JP2002538119A - Use of remifentanil for lowering blood pressure - Google Patents

Abstract

  (57) [Summary] The present invention provides a reversible blood pressure lowering method comprising administering a blood pressure lowering effective amount of a long acting opioid. The present invention also provides administration of remifentanil, a short-acting opioid effective in reducing blood pressure, in a perioperative or intensive care setting, reversibly lowering blood pressure and providing analgesia and anesthesia. And / or a method of inducing conscious sedation. Here, the effective amount is capable of reversibly lowering the blood pressure of the mammal, causing analgesia, anesthesia and / or inducing sedation of consciousness.

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method for lowering blood pressure and providing analgesia, anesthesia and / or producing conscious sedation, comprising the administration of the long-acting opioid remifentanil.

[0002] Remifentanil hydrochloride is available under the trade name ULTIVA® (registered trademark) for injection.
(Mifentanil hydrochloride) is commercially available from Glaxo Wellcome Inc. UL
TIVA® provides (1) general anesthesia for the treatment of inpatients and outpatients.
As an analgesic used for induction and maintenance, (2) a postoperative anesthesia management device or
Analgesics to be continued immediately after surgery under direct anesthesiologist intervention in intensive care
And (3) as an analgesic component for monitoring anesthesia management.
It is a required μ-opioid agonist. ULTIVA® is a chemical
Specifically, 3- [4-methoxycarbonyl] -4-[(1-oxopropyl) phene
Nylamino] -1-piperidine] propanoic acid methyl ester, hydrochloride, C₂₀H ₂₈ N₂O₅-HCl, with a molecular weight of 412.91, and the following chemical
Construction:

Embedded image Having.

[0003] The use of remifentanil to provide analgesia is disclosed in US Pat.
19,583, and Feldman PL, James MK, Brackeen MF, Bilotta JM, Sch
uster SV, Lahey AP, Lutz MW, Johnson MR, Leighton HJ ”Design, Synthesis
and Pharmacological Evaluation of Ultrashort to Long-Acting Opioid Anal
gesics "J Med Chem 34: 2202-2208 (1991), which are incorporated herein by reference. Use of remifentanil to produce anesthesia and induce sedation Is described in U.S. Patent No. 5,466,700, which is also incorporated herein by reference, U.S. Patent No. 5,866,591 discloses various ULTIVA for injection. US Pat. No. 5,599,938 extends to methods for the synthesis of intermediates of remifentanil, both of which are incorporated herein by reference.

[0004] Remifentanil contains two types of alkyl esters, one with steric hindrance and the other without steric hindrance. Unsterically hindered esters are believed to be susceptible to hydrolysis by water and by esterases in blood and tissues. The main product of hydrolysis is a monocarboxylic acid that is significantly less potent than remifentanil and does not have adequate opioid activity. Thus, the rapid inactivation of remifentanil is due to hydrolysis of the sterically unhindered ester. The rapid inactivation is due to the following reasons: (1) the effect is extremely short when using remifentanil for the application of an anesthetic / analgesic agent, and (2) the difference in recovery speed even if there is a difference in liver function. And (3) no drug accumulation after repeated bolus administration or infusion, and (4) faster recovery.

There are several common medical conditions in perioperative or intensive care situations where it is desirable to provide analgesia, anesthesia and / or induce sedation and reduce blood pressure. For example, a heart attack patient may have significant chest pain and heart stress due to water pressure (
(Induced by elevated blood pressure). Accordingly, it would be advantageous to administer drugs that can reduce hydrostatic heart stress or "afterload" by reducing chest pain and lowering blood pressure. There are certain tumor procedures, such as prostate, liver, hip replacement, aortic replacement and thyroid surgery, which are extremely painful and cause excessive blood loss. Hypotension is a recognized anesthetic used to control blood loss. Therefore, for this surgery it is advantageous to administer an agent that can lower blood pressure and control pain. Typically, surgeons have to rely on two drugs under these circumstances: analgesics (eg, morphine) and antihypertensives (eg, nitroprusside).

[0006] Opioids (plant anesthetics, such as morphine and codeine-like drugs) are well known for lowering blood pressure and relieving pain. However, it is difficult for most opioids to control the rate and reduce blood pressure, so a more suitable drug such as nitroprusside must be used. Furthermore, once blood pressure drops after opioid administration, it is often difficult to re-establish blood pressure. Thus, to re-establish blood pressure, a third drug such as phenylephrine (in addition to the opioid analgesic and antihypertensive) may still be administered if the selected analgesic is a normal opioid. And the treatment becomes more complicated. For example, Sebel, PS et al "Histamine concentrations and
hemodynamic response after remifentanil ". Anesth Analog 80: 990-993, Seb
el PS et al "Cardiovascular effects of alfentanil anesthesia," Br JA
naesth 54: 1185-1190 and Sebel PS and Bovill JG "Cardiovascular eff
ects of sufentanil anesthesia, "Anesth Analg 61: 115-119.

[0007] Opioids typically provide a long lasting decrease in blood pressure by releasing histamine into the body's circulation. Histamine directly lowers blood pressure and has a long-lasting effect. Rosow CE et al "Histamine release during morphine
and fenanyl anesthesia, "Anesthesiology 56: 93-96 (1982) and Rosow CE
et al "Hemodynamics and histamine release during induction with sufenta
nil or fentanyl, "Anesthesiology 60: 489-491 (1984). This effect of histamine is inhibited by drugs such as promethazine or clophenylamine.
However, they are anticholinergic and cause tachycardia, which is clinically undesirable. Glycopyrrolate can also be used, but also causes tachycardia. Thus, the re-establishment of blood pressure in patients treated with normal opioids introduces a new set of complications in managing critically ill patients during surgery or in highly dependent cardiac medical devices.

[0008] Restoring blood pressure is important both in managing heart attack patients and in managing patients during surgery.
The restoration of blood pressure during surgery is necessary before being released from direct anesthesiologist intervention. Similarly, heart attack patients are typically managed in a sitting position because they need to avoid left ventricular insufficiency, which can result in inadequate cerebral blood pressure. Intensive care physicians must therefore carefully balance maintaining a sufficient blood supply to the brain without overloading the heart.

Thus, (a) the decrease in blood pressure is not mediated by the release of histamine, (b) the rate of decrease in blood pressure can be controlled appropriately, and (c) the decrease in blood pressure can be reversed in a relatively short time, Methods that differ from the known opioid action of lowering blood pressure are extremely valuable. The non-opioids used to lower blood pressure are either irreversible or have insufficient desired effects to simultaneously induce analgesia and anesthesia / sedation. A single agent that can reversibly lower blood pressure and provide analgesia, anesthesia, and / or induce conscious sedation, greatly simplifies the treatment of patients in perioperative or intensive care states, Improve it.

[0010] The present invention comprises the administration of a blood pressure-lowering effective amount of a short-acting opioid.
A method for reversibly lowering blood pressure is provided. The present invention also provides for analgesia, anesthesia, reversibly lowering blood pressure, comprising administering a short-acting opioid, remifentanil effective in reducing blood pressure, in a perioperative or intensive care state, And / or a method of inducing sedation is provided, wherein the effective amount is capable of reversibly lowering the blood pressure of the mammal and providing analgesia, anesthesia, and / or inducing sedation.

A first aspect of the present invention provides a method for reversibly lowering blood pressure in a mammal, comprising administering a blood pressure lowering effective amount of remifentanil or a pharmaceutically acceptable salt or solvate thereof. I will provide a. 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 by infusion. Another particular embodiment of the first aspect of the invention is that of administering about 0.02-0.2 μg / kg / min of remifentanil or a pharmaceutically acceptable salt or solvate thereof by infusion. Comprising. Yet another specific embodiment of the first aspect of the invention is that of administering about 0.03-0.1 μg / kg / min of remifentanil or a pharmaceutically acceptable salt or solvate thereof by infusion. Comprising.

A second aspect of the invention is a method of reversibly lowering blood pressure and providing analgesia in a mammal comprising administering an effective amount of remifentanil or a pharmaceutically acceptable salt or solvate thereof. Wherein the effective amount is capable of reversibly lowering the blood pressure of the mammal and providing analgesia to the 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 by infusion. Another particular embodiment of the second aspect of the invention is that of administering about 0.02-0.2 μg / kg / min of remifentanil or a pharmaceutically acceptable salt or solvate thereof by infusion. Comprising. Yet another specific embodiment of the second aspect of the invention is that of administering about 0.03-0.1 μg / kg / min of remifentanil or a pharmaceutically acceptable salt or solvate thereof by infusion. Comprising. Yet another specific embodiment of the second aspect of the invention comprises administering a bolus of remifentanil or a pharmaceutically acceptable salt or solvate thereof at about 0.05-10 μg / kg. Become. Yet another specific embodiment of the second aspect of the invention comprises administering a bolus of remifentanil or a pharmaceutically acceptable salt or solvate thereof at about 0.1-2 μg / kg. Become. Yet another specific embodiment of the second aspect of the present invention is the method of about 0.25
Administering a bolus of ミ 0.75 μg / kg of remifentanil or a pharmaceutically acceptable salt or solvate thereof.

[0013] A third aspect of the invention is a method of reversibly lowering blood pressure in a mammal and providing anesthesia comprising administering an effective amount of remifentanil or a pharmaceutically acceptable salt or solvate thereof. Wherein the effective amount is capable of reversibly lowering the blood pressure of the mammal and providing anesthesia to the mammal. A particular embodiment of the third aspect of the invention comprises administering about 0.01 to 10 μg / kg / min of remifentanil or a pharmaceutically acceptable salt or solvate thereof by infusion. Another particular embodiment of the third aspect of the invention is that of administering about 0.02-0.2 μg / kg / min of remifentanil or a pharmaceutically acceptable salt or solvate thereof by infusion. Comprising. Yet another specific embodiment of the third aspect of the invention provides administering about 0.05-1 μg / kg / min of remifentanil or a pharmaceutically acceptable salt or solvate thereof by infusion. Comprising.

A fourth aspect of the invention provides a method for reversibly lowering the blood pressure of a mammal and inducing conscious sedation, comprising administering an effective amount of remifentanil or a pharmaceutically acceptable salt or solvate thereof. Wherein the effective amount is capable of reversibly lowering the blood pressure of the mammal and inducing sedation in the mammal.
Particular embodiments of the fourth aspect of the invention are those wherein the infusion is about 0.01-0.5 μg / k.
administering g / min of remifentanil or a pharmaceutically acceptable salt or solvate thereof. Another specific embodiment of the fourth aspect of the invention is that of administering about 0.02-0.25 μg / kg / min of remifentanil or a pharmaceutically acceptable salt or solvate thereof by infusion. Comprising. Fourth Embodiment of the Present Invention
Yet another specific embodiment of the embodiment is wherein about 0.05-0.1 μg by infusion.
/ Kg / min of remifentanil or a pharmaceutically acceptable salt or solvate thereof.

[0015] A fifth aspect of the present invention provides a chromaffin cell tumor comprising administering a blood pressure-reducing effective amount of remifentanil or a pharmaceutically acceptable salt or solvate thereof.
Pheochromocytoma), malignant hypertension, myocardial infarction, or acute left ventricle. Particular examples of the fifth aspect of the present invention include:
Administering about 0.01 to 10 μg / kg / min of remifentanil or a pharmaceutically acceptable salt or solvate thereof by 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 by infusion. It becomes. Yet another specific embodiment of the fifth aspect of the invention is that of administering about 0.03 to 0.1 μg / kg / min of remifentanil or a pharmaceutically acceptable salt or solvate thereof by infusion. Comprising.

For each embodiment of the present invention, blood pressure reduction is dose-dependent, and thus, when administered by infusion, is titratable for the first approximately 5 minutes after infusion. Once the desired blood pressure has been reached, it may be maintained in a controlled manner for several days or more by continuing the infusion at the same rate or at a rate suitable for correction of variables known to those skilled in the art. "Reversibly lowering blood pressure" described in each specific example means that blood pressure can be restored to "pre-administration level" within about 1 to 10 minutes after discontinuing remifentanil infusion, or clinically. It means that it can recover to some degree to the desired level.
"Pre-administration level" refers to (a) the blood pressure of a suitable control mammal group (or its range acceptable in the art), or (b) the blood flow of another vasoactive agent (external or internal). Means the blood pressure of the experimental mammal population immediately prior to remifentanil administration, which is assured that no non-remifentanil-induced vasoactivity will occur after administration of remifentanil.

As used herein, the amount or concentration of remifentanil (or a pharmaceutically acceptable salt or solvate thereof) is calculated based on the molecular weight of remifentanil free base.

In the present invention, the pharmaceutically acceptable preparations described in US Pat. No. 5,866,591 may be used. Such formulations may range from pH 1.5 to pH 5, or more preferably from pH 2.5 to pH 3.5, or most preferably from pH 2.8 to pH 3.
. Buffer to range 2. That is, they are solutions in the pH range indicated when dissolved in a fixed volume of water to make the composition suitable for intravenous administration to a patient. Typically, a suitable diluting solution for administration contains 1 mg remifentanil per 10-1000 ml of solution. For example, one glycine-containing composition of the invention in solution in the initial pH range of pH 2.8 to pH 3.2 is still a solution in the range of pH 2.5 to pH 3.5 after storage at room temperature for at least 2 years. Was.

Such a formulation may be provided as a solid composition. Dry powder formulations can also be prepared. However, making the active drug substance homogeneous and stable in the dry powder formulation presents a significant handling challenge. A particularly preferred composition of the present invention is a lyophilized powder for reconstitution.

The compositions of the present invention are diluted at the time of use with isotonic saline or other suitable intravenous solution and then administered intravenously to the patient. Preferred intravenous solutions do not adversely affect the buffer, and Ringer's lactic acid solution is not preferred.

Example 1 For several patients with coronary artery disease, surgery to replace or bypass the occluded surrounding artery (coronary artery bypass graft or CABG) was planned. The procedure used was to induce general anesthesia to paralyze the patient and place the patient on a ventilator ("ventilator"). After exposing the patient's beating heart (by incising the patient's chest and opening the rib cage), the patient's blood was diverted to the cardiopulmonary pump, which pumps oxygen to the patient's body blood. This allows the ventilator to be turned off, paralyzing and stopping the heart, thus allowing the surgeon to operate. The patient's temperature was maintained by a heating pad and / or by a heating device in the cardiopulmonary unit. In this state, the patient is in a so-called "bypass" state. After the completion of CABG, the procedure of the above steps was traced, and the chest was closed with a wire. Thereafter, the patient was moved from the operating room to the intensive care unit, and the ventilator was continuously operated for 24 hours if necessary.

[0022] These patients received two or five bolus boluses of remifentanil at 5 μg / kg body weight immediately prior to the “bypass” treatment. The patient's arterial blood was then sampled several times within 30 minutes. These samples were then immediately stabilized to avoid in vitro degradation of remifentanil. The stabilized samples were assayed for remifentanil concentration. FIG. 1 shows these two doses (5 μg / kg = Series 1; 2
μg / kg = series 2) shows the remifentanil concentration peak after administration. FIG. 2 shows the effect of these remifentanil doses on the blood pressure of these patients. A sharp drop in mean blood pressure was seen, which recovered spontaneously and did not persist 10 to 15 minutes after further administration of remifentanil.

FIG. 3 shows the relationship between arterial blood remifentanil concentration and its effect on arterial blood pressure. The peak concentrations achieved with the two different doses (5 μg / kg = Series 1; 2 μg / kg = Series 2) are excellent and are required for maximal effects on blood pressure. As remifentanil was cleared from the blood, blood pressure recovered in a predictable manner, i.e., even though one dose was 2.5 times the other, blood levels dropped to the same amount at which blood pressure recovered Do not mean.

In addition, disappearance of remifentanil was estimated. FIG. 4 shows that the percentage of drug remaining at all times except 1 minute when normalized to the initial dose is the same and can be estimated. The elimination of large doses of remifentanil is the same as for small doses, except for the short distribution period, and thus allows an estimation of the infusion rate of remifentanil required to maintain the blood pressure lowering effect of the patient.

Example 2 In this study, midazolan was previously administered to a human patient under general anesthesia, and anesthesia was induced with etomidate and vecuronium. The patient was evacuated to the trachea and a ventilator was used while the patient remained paralyzed. Thereafter, anesthesia was maintained using three inhaled gas mixtures of oxygen, nitric oxide and isoflurane. The relative ratio can be changed as needed during the patient's surgery. Glycopyrrolate was administered. Blood pressure and histamine release were measured after intravenous administration of remifentanil.

Four doses of 2, 5, 15, and 30 μg / kg body weight of remifentanil were administered using a syringe pump (to produce anesthesia). A different group of 6 patients (3 men, 3 women) were administered each dose.

FIG. 5 shows a comparison with the amount of circulating histamine before administration of remifentanil, and no increase was observed at all the doses examined within 5 minutes of administration. this is,
It differs significantly from the well-known properties of other opioids that cause histamine release (eg, morphine) (Rosow et al, 1982, supra). As shown in FIG. 2, this is not due to histamine release, as this 5 minute time is equivalent to that required for the blood pressure lowering effect of remifentanil.

Example 3 A study was conducted on 38 patients requiring conscious sedation for short surgery on one eye. Remifentanil 0.05 μg / kg in half of patients randomly selected
/ Min, and the other half received 0.5 μg / kg / min alfentanil (an alternative effective opioid). These patients consciously worked with the surgeon during the surgery and frequently measured their blood pressure as part of the standard care of such conscious patients. This is an advantageous clinical condition for the patient because a reduction in blood pressure is accompanied by a secondary reduction in intraocular pressure, which causes damage to the eye. The table below shows the recorded mean systolic blood pressure (mmHg).

Stages of Table Surgery Preoperative Sedation At Surgery Termination Before Excretion Remifentanil 142 ± 17 142 ± 19 132 ± 14 133 ± 20
Alfentanil 147 ± 19 151 ± 25 144 ± 22 133 ± 12

These results indicate that remifentanil was associated with intraoperative blood pressure reduction at doses that induced sedation. In this type of surgery, the blood pressure of these conscious patients typically rises when the patient finds that the surgeon has begun opening his or her eye. If elevated blood pressure can exacerbate or cause retinal detachment, and if it can exacerbate or cause bleeding into the transparent structures (lenses and vitreous humor) in the center of the eye through which people normally see, Is not desirable for surgical procedures. Blood pressure measured "at sedation" represents the start of surgery. In patients treated with alfentanil (current standard care), the increase in blood pressure is about 4 mmH
g. It decreases towards baseline at the end of surgery and further decreases when the procedure is completed and the patient has excreted. In contrast, patients treated with remifentanil did not show an increase in blood pressure at the start of surgery,
Although the blood pressure is sufficiently lower than that of the patient treated with alfentanil, it can be seen that there is no problem in maintaining the normal blood pressure thereafter. These data demonstrate that remifentanil controls blood pressure to the following at the net time of the surgical procedure with remifentanil, and that alfentanil treatment does not: Things.

Example 4 As described in US Pat. No. 5,866,591, a 2 mg remifentanil hydrochloride lyophilized dosage form was prepared by the following method. About 85 liters of water for injection USP was added to the compounding vessel, and 1.650 kg of glycine USP was dissolved with shaking.
A sufficiently diluted hydrochloric acid aqueous solution NF is added to this solution at a pH of about pH 3.1 (pH 3.0 to 3.0).
(range of pH 3.5). A total of 243.3 g of remifentanil hydrochloride was dispersed in a minimum amount of water for injection USP and transferred to a compound container. The dispersion was shake mixed until all solids were dissolved. The pH of the final solution was adjusted to pH 3.0 (ranging from pH 2.8 to pH 3.2) by further adding a dilute aqueous solution of hydrochloric acid NF. Sufficient water for injection USP was added to bring the volume to 110.0 liters.

The bulk solution of remifentanil hydrochloride is filtered through a sterile membrane filter,
Collected in sterile holding containers. 1.0 ml of a 2.0 mg / ml remifentanil hydrochloride solution was dispensed into a glass vial using an automatic filling machine. The filled vials were placed in a sterile freeze dryer with some stoppers. The vial is under 250 micron vacuum,
At the beginning, at -45 ° C, the freeze-drying shelf was freeze-dried while gradually warming to + 40 ° C.
Lyophilization was complete after about 14 hours. The stable remifentanil hydrochloride lyophilized formulation contained less than 3% (wt%) water. Reversed-phase high-performance liquid chromatography (
Analysis by RP-HPLC) showed no loss of active drug substance (100% of initial analysis). Stability studies have shown that the formulation maintained stability at room temperature for a storage period of 2 years (ie, the drug substance remifentanil hydrochloride hydrolyzed was less than 10% in 2 years). Was.

Example 5 As described in US Pat. No. 5,866,591, a 5 mg remifentanil hydrochloride lyophilized dosage form was prepared by the following method. About 60 liters of Water for Injection USP was added to the compounding vessel, and 1.125 kg of Glycine USP was dissolved with shaking.
A sufficiently diluted hydrochloric acid aqueous solution NF is added to this solution at a pH of about pH 3.1 (pH 3.0 to 3.0).
(range of pH 3.5). A total of 414.7 g of remifentanil hydrochloride was dispersed in a minimal amount of Water for Injection USP and transferred to a compounding vessel. The dispersion was shake mixed until all solids were dissolved. The pH of the final solution was adjusted to pH 3.0 (ranging from pH 2.8 to pH 3.2) by further adding a dilute aqueous solution of hydrochloric acid NF. Sufficient water for injection USP was added to bring the volume to 750.0 liters.

The bulk solution of remifentanil hydrochloride is filtered through a sterile membrane filter,
Collected in sterile holding containers. 1.0 ml of a 5.0 mg / ml remifentanil hydrochloride solution was dispensed into glass vials using an automatic filling machine. The filled vials were placed in a sterile freeze dryer with some stoppers. The vials were lyophilized under a 250 micron vacuum, starting at -45 ° C, while gradually warming the lyophilization shelf to + 40 ° C. Lyophilization was complete after about 14 hours. The stable remifentanil hydrochloride lyophilized formulation contained less than 3% (wt%) water. Reversed-phase high-performance liquid chromatography (R
Analysis by P-HPLC) showed no loss of active drug substance (100% of initial analysis). Stability studies have shown that the formulation maintained stability at room temperature for a storage period of 2 years (ie, the drug substance remifentanil hydrochloride hydrolyzed was less than 10% in 2 years). Was.

[Brief description of the drawings]

FIG. 1 Remifentanil (5 μg / kg = Series 1; 2 μg / kg = Series 2)
5 shows the remifentanil concentration peak after administration of the compound.

FIG. 2 shows the effect of remifentanil dose on blood pressure of a patient.

FIG. 3 shows the relationship between the arterial blood remifentanil concentration and its effect on arterial blood pressure.

FIG. 4 shows the concentration of remifentanil when normalized to the initial dose.

FIG. 5 is a graph showing the amount of histamine in the circulation before administration of remifentanil.

[Procedure amendment]

[Submission date] October 2, 2001 (2001.10.2)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Claims

[Correction method] Change

[Contents of correction]

[Claims]

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 25/04 A61P 25/04 25/20 25/20 C07D 211/66 C07D 211/66 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN , CR, CU, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG , SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, UZ, VN, YU, ZA, ZW. Battenhorst, North Carolina, USA, Research, Triangle, Park, Five, Moore, Drive, GlaxoSmithKline (72) Inventor Anthony, William, Fox North Carolina, North Carolina, Research, Triangle, Park, Five , Moore, Drive, GlaxoSmithKline (72) Inventor Brenda, Diane, Jemason, North Carolina, United States, Research, Triangle, Park, Five, Moore, Drive, GlaxoSmithKline F-term (reference) 4C054 AA02 CC03 DD01 EE01 FF33 4C086 AA01 AA02 BC21 MA01 MA66 NA14 ZA04 ZA05 ZA36 ZA40 ZA42

Claims (28)

[Claims] Use of remifentanil or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a therapeutic agent for reversibly lowering blood pressure. 2. Use of remifentanil or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for reversibly lowering blood pressure and providing analgesia. 3. Use of remifentanil or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for reversibly lowering blood pressure and producing anesthesia. 4. Remifentanil or a pharmaceutically acceptable salt or solvent thereof in the manufacture of a medicament for reversibly lowering blood pressure in a patient with pheochromocytoma, malignant hypertension, myocardial infarction, or acute left ventricular insufficiency. Use of Japanese products. 5. Use of remifentanil or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for reversibly lowering blood pressure and inducing sedation in a patient. 6. A method for reversibly lowering the blood pressure of a mammal, comprising administering a blood pressure lowering effective amount of remifentanil or a pharmaceutically acceptable salt or solvate thereof. 7. A method for reversibly lowering blood pressure and providing analgesia in a mammal, comprising administering an effective amount of remifentanil or a pharmaceutically acceptable salt or solvate thereof, wherein the effective amount is remifentanil. Can reversibly lower the blood pressure of the mammal and cause analgesia in the mammal. 8. A method of reversibly lowering blood pressure in a mammal and providing anesthesia comprising administering an effective amount of remifentanil or a pharmaceutically acceptable salt or solvate thereof, wherein said effective amount Can reversibly lower the blood pressure of the mammal and effect anesthesia in the mammal. 9. A method for reversibly lowering the blood pressure of a mammal and inducing sedation, comprising administering an effective amount of remifentanil or a pharmaceutically acceptable salt or solvate thereof. A method wherein the effective amount is capable of reversibly reducing the blood pressure of the mammal and inducing sedation in the mammal. 10. A method for reversibly reducing blood pressure in a mammal with pheochromocytoma, malignant hypertension, myocardial infarction, or acute left ventricular insufficiency, wherein the blood pressure-reducing effective amount of remifentanil or a pharmaceutical thereof. And administering a pharmaceutically acceptable salt or solvate. 11. The method of claim 10, wherein the effective amount is about 0.01 to 10 μg / kg / min. 12. The method according to claim 10, wherein the effective amount is about 0.02 to 2 μg / kg / min. 13. The method of claim 10, wherein the effective amount is about 0.03-0.1 μg / kg / min. 14. The method of claim 9, wherein the effective amount is about 0.01-0.5 μg / kg / min. 15. The method of claim 9, wherein the effective amount is about 0.02-0.25 μg / kg / min. 16. The method of claim 9, wherein the effective amount is about 0.05-0.1 μg / kg / min. 17. The method of claim 8, wherein the effective amount is about 0.01 to 10 μg / kg / min. 18. The method of claim 8, wherein the effective amount is about 0.02-2 μg / kg / min. 19. The method of claim 8, wherein the effective amount is about 0.05-1 μg / kg / min. 20. The method of claim 7, wherein the effective amount is about 0.01 to 10 μg / kg / min by infusion. 21. The method of claim 7, wherein the effective amount is about 0.02-0.2 μg / kg / min by infusion. 22. The method of claim 7, wherein the effective amount is about 0.03-0.1 μg / kg / min by infusion. 23. The method of claim 7, wherein the effective amount is a bolus of about 0.05-10 μg / kg. 24. The method of claim 7, wherein the effective amount is a bolus of about 0.1-2 μg / kg. 25. The method of claim 7, wherein the effective amount is a bolus of about 0.25 to 0.75 μg / kg. 26. An effective amount of remifentanil by infusion of about 0.01 to 10 remifentanil.
The method according to claim 6, wherein the amount is μg / kg / min. 27. An effective amount of remifentanil is about 0.02-0.
The method according to claim 6, wherein the amount is 2 µg / kg / min. 28. An effective amount of remifentanil is about 0.03-0.
The method according to claim 6, wherein the amount is 1 μg / kg / min.