Clinical pharmacology and therapeutics
-
Clin. Pharmacol. Ther. · Aug 2008
Randomized Controlled TrialDevelopment of procedures for early screening of smoking cessation medications in humans.
Candidate medications for smoking cessation may be screened more efficiently if initial evaluations in humans combine the practical advantages of laboratory studies with the clinical validity of clinical trials, such as by increasing participants' "quit motivation" during brief testing. We manipulated "intrinsic" quit motivation by recruiting smokers who either did intend to quit soon ("treatment seekers," N = 47) or did not ("nonseekers," N = 93), and "extrinsic" quit motivation by providing or not providing reinforcement for abstinence ($12/day). ⋯ Reinforcement had a main effect on abstinence but did not moderate the effects of the nicotine patch or treatment-seeking status. Intrinsic, but not extrinsic, quit motivation of participants may enhance the validity of brief tests of medication efficacy for smoking cessation.
-
Clin. Pharmacol. Ther. · May 2008
Randomized Controlled Trial Comparative StudyAutonomic cardiovascular control during a novel pharmacologic alternative to ganglionic blockade.
The purpose of this study was to compare ganglionic blockade with trimethaphan (TMP) and an alternative drug strategy using combined muscarinic antagonist (glycopyrrolate, GLY) and alpha-2 agonist (dexmedetomidine, DEX). Protocol 1: incremental phenylephrine was administered during control and combined GLY-DEX, or control and TMP on two control combined GLY and DEX or TMP infusion on two randomized days. Protocol 2: muscle sympathetic nerve activity (MSNA) and the baroreflex MSNA relationship was determined before and after GLY-DEX. ⋯ Both GLY-DEX and TMP infusion inhibited norepinephrine release (P<0.01 vs control). GLY-DEX inhibited baseline MSNA (P<0.05) and baroreflex changes in MSNA (P<0.01). We conclude that the GLY-DEX alternative drug strategy can be used as a reasonable alternative to pharmacologic ganglionic blockade to examine autonomic cardiovascular control.
-
Clin. Pharmacol. Ther. · Mar 2008
Randomized Controlled Trial Comparative StudyIntravenous parecoxib rapidly leads to COX-2 inhibitory concentration of valdecoxib in the central nervous system.
Evidence in animal studies supports widespread induction of cyclooxygenase-2 (COX-2) in the central nervous system (CNS) following tissue injury, probably mediated by cytokines, transducing the signal across the blood-brain barrier. CNS COX-2 blockade is a possible therapeutic target for drugs that are able to reach adequate CNS levels and abolish the prostaglandin E2-induced central sensitization. This human pharmacokinetic study investigated valdecoxib cerebrospinal fluid (CSF) and plasma concentrations over time in 37 patients following 40 mg of single-dose intravenous parecoxib. ⋯ Valdecoxib was first detectable in the CSF at 15 min postdosing, increased rapidly until 50 min, and thereafter remained between 6 and 14 ng/ml. This is the first human study demonstrating CNS COX-2 inhibitor penetration as early as 15 min. CSF valdecoxib concentration rapidly reached in vitro IC50 (inhibitory concentration 50) (1.57 ng/ml) by 17 min and remained consistently higher thereafter.
-
Clin. Pharmacol. Ther. · Jan 2008
Randomized Controlled TrialEnhanced buprenorphine analgesia with the addition of ultra-low-dose naloxone in healthy subjects.
Animal studies have demonstrated that co-administration of an ultra-low-dose opioid antagonist with an opioid agonist may result in enhanced analgesia. Investigation of this effect in humans has been limited and produced inconsistent findings, with previous reports suggesting that dose ratio may be critical to analgesic potentiation. ⋯ Importantly, this enhanced analgesia occurred without an increase in adverse effects; indeed at some ratios, respiratory depression was attenuated. These findings demonstrate that the addition of ultra-low-dose naloxone can enhance the analgesic effect of buprenorphine in humans without a concurrent increase in side effects.
-
Clin. Pharmacol. Ther. · Jul 2007
Randomized Controlled TrialReversal of opioid-induced bladder dysfunction by intravenous naloxone and methylnaltrexone.
Peripheral mechanisms may be involved in opioid actions on the urinary bladder. This double-blind study investigated whether opioid inhibition of bladder function is reversed by methylnaltrexone, a peripheral opioid antagonist. Thirteen healthy male volunteers received an intravenous (i.v.) infusion of remifentanil, 0.15 mcg/kg/min, then a single i.v. dose of study medication (methylnaltrexone 0.3 mg/kg, naloxone 0.01 mg/kg, or saline). ⋯ Remifentanil caused marked miosis that was reversed by naloxone, but not methylnaltrexone or placebo (P<0.0001). The pupil data confirm that methylnaltrexone did not reverse central opioid effects. Reversal of urinary retention by methylnaltrexone indicates that peripheral mechanisms may play a role in opioid-induced bladder dysfunction.