The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Feb 1979
Some measurements of autonomic nervous system influence on production of cerebrospinal fluid in the cat.
The effects on cerebrospinal fluid (CSF) production of specific agonists and antagonists for the autonomic nervous system were studied during ventriculocisternal perfusion in cats. Both carbachol and phenylephrine increased the rate of CSF formation 11 microliter/min from control rates of 17 and 11 microliter/min, resepctively; albuterol increased formation 6 microliter/min above the control 16 microliter/min. Atropine or phentolamine administered alone caused slight but significant decreases in CSF production; propranolol had no effect. ⋯ These observations were taken to indicate that phenylephrine increased CSF production by stimulating a cholinergic pathway to the choroid plexus. Bilateral electrical stimulation of the cervical sympathetic trunks decreased CSF formation. Agents which increased CSF production caused no significant changes in cerebral or choroid plexus blood flow, possibly indicating that their effect is a direct action on the choroid plexus secretory mechanisms.
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J. Pharmacol. Exp. Ther. · Nov 1978
Comparative StudyThe rates of interaction of local anesthetics with sodium channels in nerve.
Voltage clamp experiments were carried out on Rana catesbiana nodes of Ranvier in order to test predictions regarding the relationship between local anesthetic lipid solubility and the rate of development of and recovery from frequency-dependent increments of sodium channel block. Contrary to expectations, the drugs of greater lipid solubility than lidocaine showed slower rates of development of frequency-dependent block and, in addition, induced longer rather than shorter memories for recent frequency-depent increments in channel block. Relaxation time constants for bupivacaine (50 micrometer), etidocaine (15 micrometer) and tetracaine (0.7 micrometer) measured 50, 8 and 8 sec, respectively, compared to shorter time constant of 2 sec for lidocaine (250 micrometer). ⋯ Open channels displayed a 130- to 6000-fold greater affinity for the local anesthetics than did closed channels, verifying an important feature of the "modulated receptor" hypothesis. In addition, binding to closed channels was enhanced by holding the membrane at more depolarizing potentials, which favored the development of inactive channel states. The exceptionally large binding constants of lidocaine for interactions with both closed and open channels cannot be attributed to its lipid solubility characteristics alone.
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J. Pharmacol. Exp. Ther. · Oct 1978
Comparative Study Clinical Trial Controlled Clinical TrialAnalgesic studies of codeine and oxycodone in patients with cancer. I. Comparisons of oral with intramuscular codeine and of oral with intramuscular oxycodone.
The relative analgesic potency of oral and intramuscular codeine was evaluated in a double-blind crossover comparison of graded single doses in patients with chronic pain due to cancer. When both duration and intensity of analgesia are considered (total effect), oral codeine was 6/10 as potent as the intramuscular form. ⋯ Like codeine, oxycodone retained at least 1/2 of its analgesic activity when administered orally. We hypothesize that the high oral/parenteral relative potency ratios of codeine and oxycodone relative to morphine and its congeners are not due to more efficient absorption after oral administration, but rather that methylation at position 3 in codeine and oxycodone protects these drugs from rapid first-pass metabolism.
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J. Pharmacol. Exp. Ther. · Oct 1978
Comparative Study Clinical Trial Controlled Clinical TrialAnalgesic studies of codeine and oxycodone in patients with cancer. II. Comparisons of intramuscular oxycodone with intramuscular morphine and codeine.
The relative analgesic potency of single graded intramuscular doses of oxycodone and morphine was evaluated in a double-blind study in patients with chronic pain due to cancer. When both intensity and duration of analgesia are considered (total analgesic effect), oxycodone was 2/3 to 3/4 as potent as morphine, while in terms of peak analgesia, it was 8/10 to equipotent. In doses producing equivalent peak effect, oxycodone had a shorter duration of action than morphine. ⋯ In terms of total analgesic effect, oxycodone was 10 times as potent as codeine, while in terms of peak analgesia it was 12 times as potent. These relative potency relationships of oxycodone, taken in conjunction with the oral/parenteral potency ratios of codeine and oxycodone established in the previous paper and several previous relative potency assays involving morphine, oxymorphone and codeine, demonstrate a highly consistent pattern of analgesic structure-activity relationships encompassing morphine, oxymorphone, codeine and oxycodone. The results of these studies do not appear to support the hypothesis that, in man, the analgesic activity of codeine is due to its O-demethylation to morphine.
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J. Pharmacol. Exp. Ther. · Dec 1977
Nitrous oxide analgesia: reversal by naloxone and development of tolerance.
The objective of this study was to characterize further the nature of nitrous oxide analgesia and to establish if tolerance to nitrous oxide occurs. Methods for studying the analgesic action of a gas are described. In mice, nitrous oxide is analgesic in the phenylquinone and acetic acid abdominal constriction tests. ⋯ Lower doses of the antagonist were not effective. Tolerance developed to the effects of nitrous oxide in both rats and mice after prolonged exposure. These data lend support to the hypothesis that nitrous oxide and opiates have a significant pharmacologic resemblance and may ultimately produce similar molecular events in the brain leading to the relief of pain.