Summary
We have studied 16 healthy men to evaluate preliminary pharmacodynamics and kinetics of BW443C given by i.v. infusions. Four volunteers received escalating doses at weekly intervals, starting at 0.1 µg·kg−1 for 60 min and increasing to a maximum of 2.0 µg·kg−1·min−1 for 180 min. Subsequently 12 different subjects received single i.v. infusions of 10 µg·kg−1·min−1 for 20 min. Subjective effects were reported and objective measurements made of central nervous and cardiovascular effects. Blood was sampled at intervals on all occasions, plasma concentrations were determined by radioimmunoassay and pharmacokinetic profiles were analysed using NONLIN.
Dry mouth and some nasal stuffiness were reported and postural hypotension occurred in 5/16 subjects at plasma concentrations >0.8 µg·ml−1. Supine blood pressure was well maintained in all subjects and hypotension resolved within 60–90 min of discontinuing the infusion. There was no evidence of sedation, mood change, nausea, vomiting, miosis, change in accomodation or respiratory depression. Rapid infusions produced transient feelings of warmth, heavy eyelids, heavy legs, and increased bowel sounds, which resolved despite increasing plasma concentrations.
The disposition of the peptide was adequately described by a 2-compartment model with a mean ± SD plasma clearance of 123±18 ml·min−1 and a half-life of 2.0±0.4 h.
Similar content being viewed by others
References
Ferreira SH, Nakamura M (1979) Prostaglandin hyperalgesia: The peripheral analgesic activity of morphine, enkephalins and opioid antagonists. Prostaglandins 18: 191–200
Follenfant RL, Hardy GW, Lowe LA, Smith TW (1987) Antinociceptive effects of a novel, peripherally acting opioid peptide, Tyr·D·Arg·Gly·Phe(4NO2)·Pro·NH2 (BW443C). Br J Pharmacol 90: 68P
Lorenzetti BB, Ferreira SH (1987) On the mode of analgesic action of Tyr·D·Arg·Gly·Phe(4NO2)·Pro·NH2 (BW443C). Br J Pharmacol 90: 69P
Adcock JJ, Allan G, Richardson PJ, Schneider C, Smith TW (1987) Antitussive effects and inhibition of vagal sensory nerve activity by Tyr·D·Arg·Gly·Phe(4NO2)·Pro·NH2 (BW443C). Br J Pharmacol 90: 143P
Smith TW, Buchan P, Parsons DN, Wilkinson S (1982) Peripheral antinociceptive effects of N-methyl morphine. Life Sci 31: 1205–1208
Posner J, Dean K, Jeal S, Moody G, Peck AW, Rutter G, Telekes A (1987) Tolerance and pharmacokinetics of a novel opioid peptide BW443C in healthy volunteers. Br J Clin Pharmacol 24: 266P
Read DJC (1967) A clinical method for assessing the ventilatory response to carbon dioxide. Aust Ann Med 16: 20–32
Metzler DM, Elfring GL, McEwen AJ (1974) A package of computer programmes for pharmacokinetic modelling. Biometrics 30: 362
Graffenried von B, Pozo del E, Roubicek J, Krebs E, Poldinger W, Burmeister P, Kerp L (1978) Effects of the synthetic enkephalin analogue FK33824 in man. Nature 272: 729–730
Calimlim JF, Wardell WM, Sriwatanakul K, Cox C (1982) Analgesic efficacy of parenteral metkephamid acetate in treatment of post-operative pain. Lancet 1: 1374–1375
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Posner, J., Dean, K., Jeal, S. et al. A preliminary study of the pharmacodynamics and pharmacokinetics of a novel enkephalin analogue [Tyr-D.Arg-Gly-Phe(4NO2)·Pro·NH2 (BW443C)] in healthy volunteers. Eur J Clin Pharmacol 34, 67–71 (1988). https://doi.org/10.1007/BF01061420
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01061420