The Toxicology Investigators Consortium Case Registry-the 2015 Experience.

The American College of Medical Toxicology established the Toxicology Investigators Consortium (ToxIC) Case Registry in 2010. The Registry contains all medical toxicology consultations performed at participating sites. The Registry has continued to grow since its inception, and as of December 31, 2015, contains 43,099 cases. This is the sixth annual report of the ToxIC Registry, summarizing the additional 8115 cases entered in 2015. Cases were identified by a query of the Registry for all cases entered between January 1 and December 31, 2015. Specific data reviewed for analysis included demographics (age, race, gender), source of consultation, reason for consultation, agents and agent classes involved in exposures, signs, symptoms, clinical findings, fatalities, and treatment. By the end of 2015, there were 50 active sites, consisting of 101 separate health-care facilities; 51.2 % of cases involved females. Adults between the ages of 19 and 65 made up the majority (64.2 %) of Registry cases. Caucasian race was the most commonly reported (55.6 %); 9.6 % of cases were identified as Hispanic ethnicity. Inpatient and emergency department referrals were by far the most common referral sources (92.9 %). Intentional pharmaceutical exposures remained the most frequent reason for consultation, making up 52.3 % of cases. Of these intentional pharmaceutical exposures, 69 % represented an attempt at self-harm, and 85.6 % of these were a suicide attempt. Nonopioid analgesics, sedative-hypnotics, and antidepressant agents were the most commonly reported agent classes in 2015. Almost one-third of Registry cases involved a diagnosed toxidrome (32.8 %), with a sedative-hypnotic toxidrome being the most frequently described. Significant vital sign abnormalities were recorded in 25.3 % of cases. There were 98 fatalities reported in the Registry (1.2 %). Adverse drug reactions were reported in 4.3 % of cases. Toxicological treatment was given in 65.3 % of cases, with 33.0 % receiving specific antidotal therapy. Exposure characteristics and trends overall were similar to prior years. While treatment interventions were required in the majority of cases, fatalities were rare.

Semisynthetic analogues of toxiferine I and their pharmacological properties at α7 nAChRs, muscle-type nAChRs, and the allosteric binding site of muscarinic M2 receptors.

A new series of analogues of the calabash curare alkaloid toxiferine I was prepared and pharmacologically evaluated at α7 and muscle-type nAChRs and the allosteric site of muscarinic M2 receptors. The new ligands differ from toxiferine I by the absence of one (2a-c) or two (3a-c) hydroxy groups, saturation of the exocyclic double bonds, and various N-substituents (methyl, allyl, 4-nitrobenzyl). At the muscle-type nAChRs, most ligands showed similar binding to the muscle relaxant alcuronium, indicating neuromuscular blocking activity, with the nonhydroxylated analogues 3b (Ki = 75 nM) and 3c (Ki = 82 nM) displaying the highest affinity. At α7 nAChRs, all ligands showed a moderate to low antagonistic effect, suggesting that the alcoholic functions are not necessary for antagonistic action. Compound 3c exerted the highest preference for the muscle-type nAChRs (Ki = 82 nM) over α7 (IC50 = 21 µM). As for the allosteric site of M2 receptors, binding was found to be dependent on N-substitution rather than on the nature of the side chains. The most potent ligands were the N-allyl analogues 2b and 3b (EC0.5,diss = 12 and 36 nM) and the N-nitrobenzyl derivatives 2c and 3c (EC0.5,diss = 32 and 49 nM). The present findings should help delineate the structural requirements for activity at different types of AChRs and for the design of novel selective ligands.

Strychnobaillonine, an unsymmetrical bisindole alkaloid with an unprecedented skeleton from Strychnos icaja roots.

A reinvestigation of the roots of Strychnos icaja resulted in the isolation of a new bisindole alkaloid named strychnobaillonine (1) with original C-17-N-1' and C-23-C-17' junctions, in addition to sungucine, bisnordihydrotoxiferine, and strychnohexamine (2). Compound 1 showed potent activity against the chloroquine-sensitive 3D7 strain of Plasmodium falciparum in vitro with an IC50 value of 1.1 µM. The structures of the compounds were defined by detailed spectroscopic analyses, especially 1H and 13C NMR, DEPT, HSQC, COSY, NOESY, HMBC, and HRESIMS. The proposed absolute configuration was based on biosynthetic considerations and spectroscopic data (CD, NMR) supported by molecular modeling.

iso-caracurine V, a novel unexpected decomposition product of caracurine V.

The structure of iso-caracurine V (3), an unexpected decomposition product of the Strychnos alkaloid caracurine V (1), was determined by NMR spectroscopy. Compound 3, which was probably previously regarded as bisnortoxiferine I (2), is a one-sided ring closed product of 2.

[Atracurium--increased duration of its effect following alcuronium]. / Atracurium--Verlängerte Wirkdauer nach Alcuronium.

The duration of action of a supplementary dose of Atracurium 0.125 mg/kg after an initial dose of Atracurium 0.5 mg/kg respectively Alcuronium 0.25 mg/kg was investigated in 2 groups of 7 patients each. The average duration of action of Atracurium after Alcuronium (44.62 +/- 9.95 min) was 1.75 times longer than that of Atracurium after Atracurium (25.49 +/- 4.08 min). The difference is statistically significant (p = 0.05). For the clinical application of a combination of Atracurium with Alcuronium, 2 conclusions which might appear contradictory can be considered: 1. the pretreatment with Alcuronium can enhance intentionally the duration of action of Atracurium and spare total dosage of muscle relaxants at the same time. Prompt antagonism of muscle blockade of Atracurium remains unchanged according to our experience. 2. the pretreatment with Alcuronium may be dangerous whenever Atracurium is administered close to the end of the operation because of the possibility of prolonged postoperative muscle relaxation.

The interaction of neuromuscular relaxants with rabbit lung muscarinic receptors.

The interaction of muscle relaxants with airway muscarinic receptors of rabbit lung was investigated in vitro by the [3H]QNB binding technique. Pancuronium, vecuronium, alcuronium and succinyl choline chloride (SCC) inhibited the binding of [3H]QNB to rabbit lung muscarinic receptors in a dose-dependent manner. The values of IC50 (the concentration giving 50% inhibition) of pancuronium, vecuronium, alcuronium and SCC were 1.54 x 10(-5), 2.52 x 10(-5), 8.40 x 10(-5), and 4.00 x 10(-3) mol/l respectively. As the values of Kd increased with minimal change in the value of Bmax, while not influencing the number of receptors, these muscle relaxants had an inhibitory action on the affinity of muscarinic receptors to [3H]QNB in the order: pancuronium greater than or equal to vecuronium greater than alcuronium greater than SCC. Applying IC50 values to human conditions, clinical doses of these muscarinic relaxants are unlikely to exhibit any significant vagolytic action in lung tissue.

The use of tacrine (THA) and succinylcholine compared with alcuronium during laparoscopy.

Either tacrine (THA) with succinylcholine or alcuronium was used on a randomized basis for laparoscopic procedures in twenty young females. The technique using THA with succinylcholine was found to be more suitable and predictable for this procedure and gave a smoother anaesthetic course, brighter recovery and minimal postoperative complications.

Effects of precurarisation on suxamethonium-induced postoperative myalgia during the first trimester of pregnancy.

Two hundred and fifty women undergoing termination of pregnancy during the first trimester under general anaesthesia were studied to determine the effects of precurarisation on suxamethonium-induced postoperative myalgia and on the need for postoperative analgesics after suxamethonium. Either alcuronium (0.03 mg/kg), atracurium (0.04 mg/kg), tubocurarine (0.05 mg/kg), vecuronium (0.01 mg/kg) or saline was administered in a double-blind manner 4 min before giving suxamethonium. An additional 50 patients were studied who received isoflurane rather than precurarisation and suxamethonium. Every pretreatment prevented fasciculations better than did saline (P less than 0.001). In the saline group, 92% of patients had fasciculations and in the other groups this ranged from 8 to 32%, respectively. On the first postoperative day, 76% of the patients in the saline group had myalgia while myalgia was manifested in 28, 54 and 34% of patients given alcuronium, tubocurarine or vecuronium, respectively (P less than 0.05). Atracurium failed in this effect with 62% having myalgia. In the isoflurane group, none of the patients complained of myalgia on the first postoperative morning. The need for analgesics was less (P less than 0.005) in the isoflurane group (8%) and in the pretreatment groups (18-27%) than in the saline group (42%). It is concluded that precurarisation with tubocurarine, vecuronium or, most effectively, with alcuronium but not with atracurium decreases suxamethonium-induced postoperative myalgia and seems to be necessary also during the first trimester of pregnancy.

Comparison of thumb acceleration and thenar EMG in a pharmacodynamic study of alcuronium.

We compared thumb acceleration (Acc) and thenar electromyography (EMG) techniques by evaluating the neuromuscular blocking properties of alcuronium in 14 ASA physical status I patients. The dose-response curves determined by the two techniques were parallel but the EMG-curve was shifted 25% to the right (P less than 0.001). Acc reflected 8-11% greater neuromuscular block than simultaneous EMG in every patients (P less than 0.05). Concurrently, the duration of greater than 90% neuromuscular block maintained by alcuronium 280 micrograms/kg was significantly longer when measured by the Acc transducer (30 vs. 19 min, P less than 0.001). Although the TOF ratios were in good correlation (r2 = 0.82), clinically significant differences existed between the two simultaneous techniques. The results underline the importance of the method of assessment of neuromuscular transmission when evaluating the action of neuromuscular blocking drugs.

Priming with alcuronium and tubocurarine accelerates the onset of neuromuscular block.

The individual rate of onset of action of tubocurarine and alcuronium has been examined with and without a priming dose of the same agent or the other agent, by measurement of changes in the evoked compound electromyogram of the adductor pollicis muscle. Priming was associated with acceleration of the onset of neuromuscular block.

Adverse reactions to atracurium and alcuronium. A prospective surveillance study.

A multicentre prospective surveillance study was undertaken to compare the incidence and severity of adverse reactions attributed to atracurium and alcuronium. Clinical manifestations were used by the anaesthetist to diagnose an adverse reaction (a cutaneous reaction, a greater than 20% change in arterial pressure or heart rate, and bronchospasm). Of the 1956 patients receiving atracurium, 10.1% had adverse reactions compared with 17.9% of the 1425 patients receiving alcuronium (P less than 0.001). There were no longterm sequelae. The atracurium group had a markedly lower incidence of hypotension (3.4% v. 13.7%; P less than 0.0001), but a higher incidence of cutaneous reactions (4.6% v. 2.3%; P less than 0.005) which were not associated with other adverse reactions. There was a low incidence of bronchospasm in both groups (0.2% v. 0.1%).

Recovery of neuromuscular function and postoperative morbidity following blockade by atracurium, alcuronium and vecuronium.

Recovery of neuromuscular function and postoperative morbidity were studied in 51 fit female patients who had nonemergency gynaecological laparoscopy as inpatients. They were allocated randomly to one of three groups to receive either atracurium 0.31 mg/kg, alcuronium 0.25 mg/kg, or vecuronium 0.06 mg/kg as part of an otherwise standard anaesthetic technique. There were neither differences in intubation conditions nor in the occurrence of postoperative diplopia whichever muscle relaxant was used. Deficits in grip strength and expiratory force were seen at one hour after reversal with atropine 1.2 mg and neostigmine 2.5 mg in all patients, deficits which persisted for 3 hours in those who received alcuronium. The recovery of inspiratory force was slower and less complete at up to 3 hours in those who received alcuronium and there was a high incidence of minor postoperative morbidity at up to 24 hours in each of the three groups. The only statistical difference in symptomatic morbidity was an increase in muscle weakness in those who received alcuronium compared with atracurium at 3 hours after laparoscopy. Only 25%, 20% and 31% of the patients who received atracurium, alcuronium and vecuronium respectively said that they would have liked to be day stay patients.

Recurarisation following a suxamethonium-alcuronium sequence in patients with atypical cholinesterase.

Alcuronium 10 mg was administered to maintain muscle relaxation in two patients before recovery from suxamethonium neuromuscular blockade to facilitate tracheal intubation. This sequence resulted in a markedly prolonged block which could not be antagonised adequately by neostigmine 0.05 mg/kg; initial antagonism was followed rapidly by prolonged recurarisation. Estimation of plasma cholinesterase activity revealed that the two patients were homozygous for the atypical and silent genes. respectively.

Optimal time interval between pretreatment with alcuronium and suxamethonium during anaesthetic induction.

Alcuronium 0.03 mg/kg was studied in a double-blind randomized fashion as a pretreatment before suxamethonium using different time intervals between the administration of the drugs in 78 patients (ASA I-II) undergoing otolaryngological surgery. Alcuronium was given 1, 2 or 3 min before suxamethonium 1.5 mg/kg. The control group received saline as a pretreatment and suxamethonium 1 mg/kg. Anaesthesia was induced with thiopental 5.5 mg/kg over 60 s. Muscle fasciculations, intubating conditions, cardiovascular responses to endotracheal intubation and duration of neuromuscular block were assessed. Muscle fasciculations were statistically and similarly inhibited (P less than 0.01) at all time intervals between alcuronium and suxamethonium. Intubating conditions were worse (P less than 0.05) in the 3-min group than in the other groups. Cardiovascular responses to endotracheal intubation were similar in all groups. The neuromuscular block after suxamethonium was significantly shorter (P less than 0.05) in the 2- and 3-min groups than in the other groups. In conclusion, from the clinical point of view the 1-min time interval between alcuronium and suxamethonium is optimal since muscle fasciculations are inhibited and intubating conditions are satisfactory.

[Comparison of the action kinetics of alcuronium and vecuronium by electromyographic monitoring]. / Comparaison de la cinétique d'action de l'alcuronium et du vécuronium par monitorage électromyographique.

Twenty-eight ASA I or ASA II adults undergoing microsurgery were anaesthetized according to a standard protocol using droperidol, phenoperidine and thiopentone followed by enflurane. The patients were randomly assigned to two homogeneous groups: the first group (n = 14) received 0.2 mg.kg-1 alcuronium, whereas the second group (n = 14) received 0.08 mg.kg-1 vecuronium. There was no reinjection of either drug and curarization tapered off spontaneously. Neuromuscular monitoring was begun once anaesthesia was stable and after intentional isovolaemic haemodilution. The type of stimulus used was the train-of-four, delivered by a Relaxograph monitor to the ulnar nerve. Muscle response was measured at the hypothenar eminence. The kinetic study considered the time interval required between the injection of the muscle relaxant and the appearance of the minimal value of the twitch (first response of the train-of-four = T1min). The times to recovery of the twitch height to 25, 75 and 100% of the reference value (T1/T0) and of the fourth response of the train-of-four to 25 and 75% of the ratio (T4/T1) were also recorded. Finally, the recovery indexes represented by the times required for T1/T0 and T4/T1 to rise from 25% to 75% respectively were studied. The maximal twitch height inhibition was significantly greater (p less than 0.001) in the vecuronium group (T1min = 0.36 +/- 1.33%) than in the alcuronium group (T1min = 4.36 +/- 5.08%); it occurred significantly more quickly (p less than 0.001) with vecuronium (139 +/- 48 s) than with alcuronium (316 +/- 133 s).(ABSTRACT TRUNCATED AT 250 WORDS)

Antidiarrhoeal activity of bisnordihydrotoxiferine isolated from the root bark of Strychnos trinervis (Vell.) Mart. (Loganiaceae).

Bisnordihydrotoxiferine, a dimeric tertiary indole alkaloid obtained from the root bark of Strychnos trinervis (Vell.) Mart. (Loganiaceae), inhibited normal defaecation and castor oil, arachidonic acid, and magnesium sulphate-induced diarrhoea on intraperitoneal administration in mice. The effect may be related to the ability of the compound to decrease normal and castor oil-stimulated gastric emptying, small intestinal transit and water and electrolyte accumulation, and inhibition of normal colonic transit. As prostaglandins are involved in gastrointestinal functions, inhibition of their synthesis is likely to contribute to the anticathartic activity, which has never been reported before for an indole alkaloid.

Liver tumours and muscle relaxants. Electromyographic studies in children.

Electromyographic studies of the onset of action of tubocurarine or alcuronium were performed on eight occasions in five patients who had liver masses. There was a slow onset of action and an increased dose requirement in those with malignant disease. Normal responses were found in a patient with benign nodular hyperplasia and in another where the malignant tumour was successfully treated with chemotherapy.