB and VPA produced clear-cut anticonvulsant effects against PTZ-induced clonic seizures in mice and their DRRCs were not parallel to one another. The type I isobolographic analysis for non-parallel DRRCs revealed that the combination of TGB with VPA at the fixed-ratio of 1:1 exerted additive interaction against PTZ-induced clonic seizures in mice. With FPIA, it was found that TGB did not affect total brain VPA concentrations in experimental animals. Moreover, VPA had no significant impact on total brain concentrations of TGB in mice, as measured with HPLC. CONCLUSION: The additive interaction between TGB and VPA at the fixed-ratio of 1:1 in the mouse PTZ model was pharmacodynamic in nature.

Increase in tiagabine serum concentration with coadministration of gemfibrozil.

OBJECTIVE: To report a case of possible acute tiagabine toxicity secondary to administration of gemfibrozil. CASE SUMMARY: A 39-year-old male was taking tiagabine 16 mg orally 3 times per day and carbamazepine 500 mg orally twice per day for complex partial seizures secondary to mesial temporal sclerosis. He was found to have type IV hypertriglyceridemia and was prescribed gemfibrozil. Because he reported severe confusion and altered consciousness shortly after a single 600-mg dose of gemfibrozil, he was admitted for controlled challenge with that drug. A single 300-mg dose of gemfibrozil resulted in lightheadedness and led to a 59% and 75% increase in total tiagabine serum concentrations at 2 and 5 hours, respectively, without significant change in baseline carbamazepine concentrations. DISCUSSION: This is the first report of an interaction between the widely used antihyperlipidemic drug gemfibrozil and tiagabine. Since tiagabine, which was originally developed as an antiepileptic medication, is now being used widely for a variety of other indications such as anxiety and depression, there is an increased risk for clinically significant interactions with gemfibrozil. CONCLUSIONS: Increased total and unbound tiagabine concentrations following a single 300-mg dose of gemfibrozil and reproduction of clinical symptoms with gemfibrozil rechallenge suggests the toxicity our patient experienced was due to a pharmacokinetic drug interaction. Use of the Horn Drug Interaction Probability Scale showed a probable interaction between gemfibrozil and tiagabine.