Cardiopulmonary Effects of the Novel Neuromuscular Blocking Drug GW280430A (AV430A) in Dogs

Background This investigation determined the cardiopulmonary side effects of a novel nondepolarizing neuromuscular blocking drug with an ultrashort duration of action in anesthetized male beagles. Methods The ED95 for GW280430A was first determined in four animals. These data were then used to guide bolus dosing in multiples of ED95 in six dogs instrumented for hemodynamic measurements as well as inspiratory pressure and pulmonary compliance. Cardiopulmonary data were compared before and after the conclusion of a 60- to 90-min GW280430A infusion and in response to subsequent incremental bolus dosing starting with 3.125 x ED95. An adverse response was regarded as an alteration of 10% or greater in any variable. Arterial blood was obtained for histamine analysis before and 1 min after each dose. Results The ED95 of GW280430A was 0.064 +/- 0.01 mg/kg, and stable neuromuscular blockade was maintained with infusion of 0.012 +/- 0.002 mg.kg(-1).min(-1). With the exception of a late 14% increase in heart rate, there were no cardiopulmonary changes during infusion. Bolus dosing produced no cardiopulmonary change until a decrease in mean arterial pressure was elicited in four of six dogs at 25 x ED95. This response was modest, transient, and associated with a concomitant increase in plasma histamine concentration. There were no accompanying changes indicative of direct myocardial depression, pulmonary vasoconstriction, or bronchospasm. Conclusions These data indicate that GW280430 does not produce demonstrable cardiovascular effects in the anesthetized dog until doses far in excess of the ED95 are administered as a bolus.

Increased Plasma Histamine Levels in Uraemic Pruritus

1. We determined plasma levels of histamine in uraemic patients and examined their correlation with the presence of pruritus. 2. In 27 patients with chronic renal failure, plasma histamine levels were analysed by radioimmunoassay and were compared with those of 40 healthy adult subjects. The control population showed plasma histamine concentrations of 185 ∓ 33 pg/ml, which were significantly lower than those of the patients with renal insufficiency. The highest levels (552 ± 116 pg of histamine/ml) were found in 16 patients with chronic renal failure (mean serum creatinine 5.1 ∓ 1.0 mg/dl) and severe itching. 3. Twelve patients with pronounced pruritus who were on maintenance haemodialysis (serum creatinine 9.2 ±1.2 mg/dl) had a mean plasma histamine concentration of 515 ± 81 pg/ml. Fifteen patients on regular haemodialysis (serum creatinine 9.0 ± 1.5 mg/dl) and who experienced itching had plasma histamine levels (322 ±40 pg/ml) which were significantly lower (P < 0.01) than those of the patients with pruritus but which were elevated compared with those of the control population (P < 0.01). 4. No correlation could be found between increased plasma histamine levels and the type of dialysis membrane used or the method of sterilization of the membrane. 5. Haemodialysis alone did not reduce plasma histamine concentrations, although high concentrations could be detected in the ultrafiltrate. In six patients a rapid decrease in plasma histamine concentration from 565 ∓ 134 pg/ml to within the normal range could be detected after 60 min of combined haemodialysis and haemoperfusion. 6. Our results show that increased plasma levels of histamine are found in patients with renal insufficiency and pruritus, and we conclude that this mediator might be involved in the genesis of uraemic pruritus.