Disease relevance of EMD 61753

• Systemic and intrathecal nor-binaltorphimine partially inhibited the effect of asimadoline against formalin-evoked hyperalgesia in diabetic rats [1].
• These data suggest that further studies should explore the potential benefit of asimadoline in treatment of pain in irritable bowel syndrome patients [2].
• The objective of the present study was to evaluate the effects of EMD 61753 (asimadoline), a kappa-opioid receptor agonist with restricted access to the central nervous system, on postoperative pain in patients who underwent knee surgery and on nociceptive thresholds and inflammation in rats treated with Freund's complete adjuvant [3].
• Results of Phase III trials of fedotozine against irritable bowel syndrome and dyspepsia have, however, ultimately been disappointing, whereas asimadoline is currently in Phase II clinical trials against pain of rheumatic and osteoarthritic origin [4].

Psychiatry related information on EMD 61753

• Effects of a kappa-opioid agonist, asimadoline, on satiation and GI motor and sensory functions in humans [5].
• RESULTS: On asimadoline, pain threshold (mean +/- s.d.) (29.8 +/- 7.2 mmHg) was higher than on placebo (26.3 +/- 7.8 mmHg), difference not statistically significant (P = 0.1756, ANOVA) [2].

High impact information on EMD 61753

• Exploiting the presence and elevated levels of KOR in the periphery, we investigated the effect of the peripheral KOR agonist asimadoline on formalin-evoked hyperalgesia and tactile allodynia in diabetic rats [1].
• Area under curve of pain intensity rated at each distension step was significantly lower on asimadoline (89.3 +/- 33.9, ANOVA) than on placebo (108.1 +/- 29.7) (P = 0.0411) [2].
• CONCLUSION: An altered balance, therefore, in the pro- and anti-inflammatory effects of TGF-beta by asimadoline might explain its striking anti-arthritic actions [6].
• To elucidate possible mechanisms, we investigated the effects of asimadoline (5 mg/kg/day i.p.) or vehicle on in vivo cytokine expression and T-cell recruitment in adjuvant arthritis [6].
• The kappa-opioid agonist, asimadoline, alters cytokine gene expression in adjuvant arthritis [6].

Biological context of EMD 61753

• 2. EMD 61753 binds with high affinity (IC50 5.6 nM) and selectivity (kappa:mu:delta:sigma binding ratio 1:536:125: > 1,786) to kappa-opioid receptors and is a full and potent (IC50 54.5 nM) agonist in an in vitro assay for kappa-opioid receptors (rabbit vas deferens preparation) [7].
• Without effects on blood pressure, heart rate, GFR or urine electrolyte excretion, urine volume increased after 1-2 h after administration of 5 and 10 mg asimadoline from 3.3+/-1.3 to 5.6+/-1.4 (P<0.05) and from 3.2 +/-1.6 to 5.5+/-2.2 ml min(-1) (P<0.01), respectively [8].

Anatomical context of EMD 61753

• Role of blood-brain barrier P-glycoprotein in limiting brain accumulation and sedative side-effects of asimadoline, a peripherally acting analgaesic drug [9].
• Using a pig-kidney polarized epithelial cell line transfected with mdr cDNAs, we demonstrate that asimadoline is transported by the mouse mdr1a P-gp and the human MDR1 P-gp [9].
• The kappa-opioid receptor agonist asimadoline inhibits epithelial transport in mouse trachea and colon [10].
• In Ussing chamber experiments, asimadoline (100 microM) decreased short-circuit currents in airways and colon epithelium [10].
• AIMS: The purpose of the study was to investigate the effects of asimadoline, a new kappa-opioid agonist, on renal function and on hormones related to body fluid balance as well as its tolerability in healthy subjects [8].

Associations of EMD 61753 with other chemical compounds

• Hexobarbitone-induced sleeping in mice was prolonged by EMD 61753 at threshold doses of 10 mg kg-1, s.c., and 100 mg kg-1, p.o., whereas the motor performance of rats in the rotarod test was impaired by EMD 61753 with an ID50 value of 453 mg kg-1, s.c. 5 [7].
• Effects of the peripherally selective kappa-opioid asimadoline, on substance P and CGRP mRNA expression in chronic arthritis of the rat [11].

Gene context of EMD 61753

• Furthermore, we show that in mdr1a/1b double knockout mice, the absence of P-gp leads to a 9 fold increased accumulation of asimadoline in the brain [9].
• The effect of asimadoline on SP levels was time dependent: reduction of SP content after 3 days but an increase after 12 or 21 days treatment, paradoxically with clinical improvement in each case [12].
• RESULTS: Asimadoline significantly decreased arthritis severity at day 13, with a concomitant decrease in synovial membrane expression of cytokines interleukin-17 and transforming growth factor-beta (TGF-beta) mRNA at day 13, and no change in T cell numbers in the joints of arthritic rats [6].
• Asimadoline (EMD 61753) is a peripherally selective kappa-opioid receptor agonist which is under development as a therapeutic analgaesic [9].
• Plasma AVP was suppressed only by the 10 mg dose of asimadoline in six of eight subjects during the 2.5% saline infusion [8].

Analytical, diagnostic and therapeutic context of EMD 61753

• Behavioural assessments of paw tactile sensitivity and formalin-evoked hyperalgesia were performed in normal and diabetic rats before and after treatment with asimadoline [1].
• OBJECTIVE: We have previously found that the kappa-opioid agonist, asimadoline, attenuates adjuvant arthritis in a dose-dependent, antagonist-reversible manner [6].
• These data show differentially mediated peripheral actions of EMD 61753: kappa-opioid receptor-induced analgesia and nonopioid, non-N-methyl-D-aspartic acid hyperalgesic and proinflammatory effects [3].
• Patients treated with EMD 61753 (10 mg p.o.) tended to report an increase in pain, as evaluated by a visual analog scale and by the time to the first request for and the total amount of supplemental analgesic medication [3].
• CONCLUSION: A single oral administration of asimadoline decreases satiation and postprandial fullness in humans independently of its effects on gastric volume [13].

References