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|Systematic (IUPAC) name|
|Bioavailability||100% (IV)|
|Synonyms||Chandonium iodide; HS-310|
|Molar mass||640.47 g/mol|
|(what is this?)|
Candocuronium iodide (INN, formerly chandonium, HS-310) is the prototypical[editorializing][not verified in body] azasteroidal neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs. Its potential adjunctive use in anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation was briefly evaluated in clinical studies in India, but further development was discontinued because of attendant undesirable cardiovasular effects, primarily tachycardia that was no worse than but also not an improvement over the clinically established pancuronium bromide. Candocuronium demonstrated a short duration and a rapid onset of action, with little or no ganglion blocking activity, and it was only slightly less potent than pancuronium.
As with other established neuromuscular blocking agents, candocuronium preferentially antagonizes competitively the nicotinic subtype of acetylcholine receptors. The agent was developed by the laboratory of Harkishan Singh, Panjab University, Chandigarh, India, as part of the search for "the Holy Grail of neuromuscular blocking agents":[attribution needed] a non-depolarizing replacement for the most popular clinically used depolarizing agent, suxamethonium (succinylcholine).
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 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. 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). 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]
Modifications to the candocuronium design
However, 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 promising compounds,[editorializing] HS-692, HS-693, HS-704 and HS-705,[clarification needed] whose onset and duration were indinguishable from candocuronium, but, unfortunately,[editorializing] all demonstrated profound vagolytic effects and much weaker potencies than candocuronium. To improve on potency, further modifications of the candocuronium nucleus were undertaken,[clarification needed] leading to the identification of yet another promising compound,[editorializing] HS-626. Unfortunately, upon further preclinical evaluation in the cat and isolated preparations, 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, but the admirable undaunted persistence[peacock term][neutrality is disputed] has not yet yielded an agent worthy of expanded evaluation to clinical testing in this azasteroidal class of neuromuscular blocking agents.
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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. PMID 2151453.
- 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. PMID 3397166.
- 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. PMID 2148735.
- 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. doi:10.1111/j.2042-7158.1976.tb02812.x. PMID 11309.
- Singh H, Paul D (1974). "Steroids and related studies. XXV. Chandonium iodide (17a-methyl-3beta-pyrrolidino-17a-aza-D-homoandrost-5-ene dimethiodide) and other quaternary ammonium steroid analogues". J Chem Soc Perkin 1. 12: 1475–1479. doi:10.1039/p19740001475. PMID 4472321.
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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. doi:10.1016/0014-2999(73)90002-2. PMID 4715215.
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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. doi:10.1016/s0223-5234(00)01205-8. PMID 11311750.
- Jindal DP, Piplani P, Fajrak H, Prior C, Marshall IG (Nov 2002). "Synthesis and neuromuscular blocking activity of 16β-N-methylpiperazino steroidal derivatives". Eur J Med Chem. 37 (11): 901–908. doi:10.1016/s0223-5234(02)01413-7. PMID 12446049.