Biomedical subjects

Chris Rundfeldt

Publications and source records attributed to Chris Rundfeldt.

9 recordsLinked to original sources

PubMed2007

Retigabine.

Retigabine is a novel antiseizure drug that acts through potassium channels and has activity in a broad range of animal models of epilepsy. It is also effective in several preclinical pain models. The drug has been extensively studied in phase I and II studies, with very promising results. The maximal tolerated dose for most patients is 1,200 mg/day. Adverse effects have been largely CNS-related and mild; most have occurred during the titration periods in the various studies. At present, retigabine is in two pivotal phase III studies.

Animals↗

PubMed2006

The novel anxiolytic ELB139 displays selectivity to recombinant GABA(A) receptors different from diazepam.

A chemically heterogeneous group of compounds acts at the benzodiazepine (BZ) recognition site of the diverse gamma-aminobutyric acid type A (GABA(A)) receptor complexes which can assemble from more than 16 known subunits. Most 1,4-BZs like diazepam recognize all GABA(A)/BZ receptors containing the alpha1-3 or alpha5 together with any beta and the gamma2 subunit. Other compounds differentiate less, e.g. Ro15-4513, that additionally recognizes alpha4- and a6-containing receptors, or differentiate more, e.g. zolpidem, that recognizes preferentially alpha1-containing receptors. Here we describe the functional properties of 1-(4-chloro-phenyl)-4-piperidin-1-yl-1,5-dihydro-imidazol-2-on (ELB139) in the presence and absence of the BZ receptor antagonist flumazenil (Ro15-1788) on recombinant alphaibeta2gamma2 (i=1-5) receptor subtypes expressed in HEK 293 cells. The properties were measured with the whole-cell variation of the patch-clamp technique and compared to those of diazepam. Like the latter, ELB139 did not potentiate GABA-induced currents in alpha4-containing receptors, but it displays functional subtype specificity between alpha1, alpha2, alpha3, and alpha5beta2gamma2 receptors with highest potency in alpha3-containing receptors but highest efficacy in alpha1- or alpha2-containing receptors, respectively. ELB139 acted as a partial agonist on these receptor subtypes reaching 40-50% of the efficacy of diazepam.

Animals↗

PubMed2006

Synthesis, pharmacology, and structure-activity relationships of novel imidazolones and pyrrolones as modulators of GABAA receptors.

New series of imidazolones and pyrrolones were synthesized. The compounds were tested regarding their anxiolytic properties due to modulation of the GABAA receptor response. Several derivatives exhibit considerable pharmacological activity while lacking the typical side effects of benzodiazepine receptor agonists. 1-(4-chlorophenyl)-4-morpholin-1-yl-1,5-dihydro-imidazol-2-one (2) and 1-(4-chlorophenyl)-4-piperidin-1-yl-1,5-dihydro-imidazol-2-one (3) were protective in the pentylenetetrazole test in rats with oral ED50 of 27.4 and 12.8 mg/kg and TD50 (rotarod) of >500 and 265 mg/kg, respectively. The minimum effective dose in the Vogel conflict test was 3 mg/kg for both compounds. Common structure-activity relationship and comparative molecular field analysis models of the various series of derivatives could be established which are in accordance with a GABAA mediated pharmacological action. The findings fit well into an established pharmacophore model. This model is refined by an additional steric restriction feature.

Administration, Oral↗

PubMed2006

Anticonvulsant activity and tolerance of ELB138 in dogs with epilepsy: a clinical pilot study.

A new antiepileptic and anxiolytic drug, ELB138, was evaluated in a clinical pilot study in dogs with newly diagnosed or chronic idiopathic epilepsy. The purpose was to verify clinically the anticonvulsant effectiveness of this substance, which had already been demonstrated experimentally. Data from 29 dogs treated with ELB138 were compared with results obtained retrospectively from 82 dogs treated with conventional antiepileptic medication. The reduction in seizure frequency using ELB138 in dogs with newly diagnosed idiopathic epilepsy was comparable to the reduction in dogs treated either with phenobarbital or primidone. In dogs with chronic epilepsy and add-on therapy with either ELB138 or potassium bromide, such supplementation reduced the seizure frequency and the duration and severity of seizures. The most obvious difference between ELB138 treatment and conventional medications became clear in the evaluation of side effects, which in those dogs treated with ELB138 were rare, and consisted mostly of transient polyphagia. This pilot study confirmed that ELB138 has a potent anticonvulsant effect in dogs with idiopathic epilepsy. These results will form the basis for a multicentre, blinded study.

Animals↗

PubMed2005

Characterization in rats of the anxiolytic potential of ELB139 [1-(4-chlorophenyl)-4-piperidin-1-yl-1,5-dihydro-imidazol-2-on], a new agonist at the benzodiazepine binding site of the GABAA receptor.

Benzodiazepines are among the most effective drugs for the treatment of anxiety disorders. However, their use is limited by undesired side effects, including sedation, development of tolerance, and drug abuse. The aim of this study was to evaluate the pharmacological profile of ELB139 [1-(4-chlorophenyl)-4-piperidin-1-yl-1,5-dihydro-imidazol-2-on] in different models of anxiety and to correlate these effects with its activity in vitro. ELB139 binds with an IC(50) of 1390 nM to the flunitrazepam binding site in rat forebrain cortical membranes. In rat hippocampal neurons, ELB139 potentiated GABA-induced currents without reaching the maximum effect of diazepam, indicating a partial benzodiazepine agonism. The potentiation was antagonized by the benzodiazepine antagonist flumazenil. ELB139 (10 and 30 mg/kg p.o.) was active in three different animal models of anxiety, i.e., in the elevated plus-maze, the light and dark box, and the Vogel conflict test. The anxiolytic activity in the elevated plus-maze was almost completely reversed by flumazenil (5 mg/kg i.p.), indicating that interaction with the benzodiazepine binding site is central to the pharmacological activity. No hint of sedation was observed at the doses tested in the three anxiety models and the open field. Also, no development of tolerance was observed within 6 weeks b.i.d. treatment with ELB139 in the elevated plus-maze test. In summary, ELB139 elicits strong effects on anxiety-related behavior in rats mediated by its benzodiazepine-like activity without showing sedation or the development of tolerance, a major side effect of benzodiazepines. These characteristics make the compound a prime candidate for clinical development.

Animals↗

PubMed2005

The phosphodiesterase 4 inhibitor AWD 12-281 is active in a new guinea-pig model of allergic skin inflammation predictive of human skin penetration and suppresses both Th1 and Th2 cytokines in mice.

The selective phosphodiesterase 4 (PDE4) inhibitor AWD 12-281 is structurally optimized for topical administration. It has potent effects in models of lung inflammation if administered as a dry powder inhalation. It has also demonstrated its anti-inflammatory property in a mouse model of cutaneous inflammation after topical administration. The aim of this study was to evaluate whether AWD 12-281 may be capable of penetrating human skin. Therefore a new guinea-pig model of allergic skin inflammation had to be developed. In ovalbumin-sensitized guinea-pigs, intracutaneous administration of ovalbumin results in a rapid development of allergic skin wheals. Topically administered AWD 12-281 was capable of reducing the development of wheals, indicating that this compound can penetrate the stratum corneum of guinea-pig skin as a predictor of human skin penetration. A secondary aim was the evaluation of a T cell subtype preference of AWD 12-281 since PDE4 inhibitors are said to preferentially inhibit Th2-type cytokines. Therefore, the effects of AWD 12-281 on a broad spectrum of Th1- and Th2-type cytokines were studied in tissue homogenates after allergen challenge in sensitized mice and in supernatants of anti CD3/anti-CD28-stimulated peripheral blood mononuclear cells (PBMCs). In both models, AWD 12-281 suppressed both T cell subtype cytokines indicating a broad spectrum activity of AWD 12-281. A further issue was to determine the duration of action and the concentration-response relationship of the topical activity of AWD 12-281 using a model of acute local inflammation--the arachidonic-acid-induced mouse ear oedema. The compound exhibited a dose-dependent effect with a minimally effective concentration of 0.3%; after repeated administration the minimally effective concentration was found to be 0.03%. A single administration of a 3% solution resulted in significant suppression of inflammation even 48 h after treatment. In conclusion, our results indicate that AWD 12-281 is a very promising drug candidate not only for the treatment of lung inflammation using inhalative administration but also for the treatment of atopic dermatitis.

Amides↗

PubMed2004

Anticonvulsant efficacy of the low-affinity partial benzodiazepine receptor agonist ELB 138 in a dog seizure model and in epileptic dogs with spontaneously recurrent seizures.

PURPOSE: Ataxia, sedation, amnesia, ethanol and barbiturate potentiation, loss of efficacy (tolerance), development of dependence, and the potential for drug abuse limit the clinical use of benzodiazepines (BZDs) for long-term treatment of epilepsy or anxiety. BZD ligands that are in current use act as full allosteric modulators of gamma-aminobutyric acid (GABA)-gated chloride channels and, on long-term administration, trigger a functional uncoupling between the GABAA and BZD recognition sites. Partial allosteric modulators, which have a low intrinsic activity at the BZD recognition site of the GABAA receptor, might eventually overcome the limitations of full agonists such as diazepam (DZP). METHODS: In the present study, the new low-affinity partial BZD-receptor agonist ELB 138 [former name AWD 131-138; 1-(4-chlorophenyl)-4-morpholino-imidazolin-2-one] was evaluated in a dog seizure model and in epileptic dogs with spontaneously recurrent seizures. RESULTS: ELB 138 was shown to increase potently the pentylenetetrazole (PTZ) seizure threshold in dogs. Prolonged oral administration with twice-daily dosing of ELB 138 with either 5 or 40 mg/kg over a 5-week period was not associated with loss of anticonvulsant efficacy in the PTZ dog model. To study whether physical dependence developed during long-term treatment, the BZD antagonist flumazenil was injected after 5 weeks of treatment with ELB 138. Compared with prolonged treatment with DZP, only relatively mild abstinence symptoms were precipitated in dogs treated with ELB 138, particularly at the lower dosage (5 mg/kg, b.i.d.). In a prospective trial in dogs with newly diagnosed epilepsy, ELB 138 markedly reduced seizure frequency and severity without significant difference to standard treatments (phenobarbital or primidone) but was much better tolerated than the standard drugs. In dogs with chronic epilepsy, most dogs exhibited a reduction in seizure frequency and severity during add-on treatment with ELB 138. CONCLUSIONS: The data demonstrate that the partial BZD receptor agonist ELB 138 exerts significant anticonvulsant efficacy without tolerance in a dog seizure model as well as in epileptic dogs with spontaneously recurrent seizures. These data thus substantiate that partial agonism at the BZD site of GABAA receptors offers advantages versus full agonism and constitutes a valuable approach for treatment of seizures.

Animals↗

PubMed2003

Anti-inflammatory potential of the selective phosphodiesterase 4 inhibitor N-(3,5-dichloro-pyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]-glyoxylic acid amide (AWD 12-281), in human cell preparations.

AWD 12-281 is a potent (IC(50) = 9.7 nM) and highly selective inhibitor of the phosphodiesterase 4 (PDE4) isoenzyme with low affinity to the high-affinity rolipram-binding site. The compound was optimized for topical treatment of asthma, chronic obstructive pulmonary disease (COPD), and allergic rhinitis. The aim of the present study was to assess the effect of AWD 12-281 in human inflammatory cells. Peripheral blood mononuclear cells (PBMCs), diluted whole blood, and human nasal polyp cells derived from surgically resected nasal polyps from patients with polyposis comprise sources of target tissue cells that can be used to predict anti-inflammatory effects in patients. AWD 12-281 was capable of suppressing the production of cytokines in stimulated PBMCs: interleukin-2 (IL-2, phytohemagglutinin stimulation), IL-5 (concanavalin A stimulation), IL-5 and IL-4 (anti-CD3/anti-CD28 costimulation), and lipopolysaccharide-stimulated release of tumor necrosis factor alpha (TNF alpha). The corresponding values for half-maximum inhibition, EC(50), for AWD 12-281 were within a narrow range (46-121 nM). Comparing the effect of AWD 12-281 with roflumilast, cilomilast (SB 207499), rolipram (RPR-73401), and 1-(3-nitrophenyl)-3-(4-pyridylmethyl)pyrido[2,3-d]pyrimidin-2,4(1H,3H)-dione (RS-25344-000), it could be shown that the PDE4 inhibitory activity was closely correlated with inhibitory potential as measured by the above-described assays. AWD 12-281 was also shown to suppress TNF alpha release in dispersed nasal polyps (EC(50) = 111 nM) and in diluted whole blood (EC(50) = 934 nM). The reduced activity in human blood may be related to high plasma protein binding. Currently, phase II clinical studies are under way to evaluate the therapeutic potential of AWD 12-281 in asthma, COPD, and allergic rhinitis.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2003

AWD 12-281, a highly selective phosphodiesterase 4 inhibitor, is effective in the prevention and treatment of inflammatory reactions in a model of allergic dermatitis.

AWD 12-281 (N-(3,5-dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide), a phosphodiesterase 4 inhibitor, which is optimized for topical administration, was tested in a model of allergic dermatitis in mice. To obtain an allergic dermatitis, BALB/c mice were sensitized to toluene-2,4-diisocyanate (TDI). The allergic reaction was challenged by topical administration of TDI onto the mice ears. AWD 12-281 was tested for its anti-inflammatory potential by oral, intraperitoneal and topical administration. The phosphodiesterase 4 inhibitor, cilomilast (SB 207499), and/or the corticosteroid, diflorasone diacetate, were used as reference compounds. Given orally and intraperitoneally 2 h before as well as 5 and 24 h after TDI challenge, AWD 12-281 showed no, or only a transient inhibition of the allergen-induced ear swelling, whereas cilomilast significantly inhibited this ear swelling. Applied topically onto the ears before TDI challenge, AWD 12-281, cilomilast and diflorasone diacetate caused total inhibition of ear swelling 24 h after challenge, confirmed by a decrease of the pro-inflammatory cytokines interleukin-4, interleukin-6 and macrophage inhibitory protein-2. Administered topically after TDI challenge as therapeutic intervention, AWD 12-281 and diflorasone diacetate caused significant inhibition of ear swelling; cilomilast failed to do so. These results indicate that topically administered AWD 12-281 may be potent in the prevention and treatment of allergic/inflammatory skin diseases.

3',5'-Cyclic-AMP Phosphodiesterases↗