|This article may rely excessively on sources too closely associated with the subject, potentially preventing the article from being verifiable and neutral. (June 2014)|
|Systematic (IUPAC) name|
- Discontinued from clinical development
Chandonium iodide; HS-310|
| 14px (what is this?) (verify)|
Candocuronium iodide (INN, formerly chandonium, HS-310) is the prototypical 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": 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 led to two other notable agents, 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.
Modifications to the candocuronium design
However, candocuronium did not provide the desired profile, and a further extension of research was undertaken to overcome its limitations. This led to four more promising compounds, HS-692, HS-693, HS-704 and HS-705, whose onset and duration were indinguishable from candocuronium, but, unfortunately, all demonstrated profound vagolytic effects and much weaker potencies than candocuronium. To improve on potency, further modifications of the candocuronium nucleus were undertaken, leading to the identification of yet another promising compound, 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 has not yet yielded an agent worthy of expanded evaluation to clinical testing in this azasteroidal class of neuromuscular blocking agents.
- ↑ 1.0 1.1 1.2 Gandiha 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 Phamacol 26 (11): 871–877. PMID 4156557. doi:10.1111/j.2042-7158.1974.tb09195.x.
- ↑ 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. PMID 11309. doi:10.1111/j.2042-7158.1976.tb02812.x.
- ↑ 7.0 7.1 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. PMID 4472321. doi:10.1039/p19740001475.
- ↑ 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. PMID 4146581. doi:10.1111/j.2042-7158.1973.tb09130.x.
- ↑ 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. PMID 4715215. doi:10.1016/0014-2999(73)90002-2.
- ↑ 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. PMID 237641. doi:10.1111/j.1440-1681.1975.tb01830.x.
- ↑ 11.0 11.1 Teerapong 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. PMID 39992. doi:10.1111/j.2042-7158.1979.tb13576.x.
- ↑ Singh H, Chaudhary AK (May 1985). "Pharmacokinetics and disposition of chandonium iodide in rat". Indian J Exp Biol 23 (5): 253–257. PMID 4077122.
- ↑ Singh H, Chaudhary AK (May 1985). "Pharmacokinetics and disposition of chandonium iodide in monkey". Indian J Exp Biol 23 (5): 258–261. PMID 4077123.
- ↑ Singh H, Bhardwaj TR, Ahuja NK, Paul D (1979). J Chem Soc, Perk Trans I: 305.
- ↑ Singh H, Bhardwaj TR, Paul D (1979). J Chem Soc, Perk Trans I: 2451.
- ↑ 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. PMID 6115032. doi:10.1111/j.2042-7158.1981.tb13831.x.
- ↑ 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. PMID 11311750. doi:10.1016/s0223-5234(00)01205-8.
- ↑ 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. PMID 12446049. doi:10.1016/s0223-5234(02)01413-7.