William B. Wastila

Clinical Pharmacology of Doxacurium Chloride A New Long-acting Nondepolarlzlng Muscle Relaxant

Doxacurium chloride (BW A938U) is a bis-quaternary benzyl-isoquinolinium diester nondepolarizing neuromuscular blocking compound that is minimally hydrolyzed by human plasma cholinesterase. The effect of bolus doses of doxacurium ranging from 10 to 80 Mg/kg were studied in 81 consenting ASA physical status I and II patients anesthetized with nitrous oxide-oxygenfentanyl-thiopental. The neuromuscular and cardiovascular effects of doxacurium were compared with those of eight patients receiving 100 μg/kg of pancuronium receiving identical anesthesia. The calculated ED95 for evoked twitch inhibition of the adductor pollicis at 0.15 Hz was 30 μg/kg. At 1.3 times the EDg5 dose of doxacurium, recovery times to 5% and 25% of control twitch height were 59.2 ± 4.1 (n = 23 of 26) and 75.7 ± 5.6 (n = 23 of 26) min respectively. For pancuronium comparable recovery times were 81.7 ± 10.3 (n = 8 of 8) and 83.0 ± 8.4 (n = 5 of 8) min. Residual doxacurium blockade was readily antagonized by neostigmine. No dose-related effect on heart rate or mean arterial pressure was seen with doxacurium at doses up to and including 2.7 times the ED95 (80 μg/kg). Doxacurium administration did not result in any elevation of plasma histamine at doses up to and including 2.7 times the ED05. In this study doxacurium appears to be a long-acting nondepolarizing relaxant with readily reversible neuromuscular blocking effects and devoid of cardiovascular effects. This profile offers clinical advantages over current long-acting agents and further clinical trials seem appropriate.

Preclinical pharmacology of GW280430A (AV430A) in the rhesus monkey and in the cat: a comparison with mivacurium.

BackgroundNo replacement for succinylcholine is yet available. GW280430A (AV430A) is a representative of a new class of nondepolarizing neuromuscular blocking drugs called asymmetric mixed-onium chlorofumarates. It undergoes rapid degradation in plasma by chemical hydrolysis and inactivation by cysteine adduction, resulting in a very short duration of effect. The neuromuscular, cardiovascular, and autonomic pharmacology of GW280430A is compared herein with that of mivacurium. MethodsAdult male rhesus monkeys and adult male cats were anesthetized with nitrous oxide–oxygen–halothane and chloralose–pentobarbital, respectively. The neuromuscular blocking properties of GW280430A and mivacurium were compared at a stimulation rate of 0.15 Hz in the extensor digitorum of the foot (monkey) and the tibialis anterior (cat). Sympathetic responses were assayed in the cat in the nictitating membrane preparation, and vagal effects were evaluated in the cat via observation of bradycardic responses after stimulation of the cervical right vagus nerve. ResultsGW280430A and mivacurium were equipotent in the monkey (ED95 was 0.06 mg/kg in each case). GW280430A was half as potent as mivacurium in the cat. The total duration of action of GW280430A was less than half that of mivacurium in the monkey; recovery slopes were more than twice as rapid. The 25–75% recovery index of GW280430A did not vary significantly after various bolus doses or infusions, averaging 1.4–1.8 min in the monkey, significantly shorter than the same time interval (4.8–5.7 min) for mivacurium. Dose ratios for autonomic versus neuromuscular blocking properties in the cat were greater than 25 for both GW280430A and mivacurium. The ratio ED Hist:ED95 Neuromuscular Block in the monkey was significantly greater (approximately 53 vs. 13) for GW280430A, indicating approximately four times less relative prominence of the side effects of skin flushing and decrease of blood pressure, which are associated with release of histamine. ConclusionsThese experiments show a much shorter neuromuscular blocking effect and much-reduced side effects in the case of GW280430A vis-à-vis mivacurium. These results, together with the novel chemical degradation of GW280430A, suggest further evaluation in human subjects.

Neuromuscular blocking agents. Some approaches to short acting compounds

Abstract A series of amidic and N -methylamidic methyl and trideuteromethyl quaternary analogues of atracurium have been prepared. All were less potent and longer acting neuromuscular blocking agents than atracurium, and all showed appreciable vagal blockade at neuromuscular blocking doses. Replacement of NCH 3 by NCD 3 failed to affect potency. Fluorosubstitution in the central chain did not reduce duration of action. Attachment of acyloxy substituents to the interquaternary chain of atracurium and related compounds adjacent to their ester groups shortened the duration of action significantly. Diformyloxy substitution was the most effective in reducing duration without adversely affecting other properties apart from potency, which was significantly less than that of atracurium.

Neuromuscular blocking agents. Approaches to short-acting compounds 2. Bis-thiazolium salts

Abstract A series of bis-thiazolium diesters has been prepared. All were substantially less potent than atracurium and all showed appreciable vagal blockade at neuromuscular blocking doses. N -Benzyl quaternary substituents shortened the duration of neuromuscular blockade significantly. Neuromuscular blocking potency was greater and duration of action least in bis- N -3,4,5-trimethoxybenzylthiazolium salts, though each of these effects was at its optimum at differing interquaternary chain separations.

The Clinical Pharmacology of BW A444U A Nondepolarizing Ester Relaxant of Intermediate Duration

The clinical pharmacology of BW A444U, a nondepolarizing ester relaxant, was evaluated in 56 consenting ASA class I subjects under nitrous oxide/oxygen-fentanyl-thiopental anesthesia. Using repetitive train-of-four stimulation, the ED95 for inhibition of the first twitch in the train (T1) was 0.11 mg/kg. At 0.12 mg/kg, 97% inhibition of T1 developed within 4.6 ± 0.6 (SE) min from injection; recovery of T1 to 95% of the control height occurred within 52.3 ± 3.1 min. In a comparative group of subjects given 0.5 mg/kg d-tubocurarine, onset and depth of block were not significantly different, but the duration of recovery of T1 to 75% of control was at least three times longer (P < 0.001). The duration of BW A444U-induced block therefore may be classified as intermediate between d-tubocurarine and succinylcholine. There was little cumulative effect, since 5 ± 25 and 25 ± 75% recovery times did not vary significantly on either repetitive or increasing dosage. These properties may be explained at least in part by the finding that BW A444U is hydrolyzed relatively slowly in vitro by human plasma cholinesterase, at 5.4% the rate of succinylcholine. Consistent with these observations, at the ED100 (0.2 mg/kg) there was a significant inverse linear correlation between the duration of block and plasma cholinesterase activity. Neuromuscular block by BW A444U was antagonized readily by neostigmine.No changes in arterial pressure or heart rate were noted at up to 0.12 mg/kg (97% block). At higher dosages (0.16–0.20 mg/kg), brief (2 to 5 min), moderate decreases in mean arterial pressure, slight increases in heart rate, and facial erythema were observed occasionally. These changes correlated well with small increases in serum histamine.The human neuromuscular pharmacology of BW A444U suggests that nondepolarizing relaxants of intermediate duration of action may be produced from ester materials slowly hydrolyzed by plasma cholinesterase, and that BW A444U may have certain clinical pharmacologic advantages over current nondepolarizing relaxants.

Neuromuscular blocking activity of bis-4-benzyltetrahydroisoquinolinium esters in the cat

Abstract The purpose of this work was to identify a new ultra-short-acting neuromuscular blocking agent devoid of the potential to produce histamine-like cardiovascular effects at ≥ED 95 doses. Eight new bis -4-benzyltetrahydroisoquinolinium esters, derivatives of ( E )-oct-4-ene-1,8-dioyl acid, were tested for neuromuscular blocking activity in the cat and compared with mivacurium chloride. All compounds were more than ten times less potent than mivacurium but exhibited a rapid onset of action (≊0.9–1.8 min from injection to maximum neuromuscular block) and an ultra-short duration of neuromuscular block (≊5–8 min from injection to 95% recovery) at approximately ED 95 doses; however, at these and even lesser doses, they also produced histamine-like cardiovascular effects and inhibited the response to vagal stimulation. The data suggest that, in the benzyltetrahydroisoquinolinium class of neuromuscular blocking agents, 4-benzyl substitution may offer the desired rapid onset and ultra-short duration of action at ED 95 doses, but these advantages are offset by the adverse cardiovascular and autonomic effects which occur at ≤ED 95 doses.

Neuromuscular blocking activity of cyclic and acyclic bis-quaternary ammonium analogues of mivacurium chloride in the cat

Abstract The purpose of this work was to identify a new ultra-short-acting neuromuscular blocking agent devoid of the potential to produce cardiovascular effects at ≥ED 9 5 doses. Four new bis -quaternary mivacurium analogues that are acyclic with respect to the bis -isoquinolinium nuclei and seven new bis -quaternary mivacurium analogues that are derivatives of ( E )-oct-4-enedioic acid, ( E )-oct-2-enedioic acid, and ( E )-oct-4-enedithioic acid, were synthesised and tested for neuromuscular blocking activity in the cat. In general, compared with mivacurium, the acyclic analogues were of much lower potency but showed a faster onset (time from injection to maximum neuromuscular block) and a much shorter duration of action (time from injection to 95% recovery) at approximately ED 9 5 doses. However, these acyclic analogues had a considerably narrower safety margin (i.e., the ratio of doses that produce unwanted cardiovascular or autonomic effects to those that produce neuromuscular block) than mivacurium. The ( E )-oct-4-enedioate and ( E )-oct-4-enedithioate analogues showed a neuromuscular blocking profile similar to the acyclic analogues. The ( E )-oct-2-enedioate isomer of mivacurium did not have any advantageous neuromuscular blocking properties over mivacurium and, in fact, elicited cardiovascular and autonomic effects at much lower multiples of ED 95 . Structural changes to mivacurium, however minor, to either the inter-onium chain or the onium centres (or both) result in compounds whose cardiovascular and autonomic safety profiles are highly compromised in return for the desirable rapid onset and brevity of neuromuscular blocking action at ≥ED 95 doses. The intact isoquinolinium nucleus appears to confer a superior safety profile over that of an acyclic onium nucleus.

Future Goals of the Benzylisoquinolinium Ester Program

This program originally sought to produce three nondepolarizing relaxants: short-, intermediate- and long-acting drugs which at the time (1975)1 were unknown. The proposed compounds are described in Fig 1. Now, twenty years later, much progress has been made, yet there is still room for additional improvement.

Preclinical Pharmacology in the Rhesus Monkey of CW 1759-50, a New Ultra-short Acting Nondepolarizing Neuromuscular Blocking Agent, Degraded and Antagonized by L-Cysteine

What We Already Know about This Topic Gantacurium is an ultra-short acting nondepolarizing neuromuscular blocking agent in the monkey and in man that is degraded nonenzymatically by adduction of L-cysteine under physiologic conditions Administration of gantacurium results in decreased mean arterial pressure and increased heart rate What This Article Tells Us That Is New CW 1759-50 is a new nondepolarizing neuromuscular blocking agent that may have a clinical profile that is superior to that of gantacurium Studies in rhesus monkeys comparing CW 1759-50 with gantacurium found both of them to be ultra-short acting because of their rapid degradation by L-cysteine adduction The effects of CW 1759-50 on mean arterial pressure and heart rate were substantially less than those of gantacurium Background: Structure–activity studies were performed to identify a new neuromuscular blocking agent retaining the ultra-short acting characteristics of gantacurium, including degradation and reversal by L-cysteine, but lacking its histaminoid properties in man. CW 1759-50 has emerged from this program. Methods: Adduction of CW 1759-50 with L-cysteine was studied by high-performance liquid chromatography and mass spectrometry. Institutional Animal Care and Use Committee–approved comparisons of CW 1759-50 to gantacurium were performed in rhesus monkeys. ED95 for neuromuscular blockade was established. Spontaneous recovery was compared to reversal by L-cysteine in paired studies of boluses or infusions. In addition, changes in mean arterial pressure and heart rate after very large doses of 15 to 60 × ED95 were compared. Results: The half-time of adduction of L-cysteine to CW 1759-50 in vitro was 2.3 min. The ED95 of CW 1759-50 was 0.069 ± 0.02 mg/kg; ED95 of gantacurium was 0.081 ± 0.05 mg/kg (P = 0.006). Duration of action (recovery to 95% twitch height after 98 to 99% blockade) was as follows: CW 1759-50, 8.2 ± 1.5 min; and gantacurium, 7.4 ± 1.9 min; (n = 8 and 9, P = 0.355). Administration of L-cysteine (30 mg/kg) shortened recovery (i.e., induced reversal) from CW 1759-50 after boluses or infusions (P always less than 0.0001). Recovery intervals (5 to 95% twitch) ranged from 6.1 to 6.7 min (and did not differ significantly) after boluses of 0.10 to 0.50 mg/kg, as well as control infusions (P = 0.426 by analysis of variance). Dose ratios comparing changes of 30% in mean arterial pressure or heart rate to ED95 for neuromuscular blockade (ED 30% &Dgr; [mean arterial pressure or heart rate]/ED95) were higher for CW 1759-50 than for gantacurium. Conclusions: CW 1759-50, similar to gantacurium, is an ultra-short acting neuromuscular blocking agent, antagonized by L-cysteine, in the monkey. The circulatory effects, however, are much reduced in comparison with gantacurium, suggesting a trial in humans.