USE OF REMIFENTANYL FOR REDUCING BLOOD PRESSURE

Abstract: The present invention provides methods of reversibly lowering blood pressure comprising administration of a blood pressure-lowering effective amount of an ultra-short acting opioid. The present invention also provides methods of reversibly lowering blood pressure while also providing analgesia, anesthesia and/or creating conscious sedation comprising administration of a blood pressure-lowering effective amount of the ultra-short acting opioid, remifentanil, in peri-operative or intensive care settings wherein said effective amount is capable of reversibly lowering blood pressure in said mammal while also providing analgesia, anesthesia and/or creating conscious sedation.

Description: USE OF REMIFENTANYL FOR REDUCING BLOOD PRESSURE The present invention relates to methods of lowering blood pressure while also providing analgesia, anesthesia and/or creating conscious sedation comprising administration of the ultra-short acting opioid, remifentanil. The hydrochloride salt of remifentanil is commercially available from Glaxo Wellcome Inc. under the tradename ULTIVA® (remifentanil hydrochloride) for Injection. ULTIVA® is a μ-opioid agonist indicated for IV administration as (1) an analgesic agent for use during the induction and maintenance of general anesthesia for inpatient and outpatient procedures, (2) for continuation as an analgesic into the immediate postoperative period under the direct supervision of an anesthesia practitioner in a postoperative anesthesia care unit or intensive care setting, and (3) as an analgesic component of monitored anesthesia care. ULTIVA® is chemically designated as a 3-[4-methoxycarbonyl-4-[(1-oxopropyl)phenylamino]-1- piperidine]propanoic acid methyl ester, hydrochloride salt, C- 2 oH 28 N 2 0 5 »HCI, with a molecular weight of 412.91 and has the following chemical structure: Use of remifentanil to provide analgesia is also described in U.S. 5,019,583, and Feldman PL, James MK, Brackeen MF, Biiotta JM, Schuster SV, Lahey AP, Lutz MW, Johnson MR, Leighton HJ "Design, Synthesis and Pharmacological Evaluation of Ultrashort to Long-Acting Opioid Analgesics," J Med Chem 34:2202-2208 (1991 ) incorporated by reference herein. Use of remifentanil to provide anesthesia and create conscious sedation is described in U.S. 5,466,700 incorporated by reference herein. U.S. 5,866,591 covers various formulations of ULTIVA® for Injection and U.S. 5,599,938 covers processes for synthesizing intermediate(s) of remifentanil, both incorporated by reference herein. Remifentanil contains two alkyl esters, one sterically hindered and the other sterically unhindered. The sterically unhindered ester is believed to be susceptible to aqueous hydrolysis and hydrolysis by esterases in blood and tissues. The major hydrolysis product is the monocarboxylic acid which is significantly less potent than remifentanil and has no appreciable opioid activity. Thus the rapid inactivation of remifentanil is caused by hydrolysis of the sterically unhindered ester. Rapid inactivation provides the following advantages for using remifentanil in anesthetic/analgesic applications: (1 ) ultra-short duration of action (2) less variability in recovery rate even with differences in hepatic function (3) no accumulation of drug during repeated bolus doses or infusion; and (4) more rapid recovery. There are several common medical conditions in peri-operative or intensive care settings where providing analgesia, anesthesia and/or creating conscious sedation and with simultaneous reduction of blood pressure are desired. For example, heart attack victims suffer both severe chest pain and hydraulic heart stress (induced by increased blood pressure). Thus it would be advantageous to administer an agent capable of reducing the chest pain while also relieving the hydraulic heart stress or "after-load" by reducing the blood pressure. There are also certain types of surgery that are both very painful and which result in excessive blood loss, e.g., prostate, liver, hip replacement, aortic replacement and thyroid surgery. Reducing blood pressure is a recognized anesthetic tactic employed to control blood loss. Thus, in this surgical context, administering an agent capable of reducing the blood pressure while controlling the pain would again be advantageous. Typically, physicians must resort to using two agents under these conditions, i.e., an analgesic (e.g., morphine) and a hypotensive agent (e.g., nitroprusside). It is well known that opioids (drugs that resemble botanical narcotics, e.g., morphine and codeine) can reduce blood pressure as well as relieve pain. However, with most opioids it is difficult to lower blood pressure at a controlled rate and therefore a more suitable agent such as nitroprusside must be employed. Furthermore, once blood pressure falls after administering an opioid, it is often difficult to re-establish the blood pressure. Thus if the analgesic of choice is a conventional opioid, yet a third drug such as phenylephrine (in addition to the opioid analgesic and hypotensive agent) must be administered in order to re-establish blood pressure - further complicating treatment. See, e.g., Sebel, P.S. et al "Histamine concentrations and hemodynamic responses after remifentanil". Anesth Analg 80: 990-993. Sebel P.S et al "Cardiovascular effects of alfentanil anesthesia," BrJ Anaesth 54: 1185-1190 and Sebel P.S. and Bovill J.G "Cardiovascular effects of sufentanil anesthesia," Anesth Analg 61 : 115-119. Opioids typically cause long-lasting falls in blood pressure by causing the body to release histamine into the circulation. It is the histamine that directly causes the fall in blood pressure, and which has long-lasting effects. Rosow C.E. et al "Histamine release during morphine and fentanyl anesthesia," Anesthesiology 56: 93-96 (1982) and Rosow C.E. et al "Hemodynamics and histamine release during induction with sufentanil or fentanyl," Anesthesiology 60: 489-491 (1984). The effects of histamine can be antagonized by drugs like promethazine or chlopheniramine. However, since they are anticholinergic, they will result in tachycardia, which is clinically undesirable. Glycopyrrholate may also be used but will also cause tachycardia. Thus re-establishing blood pressure in patients treated with conventional opioids brings on a new set of complications in the management of critically ill patients during surgery or in the high-dependency cardiac care unit. Recovery of blood pressure is important in managing both a heart attack victim and a patient undergoing surgery. During surgery, recovery of blood pressure is required before the patient can be released from the anesthesiologist's direct care. Similarly, heart attack victims are typically managed in the sitting position due to the need to avoid left ventricular failure, which can result in insufficient blood pressure to the brain. Thus, the intensive care physician must carefully balance unloading the heart while maintaining adequate blood supply to the brain. A method that is distinct from the known effects of opioids to reduce blood pressure, in that (a) the reduction in blood pressure is not mediated by histamine release (b) the rate at which the blood pressure is reduced may be precisely controlled and (c) the reduction in blood pressure may be reversed in a relatively short period would thus be of great value. Non-opioid agents used to reduce blood pressure may either be non-reversible, or lack the desired effects of concomitant induction of analgesia and anesthesia/sedation. It is apparent that a single agent capable of reversibly lowering blood pressure while also providing analgesia, anesthesia and/or creating conscious sedation would greatly simplify and thereby enhance treatment of patients in the peri-operative or intensive care settings. The present invention provides methods of reversibly lowering blood pressure comprising administration of a blood pressure-lowering effective amount of an ultra-short acting opioid. The present invention also provides methods of reversibly lowering blood pressure while also providing analgesia, anesthesia and/or creating conscious sedation comprising administration of a blood pressure-lowering effective amount of the ultra-short acting opioid, remifentanil, in peri-operative or intensive care settings wherein said effective amount is capable of reversibly lowering blood pressure in said mammal while also providing analgesia, anesthesia and/or creating conscious sedation. A first aspect of the present invention provides a method of reversibly lowering blood pressure in mammals comprising administration of a blood pressure-lowering effective amount of remifentanil or a pharmaceutically acceptable salt or solvate thereof. A particular embodiment of the first aspect of the invention comprises administering about 0.01 to 10 μg/kg/min of remifentanil or a pharmaceutically acceptable salt or solvate thereof via infusion. Another particular embodiment of the first aspect of the invention comprises administering about 0.02 to 0.2 μg/kg/min of remifentanil or a pharmaceutically acceptable salt or solvate thereof via infusion. Yet another particular embodiment of the first aspect of the invention comprises administering about 0.03 to 0J μg/kg/min of remifentanil or a pharmaceutically acceptable salt or solvate thereof via infusion. A second aspect of the present invention provides a method of reversibly lowering blood pressure in a mammal while also providing analgesia comprising administration of an effective amount of remifentanil or a pharmaceutically acceptable salt or solvate thereof wherein said effective amount is capable of reversibly lowering blood pressure in said mammal while also providing analgesia to said mammal. A particular embodiment of the second aspect of the invention comprises administering about 0.01 to 10 μg/kg/min of remifentanil or a pharmaceutically acceptable salt or solvate thereof via infusion. Another particular embodiment of the second aspect of the invention comprises administering about 0.02 to 0.2 μg/kg/min of remifentanil or a pharmaceutically acceptable salt or solvate thereof via infusion. Yet another particular embodiment of the second aspect of the invention comprises administering about 0.03 to 0J μg/kg/min of remifentanil or a pharmaceutically acceptable salt or solvate thereof via infusion. Yet another particular embodiment of the second aspect of the invention comprises administering a bolus of about 0.05 to 10 μg/kg of remifentanil or a pharmaceutically acceptable salt or solvate thereof. Yet another particular embodiment of the second aspect of the invention comprises administering a bolus of about 0J to 2 μg/kg of remifentanil or a pharmaceutically acceptable salt or solvate thereof. Yet another particular embodiment of the second aspect of the invention comprises administering a bolus of about 0.25 to 0.75 μg/kg of remifentanil or a pharmaceutically acceptable salt or solvate thereof. A third aspect of the present invention provides a method of reversibly lowering blood pressure in a mammal while also providing anesthesia comprising administration of an effective amount of remifentanil or a pharmaceutically acceptable salt or solvate thereof wherein said effective amount is capable of reversibly lowering blood pressure in said mammal while also providing anesthesia to said mammal. A particular embodiment of the third aspect of the invention comprises administering about 0.01 - 10 μg/kg/min of remifentanil or a pharmaceutically acceptable salt or solvate thereof via infusion. Another particular embodiment of the third aspect of the invention comprises administering about 0.02 to 2 μg/kg/min of remifentanil or a pharmaceutically acceptable salt or solvate thereof via infusion. Yet another particular embodiment of the third aspect of the invention comprises administering about 0.05 to 1 μg/kg/min of remifentanil or a pharmaceutically acceptable salt or solvate thereof via infusion. A fourth aspect of the present invention provides a method of reversibly lowering blood pressure in a mammal while also inducing conscious sedation comprising administration of an effective amount of remifentanil or a pharmaceutically acceptable salt or solvate thereof wherein said effective amount is capable of reversibly lowering blood pressure in said mammal while also inducing conscious sedation in said mammal. A particular embodiment of the fourth aspect of the invention comprises administering about 0.01 to 0.5 μg/kg/min of remifentanil or a pharmaceutically acceptable salt or solvate thereof via infusion. Another particular embodiment of the fourth aspect of the invention comprises administering about 0.02 to 0.25 μg/kg/min of remifentanil or a pharmaceutically acceptable salt or solvate thereof via infusion. Yet another particular embodiment of the fourth aspect of the invention comprises administering about 0.05 to 0J μg/kg/min of remifentanil or a pharmaceutically acceptable salt or solvate thereof via infusion. A fifth aspect of the present invention provides a method of reversibly lowering blood pressure in a mammal suffering from phaeochromocytoma, malignant hypertension, myocardial infarction or acute left ventricular failure comprising administration of a blood pressure-lowering effective amount of remifentanil or a pharmaceutically acceptable salt or solvate thereof. A particular embodiment of the fifth aspect of the invention comprises administering about 0.01 to 10 μg/kg/min of remifentanil or a pharmaceutically acceptable salt or solvate thereof via infusion. Another particular embodiment of the fifth aspect of the invention comprises administering about 0.02 to 2 μg/kg/min of remifentanil or a pharmaceutically acceptable salt or solvate thereof via infusion. Yet another particular embodiment of the fifth aspect of the invention comprises administering about 0.03 to 0J μg/kg/min of remifentanil or a pharmaceutically acceptable salt or solvate thereof via infusion. For each of the embodiments of the invention, the reduction in blood pressure is dose-dependent and therefore is titratable during about the first 5 minutes after injection when administered by infusion. Once the desired blood pressure is achieved, it may be maintained in a controlled fashion for up to several days or more by continuing the infusion at the same rate or a rate suitable to compensate for variables known by those skilled in the art. The phrase "reversibly lowering blood pressure" as described in each embodiment means that blood pressure may be restored to "pre-administration levels" or partially restored to a clinically desirable level within about 1 to 10 minutes after discontinuation of remifentanil infusion. The term "pre-administration levels" means the blood pressure (or range thereof acceptable in the art) of (a) an appropriate control group mammal or of (b) the blood pressure of an experimental group mammal just prior to the administration of remifentanil assuming that no other vasoactive agents (exogenous or endogenous) are released in the bloodstream and assuming no non-remifentanil induced- vasoactive events occur after administration of remifentanil. Amounts or concentrations of remifentanil (or pharmaceutically acceptable salts or solvates thereof) referred to herein are calculated based upon the molecular weight of remifentanil free base. The present invention may employ the pharmaceutically acceptable formulations described in U.S. 5,866,591. Such formulations are buffered to a range of pH 1.5 - pH 5, or more preferably to a pH range of pH 2.5 - pH 3.5, or most preferably to a pH range of pH 2.8 - pH 3.2. That is, they give a solution in the stated pH ranges when dissolved in an amount of water to give a composition suitable for intravenous administration to a patient. Typically the diluted solutions suitable for administration will contain from 1 mg remifentanil per 10 to 1 ,000 ml of solution. For example, certain giycine- containing compositions of this invention prepared to give solutions with an initial pH range of pH 2.8 - pH 3.2, still gave solutions with a pH range of pH 2.5 - pH 3.5 after storage at room temperature for at least two years. Such formulations may be present as solid compositions. Dry powder blends can be prepared. However, uniformity of mixing of this highly potent drug substance in a dry powder blend and sterilization presents significant operational challenges. Particularly preferred compositions of this invention are lyophilized powders for reconstitution. In use, the compositions of this invention are diluted with isotonic saline, or other suitable iv fluids, and then administered intravenously to the patient. Preferred iv fluids are those that do not adversely affect the buffer. Ringer's lactate solution is not preferred. Example 1 Seven human patients with coronary artery disease were scheduled for surgery to replace or divert arteries around those which had become blocked (coronary artery bypass grafting or CABG). The procedure used was to induce general anesthesia, paralyze the patient, and place the patient onto an artificial breathing machine (a "ventilator"). After exposing the patient's beating heart (by opening the patient's chest and spreading the rib cage apart), the patient's blood was then diverted into a heart-lung that would pump oxygenated blood around the patient's body. This enables the ventilator to be switched off and paralyzes the heart to a standstill so the surgeon can operate. The patients body temperature was maintained by heating pads and/or by warming elements in the heart-lung machine. In this state the patient is said to be "on bypass". After the CABG is complete, the above steps procedures were reversed and the chest was wired shut. The patient was then transferred from the operating theatre to an intensive care unit for 24 hours where the ventilator could be kept running, if necessary. Just prior to going "on bypass", these patients received a bolus dose of remifentanil of either 2 or 5 μg / kg body weight. Their arterial blood was sampled several times within the next 30 minutes. These samples were then immediately stabilized to prevent remifentanil from breaking down outside of the body. The stabilized samples were assayed for the concentrations of remifentanil. Figure 1 shows the peak remifentanil concentrations after administering these two doses (5 μg / kg = Series 1 ; 2 μg / kg = Series 2). Figure 2 shows the effects of these doses of remifentanil on the blood pressure of these patients. There was an abrupt reduction in mean blood pressure that spontaneously recovered 10-15 minutes after administration of more remifentanil was discontinued. Figure 3 shows the relationship between remifentanil concentration in the arterial blood and the effect on arterial blood pressure. The peak concentrations that were achieved by the two different doses (5 μg / kg = Series 1 ; 2 μg / kg = series 2) exceeded that needed to create the maximal effect on blood pressure. As remifentanil was cleared from the blood, the blood pressure recovered in a predictable manner, i.e., even though one dose was 2.5 times the other, it was not until the blood concentrations had fallen to the same amount that the blood pressure recovered. The elimination of remifentanil was also predictable. Figure 4 shows that, when standardized for initial dose size, the proportions of drug remaining at all time points except at 1 minute are similar and predictable. Elimination of large doses of remifentanil is similar to that of small doses, except for a brief distribution phase, thus making predictable the infusion rates of remifentanil needed to maintain blood pressure lowering effects in the patient. Example 2 In this study, human patients undergoing general anesthesia were premedicated with midazolam and had anesthesia induced with etomidate and vecuronium. A tube was placed into the windpipe of the patients and a mechanical ventilator used while the patients remained paralyzed. Anesthesia was then maintained using a mixture of three inhaled gases: oxygen, nitrous oxide and isoflurane, whose relative proportions could be varied as necessary during their surgical operations. Glycopyrrolate was administered. Blood pressure and histamine release was measured after intravenous doses of remifentanil. Four doses of remifentanil were administered (to provide analgesia) using a syringe pump: 2, 5, 15, and 30 μg /kg body weight. Each dose was administered to a different group of six human patients (three men and three women). Figure 5 shows that in comparison to the amount of histamine circulating before administration of remifentanil, there was no increase for all the doses studied within 5 minutes of administration. This is very different from the well-known property of other opioids (e.g., morphine) to cause histamine release (Rosow et al, 1982, supra). As can be seen in Illustration 2, this five minute interval is the same as that needed for the blood pressure lowering effects of remifentanil, which are therefore not due to histamine release. Example 3 Thirty-eight human patients who needed conscious sedation for short surgeries on one eye were studied. Half of the patients, randomly selected, received an infusion of 0.05 μg/kg/min of remifentanil and the other half received 0.5 μg/kg/min alfentanil (an alternative potent opioid). These patients remained conscious and co-operative with the surgeon throughout the surgery, and their blood pressure was measured frequently as part of the standard of care of such a conscious patient. This is a clinical situation where lowering of blood pressure is of benefit to the patient because it is accompanied by a secondary reduction of intra-ocular pressure, which is damaging to the eye. The following table shows the mean systolic blood pressures (mm Hg) that were recorded: These results show that remifentanil, at doses that created conscious sedation, was associated with a lowering blood pressure during the surgical procedure. In this type of surgery, the blood pressure of these conscious patients typically rises when they see the surgeon begin the cutting of their eye. Elevations of blood pressure are undesirable in eye surgery, when it can worsen or cause separation of the retina, and worsen or cause bleeding into the clear structures (lens and vitreous humor) of the center of the eyeball through which one normally sees. The blood pressures measured "at sedation" represent the start of the surgical procedure. In patients treated with alfentanil (a current standard of care) and elevation of blood pressure is evident of about 4 mmHg. This declines at the end of surgery towards baseline, and falls further when the procedure is over and the patient is discharged. In comparison, it can be seen that patients treated with remifentanil have no increase in blood pressure when surgery begins, have a blood pressure that is satisfactorily lower than alfentanil-treated patients, but have no problem maintaining a normal blood pressure thereafter. These data demonstrate how blood pressure is controlled by remifentanil for the precise period of surgical manipulation when remifentanil was used, and that this was not achieved with alfentanil treatment. Example 4 As described in U.S. 5,866,591 , 2 mg remifentanil hydrochloride lyophilized dosage form was prepared by the following method. Approximately 85 liters of Water for Injection USP was added into a compounding vessel and 1 ,650 kilograms of glycine USP was dissolved with agitation. Sufficient dilute aqueous hydrochloric acid NF was added to the solution until the pH was approximately pH 3J (range pH 3.0 - pH 3.5). A total of 243.3 grams of remifentanil hydrochloride was dispersed in a minimal volume of Water For Injection USP and transferred to the compounding vessel. This dispersion was mixed by agitation until all solids had dissolved. The final pH of the solution was adjusted to pH 3.0 (range pH 2.8 - pH 3.2) with the addition of additional dilute aqueous hydrochloric acid NF. Sufficient Water for Injection USP was added to bring the volume to 110.0 liters. The bulk solution of remifentanil hydrochloride was filtered through a sterilizing-grade membrane filter and collected in a sterilized holding vessel. An automated filling unit dispensed 1.0 ml of the 2.0 mg/ml solution of remifentanil hydrochloride into glass vials. The filled vials were partially stoppered and loaded into a sterilized lyophilizer. The vials were lyophilized at a temperature beginning at - 45 degrees C and slowly warming the lyophilizer shelves to + 40 degrees C under a 250 micron vacuum. Lyophilization was complete after approximately 14 hours. The stable lyophilized formulation of remifentanil hydrochloride contained less than 3% water (weight/weight % basis). Analysis by reverse phase high performance liquid chromatography (RP-HPLC) indicated no loss of active drug substance (100% of initial analysis). Stability studies showed that this formulation maintained a room temperature shelf life stability of two years (i.e. the drug substance remifentanil hydrochloride degraded by hydrolysis to an extent of less than 10% in two years). Example 5 As described in U.S. 5,866,591 , a 5 mg remifentanil hydrochloride lyophilized dosage form was prepared by the following method. Approximately 60 liters of Water for Injection USP was added into a compounding vessel and 1 J25 kilograms of glycine USP was dissolved with agitation. Sufficient dilute aqueous hydrochloric acid NF was added to the solution until the pH was approximately 3J (range pH 3.0 - pH 3.5). A total of 414.7 grams of remifentanil hydrochloride was dispersed in a minimal volume of Water for Injection USP and transferred to the compounding vessel. This dispersion was mixed by agitation until all solids had dissolved. The final pH of the solution was adjusted to pH 3.0 (range pH 2.8 - pH 3.2) with the addition of additional dilute aqueous hydrochloric acid NF. Sufficient Water for Injection USP was added to bring the final volume to 750.0 liters. The bulk solution of remifentanil hydrochloride was filtered through a sterilizing-grade membrane filter and collected in a sterilized holding vessel. An automated filling unit dispensed 1.0 ml of the 5.0 mg/ml solution of remifentanil hydrochloride into glass vials. The filled vials were partially stoppered and loaded into a sterilized lyophilizer. The vials were lyophilized at a temperature beginning at - 45 degrees C and slowly warming the lyophilizer shelves to + 40 degrees C under a 250 micron vacuum. Lyophilization was complete after approximately 14 hours. The stable lyophilized formulation of remifentanil hydrochloride contained less than 3% water (weight / weight % basis). Analysis by reverse phase high performance liquid chromatography (RP-HPLC) indicated no loss of active drug substance (100% of initial analysis). Stability studies showed that this formulation maintained a room temperature shelf life stability of two years (i.e. the drug substance remifentanil hydrochloride degraded by hydrolysis to an extent of less than 10% in two years).

Claims: What is claimed is: 1. The use of remifentanil or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a therapeutic agent for reversibly lowering blood pressure. 2. The use of remifentanil or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a therapeutic agent for reversibly lowering blood pressure whilst also providing analgesia. 3. The use of remifentanil or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a therapeutic agent for reversibly lowering blood pressure whilst also providing anesthesia. 4. The use of remifentanil or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a therapeutic agent for reversibly lowering the blood pressure in a patient suffering from phaeochromocytoma, malignant hypertension, myocardial infarction or acute left ventricular failure. 5. The use of remifentanil or a pharmaceutically acceptable salt or solvate in the manufacture of a therapeutic agent for reversibly lowering the blood pressure while also inducing a state of conscious sedation in a patient. 6. A method of reversibly lowering blood pressure in mammals comprising administration of a blood pressure-lowering effective amount of remifentanil or a pharmaceutically acceptable salt or solvate thereof. 7. A method of reversibly lowering blood pressure in a mammal while also providing analgesia comprising administration of an effective amount of remifentanil or a pharmaceutically acceptable salt or solvate thereof wherein said effective amount is capable of reversibly lowering blood pressure in said mammal while also providing analgesia to said mammal. 8 A method of reversibly lowering blood pressure in a mammal while also providing anesthesia comprising administration of an effective amount of remifentanil or a pharmaceutically acceptable salt or solvate thereof wherein said effective amount is capable of reversibly lowering blood pressure in said mammal while also providing anesthesia to said mammal. 9. A method of reversibly lowering blood pressure in a mammal while also inducing conscious sedation comprising administration of an effective amount of remifentanil or a pharmaceutically acceptable salt or solvate thereof wherein said effective amount is capable of reversibly lowering blood pressure in said mammal while also inducing conscious sedation in said mammal. 10. A method of reversibly lowering blood pressure in a mammal suffering from phaeochromocytoma, malignant hypertension, myocardial infarction or acute left ventricular failure comprising administration of a blood pressure-lowering effective amount of remifentanil or a pharmaceutically acceptable salt or solvate thereof. 11. The method of claim 10 wherein said effective amount is about 0.01 to 10 μg/kg/min. 12. The method of claim 10 wherein said effective amount is about 0.02 to 2 μg/kg/min. 13. The method of claim 10 wherein said effective amount is about 0.03 to 0J μg/kg/min. 14. The method of claim 9 wherein said effective amount is about 0.01 to 0.5 μg/kg/min. 15. The method of claim 9 wherein said effective amount is about 0.02 to 0.25 μg/kg/min. 16. The method of claim 9 wherein said effective amount is about 0.05 to 0J μg/kg/min. 17. The method of claim 8 wherein said effective amount is about 0.01 - 10 μg/kg/min. 18. The method of claim 8 wherein said effective amount is about 0.02 to 2 μg/kg/min. 19. The method of claim 8 wherein said effective amount is about 0.05 to 1 μg/kg/min. 20. The method of claim 7 wherein said effective amount is about 0.01 to 10 μg/kg/min via infusion. 21. The method of claim 7 wherein said effective amount is about 0.02 to 0.2 μg/kg/min via infusion. 22. The method of claim 7 wherein said effective amount is about 0.03 to 0J μg/kg/min via infusion. 23. The method of claim 7 wherein said effective amount is a bolus of about 0.05 to 10 μg/kg. 24. The method of claim 7 wherein said effective amount is a bolus of about 0J to 2 μg/kg. 25. The method of claim 7 wherein said effective amount is a bolus of about 0.25 to 0.75 μg/kg. 26. The method of claim 6 wherein said effective amount of remifentanil is about 0.01 to 10 μg/kg/min of remifentanil via infusion. 27. The method of claim 6 wherein said effective amount of remifentanil is about 0.02 to 0.2 μg/kg/min of remifentanil via infusion. 28. The method of claim 6 wherein said effective amount of remifentanil is about 0.03 to 0J μg/kg/min of remifentanil via infusion.

Inventors: BATENHORST RANDAL L, FOX ANTHONY WILLIAM, JAMERSON BRENDA DIANE, BATENHORST, RANDAL, L., FOX, ANTHONY, WILLIAM, JAMERSON, BRENDA, DIANE
Applicants: GLAXO GROUP LTD, GLAXO GROUP LIMITED
Application year: 2000
Main classification: A61K31
IPC codes: A61K31