indantadol and Pain

Indantadol is an oral and nonselective monoamine oxidase inhibitor and NMDA antagonist that is being developed by Vernalis plc, under license from Chiesi Farmaceutici SpA, for the potential treatment of neuropathic pain. In preclinical studies, indantadol exhibited neuroprotective effects after kainite-induced seizures, and displayed anticonvulsant and antihyperalgesic activity. Indantadol also caused a dose-dependent decrease in exploratory motility. In a human heat-capsaicin-induced pain model, indantadol at a dose of 500 mg effectively reduced the area of secondary hyperalgesia to 67%. Indantadol undergoes extensive liver metabolism, withthe formation of two major metabolites - CHF-3567 and 2-aminoindane. The drug is excreted in urine partially as the parent compound, but mostly as CHF-3567. The tolerability profile of indantadol at single doses up to 600 mg and twice-daily doses up to 400 mg in clinical trials was significantly more favorable than for other NMDA antagonists. Most side effects have been observed to be mild, and include dizziness and asthenia. Indantadol is currently in phase II clinical trials in patients with diabetic peripheral neuropathic pain. Given the results available to date, indantadol may have a role in the treatment of neuropathic pain if the favorable pharmacokinetic profile and efficacy of the drug are maintained in more extensive clinical trials.

Topics: Analgesics; Animals; Anticonvulsants; Clinical Trials as Topic; Diabetic Neuropathies; Glycine; Humans; Indans; Monoamine Oxidase Inhibitors; N-Methylaspartate; Pain

CHF 3381 is an NMDA antagonist and monoamine oxidase inhibitor under development with Chiesi for the treatment of neuropathic pain. Preclinical studies show that the agent acts as a reversible and competitive inhibitor of human monoamine oxidases A and B. At the 1st Annual BioPartnering North America (BPN-2003) it was stated that CHF 3381 is being evaluated for the treatment of neuropathic pain. Preliminary data also suggested that CHF 3381 may have neuroprotective activity. In June 2003, Chiesi announced the completion of a phase I trial in France, and is proceeding with a proof-of-concept study in Denmark. CHF 3381 is covered by European patent application EP 951465 (expires on 15 July 2017), and US patent No. 6,114,391 (issued on 5 September 2000). Other patents are granted or pending in 20 countries. Chiesi also has rights to the European patent application for use of glycinamide derivatives (including CHF 3381) in the treatment of chronic pain.

Topics: Animals; Drugs, Investigational; Glycine; Humans; Indans; Monoamine Oxidase Inhibitors; Pain

CHF3381 is a new low-affinity, noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist and reversible monoamine oxidase-A (MAO-A) inhibitor. The analgesic activity of CHF3381 was investigated in the heat-capsaicin human pain model and compared with those of gabapentin. Twenty-seven young, healthy male volunteers received a single oral dose of CHF3381 (500 mg), gabapentin (1,200 mg), or placebo in a randomized, double-blind, crossover study design. Measurements were done before and 135 to 145 minutes after treatment administration and included area of secondary hyperalgesia around the sensitized skin of the forearm (45 degrees C for 5 minutes followed by topical capsaicin for 30 minutes), area of secondary hyperalgesia after thermal sensitization of the thigh (45 degrees C for 3 minutes), heat pain detection thresholds (degrees C), and pain on a visual analogue scale after long thermal stimulation (45 degrees C for 1 minute). Compared with placebo, both gabapentin and CHF3381 significantly reduced the area of secondary hyperalgesia on the dominant forearm. Median (and interquartile range) percent values over baseline were 86% after placebo (69% to 100%), 56% (41% to 76%) after gabapentin (P < .001), and 67% (49% to 88%) after CHF3381 (P < .009). Both drugs also significantly decreased the area of secondary hyperalgesia on the dominant thigh. The other pain variables were not significantly affected. Adverse events, mainly fatigue and dizziness, were mild to moderate.. This article presents the antihyperalgesic effect of CHF3381, a new NMDA receptor antagonist and reversible MAO-A inhibitor, in a human pain model and might guide the proper selection of CHF3381 doses to be used in Phase 2 studies in patients with neuropathic pain.

Topics: Adult; Amines; Analgesics; Capsaicin; Cross-Over Studies; Cyclohexanecarboxylic Acids; Double-Blind Method; Excitatory Amino Acid Antagonists; Gabapentin; gamma-Aminobutyric Acid; Glycine; Humans; Hyperalgesia; Indans; Male; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Pain; Pain Measurement; Receptors, N-Methyl-D-Aspartate

To evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic profiles of CHF3381, a dual NMDA and MAO-A inhibitor, after multiple oral doses in healthy subjects.. Forty-eight young males received CHF3381 at doses of 100 mg twice daily, 200 mg twice daily, 400 mg twice daily or placebo for 2 weeks according to a double-blind, randomized, parallel group design. Plasma and urine concentrations of the parent drug and of two major metabolites (CHF3567 and 2-aminoindane) were measured over time. MAO-A activity in plasma was estimated by measuring plasma concentrations of 3,4-dihydroxyphenylglycol. Sustained attention, memory and sedation were assessed throughout the study with standard psychometric tests.. Most of the adverse events were mild in intensity, with dose regimens of 100 mg twice daily and 200 mg twice daily being indistinguishable from placebo. After 400 mg twice daily, the most frequent adverse events were mild dizziness, asthenia and insomnia. At steady-state, 400 mg twice daily slightly increased supine heart rate (+ 9 +/- 2 beats min(-1)) and diastolic blood pressure (+6 +/- 2 mmHg) compared with placebo. There were no dose-dependent or consistent effects of CHF3381 on attention, motor co-ordination or memory, but 400 mg twice daily significantly decreased alertness compared with placebo. Plasma concentrations of CHF3381 peaked at around 3 h and were dose-proportional. The elimination half-life of CHF3381 was estimated to be 4-6 h. At steady-state, significant CHF3381 plasma concentrations were detected at predose with a modest accumulation (1.3-1.5 times), showing that the drug given twice daily is active over the entire 24 h period. Plasma concentrations of CHF3567 and of 2-aminoindane were also proportional to the dose of CHF3381. CHF3381 dose-dependently inhibited MAO-A activity with peak effects at steady-state of 27 +/- 4%, 46 +/- 2% and 65 +/- 5% after 100 mg twice daily, 200 mg twice daily and 400 mg twice daily, respectively. There were no significant effects of CHF3381 on attention (rapid visual information processing), motor co-ordination (body sway) or memory (learning memory task) at any of the doses. At steady-state, there was a significant decrease in alertness (Bond & Lader visual analogue scale) in the 400 mg twice daily group compared with placebo.. A twice daily regimen of CHF3381 appears to be adequate from a pharmacokinetic and pharmacodynamic perspective. Plasma concentrations reached with 400 mg twice daily exceeded those observed in animals receiving pharmacologically active doses in chronic pain models.

Topics: Administration, Oral; Adolescent; Adult; Analgesics; Area Under Curve; Attention; Central Nervous System; Dose-Response Relationship, Drug; Double-Blind Method; Glycine; Half-Life; Humans; Indans; Male; Memory; Pain; Psychomotor Performance

Here, we have examined the effect of the novel antinociceptive agent CHF3381 on the development of nocifensive behaviour as well as secondary mechanical allodynia and hyperalgesia induced by intraplantar injection of capsaicin in rats. Vehicle, CHF3381 or gabapentin were orally administered 1 h before capsaicin injection. The duration of nocifensive behaviour was measured during the first 5 min after capsaicin injection. Secondary mechanical allodynia and hyperalgesia were measured at 5 and 15 min after capsaicin injection, respectively. CHF3381 produced a significant suppression of nocifensive behaviour and completely blocked the development of mechanical allodynia and hyperalgesia at 100 and 200 mg/kg. Gabapentin weakly inhibited the development of nocifensive behaviour and mechanical allodynia. On the contrary, gabapentin (100 mg/kg) completely prevented the development of mechanical hyperalgesia. In conclusion, CHF3381 had full efficacy for all the capsaicin-induced pain parameters tested, suggesting that CHF3381 may have a therapeutic utility in the management of pain states involving central sensitisation.

Topics: Administration, Oral; Amines; Analgesics; Animals; Behavior, Animal; Capsaicin; Cyclohexanecarboxylic Acids; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Gabapentin; gamma-Aminobutyric Acid; Glycine; Hindlimb; Hyperalgesia; Indans; Male; Pain; Rats; Rats, Sprague-Dawley

N-(2-Indanyl)-glycinamide hydrochloride (CHF3381) is a novel low-affinity, noncompetitive N-methyl-d-aspartate receptor antagonist. The current study compared the antinociceptive effects of CHF3381 with those of gabapentin and memantine in in vitro and in vivo models of pain. In isolated rat spinal cord, CHF3381 and memantine, but not gabapentin, produced similar inhibition of the wind-up phenomenon. CHF3381 suppressed the maintenance of carrageenan-induced thermal and mechanical hyperalgesia in the rat with a minimum significantly effective dose (MED) of 30 mg/kg p.o. Memantine produced a partial reversal of both thermal and mechanical hyperalgesia (MED = 10 and 15 mg/kg i.p., respectively). Gabapentin reversed mechanical hyperalgesia (MED = 10 mg/kg s.c.), but did not affect thermal hyperalgesia. In the mouse formalin test, CHF3381 and memantine preferentially inhibited the late phase (MED = 30 and 20 mg/kg i.p., respectively); gabapentin inhibited only the late phase (MED = 30 mg/kg s.c.). Unlike morphine, CHF3381 chronic administration was not accompanied by the development of tolerance in the formalin test. Furthermore, morphine tolerance did not cross-generalize to CHF3381. In rats with a sciatic nerve injury, CHF3381 relieved both cold and mechanical allodynia (MED = 100 mg/kg p.o.). In contrast, memantine was inactive. Gabapentin blocked cold allodynia (MED = 30 mg/kg s.c.), but had marginal effects on mechanical allodynia. In diabetic neuropathy, CHF3381 reversed mechanical hyperalgesia (MED = 50 mg/kg p.o.). Memantine (15 mg/kg i.p.) produced an antinociceptive effect, whereas gabapentin (100 mg/kg p.o.) had no significant effect. Thus, CHF3381 may be useful for the therapy of peripheral painful neuropathies.

Topics: Animals; Carrageenan; Cold Temperature; Diabetes Mellitus; Disease Models, Animal; Drug Tolerance; Excitatory Amino Acid Antagonists; Glycine; Hot Temperature; Hyperalgesia; Indans; Inflammation; Mice; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Streptozocin