The effects of chronic tacrine therapy on d-tubocurarine blockade in the soleus and tibialis muscles of the rat.
Tacrine (THA) is an anticholinesterase drug used to manage Alzheimer's dementia, but it is not clear how its chronic use might affect response to nondepolarizing muscle relaxants. We determined the magnitude and time course of the effects of chronic oral THA and of intravenous (IV) THA on d-tubocurarine (dTC) blockade at the soleus and tibialis muscles. Six groups of adult rats were given 10 mg/kg THA twice daily by gavage for 1, 2, 4, or 8 wk (chronic THA groups), or 1 mL of saline twice daily by gavage for 1-8 wk (control), or IV THA approximately 20 min before (acute), and the cumulative dose-response curves of dTC at the tibialis and soleus muscles were determined during indirect train-of-four stimulation in the anesthetized, mechanically ventilated rat. The 50% effective dose (ED50) and 95% effective dose (ED95) of dTC in control rats were (mean +/- SD) 30 +/- 10 and 61 +/- 18 microg/kg in the tibialis and 32 +/- 8 and 75 +/- 19 microg/kg in the soleus; respectively. IV THA increased the ED95 of dTC 2.5- to 3-fold (P < 0.05) but did not alter the ED50. Chronic THA increased both the ED50 and ED95 of dTC 1.5- to 2-fold (P > or = 0.05), and this effect tended to decrease with duration of THA therapy. We conclude that chronic THA therapy in rats causes resistance to dTC, with a tendency for the resistance to decrease with time, probably because of down-regulation of postsynaptic acetylcholine receptors. The same may apply to Alzheimer's patients taking THA chronically.
Ibebunjo
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C
Department of Anaesthesia, Royal Victoria Hospital and McGill University, Montréal, Québec, Canada. cibe@warren.med.harvard.edu
Donati
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F
Fox
G S
GS
Eshelby
D
D
Tchervenkov
J I
JI
D000284:Administration, Oral; D000544:Alzheimer Disease / Q000188:drug therapy; D000768:Anesthesia, General; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004347:Drug Interactions; D004351:Drug Resistance; D004558:Electric Stimulation; D005260:Female; D007275:Injections, Intravenous; D009119:Muscle Contraction / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects*; D019148:Neuromuscular Blockade; D003473:Neuromuscular Nondepolarizing Agents / Q000008:administration & dosage*; D018697:Nootropic Agents / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D011950:Receptors, Cholinergic / Q000187:drug effects; D012121:Respiration, Artificial; D013569:Synapses / Q000187:drug effects; D013619:Tacrine / Q000008:administration & dosage / Q000627:therapeutic use*; D013997:Time Factors; D014403:Tubocurarine / Q000008:administration & dosage*
D002800:Cholinesterase Inhibitors; D003473:Neuromuscular Nondepolarizing Agents; D018697:Nootropic Agents; D011950:Receptors, Cholinergic; D013619:Tacrine; D014403:Tubocurarine