The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Sep 1997
Randomized Controlled Trial Comparative Study Clinical TrialComparing the subjective, psychomotor and physiological effects of intravenous buprenorphine and morphine in healthy volunteers.
The purposes of this study were to characterize the subjective, psychomotor and physiological effects of buprenorphine in nondrug-abusing volunteers and to compare and contrast the effects of equianalgesic doses of buprenorphine and morphine. Sixteen subjects without histories of opiate dependence were injected in an upper extremity vein with 0, 0.075, 0.15 or 0.3 mg/70 kg buprenorphine, or 10 mg/70 kg morphine, using a randomized, double-blind, cross-over design. The 0.3-mg buprenorphine dose and 10-mg morphine dose are considered to be equianalgesic and are doses commonly given for relief of postoperative pain. ⋯ Buprenorphine, but not morphine, decreased respiration rate. The results of our study demonstrate that 0.075 to 0.3 mg buprenorphine had orderly, dose-related effects on subjective, psychomotor and physiological variables. Further, a clinically relevant dose of buprenorphine, 0.3 mg, produced a greater magnitude of subjective and psychomotor-impairing effects than did an equianalgesic dose of morphine.
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J. Pharmacol. Exp. Ther. · Sep 1997
Clinical Trial Controlled Clinical TrialPhase I safety and pharmacokinetic profile of an intercellular adhesion molecule-1 antisense oligodeoxynucleotide (ISIS 2302).
Healthy male volunteers received single or multiple intravenous infusions of an intercellular adhesion molecule-1 antisense phosphorothioate oligodeoxynucleotide, ISIS 2302, in a rising-dose (0.06-2.00 mg/kg infused over 2 hr), double-blind, placebo-controlled trial. Brief, dose-related increases in activated partial thromboplastin time were seen at the time of peak plasma concentration (C(max)). Clinically insignificant increases in C3a were seen after higher, repeated doses, but C5a, blood pressure and pulse were unaffected. ⋯ Nonlinear changes in area under the plasma concentration/time curve and steady-state volume of distribution with increasing dose suggested a saturable component to disposition. Metabolites co-migrating with n-1, n-2 and n-3 chain-shortened versions of ISIS 2302 appeared very rapidly in plasma, and disposition and metabolism appeared unaltered by repeated dosing. ISIS 2302 was well tolerated and behaved reproducibly with respect to plasma pharmacokinetics and expected side effects.
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J. Pharmacol. Exp. Ther. · Sep 1997
Folate depletion induced by methotrexate affects methionine synthase activity and its susceptibility to inactivation by nitrous oxide.
We compared the effects of methotrexate (MTX) and nitrous oxide on the methionine (Met) synthase system in two variants of a human glioma cell line. The cells were protected from cytotoxic effect of MTX by adding thymidine and hypoxanthine to the cell culture medium. MTX (0-1 microM) was associated with a dose- and time-dependent reduction in 5-methyltetrahydrofolate (5-methyl-THF) in both cell lines. ⋯ In conclusion, our data show that MTX through depletion of 5-methyl-THF reduces both the Met synthase activity and the cellular CH3Cbl level. Moreover, the effect of MTX on the Hcy remethylation is more pronounced than the inhibition caused by nitrous oxide. These observations should be taken into account in studies on MTX pharmacodynamics.
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J. Pharmacol. Exp. Ther. · Sep 1997
Allopregnanolone affects sleep in a benzodiazepine-like fashion.
Recent research in rats and humans has shown that exogenous progesterone evokes a sleep profile similar to that induced by agonistic modulators of gamma-aminobutyric acid(A) receptors, such as benzodiazepines. This finding suggests the involvement of the neuroactive metabolite of progesterone, allopregnanolone. In the vehicle-controlled study reported here, we assessed the sleep effects of two doses of allopregnanolone (7.5 and 15 mg/kg), mixed with oil, administered intraperitoneally at light onset in 8 rats. ⋯ Analysis of the plasma and brain concentrations of allopregnanolone in 45 rats revealed long-lasting increases, which reached maximal levels during the first postinjection hour. The sleep effects of allopregnanolone are very similar to those elicited by larger doses of progesterone, which produce comparable brain levels of allopregnanolone. These data indicate that the steroid allopregnanolone has benzodiazepine-like effects on sleep.
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J. Pharmacol. Exp. Ther. · Sep 1997
Evaluation of gabapentin and S-(+)-3-isobutylgaba in a rat model of postoperative pain.
Gabapentin and S-(+)-3-isobutylgaba are anticonvulsant agents that selectively interact with the alpha2delta subunit of voltage-dependent calcium channels. This report describes the activities of these two compounds in a rat model of postoperative pain. An incision of the plantaris muscle of a hind paw induced thermal hyperalgesia and tactile allodynia lasting at least 3 days. ⋯ The administration of morphine (1-6 mg/kg s.c.) 0.5 h before surgery prevented the development of thermal hyperalgesia with a MED of 1 mg/kg. However, unlike gabapentin and S-(+)-3-isobutylgaba, it had little effect on the development of tactile allodynia. It is suggested that gabapentin and S-(+)-3-isobutylgaba may be effective in the treatment of postoperative pain.