Address all correspondence and reprint requests to:<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" /> Baoguo Wang, MD.* Jun Tang, M.D.* Paul F. White, PhD., MD., FANZCA.* Alan C. Foster, Ph.D.# Heather M. Grettenberger, BA.# Joe Kopcho, PhD.# and Ronald H. Wender, M.D.& * Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center at Dallas,Dallas,Texas;
# Gensia Inc., San Diego, California;
& Department of Anesthesiology, Cedars-Sinai Medical Center, Los Angeles ,California Abbreviated title: GP683 decreases the MAC of desflurane Summary statement: The adenosine kinase inhibitor, GP683, produced dose-dependent decreases in the desflurane anesthetic requirement in dogs. Background:The availability of an analgesic compound devoid of the side effects associated with the commonly used opioid and nonsteroidal antiinflammatory drugs would be useful during the perioperative period. Although adenosime has analgesic and anesthetic-sparing properties, it also produces does-dependent cardiovascular depression.Inhibitors of adenosine kinase may be able to provide analgesia without producing acute cardiovascular or respiratory depression. The preliminary study investigated the effects of a novel adenosine kinase-inhibiting drug, GP683, on the minimum alveolar anesthetic concentration (MAC )of desflurane in dogs. Methods:Seven mongrel dogs were administered one of three deferent GP683 dose regiments (or the solvent ) by intravenous infusion on separate occasions according to a cross-over study design. After determining the baseline desflurane MAC value, GP683 was infused at 75, 150 or 300 mg/kg/min for 5 min as a loading dose, followed by 15, 30 or 60 mg/kg/min for an additional 85 min to maintain a stable plasma drug level. The desflurane MAC was redetermined 30-90 min after starting the study drug or vehicle infusion, and 30-90 min and 120-180 min after termination of the infusion. Cardiovascular variables and plasma concentrations of GP683 were determined at specific intervals before, during, and after the MAC determinations. Results:The three GP683 dose regimens produced 22%, 31% and 50% decreases in the desflurane MAC, respectively. In addition ,there was good correlation between the decrease in desflurane MAC and the plasma GP683 concentrations(r=-0.78). Although the mean arterial pressure (MAP) was decreased up to 25% by the highest infusion rate of GP683,adjustments in the desflurane concentration to an equi-MAC value resulted in normalization of the MAP values. Furthermore GP683 produced no changes in the heart rate.In conclusion , the adenosine kinase- inhibiting drug, GP683, produced dose-dependent decrease in the desflurane MAC of dogs without producing untoward hemodynamic changes.
Implications: Aninvestigational drug (GP683)that can increase the levels of an important endogenous substance in the body (adenosine )has been found to decrease the anesthtic requirement in dogs without producing adverse effects on the cardiovascular svstem. |
Analgesic compounds are widely used during surgery to reduce the requirement for volatile anesthetics and to achieve improved hemodynamic stability.However,all of the available opioid and nonopioid analgesics have the potential for producing undesirable side effects during the perioperative period.Therefore,there is interest in finding an analgesic devoid of these side effects,which could be administered during and after surgery.
Adenosine and adenosine receptor agonists possess analgesic and anesthetic-sparing effects in both animal and human studies [1-5].The analgesic properties of these compounds are mediated through receptors in the central nervous system (CNS), particularly in the spinal cord [1].However, activation of both central and peripheral adenosine receptors can produce hypotension, bradycardia and hypothermia [6,7].In addition ,the extremely short elimination half-life of exogenously administered adenosine necessitates its administration by a continuons intravenous(IV)infusion.<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" />  A novel class of drugs termed adenosine－regulating agents (ARAs) have been developed in an effort to achieve more selective adenosine－mediated effects.Experimental data suggests that ARAs activate adenosine receptors indirectly by interfering with adenosine metabolism and increasing endogenous (local)adenosine concentrations [8-10].Adenosine kinase inhibitors are a unique class of ARAs. Adenosine kinase phosphorylates adenosine to AMP and is a major route of adenosine catabolism [9]. Consequently, inhibition of adenosine kinase should increase local adenosine levels .Adenosine kinase inhibitors produce analgesic-like properties and CNS depression without hemodynamic changes in rats[11-15].
In this preliminary investigation , the ability of the selective adenosine kinas inhibitor, 4-(N-phenylamino) -5-phenyl-7- (5'-deoxyribofuranosyl) pyrrolo[2,3-d]pyrimidine (GP683) [15], to reduce the anesthetic requirement for desflurane was investigated in a dog model. The residual effects of GP683 on the desflurane minimum alveolar anesthetic concentration(MAC) was also assessed during the postinfusion period.Finally, the acute effects of the GP683 infusion on heart rate and blood pressure were measured. |
Methods Using a cross-over study design , seven healthy female mongrel dogs (weighing 17 to 23 kg) were studied up to three times at minimal intervals of 7 days with three different doses of GP683 or the solvent polyethylene glycol (PEG),under desflurane anesthesia (Table 1) .Five dogs were studied on three separate occasions ,and two dogs were anesthetized twice .The study drug ,GP683m was synthesized by Gensia Inc .(San Diego ,CA)and was solubilized in PEG(5mg /mL).The experimental protocol was approved by the institutional animal welfare committee at Cedars-Sinai Medical Center.<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" />  The animal were fasted overnight,and anesthesia was induced with thiopental, 10 mg/kg intravenously (IV). After tracheal inubation, anesthesia was maintained with desflurane 7%-9% in oxygen (O2).at a total fresh gas flow of 1.5 L/min. Controlled ventilation was used to maintain the end-tidal carbon dioxide tension (PETCO2) between 35and 40 mmHg. IV catheters were inserted percutaneously in peripheral veins on different legs. and lacerated Ringer's solution was infused at 10 ml/kg/h. During anesthesia, PETCO2, arterial O2 saturation (SpO2), inspired and expired desflurane concentrations,esophageal temperature, and a three-lead electrocardiogram were continuously monitored.The mean arterial pressure (MAP)was measured noninvasively at 2-to 5-min intervals using a small cuff placed on one of the rear legs of the dog.Body temperature was maintained at baseline values using a warming blanket and external heating lamps .
Approximately 1 h after thiopental administration, the baseline desflurane MAC was determined using the standard tail-clamp technique [5, 16]. A large metal hemostat was applied 2-4cm from the base of the dog’s tail and was moved continuously for 60 s. A positive response to the tail clamp consisted of a purposeful movement (e.g., jerking or twisting of the head, clawing movements of the extremities). The end-tidal concentration of desflurane was increased or decreased stepwise by 0.5-1.0 volume percent (vol%) after each assessment, allowing an equilibration period of at least 15 min before a subsequent tail clamping procedure was performed. The desflurane MAC was calculated as the end-tidal concentration midway between the concentration that allowed and prevented purposeful movements. The maximum difference between expired desflurane concentrations that allowed and prevented movement was 0.5 vol%.After determining the baseline desflurane MAC,one of three different dose regimens of GP683 or the vehicle PEG was administered through a venous catheter using a Harvard syringe gump (Table 1).A second MAC determination was started 30 min after initiating the maintenance infusion of GP-683 or PEG. A third MAC determination was performed 30-90 min after discontinuingthe infusion. In the large-dose GP683 group, a fourth MAC determination was performed 120-180 min after terminating the GP683 infusion.Desflurane was discontinued after all MAC values were determind ,and the awakening times were recorded. |
14. Wienser JB, Ugarkar B,Castellino AJ ,et al. Antinociceptive activity of novel adenosine kinase inhibitors. Soc Neurosci Abstr 1995; 21:314.10.<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" /> 15. Wienser JB, Zimring ST, Castellino AJ,et al . Anticonvulsant profile of a novel adenosine kinase inhibitor, GP683, in rosents. J Pharmacol Exp Ther.In press. 16. Eger EI II, Saidman LJ, Brandstater B. Minimum alveolar anesthetic concentration: a standard of anesthetic potency. Anesthesiology 1965; 26:756-63. 17. Miller RD ed. Anesthesia. 3rd ed. Vol 1. New York:Churchill Livingsone, 1990; 1001-29. 18. Murphy MR, Hug CC Jr. The anesthetic potency of fentanyl in terms of its reduction of enflurane MAC. Anesthesiology 1982; 57:485-8. 19. Muphy MR, Hug C Jr. The enflurane sparing effect of morphine, butorphanol, and nalbuphine. Anesthesiology 1982; 57:489-92. 20. Hall RI, Murphy MR, Hug C Jr. The enflurane sparing effect of sufentanil in dogs. Anesthesiology 1987; 67:518-25. 21. Hall RI, Szlam F, Hug CC Jr. The enflurane sparing effect of alfentanil in dogs. Anesth Analg 1987; 66:1287-91. 22. Hall RI, Murphy MR, Szlam F, Hug C Jr. Dezocine-MAC reduction and evidence for myocardial depression in the presence of enflurane. Anesth analg 1987; 66:1169-74. 23. Vickery RG, Sheridan BC, Segal IS, Maze M. Anesthetic and hemodynamic effects of the stereoisomers of medetomidine, an a2-adrenergic agonist, in halothane-anesthetized dogs. Anesth Analg 1988; 67:611-5. 24. Rich GF, Schacterle R, Moscicki JC, et al. Ketorolac does not decrease the MAC of halothane or depress ventilation in rats. Anesth Analg 1992; 75:99-102. Crawford MW,Lerman J,Saldivia V,et al.The effect of adenosine induced hypotension on systemic and splanchnic hemodvnamics during halothane or sevoflurane anesthesia in the rat .Anesthesiology 1994; 80:159-67. 26. Cronstein BN ,Adenosine ,an endogenous anti-inflammatory agent ,J Appl Physiol 1994; 76:5-13. 27. Sawynok J Sweeney MI, White TD. Classification of adenosine receptors mediating antinociception in the rat spinal cord.Br J Pharmacol 1986; 88:923-30. 28. Li J, Perl ER. Adenosine inhibition of synaptic transmission in the substantial gelatinosa. J Neurophy 1994; 72:1611-21. 29. Santicioli P, Del Bianco E, Tramontana M, Maggi CA. Adenosine inhibits action potential-dependent release of calcitonin gene-related peptide- and substance P-like immunoreactives from primary afferents in rat spinal cord. Neurosci Lett 1992; 144:211-4. 30. Santicioli P, Del Bianco E, Maggi CA. Adenosine A1 receptors mediate the presynaptic inhibition of calcitonin gene-related peptide by release by adenosine in the rat spinal cord. Eur J Pharmacol 1993; 231:139-42. |
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