Candocuronium iodide (
INN, formerly chandonium, HS-310)[1] is a
aminosteroidneuromuscular-blocking drug. Its use within
anesthesia for
endotracheal intubation and for providing
skeletal muscle relaxation during surgery or
mechanical ventilation was briefly evaluated in clinical studies in India, though further development was discontinued due to attendant cardiovascular effects, primarily
tachycardia that was about the same as the clinically established
pancuronium bromide.[2][3][4][5] Candocuronium demonstrated a short duration in the body, but a rapid onset of action. It had little to no ganglion blocking activity, with a greater potency than pancuronium.[1]
Background
As with other neuromuscular-blocking agents, candocuronium preferentially antagonizes competitively the
nicotinic subtype of acetylcholine receptors.[6] The agent was developed by the laboratory of Harkishan Singh, Panjab University, Chandigarh, India, as part of the search for a non-depolarizing replacement for the most popular clinical depolarizing agent,
suxamethonium (
succinylcholine).[citation needed]
Design of candocuronium
The mono- and bis-quaternary azasteroid series of compounds to which candocuronium belongs are based on the same principle that led to aminosteroids such as
pancuronium,
vecuronium and
rocuronium: use of the steroid skeleton to provide a somewhat rigid distance between the two quaternary ammonium centers, with appendages incorporating fragments of choline or acetylcholine. The discovery program initiated by Singh[7] initially led to the synthesis of the bis-quaternary non-depolarizing agent HS-342 (4,17a-dimethyl-4,17a-diaza-D-homo-5α-androstane dimethiodide) that was equipotent with tubocurarine and with one-third its duration of action, but not suitable for further clinical evaluation.[8][9] Modifications of the HS-342 structure[clarification needed] led to two other notable agents,[editorializing] HS-347 and HS-310 (subsequently named chandonium, then candocuronium).[1][7] HS-347 was equipotent with tubocurarine but exhibited considerable ganglion blocking activity; candocuronium appeared to be suitably placed for clinical trials following encouraging preclinical evaluations.[editorializing][10][11][12][13]
Modifications to the candocuronium design
Candocuronium did not provide the desired profile,[clarification needed] and a further extension of research was undertaken to overcome its limitations.[clarification needed] This led to four more potentially useful compounds,[editorializing] HS-692, HS-693, HS-704 and HS-705,[clarification needed][14] whose onset and duration were indinguishable from candocuronium, but all demonstrated profound vagolytic effects and much weaker potencies than candocuronium.[11] To improve on potency, further modifications of the candocuronium nucleus were undertaken,[clarification needed] leading to the identification of yet another potentially useful compound, HS-626.[15] Upon further preclinical evaluation,[16] HS-626 demonstrated a slightly more desirable neuromuscular-blocking profile than that of candocuronium, but its overall improvement was insufficient to warrant advancement to clinical testing.
Modifications at 3- and 16-positions of androstane nucleus
The discovery of candocuronium led to numerous related neuromuscular-blocking agents with short durations of action but also having attendant undesirable cardiovascular effects. The Marshall group then explored other modifications at the 3- and 16-positions of the androstane nucleus,[17][18] and yielded an agent that can go through expanded evaluation to clinical testing.
References
^
abcGandiha A, Marshall IG, Paul D, Singh H (Nov 1974). "Neuromuscular and other blocking actions of a new series of mono and bisquaternary aza steroids". J Pharm Pharmacol. 26 (11): 871–877.
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10.1111/j.2042-7158.1974.tb09195.x.
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^Dasgupta D, Gupta KC, Vispute AV, Karandikar SM (Apr 1990). "Comparative clinical evaluation of chandonium iodide and pancuronium bromide as muscle relaxant". J Postgrad Med. 36 (2): 95–99.
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^Dasgupta D, D'Souza M, Shah SJ, Gupta KC, Satoskar RS (Mar 1988). "Clinical evaluation of chandonium iodide as muscle relaxant". Indian J Med Res. 87: 298–302.
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^Kumar D, Bhatia VK, Yajnik S, Gaur SP, Nityanand S (Oct 1990). "Clinical evaluation of chandonium iodide as a nondepolarising muscle relaxant". Indian J Med Res. 92: 367–370.
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^Suri YV (1984). Chandonium-iodide. New non-depolarising muscle relaxant. In: "Anaesthesiology. Clinical Pharmacology" Suri YV, Singh D (Eds.) New Delhi: Vani Educational Books; 28-35.
^Harvey AL, Paul D, Rodger IW, Singh H (1976). "Actions of the muscle relaxant chandonium iodide on guinea-pig ileum and vas deferens preparations". J Pharm Pharmacol. 28 (8): 617–619.
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^
abSingh H, Paul D (1974). "Steroids and related studies. Part XXV. Chandonium iodide (17a-methyl-3β-pyrrolidino-17a-aza-D-homoandrost-5-ene dimethiodide) and other quaternary ammonium steroid analogues". Journal of the Chemical Society, Perkin Transactions 1. 12 (12): 1475–1479.
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^Marshall IG, Paul D, Singh H (Jun 1973). "Some actions of 4,17a-dimethyl-4,17a-diaza-D-homo-5alpha-androstane dimethiodide (HS-342), a new neuromuscular blocking drug". J Pharm Pharmacol. 25 (6): 441–446.
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^Marshall IG, Paul D, Singh H (May 1973). "The neuromuscular and other blocking actions of 4,17a-dimethyl-4,17a-diaza-d-homo-5 -androstane dimethiodide (HS-342) in the anaesthetized cat". Eur J Pharmacol. 22 (2): 129–134.
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^Gandiha A, Marshall IG, Paul D, Rodger IW, Scott W, Singh H (Mar–Apr 1975). "Some actions of chandonium iodide, a new short-acting muscle relaxant, in anaesthetized cats and on isolated muscle preparations". Clin Exp Pharmacol Physiol. 2 (2): 159–170.
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^
abTeerapong P, Marshall IG, Harvey AL, Singh H, Paul D, Bhardwaj TR, Ahuja NK (Aug 1979). "The effects of dihydrochandonium and other chandonium analogues on neuromuscular and autonomic transmission". J Pharm Pharmacol. 31 (8): 521–528.
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^Singh H, Chaudhary AK (May 1985). "Pharmacokinetics and disposition of chandonium iodide in rat". Indian J Exp Biol. 23 (5): 253–257.
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^Singh H, Chaudhary AK (May 1985). "Pharmacokinetics and disposition of chandonium iodide in monkey". Indian J Exp Biol. 23 (5): 258–261.
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^Singh H, Bhardwaj TR, Ahuja NK, Paul D (1979). "Steroids and related studies. Part 44. 17a-Methyl-3β-(N-pyrrolidinyl)17a-aza-D-homo-5α-androstane bis(methiodide)(dihydrochandonium iodide) and certain other analogues of chandonium iodide". Journal of the Chemical Society, Perkin Transactions 1: 305–307.
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^Singh H, Bhardwaj TR, Paul D (1979). "Steroids and related studies. Part 48. A chandonium iodide analogue possessing an acetylcholine-like moiety". Journal of the Chemical Society, Perkin Transactions 1: 2451.
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^Marshall IG, Harvey AL, Singh H, Bhardwaj TR, Paul D (Jul 1981). "The neuromuscular and autonomic blocking effects of azasteroids containing choline or acetylcholine fragments". J Pharm Pharmacol. 33 (7): 451–457.
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^Jindal DP, Piplani P, Fajrak H, Prior C, Marshall IG (Feb 2001). "Synthesis and neuromuscular blocking activity of 16β-piperidinosteroidal derivatives". Eur J Med Chem. 36 (2): 195–202.
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