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document
Influence of asimadoline , a new kappa-opioid receptor agonist , on tubular water absorption and vasopressin secretion in man . AIMS The purpose of the study was to investigate the effects of asimadoline , a new kappa-opioid agonist , on renal function and on hormones related to body fluid balance as well as its tolerability in healthy subjects . METHODS In a placebo-controlled , randomised , double-blind crossover design we studied the effects of single oral doses of 1 , 5 , and 10 mg of asimadoline , in 24 healthy volunteers . Two hour control urine collections were followed by 2 h postdose urine collections and subsequently 2.5 % saline was given i.v . at a rate of 0.3 ml min ( -1 ) kg ( -1 ) during another 2 h urine collection . Blood was obtained hourly . Arginine-vasopressin ( AVP ) , atrial natriuretic peptide ( alpha-hANP ) , endothelin ( ET-1 ) and cAMP were determined by r.i.a . or ELISA . RESULTS GC-MS measurements revealed Cmax values of asimadoline in plasma ranging from 18 ng ml ( -1 ) at the 1 mg dose , 91 ng ml ( -1 ) at the 5 mg dose , to 214 ng ml ( -1 ) at the 10 mg dose after an average of 1.1-1.4 h. Without effects on blood pressure , heart rate , GFR or urine electrolyte excretion , urine volume increased after 1-2 h after administration of 5 and 10 mg asimadoline from 3.3+/-1.3 to 5.6+/-1.4 ( P < 0.05 ) and from 3.2 +/-1.6 to 5.5+/-2.2 ml min ( -1 ) ( P < 0.01 ) , respectively . CH2O rose from 0.2+/-1.5 to 2.0+/-1.6 ( P < 0.05 ) and from 0.6+/-1.6 to 3.0+/-1.6 ml min ( -1 ) ( P < 0.01 ) . Urinary excretion of AVP was suppressed only with the 10 mg dose from 46+/-23 to 25+/-15 fmol min ( -1 ) ( P < 0.05 ) without and from 410+/-206 to 181+/-125 fmol min ( -1 ) ( P < 0.05 ) with stimulation by 2.5 % saline . Plasma AVP was suppressed only by the 10 mg dose of asimadoline in six of eight subjects during the 2.5 % saline infusion . Changes in the alpha-hANP or ET-1 systems were not affected by asimadoline . CONCLUSIONS Asimadoline is diuretic in man after single doses of 5 or 10 mg probably through a direct effect at the renal tubular level . Suppression of AVP secretion was observed only at the highest dose level of 10 mg of asimadoline .
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Intervention_Pharmacological
asimadoline
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Intervention_Pharmacological
asimadoline
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Intervention_Control
placebo-controlled
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Intervention_Pharmacological
1 , 5 , and 10 mg of asimadoline
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Intervention_Pharmacological
2.5 % saline
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Outcome_Other
effects
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Outcome_Physical
Arginine-vasopressin ( AVP ) , atrial natriuretic peptide ( alpha-hANP )
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Outcome_Physical
endothelin ( ET-1 )
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Outcome_Physical
cAMP
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Outcome_Physical
Cmax values of asimadoline in plasma
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Outcome_Physical
blood pressure
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Outcome_Physical
heart rate
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Outcome_Physical
GFR
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Outcome_Physical
urine electrolyte excretion
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Outcome_Physical
urine volume
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Outcome_Physical
CH2O
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Outcome_Physical
Urinary excretion
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Outcome_Physical
Plasma AVP
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Participant_Condition
vasopressin secretion in
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Participant_Sex
man
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Participant_Condition
.
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Participant_Condition
healthy subjects
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Participant_Sample-size
24