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1.  Diazepam Enhances Fentanyl and Diminishes Meperidine Antinociception 
Anesthesia Progress  1988;35(5):190-194.
A rabbit tooth pulp antinociceptive model was used to investigate the effect of prior administration of diazepam or muscimol on the potency and duration of fentanyl and meperidine Potency experiments compared ED50 values in all-or-none dose-response assays between both muscimol (0.25 mg/kg) and saline, and diazepam (1.5 mg/kg) and propylene glycol vehicle. An all-or-none effect was defined as doubling of voltage threshold to elicit a lick/chew evoked response. Duration experiments compared time (minutes) to 50% maximum possible effect (MPE) of an ED90 dose of fentanyl (0.04 mg/kg) and to 50% and 20% MPE of an ED98 dose of meperidine (17 mg/kg) 10 minutes after pretreatment with diazepam (1.5 mg/kg). Prior (10 minutes) injection of diazepam (1.5 mg/kg) increased the ED50 value for meperidine (3.06 mg/kg) compared with its control (1.48 mg/kg), indicating a decrease in antinociceptive potency. The same dose of diazepam decreased the ED50 value for fentanyl (1.1 μg/kg) compared with its control (13.1 μg/kg), indicating an increase in antinociceptive potency. Muscimol also had a similar effect on fentanyl (ED50, 1.8 μg/kg) compared with saline control (ED50, 13.8 μg/kg). Diazepam, vehicle, and muscimol by themselves had no effect on voltage thresholds to elicit a lick/chew response. Time to 50% MPE for diazepam-fentanyl was 38 minutes vs. 25 minutes for vehicle-fetanyl; time to 20% MPE for diazepam-meperidine was 38 minutes vs. 54 minutes for vehicle-meperidine (maximum percentage of MPE produced by diazepam-meperidine was 40% compared with 100% MPE for vehicle-meperidine). Percentages of MPE for diazepam-meperidine were significantly lower than those for vehicle-meperidine at all time intervals, whereas percentages of MPE for diazepam-fentanyl were significantly greater than those for vehicle-fentanyl over time.
PMCID: PMC2167869  PMID: 3250278
2.  The Benzodiazepine Receptor 
Anesthesia Progress  1986;33(5):213-219.
The benzodiazepines are among the most widely used drugs in the world. When first introduced, little was known about their mechanism of action. However, in the last 20 years, our understanding of the chemistry and function of the central nervous system (CNS) has increased substantially. This knowledge has shed some light on the mechanism of action of the benzodiazepines and other centrally acting drugs. It is well established that the benzodiazepines act by combining with specific receptors in the central nervous system. These receptors are anatomically in close association with gamma amino butyric acid (GABA) receptors and appear to reside on the neuronal membrane in the same supramolecular protein complex. GABA is the major inhibitory neurotransmitter of the CNS. The benzodiazepines act by increasing the affinity of the GABA receptor for its ligand, thereby augmenting the inhibitory effect of a given concentration of GABA. Two hypotheses of benzodiazepine ligand-receptor interactions in this supramolecular protein complex have been proposed: (1) multiple receptor subtypes analogous to the opioid receptors; (2) single receptor with multiple conformations. The multiple receptor hypothesis suggests that each pharmacologic effect of the benzodiazepines (i.e., anxiolysis) is mediated by interaction with a specific receptor subtype. On the other hand, the alternative hypothesis suggests that only one receptor exists which has a dynamic conformation. Experimental evidence in support of each hypothesis is presented and critically evaluated.
PMCID: PMC2177483  PMID: 3022619
3.  Relief of Dental Pain: A Controlled 12-Hour Comparison of Etodolac, Aspirin, and Placebo 
Anesthesia Progress  1985;32(4):151-156.
Single doses of the study drugs were evaluated for 12 hours by 201 out-patients reporting moderate or severe pain following oral surgery. The results of this double-blind study indicated that 50, 100, and 200 mg of etodolac as well as 650 mg of aspirin were significantly more effective than placebo. A dose-response relationship was found for the three doses of etodolac, which was significant for summed pain relief scores for up to 8 hours. In terms of total analgesic effect, etodolac 200 mg was significantly superior to placebo for 8 hours, while aspirin and the two lower doses of etodolac were similarly effective in the range of 3-6 hours postdrug. All doses showed a favorable onset of analgesia (½-1 hour). Etodolac 200 mg resulted in a duration of action which was approximately twice as long as aspirin's and also produced a peak pain relief which was significantly greater than the lower doses of etodolac and aspirin. All study medications were well tolerated with no reports of significant adverse side effects. No dose-related effects were observed with etodolac
PMCID: PMC2148530  PMID: 2934008

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