Gantacurium chloride

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Gantacurium chloride
File:Gantacurium chloride.png
Systematic (IUPAC) name
4-O-[3-[(1S,2R)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl)-3,4-dihydro-1H-isoquinolin-2-ium-2-yl]propyl]1-O-[3-[(1R,2S)-6,7-dimethoxy-2-methyl-1-[(3,4,5-trimethoxyphenyl)methyl]-3,4-dihydro-1H-isoquinolin-2-ium-2-yl]propyl](Z)-2-chlorobut-2-enedioate dichloride
Clinical data
Routes of
administration		 IV
Legal status
Legal status
  • in phase III clinical development as of March 2010
Pharmacokinetic data
Bioavailability 100% (IV)
Protein binding unknown
Metabolism rapid inactivation by endogenous cysteine adduct formation followed by slow ester hydrolysis
Biological half-life unknown
Excretion renal / hepatic
Identifiers
CAS Number 213998-46-0
PubChem CID 10772467
Chemical data
Formula C53H69Cl3N2O14
Molar mass 1064.47896 g/mol[[Script error: No such module "String".]]
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Gantacurium chloride (formerly recognized as GW280430A and as AV430A) is a new experimental neuromuscular blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in surgical anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation. Gantacurium is not yet available for widespread clinical use: it is currently undergoing Phase III clinical development.

History

Gantacurium represents the third generation of tetrahydroisoquinolinium neuromuscular blocking drugs in a long lineage of compounds invented by medicinal chemists and scientists at Burroughs Wellcome Co., Research Triangle Park, NC. Unlike all other clinically used tetrahydroisoquinolinium agents except cisatracurium, gantacurium is a stereo- and regioselective single isomer. And unlike any other traditional symmetrical predecessors in the family of bisbenzyltetrahydroisoquinolinium neuromuscular-blocking drugs, gantacurium is an asymmetric bis-onium ester of α-chlorofumaric acid: this particular feature arises solely from the (1R)-trans benzyltetrahydroisoquinolinium moiety at one onium head and a (1S)-trans phenyltetrahydroisoquinolinium moiety at the other onium head. The chlorine atom lies on the same side of the double bond as the benzyl-THIQ moiety (or the opposite side to the phenyl-THIQ moiety).

The lineage of compounds leading to the rational discovery of gantacurium stems from seminal research in tetrafluorosuccinic acid-derived bisbenzyltetrahydroisoquinolinium esters first synthesized in February 1991[1][2] by a postdoctoral Fellow (Sanjay S. Patel, PhD) and James C. Wisowaty, PhD, in the Chemical Development Laboratories at Burroughs Wellcome Co. in collaboration with John J. Savarese, MD (Chairman of Anesthesiology at the New York Presbyterian-Weill Cornell Medical Center, New York, NY). The synthesis of symmetrical halofumarate and halosuccinate esters was prompted by initial attempts to make bis-onium tetrafluorosuccinic acid esters (compound 551U91[1] and 552U91[2]) - the novel idea of a tetrafluorosuccinate linker between two onium heads being prompted by Roy A Swaringen, PhD (the then Group Director of Chemical Development Laboratories at Burroughs Wellcome Co.). It was very quickly realized, however, that the tetrafluorosuccinic acid esters were too unstable for isolation in sufficient quantities for extensive in vitro or in vivo preclinical evaluations. To circumvent the in situ instability of the fluoro derivatives, synthesis of bis-onium dichloro- and dibromosuccinates was undertaken: that in itself lead to complex intractable mixtures of mono- and di-halofumarate and halosuccinate compounds. The mixtures were inseparable initially but proved to be promising: in vivo tests of these mixtures (798W92[3] and 799W92[4]) in a cat model pointed to potential leads for a compound with the highly prized duality of a rapid onset of action and an ultrashort duration of action (see below for definition of ultrashort duration). This led to the synthesis of prototypical bisbenzyltetrahydroisoquinolinium halofumarate esters in April 1992: compounds 1710W92[5] (a monochlorofumarate) and 1975W92[6] (a dichlorofumarate), both of which were noted for their ultrashort durations of action, and would differ structurally only very slightly from the future gantacurium in their stereochemistry and symmetry. Indeed, the idea of exploring asymmetric tetrahydroisoquinolinium esters had already been seeded with parallel and earlier syntheses of another series of asymmetric potential neuromuscular blocking agents,[7] although the original concept for asymmetricity in the design of new neuromuscular blocking drugs dates back to 1962[8] with reported combinations of the respective halves of laudexium and succinylcholine (suxamethonium) modeled, presumably, on the asymmetric structure of the prototypical neuromuscular blocking agent d-tubocurarine that made its entry into anesthetic practice on 23 January 1942, at the Montreal Homeopathic Hospital.[9]

Very shortly after the breakthrough in May 1992, however, Patel relinquished his Fellowship and further progress languished until late 1993/early 1994 when the research was resumed by another team of Burroughs Wellcome Co. chemists led by Eric Bigham PhD and Evan Boswell PhD: a series of stereoselective halofumarate and halosuccinate compounds were synthesized and tested for further lead optimisation. Again, however, the untimely intervening merger between Burroughs Wellcome Co. and its rival Glaxo Inc. to form the now non-existent GlaxoWellcome Inc. during 1995 resulted in even further delays to progress in optimizing the halosuccinate and halofumarate series of neuromuscular blocking drugs.

It was not until late in 1995 that further research and lead optimization was re-initiated by yet another team of medicinal chemists at GlaxoWellcome Inc. (Research Triangle Park, NC) this time led by Eric E. Boros PhD, Robert A. Mook Jr. PhD, and Vicente Samano PhD. The team's work rapidly led to the first synthesis of GW280430A in 1996.[10][11][12] Patents for gantacurium were subsequently applied for and issued in 1998.[13][14]

Neuromuscular function parameters: definitions

The clinical arena of neuromuscular blocking agents is a minefield of jargonistic language, and some defintions below help to clarify:

  • Train-of-Four (TOF) response: stimulated muscle twitch response (e.g., the adductor pollicis) elicited in trains of four when stimuli are applied (to the ulnar nerve for example) in a burst of four stimuli versus single stimuli
  • ED95 dose: the dose of any given neuromuscular blocking agent required to produce 95% suppression of muscle twitch (e.g., the adductor pollicis) response under balanced anesthesia
  • T25% (also known as the clinical duration): the calculated difference in time between time of injection of drug and time to 25% recovery from neuromuscular block - this parameter defines the clinically effective neuromuscular block
  • T75% recovery: the calculated difference in time between time of injection of drug and time to 75% recovery from neuromuscular block
  • T95% recovery: the calculated difference in time between time of injection of drug and time to 95% recovery from neuromuscular block - this parameter effectively defines the timepoint at which full recovery from neuromuscular block is observed
  • 25%-75% recovery index: the difference in time between the time to recovery to 25% and time to recovery to 75% of baseline value - this parameter is an indicator of the rate of recovery from neuromuscular block
  • 5%-95% recovery index: the difference in time between the time to recovery to 5% and time to recovery to 95% of baseline value - another parameter that is an indicator of the rate of recovery from relatively complete block to full recovery from neuromuscular block
  • T4:T1 ≥ 0.7: a 70% ratio of the fourth twitch to the first twitch in a TOF - provides another measure of the recovery of neuromuscular function
  • T4:T1 ≥ 0.9: a 90% ratio of the fourth twitch to the first twitch in a TOF - provides another measure of the full recovery of neuromuscular function

Duration of action: definitions

In anesthetic clinical practice, neuromuscular blocking agents tend to be distinguished from each other in accordance to their duration of pharmacological action as follows:

Classification of neuromuscular blocking agents by duration of pharmacological action (minutes)
Parameter Ultra-
short Duration 		Short Duration Intermediate Duration Long Duration
Clinical Duration
(Time from injection to T25% recovery) 		6-8 12-20

30-45

>60
Recovery Time
(Time from injection to T95% recovery) 		<15 25-30

50-70

90-180
Recovery Index (T25%-T75% recovery slope) 2-3 6

10-15

>30

Preclinical pharmacology

The preclinical pharmacology development of GW280430A has been studied in the cat, dog, and monkey models[15][16] that have been the backbone of predecessor bistetrahydroisoquinolinium neuromuscular blocking drug development projects: atracurium (Tracrium®), doxacurium (Nuromax®), mivacurium (Mivacron®) and cisatracurium (Nimbex®).

Clinical Pharmacology and Pharmacokinetics

The first clinical trial of GW280430A was conducted in a small cohort of healthy US volunteers (n=31)[17] in December 1997 at the New York Presbyterian-Weill Cornell Medical Center, New York, NY. The study confirmed that, with propofol/fentanyl/N2O/O2 anesthesia, gantacurium (ED95 = 0.19 mg/kg) has a rapid onset of action (maximum neuromusuclar block ≤90 seconds at doses ranging from 2.5- to 3xED95) and an ultra-short duration of action (clinical duration of ≤10 minutes for doses up to 0.72 mg/kg). Additionally, the spontaneous recovery rate was rapid, predictable, and independent of dose administered (1- to 4xED95), indicating a lack of cumulative neuromuscular blocking effect: the 25-75% recovery index (indicating the rate of recovery) was 3 minutes, and complete recovery to TOF of 90% occurred ≤15 minutes (vs. ≤4 minutes after edrophonium administration). These data are secured from a small sample size, tempering any broad conclusions to be drawn until clinical studies with larger sample sizes are conducted.

In early 1998, shortly after conducting the first clinical study, GlaxoWellcome Inc. undertook a strategic decision to outlicense its US anesthesia research portfolio and franchise. Further clinical development of GW280430A therefore ceased until the portfolio was licensed in May 2002[18] to a now-defunct start-up company called Avera Pharmaceuticals (San Diego, CA). Meanwhile, in the intervening period, scientists at the former GlaxoWellcome Inc. had conducted further research and developed a proprietary buffer excipient formulation[19] intended to mitigate the mast cell degranulation seen upon rapid intravenous administration of high concentration doses of agents such as GW280430A that are intrinsically cationic. In 2003, a newly reformulated version of GW280430A (now renamed AV430A, and subsequently renamed again to the generic gantacurium chloride in 2004), using the licensed buffer excipient from GlaxoSmithKline, was re-investigated in a second clinical study in healthy US volunteers to compare the improvement in safety margin versus that with the original formulation. Success with the reformulated gantancurium in healthy volunteers led to initiation and conduct of a randomized, controlled, phase II multicenter European study investigating its utility for endotracheal intubation in 230 patients undergoing surgical anesthesia.[20] The phase II study was completed successfully by Spring 2006: >90% of patients administered with gantacurium were assessed to have acceptable tracheal intubation within 60 seconds of its injection.[21] However, a peer-reviewed full publication of these data from this European study has yet to be published, despite early presentation of these data as an abstract.[22]

Gantacurium is currently (as of March 2010) under phase III clinical development by Maruishi Pharmaceutical Co. Ltd. (Japan) which licensed the compound from Avera Pharmaceuticals. Maruishi is better known in the world of anesthesia for its invention of sevoflurane, a commonly used gaseous anesthetic agent.

The singular distinguishing clinical feature of gantacurium from any other non-depolarizing neuromuscular blocking drug clinically tested is that it has the desired duality of a rapid onset and an ultrashort duration of action even when administered at 3-4 times the ED95 doses. With the exception of one other clinically tested agent, BW785U77,[23][24] no other clinically administered neuromuscular blocking drug has matched this feat to date: all other non-depolarizing neuromuscular blocking drugs clinically administered at equivalent doses most certainly would result in a medium or long duration of action albeit with a rapid onset of paralyzing effect.[25][26] In this sense, gantacurium is a first in its class non-depolarizing neuromuscular blocking drug to arguably challenge the pharmacological profile of the gold-standard ultrashort acting depolarizing agent succinylcholine (suxamethonium).[17][27][28] BW785U77 was not pursued for further clinical development owing to its propensity for eliciting histamine release in humans with more intensity than that observed during pre-clinical evaluation in animals. The holy grail of research in the neuromuscular blocking drugs arena for the better part of the 1980s and 1990s has been to find a non-depolarizing replacement for succinylcholine.[27][29][30]

Preliminary in vitro investigations indicate that the in vivo pharmacological activity likely undergoes rapid "chemo-inactivation" via cysteine adduct formation followed by slow biodegradation via ester hydrolysis.[12][31] The pharmacologically inert cysteine adduct subsequently undergoes ester hydrolysis and the by-products are eliminated via renal and/or hepatic mechanisms. Unlike the pH- and temperature-dependent chemodegradation seen with atracurium and cisatracurium, the inactivation of gantacurium via cysteine adduct formation is independent of body pH and temperature.[12][31]

The use of extrinsically administered cysteine to deliberately accelerate reversal of the pharmacological effect of fumarate bis-onium neuromuscular blocking drugs (e.g., RV002 [formerly known as AV002]) is being investigated currently.[32][33][34]

Adverse Effects

Histamine release - Hypotension, Reflex tachycardia and Cutaneous Flushing

Gantacurium chloride is not associated with histamine release when administered as a rapid bolus (<5 seconds administration time) at doses up to and including 0.45 mg/kg (≤2.5xED95) according to one small study in healty human volunteers.[17] At 0.54 mg/kg (just under 3xED95 dose), one of four volunteers experienced histamine release with associated hypotension (30% maximum decrease in blood pressure and 13% maximum increase in heart rate) but no cutaneous flushing. At the highest administered dose of 0.72 mg/kg, three of four volunteers experienced histamine release with associated hypotension (17% to 34% maximum decrease in blood pressure and 16% to 25% increase in heart rate) and cutaneous flushing. These effects were transient and lasted no more than two minutes and did not require any adjunctive treatment to address the changes in blood pressure or heart rate.

The tetrahydroisoquinolinium class of neuromuscular blocking agents, in general, is associated with histamine release upon rapid administration of a bolus intravenous injection.[35][36] There are some exceptions to this rule, e.g, cisatracurium (Nimbex®) is one such agent that does not elicit histamine release even up to 5xED95 bolus doses[37] or continuous infusions.[38] On the other hand, histamine liberation is not a domain exclusive to the tetrahydroisoquinolinium agents: in vitro data confirm that the aminosteroidal agents also have the potential to evoke histamine release, though the mechanisms of mast cell activation may differ.[39] Indeed, histamine release has been reported with administration of pancuronium.[40][41][42]

The liberation of histamine is a dose-dependent phenomenon such that, with increasing doses administered at the same rate, there is a greater propensity for elicting histamine release and its ensuing sequelae.[43][44] Most commonly, the histamine release following administration of these agents is associated with observable cutaneous flushing (facial face and arms, commonly), hypotension and a consequent reflex tachycardia.[43] It should be noted though that these sequelae are very transient effects: the total duration of the cardiovascular effects is no more that one to two minutes while the facial flush may take around 3–4 minutes to dissipate - (note: half-life of plasma histamine is ~2 minutes).[43] Because these effects are so transient, there is no reason to administer adjunctive therapy to ameliorate either the cutaneous or cardiovascular effects. Thus, in the fierce battle to win market share for sales of the "steroidal" versus the terahydroisoquinolinium class of neuromuscular blocking agents, fact and information pertaining to adverse events were distorted to suit partisan taste, and, consequently, much misinformation was deliberately disseminated regarding histamine release and its effects: this was particularly so in the 1980s and 1990s shortly after the near simultaneous competitive clinical introduction of atracurium (Tracrium® - a bistetrahydroisoquinolinium neuromuscular blocking agent marketed by Burroughs Wellcome Co., now subsumed into GlaxoSmithKline) and vecuronium (Norcuron® - a steroidal neuromuscular blocking agent marketed by Organon, now subsumed into Merck & Co. Inc.). The most common misinformation seeded into the minds of anesthesiologists was the failure to categorically state that the cardiovascular effects following histamine release were transient: instead, the marketing focus was single-mindedly to regurgitate and emphasize that the tetrahydroisoquinolinium class elicited histamine release that could prove to be a danger to the cardiovascular stability of the patient during surgical procedures. There was complete failure to disseminate the true picture that these effects were not only transient but that the extent of the hypotensive effect and the reflex tachycardia were rarely of clinical significance and therefore did not require adjunctive therapy, as evidenced by the complete lack of any clinical literature advocating the need for adjunctive antihistamine use concomitantly with the administration of tetrahydroisoquinolinium neuromuscular blocking agents. Unfortunately, these ill-willed beguiling marketing notions have persisted through the decades and become ingrained with each successive generation of newly qualified anesthesiologists and CRNAs (certified registered nurse anesthetists) to the extent that the mere mention of "benzylisoquinolines" (the erroneous but commonly used class name for tetrahydroisoquinolinium neuromuscular blocking agents) immediately conjures images of histamine release, cardiovascular instability and generates unnecessary hysteria and serious anxiety.

Bronchospasm - Pulmonary compliance

Incidents of bronchospasm associated with intravenous administration of gantacurium have not been reported to date.

Antagonistic action at the airway presynaptic parasympathetic M2 muscarinic receptors or allosteric potentiation of the post-synaptic acetylcholine M3 muscarinic receptors is thought to be the mechanism that precipitates airway constriction and bronchospam. Although neuromuscular blocking agents are designed to antagonize nicotinic acetylcholine receptors, they are also suspected to antagonize the muscarinic receptors. The issue of bronchospasm acquired considerable prominence in the neuromuscular blocking agents arena after the spectacular failure of a clinically introduced neuromuscular blocking agent, rapacuronium (Raplon® - a steroidal neuromuscular blocking agent marketed by Organon, now subsumed into Merck & Co. Inc.), which had to be withdrawn voluntarily during the week of March 19, 2001[45] from clinical use (<2 years after its approval by the US FDA on August 18, 1999 - see NME Drug and New Biologic Approvals in 1999)[46] after several serious events of bronchospasm,[47][48] including five "unexplained" fatalities,[49] following its administration. That is not to say that bronchospasm was an unknown phenomenon prior to rapacuronium: occasional reports of bronchospasm have been noted also with the prototypical agents, tubocurarine[36][50][51] and succinylcholine,[52][53][54][55][56] as well as atracurium,[57][58][59][60] alcuronium,[61] pancuronium,[62][63] vecuronium,[64][65] and gallamine.[66]

Recent data from studies in Guinea pigs confirm that gantacurium (as well as cisatracurium) is devoid of significant effects at airway muscarinic receptors and therefore, unlike rapacuronium (Raplon™), not likely to cause bronchospasm at clinically relevant doses.[67]

Laudanosine - Epileptic foci

Administration of gantacurium has not been reported, to date, to result in any measured levels of laudanosine (a completely unlikely event, in any case). Laudanosine is a metabolite associated with other related neuromuscular blocking agents such as cisatracurium and atracurium and its detected presence is consequent to the in vivo Hofmann elimination of both these chemodegradable agents (cf. the initial 1985 editorial commentary by Frank G. Standaert, MD on the controversial laudanosine issue with atracurium,[68] with more detailed information on the issue in the Wikipedia article on atracurium itself).

The structural difference between gantacurium and these two agents (cisatracurium and atracurium) - in particular, the reverse positioning of the carboxyl ester and onium nitrogen groups - absolutely ensures that gantacurium will never undergo Hofmann elimination just as with mivacurium and doxacurium.

References

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Book References and Additional Reference Reading

  • Bowman WC, Rand MJ. (1980). Chapter 17: "Striated Muscle and Neuromuscular Transmission" in Textbook of Pharmacology. 2nd Ed. Blackwell Scientific Publications: Oxford. pp. 17.1-17.56. ISBN 0-632-09990-9

External links

Peripherally acting
(primarily antinicotinic,
Neuromuscular junction block)
Tertiary amines / Non-curare alkaloids
ultra-short duration: Gantacurium

short duration: Mivacurium  · Chandonium

intermediate duration: Atracurium  · Cisatracurium  · Fazadinium  · Rocuronium  · Vecuronium  · Dipyrandium  · N,N'-Dimethylconessine  · Stercuronium  · Dacuronium  · Mytolon

long duration: Doxacurium · Dimethyltubocurarine · Pancuronium · Pipecuronium  · Laudexium  · Gallamine  · Benzoquinonium  · Decaethonium  · Succinyl-bis-β-phenylcholine  · Anatruxonium  · Truxilonium  · Cyclobutonium  · Dipyronium · Pyrocurinum  · Tercuronium  · Diadonium

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proc, drug (M1A/3)

  1. ↑ 1.0 1.1 Wisowaty JC, Patel SS, Scharver JD, Swaringen RA (1991). Chemical Development Laboratories, Burroughs Wellcome Co., Research Triangle Park, NC, USA: notebook 91/0142–010.  Missing or empty |title= (help)
  2. ↑ 2.0 2.1 Wisowaty JC, Patel SS, Scharver JD, Swaringen RA (1991). Chemical Development Laboratories, Burroughs Wellcome Co., Research Triangle Park, NC, USA: notebook 91/0142–012.  Missing or empty |title= (help)
  3. ↑ Wisowaty JC, Patel SS, Scharver JD, Swaringen RA (1992). Chemical Development Laboratories, Burroughs Wellcome Co., Research Triangle Park, NC, USA: notebook 91/0929–086.  Missing or empty |title= (help)
  4. ↑ Wisowaty JC, Patel SS, Scharver JD, Swaringen RA (1992). Chemical Development Laboratories, Burroughs Wellcome Co., Research Triangle Park, NC, USA: notebook 91/0929–090.  Missing or empty |title= (help)
  5. ↑ Wisowaty JC, Patel SS, Scharver JD, Swaringen RA (1992). Chemical Development Laboratories, Burroughs Wellcome Co., Research Triangle Park, NC, USA: notebook 92/0062–038.  Missing or empty |title= (help)
  6. ↑ Wisowaty JC, Patel SS, Scharver JD, Swaringen RA (1992). Chemical Development Laboratories, Burroughs Wellcome Co., Research Triangle Park, NC, USA: notebook 92/0062–082A.  Missing or empty |title= (help)
  7. ↑ Wisowaty JC, Patel SS, Scharver JD, Swaringen RA (1991). "Compounds 1918U91, 185W92, 186W92,187W92, 871W92". Chemical Development Laboratories, Burroughs Wellcome Co., Research Triangle Park, NC, USA: notebooks 91/0455–020 and 91/0920–040 to 91/0920–050. 
  8. ↑ Gladych JMZ, Taylor EP (1962). "Synthetic neuromuscular blocking agents. Part IV. Compounds related to both laudexium and suxamethonium". J Chem Soc: 1481–1487. doi:10.1039/jr9620001481. 
  9. ↑ Griffith HR, Johnson GE (1942). "The use of curare in general anesthesia". Anesthesiol. 3: 418–420. doi:10.1097/00000542-194207000-00006. 
  10. ↑ Samano V, Ray JA, Thompson JB, Mook RA Jr, Jung DK, Koble CS, Martin MT, Bigham EC, Regitz CS, Feldman PL, Boros EE (1999). "Synthesis of ultra-short-acting neuromuscular blocker GW 0430: a remarkably stereo- and regioselective synthesis of mixed tetrahydroisoquinolinium chlorofumarates". Org Lett. 1 (12): 1993–1996. doi:10.1021/ol9911573. PMID 10836056. 
  11. ↑ Boros EE, Bigham EC, Boswell GE, Mook RA, Patel SS, Savarese JJ, Ray JA, Thompson JB, Hashim MA, Wisowaty JC, Feldman PL, Samano V (1999). "Bis- and mixed-tetrahydroisoquinolinium chlorofumarates: new ultrashort-acting nondepolarizing neuromuscular blockers". J Med Chem. 42 (2): 206–209. doi:10.1021/jm980597h. PMID 10090794. 
  12. ↑ 12.0 12.1 12.2 Boros EE, Samano V, Ray JA, Thompson JB, Jung DK, Kaldor I, Koble CS, Martin MT, Styles VL, Mook RA Jr., Feldman PL, Savarese JJ, Belmont MR, Bigham EC, Boswell GE, Hashim MA, Wisowaty JC, Patel SS, Wisowaty JC, Bowers GD, Moseley CL, Walsh JS, Reese MJ, Rutkowske RD, Sefler AM, Spitzer TD (2003). "Neuromuscular blocking activity and therapeutical potential of mixed-tetrahydroisoquinolinium halofumarates and halosuccinates in rhesus monkeys". J Med Chem. 46 (12): 2502–2515. doi:10.1021/jm020574. PMID 12773054. 
  13. ↑ Bigham EC, Boswell GE, Savarese JJ, Swaringen RA Jr., Patel SS, Boros EE, Mook RA Jr., Samano V. Substituted isoquinolines as ultra short acting neuromuscular blockers. PCT Int. Appl. (1998), 110 pp., WO 9842675, CAN 129:275845
  14. ↑ Bigham EC, Boswell GE, Savarese JJ, Swaringen RA Jr., Patel SS, Boros EE, Mook RA Jr., Samano V. Preparation of dimeric isoquinolines as ultra short acting neuromuscular blockers. PCT Int. Appl. (1998), 49 pp., WO 9842674.
  15. ↑ Savarese JJ, Belmont MR, Hashim MA, Mook RA Jr, Boros EE, Samano V, Patel SS, Feldman PL, Schultz JA, McNulty M, Spitzer T, Cohn DL, Morgan P, Wastila WB (2004). "Preclinical pharmacology of GW280430A (AV430A) in the rhesus monkey and in the cat: a comparison with mivacurium". Anesthesiol. 100 (4): 835–45. doi:10.1097/00000542-200404000-00013. PMID 15087618. 
  16. ↑ Heerdt PM, Kang R, The' A, Hashim M, Mook RJ Jr, Savarese JJ (2004). "Cardiopulmonary effects of the novel neuromuscular blocking drug GW280430A (AV430A) in dogs". Anesthesiol. 100 (4): 846–851. doi:10.1097/00000542-200404000-00014. PMID 15087619. 
  17. ↑ 17.0 17.1 17.2 Belmont MR, Lien CA, Tjan J, Bradley E, Stein B, Patel SS, Savarese JJ (2004). "Clinical pharmacology of GW280430A in humans". Anesthesiol. 100 (4): 768–773. doi:10.1097/00000542-200404000-00004. PMID 15087609. 
  18. ↑ Avera Pharmaceuticals Acquires From GlaxoSmithKline A Proprietary Series of Neuromuscular Blockers, PR Newswire, May 22, 2002
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  20. ↑ The Efficacy and Safety of Gantacurium Chloride for Injection in Tracheal Intubation in Healthy Adult Patients Undergoing Surgery Under General Anesthesia, clincaltrials.gov
  21. ↑ Avera Pharma completes Phase II trial, The Daily Transcript, June 27, 2006
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  23. ↑ Savarese JJ, Ali HH, Basta SJ, Ramsey FM, Rosow CE, Lebowitz PW, Lineberry CG, Cloutier G (1980). "Clinical neuromuscular pharmacology of Bw785u, an ultra-short-acting nondepolarizing ester neuromuscular blocking agent". Anesthesiol. 53 (3): S274. doi:10.1097/00000542-198009001-00274. 
  24. ↑ Ali HH, Savarese JJ, Basta SJ, Ramsey F, Rosow CE, Lebowitz PW (1980). "Prediction of clinical neuromuscular Ed95 of Bw785u from low dose studies in awake volunteers". Anesthesiol. 53 (3): S275. doi:10.1097/00000542-198009001-00275. 
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  27. ↑ 27.0 27.1 Caldwell JE (2004). "The continuing search for a succinylcholine replacement". Anesthesiol. 100 (4): 763–764. doi:10.1097/00000542-200404000-00002. PMID 15087607. 
  28. ↑ Naguib M, Brull SJ (2009). "Update on neuromuscular pharmacology". Curr Opin Anaesthesiol. 22 (4): 483–490. doi:10.1097/ACO.0b013e32832b8cff. PMID 19384229. 
  29. ↑ Mahajan RP (1996). "Is suxamethonium now obsolete?". Curr Anaesth Crit Care. 7: 289–294. doi:10.1016/S0953-7112(96)80049-4. 
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  31. ↑ 31.0 31.1 McNulty M, Brown A, Johnson T, Spitzer TD, Savarese J (2000). "The ultra-short acting nondepolarizing relaxant GW280430A undergoes rapid degradation by chemical mechanisms". Anesthesiol. 93: A–1037. 
  32. ↑ Lien CA, Savard P, Belmont M, Sunaga H, Savarese JJ (2009). "Fumarates: unique nondepolarizing neuromuscular blocking agents that are antagonized by cysteine". J Crit Care. 24 (1): 50–57. doi:10.1016/j.jcrc.2008.11.001. PMID 19272539. 
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  37. ↑ Sparr HJ, Beaufort TM, Fuchs-Buder T (2001). "Newer neuromuscular blocking agents: how do they compare with established agents?". Drugs. 61 (7): 919–42. PMID 11434449. 
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  44. ↑ Moss J (1995). "Muscle relaxants and histamine release". Acta Anaesthesiol Scand Suppl. 106: 7–12. PMID 8533551. 
  45. ↑ Shapse D. "Voluntary market withdrawal - Adverse Drug Reaction 27 March 2001. Raplon® (rapacuronium bromide) for Injection".  Text " PMID http://www.fda.gov/downloads/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/UCM173891.pdf" ignored (help)
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