Methods for controlling and predicting recovery after NMBA administration

Abstract

The present disclosure relates to a method of inducing paralysis or neuromuscular blockade (NMB) and recovery therefrom, comprising administering to an anesthetized human patient an effective amount of at least RP1000 or RP2000.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 093,179, filed October 17, 2020, which is incorporated herein by reference in its entirety.

[0002] Technical Field The present disclosure relates to neuromuscular blocking agents (NMBAs), and more particularly to methods for predicting and controlling spontaneous recovery in a patient after administering an NMBA to the patient. [Background technology]

[0003] background Neuromuscular blockade (NMB) is commonly used in anesthesia to facilitate endotracheal intubation, optimize surgical conditions, and support mechanical ventilation in patients with reduced lung compliance. To avoid residual postoperative effects of NMBAs, complete metabolism of NMBAs to inactive metabolites must be achieved sufficiently before extubation. Therefore, careful monitoring of the depth of paralysis is common (although not universal) as an indirect measure of active NMBAs in the patient's body. Depth of paralysis can be monitored by available neuromuscular stimulation techniques, such as train-of-four (TOF), single twitch (ST), double burst (DBS), and post-tetanic count (PTC).

[0004] The most commonly used neuromuscular sensing method is the measurement of time of failure (TOF) by electrical stimulation. TOF typically uses four short (100–300 μs) current pulses (typically less than 70 mA) at 2 Hz, repeated every 10–20 seconds. The resulting twitch is measured and quantified using electromyographic responses, force, acceleration, deflection, or other measures. The first (T1 twitch) and last (T4 twitch) are compared, and the ratio of these two (TOFR) estimates the level of NMB. Trains of stimuli are spaced at least 10 seconds apart (20 seconds is typically used to provide a safety margin) to allow a rest period for the steady state to fully recover; faster stimuli result in smaller evoked responses. Other methods for monitoring the degree of NMB include twitch (ST) measurements, double-burst stimulation (DBS), and post-tetanic counting (PTC).

[0005] However, even with careful monitoring, the use of NMBAs (especially those characterized as long-acting) still frequently causes residual paralytic effects (postoperative residual curarization (PORC)) in the postoperative period due to incomplete conversion of the administered paralytic agent to its inactive form at the neuromuscular junction. The safety of NMBAs is highly scrutinized, debated, and of paramount importance. Incomplete recovery from NMBAs after anesthesia and surgery (residual block) continues to be a common problem in postanesthesia intensive care units and poses a threat to patient safety. Adverse effects of residual block include, but are not limited to, airway obstruction, hypoxic episodes, postoperative respiratory complications, intraoperative awakening, and unpleasant symptoms of muscle weakness.

[0006] Although reversal of NMB can be achieved with a reversal agent, the most common NMBA reversal agent, an acetylcholinesterase inhibitor (AChEI), simply antagonizes the paralytic agent. It does not accelerate the metabolism of NMBA. Therefore, even with the use of an NMBA reversal agent, residual curarization can still occur as the body metabolizes the reversal agent through normal processes. Furthermore, current practice requires anesthesiologists to wait until the patient begins to recover naturally from the NMBA before administering an antagonist. This waiting period often ranges from 30 to 60 minutes or longer.

[0007] Prediction and / or control of NMB recovery can be derived from government agency guidelines. For example, the FDA mandates a maximum allowable clinical duration for NMBAs, which is the 95% effective dose (ED). 95 ) is administered at a dose twice that of the original dose, and is measured as the time to return to a twitch height 25% above baseline in the twitch response test.

[0008] What is needed is a simple method for not only inducing but also effecting recovery from NMB in patients that is effective and reduces the incidence of postoperative residual effects. Because compliance with intraoperative monitoring is not universal or always possible, the field would benefit from a method that provides a highly predictable NMBA recovery period, both in terms of timing and extent of recovery. One such method is described herein below. Summary of the Invention

[0009] overview The present disclosure relates to a method for inducing and effecting spontaneous recovery from NMB in a patient, the method comprising administering to the patient an effective amount of RP1000 or RP2000, which method provides a highly predictable period of NMBA recovery, both in terms of timing and extent of recovery. [The present invention 1001] administering an effective amount of RP2000 to an anesthetized human patient; and causing spontaneous recovery from paralysis or neuromuscular blockade (NMB) in the absence of an RP2000 antagonist, wherein the spontaneous recovery is characterized by a measured TOF ratio of at least about 0.90 in a human patient. 2. A method for inducing paralysis or NMB and recovery therefrom, comprising: [The present invention 1002] 1001. The method of claim 1001, wherein the anesthesia is inhalation anesthesia. [The present invention 1003] The effective dose of RP2000 is at least ED 95 The method of the present invention 1001 or 1002, [The present invention 1004] The effective dose of RP2000 is the ED 95 The method of any one of claims 1001 to 1003, wherein the concentration is at least 1.5 times higher than that of the control. [The present invention 1005] The effective dose of RP2000 is the ED 95 The method of any one of claims 1001 to 1004, wherein the concentration is at least twice as high as that of the control. [The present invention 1006] The method of any one of claims 1001 to 1005, wherein the effective amount of RP2000 is about 0.16 mg / kg to about 0.60 mg / kg. [The present invention 1007] The method of any of claims 1001 to 1006, wherein said spontaneous recovery is achieved within about 17 minutes after cessation of administration of RP2000. [The present invention 1008] The method of any of claims 1001 to 1007, wherein said spontaneous recovery is achieved within about 12 minutes after cessation of administration of RP2000. [The present invention 1009] The method of any of claims 1001 to 1008, wherein said spontaneous recovery is achieved within about 10 minutes after cessation of administration of RP2000. [The present invention 1010] The method of any of claims 1001 to 1009, wherein the effective amount of RP2000 is sufficient to induce a twitch height of about 5% or less of baseline within 2 minutes after the start of administration. [The present invention 1011] The method of any one of claims 1001 to 1010, wherein the anesthesia is IV anesthesia. [The present invention 1012] The effective dose of RP2000 is the ED 95 1011. The method of claim 10, wherein the number of serotonin receptors is at least three times higher than the number of serotonin receptors. [The present invention 1013] The effective dose of RP2000 is the ED 95 The method of the present invention, wherein the number of cells per 10 or 10 is at least four times the number of cells per 10 or 10. [The present invention 1014] The effective dose of RP2000 is the ED 95 The method of any one of claims 10 to 10, wherein the number of cells per 100 cells is at least 5 times the number of cells per 100 cells. [The present invention 1015] The method of any one of claims 1011 to 1014, wherein the effective amount of RP2000 is about 0.48 mg / kg to about 2.00 mg / kg. [The present invention 1016] 1016. The method of any of claims 1011 to 1015, wherein said spontaneous recovery is further characterized by a twitch height of at least 95% of baseline in a human patient. [The present invention 1017] The method of any one of claims 1011 to 1016, wherein RP2000 is administered parenterally. [The present invention 1018] (a) RP2000 in an amount sufficient to relax or block skeletal muscle activity; (b) any instructions explaining how to administer the RP1000 drug to a human patient; and (c) optionally, an RP2000 antagonist effective to reverse the effects of RP2000 in humans, and instructions on how to use the antagonist to reverse the effects of the blocker in a human patient to which RP2000 has been administered. Includes a kit. [The present invention 1019] 4-(3-(((E)-4-(3-((1R)-6,7-dimethoxy-1-(4-methoxybenzyl)-2-methyl-1,2,3,4-tetrahydro-2-isoquinolin-2-ium-2-yl)propoxy)-4-oxobut-2-enoyl)oxy)propyl)-4-(3,4-dimethoxybenzyl)morpholin-4-ium dichloride formulated into a dosage form suitable for administration at a dose of about 0.08 mg / kg to about 0.60 mg / kg body weight. [The present invention 1020] A pharmaceutical composition comprising 4-(3-(((E)-4-(3-((1R)-6,7-dimethoxy-1-(4-methoxybenzyl)-2-methyl-1,2,3,4-tetrahydro-2-isoquinolin-2-ium-2-yl)propoxy)-4-oxobut-2-enoyl)oxy)propyl)-4-(3,4-dimethoxybenzyl)morpholin-4-ium or a pharmaceutically acceptable salt thereof, and water. [The present invention 1021] 1020. A pharmaceutical composition of the present invention comprising 4-(3-(((E)-4-(3-((1R)-6,7-dimethoxy-1-(4-methoxybenzyl)-2-methyl-1,2,3,4-tetrahydro-2-isoquinolin-2-ium-2-yl)propoxy)-4-oxobut-2-enoyl)oxy)propyl)-4-(3,4-dimethoxybenzyl)morpholin-4-ium dichloride. [The present invention 1022] 1022. The pharmaceutical composition of claim 1020 or 1021, further comprising a solvent selected from one or more of an alcohol, polyethylene glycol, and dimethyl sulfoxide. [The present invention 1023] The pharmaceutical composition of any one of 1020 to 1022, whose dosage form is suitable for parenteral administration. [The present invention 1024] administering an effective amount of RP1000 to an anesthetized human patient; and causing spontaneous recovery from paralysis or neuromuscular blockade (NMB) in the absence of an RP1000 antagonist, wherein the spontaneous recovery is characterized by a measured TOF ratio of at least about 0.90 in a human patient. 2. A method for inducing paralysis or NMB and recovery therefrom, comprising: [The present invention 1025] 1024. The method of claim 1024, wherein the anesthesia is an inhalation anesthesia. [The present invention 1026] The effective dose of RP1000 is at least ED 95 The method of the present invention 1024 or 1025. [The present invention 1027] The effective dose of RP1000 is the ED 95 6. The method of any one of claims 1024 to 1025, wherein the concentration is at least 1.5 times higher than that of the control. [The present invention 1028] The effective dose of RP1000 is the ED 95 8. The method of any one of claims 1024 to 1027, wherein the concentration is at least twice as high as that of the control. [The present invention 1029] The method of any one of claims 1024 to 1028, wherein the effective amount of RP1000 is about 0.08 mg / kg to about 0.2 mg / kg. [The present invention 1030] The method of any one of claims 1024 to 1028, wherein the effective amount of RP1000 is about 0.08 mg / kg to about 0.16 mg / kg. [The present invention 1031] The method of any one of claims 1024 to 1030, wherein said spontaneous recovery is achieved within about 50 minutes after cessation of administration of RP1000. [The present invention 1032] The method of any one of claims 1024 to 1030, wherein said spontaneous recovery is achieved within about 40 minutes after cessation of administration of RP1000. [The present invention 1033] The method of any one of claims 1024 to 1030, wherein said spontaneous recovery is achieved within about 30 minutes after cessation of administration of RP1000. [The present invention 1034] The method of any of claims 1024 to 1033, wherein the effective amount of RP1000 is sufficient to induce a twitch height of about 5% or less of baseline within 2 minutes after the start of administration. [This invention 1035] Any of the methods of claims 1024 to 1034, wherein an intermediate recovery period is characterized by a transition in the human patient from a twitch height of 25% of the baseline measurement to a twitch height of 75% of the baseline measurement, and the recovery period has a duration of about 25 minutes or less. [The present invention 1036] 1024. The method of claim 1024, wherein the anesthesia is IV anesthesia. [This invention 1037] The effective dose of RP1000 is the ED 95 1036. The method of claim 1036, wherein the concentration is at least twice as high as the concentration of the hydroxylase inhibitor. [The present invention 1038] The effective dose of RP1000 is the ED 95 1036 or 1037, wherein the method of claim 1036 is at least three times as long as the method of claim 1037. [This invention 1039] The effective dose of RP1000 is the ED 95 9. The method of any one of claims 1036 to 1038, wherein the concentration is at least four times higher than that of the control. [The present invention 1040] The method of any one of claims 1036 to 1039, wherein the effective amount of RP1000 is about 0.24 mg / kg to about 0.48 mg / kg. [The present invention 1041] 1041. The method of any of claims 1036 to 1040, wherein said spontaneous recovery is further characterized by a twitch height of at least 95% of baseline in a human patient. [The present invention 1042] The method of any one of claims 1036 to 1041, wherein the administration of RP1000 is carried out parenterally. [This invention 1043] (a) RP1000 in an amount sufficient to relax or block skeletal muscle activity; (b) any instructions explaining how to administer the RP1000 drug to a human patient; and (c) optionally, an RP1000 antagonist effective to reverse the effects of RP1000 in humans, and instructions on how to use the antagonist to reverse the effects of the blocker in a human patient to which RP1000 has been administered. Includes a kit. [This invention 1044] A pharmaceutical composition comprising (2S)-1-(3,4-dimethoxybenzyl)-2-(3-(((E)-4-(3-((1R,2S)-1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-2-ium-2-yl)propoxy)-4-oxobut-2-enoyl)oxy)propyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-2-ium or a pharmaceutically acceptable salt thereof, and water. [This invention 1045] 1044. A pharmaceutical composition of the present invention comprising (2S)-1-(3,4-dimethoxybenzyl)-2-(3-(((E)-4-(3-((1R,2S)-1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-2-ium-2-yl)propoxy)-4-oxobut-2-enoyl)oxy)propyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-2-ium dichloride. [The present invention 1046] The pharmaceutical composition of any one of claims 1044 to 1045, further comprising a solvent selected from one or more of alcohol, polyethylene glycol, and dimethyl sulfoxide. [This invention 1047] The pharmaceutical composition of any one of 1044 to 1046, whose dosage form is suitable for parenteral administration. [This invention 1048] (2S)-1-(3,4-dimethoxybenzyl)-2-(3-(((E)-4-(3-((1R,2S)-1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-2-ium-2-yl)propoxy)-4-oxobut-2-enoyl)oxy)propyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-2-ium dichloride formulated into a dosage form suitable for administration at a dose of about 0.04 mg / kg to about 0.2 mg / kg body weight. [This invention 1049] A pharmaceutical composition comprising (2S)-1-(3,4-dimethoxybenzyl)-2-(3-(((E)-4-(3-((1R,2S)-1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-2-ium-2-yl)propoxy)-4-oxobut-2-enoyl)oxy)propyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-2-ium or a pharmaceutically acceptable salt thereof, and water. [The present invention 1050] 1049. A pharmaceutical composition of the present invention comprising (2S)-1-(3,4-dimethoxybenzyl)-2-(3-(((E)-4-(3-((1R,2S)-1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-2-ium-2-yl)propoxy)-4-oxobut-2-enoyl)oxy)propyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-2-ium dichloride. [This invention 1051] The pharmaceutical composition of any one of claims 1049 to 1050, further comprising a solvent selected from one or more of alcohol, polyethylene glycol, and dimethyl sulfoxide. [This invention 1052] The pharmaceutical composition of any one of 1049 to 1051, whose dosage form is suitable for parenteral administration. [This invention 1053] A method of inducing paralysis or neuromuscular blockade (NMB) comprising administering to an anesthetized human patient an effective amount of RP2000. [This invention 1054] The method of claim 1052, further comprising recovering from the paralysis or NMB. [This invention 1055] 1053. The method of claim 1053, wherein said recovery is characterized by a TOF ratio measurement of at least about 0.90 in the human patient. [This invention 1056] A method of inducing paralysis or neuromuscular blockade (NMB) comprising administering to an anesthetized human patient an effective amount of RP1000. [This invention 1057] The method of claim 1056, further comprising recovering from the paralysis or NMB. [This invention 1058] 1057. The method of claim 1057, wherein said recovery is characterized by a TOF ratio measurement of at least about 0.90 in the human patient. [Brief explanation of the drawings]

[0010] [Figure 1] 1 is a graphical representation of twitch height versus recovery interval. [Figure 2] 1 is a graphical representation of twitch height versus recovery interval. [Figure 3] Figure 1 shows the recovery curves of CW002 in healthy adult volunteers under sevoflurane / N2O anesthesia. The curves represent spontaneous recovery from 5% T1 to 95% T1 of baseline T1 after a 100% block. From left to right: 0.08 mg / kg group (n = 2); 0.01 mg / kg group (n = 6); and 0.14 mg / kg group (n = 4). These doses are approximately 1.0, 1.4, and 1.8 times the ED95. The fourth curve on the right is a composite of all three dose groups (composite curve, n = 12). ANOVA comparing the 5-95% recovery interval revealed no significant differences between groups. [Figure 4]Linear regression of a combined group (n=12) is shown. Time to recovery of T1 from 5% to T1 of 25%, 50%, 75%, and 95% of baseline. This linear relationship is significant (P=0.002), suggesting that the time required for recovery from CW002-induced NMB can be predicted with considerable accuracy in humans. DETAILED DESCRIPTION OF THE INVENTION

[0011] Detailed Description Before describing the compositions and methods, it is to be understood that the scope of the disclosure is not limited to the particular processes, compositions, or methodologies described, as these may vary. It is also to be understood that the terminology used in the description is for the purpose of describing particular versions or embodiments only, and is not intended to limit the scope of the disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the various embodiments disclosed herein, the preferred methods, devices, and materials are described herein. All publications mentioned herein are incorporated by reference for the aspects identified as describing them. Nothing in this specification should be construed as an admission that the claims appended hereto are not entitled to antedate such disclosure by virtue of prior invention.

[0012] In a typical medical procedure, a patient may be administered various chemical agents to alleviate discomfort and / or prevent movement that would interfere with the medical procedure. The patient is first administered an anesthetic to induce anesthesia. As used herein, anesthesia refers to a controlled, temporary state of loss of sensation or consciousness induced for medical purposes (e.g., surgery) and may be maintained throughout the intra-anesthetic period by continuous or intermittent administration of an anesthetic agent.

[0013] Anesthesia can be administered by inhalation or intravenously. As used herein, unless otherwise indicated, inhalation anesthesia refers to anesthesia administered by breathing vapors from a volatile liquid or gaseous anesthetic into the patient's airways and trachea. Suitable inhalational agents include, but are not limited to, nitrous oxide (NO), desflurane, sevoflurane, isoflurane, methoxyflurane, halothane, and any combination thereof. Those skilled in the art will be familiar with inhalational anesthetics and their methods of use.

[0014] As used herein, intravenous anesthesia refers to the administration of a liquid anesthetic into one or more veins of a patient, unless otherwise indicated. Suitable intravenous anesthetics include, but are not limited to, propofol, etomidate, NMDA antagonists (e.g., ketamine), dexmedetomidine, barbiturates (e.g., thiopental, methohexital), synthetic opioids (e.g., remifentanil, sufentanil), benzodiazepines (e.g., midazolam, diazepam, lorazepam), and any combination thereof. Those skilled in the art will be familiar with IV anesthetics and their methods of use.

[0015] Once anesthetized, the patient may be administered an NMBA, if necessary, for example, to intubate the patient. NMBAs are usually administered intravenously or intramuscularly.

[0016] The administration of anesthetics and NMBAs each involves an onset period extending from the time the drug is first administered until the drug takes full effect. A medical procedure, such as surgery, can be performed during the perioperative period after the anesthetic and NMBA have taken full effect. After the medical procedure is completed, the administration of the NMBA and anesthetic can be discontinued, resulting in recovery therefrom. Similar to the onset period, the cessation of anesthetics and NMB drugs involves a recovery period extending from the time the anesthetic or NMB drug is first discontinued until the drug's effects are completely reversed. At this point of complete reversal, recovery is considered to have been achieved.

[0017] As used herein, recovery from NMB is considered to be achieved when a TOF ratio (TOFR) of at least about 0.90 is measured. For example, a TOFR of about 0.90 to 1.00 may be measured. Recovery may be achieved with or without the use or administration of an NMBA antagonist. As used herein, "spontaneous recovery" is considered to be achieved when a TOFR of at least about 0.90 is measured without the use or administration of an NMBA antagonist. Optionally, other indicators may be used to characterize recovery and / or spontaneous recovery, such as, but not limited to, a twitch height of at least 95% relative to baseline.

[0018] RP1000, also known as AV002 or CW002, is a non-depolarizing, intermediate duration NMBA, as shown below. TIFF0007748737000001.tif85128

[0019] Chemically, RP1000 is sometimes referred to by its IUPAC name: (2S)-1-(3,4-dimethoxybenzyl)-2-(3-(((E)-4-(3-((1R,2S)-1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-2-ium-2-yl)propoxy)-4-oxobut-2-enoyl)oxy)propyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-2-ium dichloride.

[0020] The terms "RP1000," "AV002," and "CW002" are used interchangeably herein and refer to the above structure identified herein as RP1000. While RP1000 shown above reflects the chloride salt form of RP1000, RP1000 as used herein can also include other pharmaceutically acceptable and effective salts thereof. RP1000 was previously disclosed in U.S. Pat. No. 8,148,398 and Prabhakar, et al. (Journal of Anesthesiology and Clinical Pharmacology, 2016 Jul-Sep; 32(3): 376-378), both of which are incorporated herein by reference for their disclosure of the RP1000 (or AV002) compound, its methods of preparation, its formulations, and methods of use. Preclinical studies using RP1000 have demonstrated 100% NMB within approximately 90 seconds of administration.

[0021] Another non-depolarizing NMBA is RP2000 (also known as CW 1759-50), which is a short-acting NMBA. TIFF0007748737000002.tif62128

[0022] Chemically, RP2000 may be referred to by its IUPAC name, 4-(3-(((E)-4-(3-((1R)-6,7-dimethoxy-1-(4-methoxybenzyl)-2-methyl-1,2,3,4-tetrahydro-2-isoquinolin-2-ium-2-yl)propoxy)-4-oxobut-2-enoyl)oxy)propyl)-4-(3,4-dimethoxybenzyl)morpholin-4-ium. The terms "CW 1759-50" and "RP2000" are used interchangeably herein and refer to the above structure identified herein as RP2000. The RP2000 shown above reflects the chloride salt form of RP2000, however, RP2000 as used herein can also include other pharmaceutically acceptable and effective salts thereof.

[0023] Disclosed herein is a method for inducing and effecting spontaneous recovery from NMB in a patient, comprising administering to the patient an effective amount of at least one of RP1000 or RP2000. This method can provide a highly predictable NMBA recovery period, both in terms of timing and extent of recovery. Using the methods disclosed herein, it is possible to predict and control NMB recovery in relation to one or more other relevant events, such as the end of the intraoperative period, the anesthetic recovery period, and / or the achievement of anesthetic recovery. Furthermore, a substantially linear correlation exists between the time after cessation of administration and various measurement points during the NMB recovery period (e.g., 5% twitch, 10% twitch, 25% twitch, 50% twitch, 75% twitch, 95% twitch (all relative to baseline)), allowing for accurate prediction of the extent of recovery. This property of RP1000 allows methods of inducing NMB during anesthesia to have the ability to minimize the time spent under NMB after surgery through accurate prediction of the recovery period. For example, NMB administration can be discontinued before the end of the perioperative period, with the understanding that the surgical procedure will be completed by the time the patient begins to recover from NMB blockade.

[0024] Thus, one aspect of the present disclosure provides a method for inducing NMB, comprising administering RP1000 to a human patient under inhalation anesthesia in an amount effective to maintain twitch height no more than about 5% above baseline measurements, thereby inducing NMB in the human patient; and discontinuing administration of RP1000 to the patient after a desired duration, thereby resulting in the patient's spontaneous recovery from NMB. An "effective amount" of a compound refers to a predetermined amount calculated to achieve a desired effect (e.g., degree of NMB as measured by twitch height). An "effective amount" of a compound for therapeutic use refers to the amount of compound in a formulation that, when administered (to a mammal, such as a human) as part of a desired dosing regimen, alleviates symptoms, improves a condition, or delays the onset of a pathology, according to clinically accepted standards for the disease / condition or cosmetic purpose being treated, e.g., with a reasonable benefit / risk ratio applicable to any medical procedure. Optionally, NMB can be induced during surgery and / or during anesthesia.

[0025] In various embodiments, RP1000 can be administered to a human patient in a single dose or multiple doses, each dose being equal to or greater than the ED 95 The RP1000 contains about 1.0 to about 3.0 times the amount of RP1000 (about 0.077 mg / kg). The dose may be administered as a single IV bolus dose, multiple IV bolus doses, or as a continuous IV infusion. The administration of a single bolus of RP1000 can be carried out over a period of about 5 to about 15 seconds. Administration in this manner can be continued as needed throughout the intraoperative procedure to maintain NMB (no more than about 5% twitches compared to baseline). Alternatively, RP1000 can be administered as a slow infusion over a period of about 1 to about 2 minutes, or as a slow continuous infusion, for example, throughout at least a portion of the intraoperative period.

[0026] Specific dosages include, but are not limited to, about 0.08 mg (cation-based) to about 0.25 mg / kg of RP1000 per kg of body weight. Other contemplated dosage ranges include about 0.8 mg / kg to about 0.15 mg / kg, about 0.10 mg / kg to about 0.20 mg / kg, about 0.15 mg / kg to about 0.25 mg / kg, or about 0.10 mg / kg to about 0.25 mg / kg of RP1000. Specific dosages include, but are not limited to, any dose therebetween, such as 0.8 mg / kg, 0.1 mg / kg, 0.16 mg / kg, 0.2 mg / kg, 0.24 mg / kg, and 0.3 mg / kg of RP1000. The patient may be under inhalation anesthesia, such as nitrous oxide, desflurane, sevoflurane, isoflurane, methoxyflurane, or any combination thereof. The dose of anesthesia can be any desired dose, for example, 0.5 MAC, 0.75 MAC, 1.0 MAC, 1.25 MAC, or more. Higher doses of anesthesia will result in a deeper state of anesthesia and therefore a longer, but still predictable, recovery.

[0027] Furthermore, in one or more embodiments, a twitch height 25% above baseline can be measured in a patient within about 14 minutes, 11 minutes, or 8 minutes after cessation of administration of RP1000. In one or more embodiments, a twitch height 50% above baseline can be measured in a patient within about 28 minutes, about 22 minutes, or about 17 minutes after cessation of administration of RP1000. In one or more embodiments, a twitch height 75% above baseline can be measured in a patient within about 42 minutes, about 33 minutes, or 25 minutes after cessation of administration of RP1000. In various embodiments, the patient is under inhalation anesthesia at a concentration of about 1.5 MAC or less. In various embodiments, the patient is under inhalation anesthesia at a concentration of about 1.0 MAC or less.

[0028] RP1000 has a relatively fast onset period, providing an additional opportunity to minimize the time the patient is under NMB. Thus, optionally and additionally, administration of RP1000 to a patient during anesthesia can result in a twitch height measurement in the patient that is no more than about 5% above the baseline measurement within about 2 minutes, and more preferably within about 90 seconds, after administration begins.

[0029] The methods described herein include causing spontaneous recovery from NMB without the use of NMBA antagonists or reversals. In one or more embodiments, spontaneous recovery is achieved within about 50 minutes after cessation of administration of RP1000. More preferably, spontaneous recovery is achieved within about 40 minutes, about 30 minutes, or about 25 minutes. Additional measurements, such as measuring twitch height at least 95% of baseline, can supplement TOFR measurements.

[0030] RP2000 may also be used as an NMBA. Accordingly, another aspect of the present disclosure provides a method of inducing NMB, comprising administering RP2000 to a human patient under inhalation anesthesia in an amount effective to maintain a twitch height no more than about 5% above a baseline measurement, thereby inducing NMB in the human patient; and, after a desired duration, discontinuing administration of RP2000 to the patient, thereby resulting in spontaneous recovery of the patient from NMB. Optionally, NMB can be induced during surgery and / or during anesthesia.

[0031] In various embodiments, RP2000 can be administered to a human patient in a single dose or multiple doses, each dose being equal to or greater than the ED2000 for humans. 95The RP1000 contains RP2000 in an amount of about 1.0 to about 3.0 times the normal dose (about 0.077 mg / kg). The dose may be administered by multiple IV bolus doses or as a continuous IV infusion. A single bolus of RP1000 can be administered over a period of about 5 to about 15 seconds. Administration in this manner can be continued as needed throughout the intraoperative procedure to maintain NMB (no more than about 5% twitching compared to baseline). Alternatively, RP1000 can be administered as a slow infusion over a period of about 1 to about 2 minutes, or as a slow continuous infusion, for example, throughout at least a portion of the intraoperative period.

[0032] Because RP2000 has a shorter duration of action than RP1000, an appropriate dosage of RP2000 would be about two to three times higher than that of RP1000. For example, suitable dosages of RP2000 include, but are not limited to, about 0.16 mg (cation-based) to about 0.60 mg / kg of RP2000 administered to a patient. Other contemplated dosage ranges include about 0.16 mg / kg to about 0.60 mg / kg, about 0.16 mg / kg to about 0.50 mg / kg, about 0.16 mg / kg to about 0.40 mg / kg, or about 0.24 mg / kg to about 0.45 mg / kg of RP2000. Specific dosages include, but are not limited to, any dose therebetween, such as about 0.16 mg / kg, about 0.24 mg / kg, about 0.32 mg / kg, about 0.40 mg / kg, and about 0.50 mg / kg of RP2000. The patient may be under any of the types of inhalation anesthesia described above.

[0033] Like RP1000, RP2000 has a relatively fast onset period, providing an additional opportunity to minimize the time the patient is under NMB. Thus, optionally and additionally, administration of RP1000 to a patient during anesthesia can result in a twitch height measurement in the patient that is no more than about 5% above the baseline measurement within about 2 minutes, and more preferably within about 90 seconds, after initiation of administration.

[0034] In one or more embodiments, spontaneous recovery is achieved about 25% faster with RP2000 than with RP1000. For example, in various embodiments, spontaneous recovery can be achieved within about 17 minutes after cessation of administration of RP2000. More preferably, spontaneous recovery is achieved within about 12 minutes, within about 10 minutes, or within about 7 minutes.

[0035] Predictable spontaneous recovery from NMB represents a significant advantage over current methods of reversing NMB using NMBA antagonists, which tend to be unpredictable and difficult to control. By inducing NMB with RP1000 or RP2000, the duration of NMB and the point at which infusion can be discontinued precisely dictate the timing of spontaneous recovery. This method avoids the administration of NMBA antagonists entirely and also shortens the time spent under NMB after surgery.

[0036] RP1000 has also been proven safe. Whenever an NMBA is used, there is a possibility that important autonomic functions, such as breathing, may be blocked. In animal models (e.g., monkeys and cats), no adverse effects on the autonomic nervous system or cardiovascular system were observed (see, e.g., Sunaga, et al. (Preclinical Pharmacology of RP1000: A Nondepolarizing Neuromuscular Blocking Drug of Intermediate Duration, Degraded and Antagonized by l-cysteine ​​- Additional Studies of Safety and Efficacy in the Anesthetized Rhesus Monkey and Cat; Anesthesiology, 2016 Oct; 125(4); 732-743; incorporated herein by reference). In dogs, very high doses of RP1000 (27 and 54 × ED 95) alone produced a 20% reduction in mean arterial pressure and a 20% increase in heart rate. Furthermore, RP1000 demonstrated low bronchoconstrictor or histamine release potential.

[0037] As mentioned above, spontaneous recovery from NMB using RP1000 and RP2000 under inhalation anesthesia is quite predictable across a wide range of doses. However, it has been observed that inhalation anesthesia, such as sevoflurane, may enhance NMB (see, e.g., Ye, L., et al.; Int. J. Physicol. Pathophysiol Pharmacol; 2015 7(4), 172-177). Therefore, clinical implications suggest that lower doses of NMBAs may be used in patients undergoing inhalation anesthesia compared with the dose required for the same level of NMB under intravenous anesthesia, such as propofol. For example, a dose of approximately 0.08 mg / kg to approximately 0.25 mg / kg of RP1000 (or approximately 0.08 mg / kg to approximately 0.20 mg / kg) can be used in patients under inhalation anesthesia, whereas the same patient under IV anesthesia may require a dose of approximately 0.2 mg / kg to approximately 0.5 mg / kg to achieve the same NMB effect.

[0038] Accordingly, another aspect of the present disclosure provides a method of inducing NMB, comprising administering RP1000 to a human patient under IV anesthesia in an amount effective to maintain a twitch height no more than about 5% above a baseline measurement, thereby inducing NMB in the human patient; and discontinuing administration of RP1000 to the patient after a desired duration, thereby resulting in spontaneous recovery of the patient from NMB. Optionally, NMB can be induced during surgery and / or during anesthesia.

[0039] In various embodiments, RP1000 has an ED 95RP1000 can be administered to human patients in an amount of about 3.0 to about 6.0 times the amount of RP1000 administered. This amount can be administered as a single IV bolus dose, multiple IV bolus doses, or as a continuous IV infusion. A single bolus of RP1000 can be administered over a period of about 5 to about 15 seconds. Administration in this manner can be continued as needed (e.g., throughout the entire intraoperative procedure) to maintain NMB (no more than about 5% twitching compared to baseline). Alternatively, RP1000 can be administered as a slow infusion over a period of about 1 to about 2 minutes, or as a slow continuous infusion (e.g., for at least a portion of the intraoperative period).

[0040] Specific dosages include, but are not limited to, about 0.24 mg (cation-based) to about 0.48 mg / kg of RP1000 per kg of body weight. Other contemplated dosage ranges include about 0.24 mg / kg to about 0.40 mg / kg, about 0.24 mg / kg to about 0.32 mg / kg, about 0.32 mg / kg to about 0.40 mg / kg, or about 0.32 mg / kg to about 0.48 mg / kg of RP1000. Specific dosages include, but are not limited to, any dose therebetween, such as about 0.24 mg / kg, about 0.30 mg / kg, about 0.32 mg / kg, about 0.35 mg / kg, about 0.40 mg / kg, about 0.45 mg / kg, and about 0.48 mg / kg of RP1000. The patient may be under IV anesthesia with, for example, propofol, etomidate, ketamine, barbiturates (eg, thiopental and methohexital), or any combination thereof.

[0041] In one or more embodiments, spontaneous recovery is achieved about 25% faster under IV anesthesia than under inhalation anesthesia. For example, spontaneous recovery can be achieved within about 38 minutes after cessation of administration of RP1000. More preferably, spontaneous recovery is achieved within about 30 minutes, within about 25 minutes, within about 22.5 minutes, or within about 20 minutes.

[0042] RP2000 can also be utilized to induce NMB during IV anesthesia. Accordingly, another aspect of the present disclosure provides a method of inducing NMB, comprising administering RP2000 to a human patient under IV anesthesia in an amount effective to maintain a twitch height no more than about 5% above a baseline measurement, thereby inducing NMB in the human patient; and discontinuing administration of RP2000 to the patient after a desired duration, thereby resulting in spontaneous recovery of the patient from NMB. Optionally, NMB can be induced during surgery and / or during anesthesia.

[0043] In various embodiments, RP2000 has an ED 95 RP2000 can be administered to human patients in amounts of about 3.0 to about 6.0 times the amount of RP2000 administered. This amount may be administered as a single IV bolus dose, multiple IV bolus doses, or as a continuous IV infusion. The bolus administration of RP2000 can be performed over a period of about 5 to about 15 seconds, or as a slow infusion over a period of about 1 to about 2 minutes. Administration in this manner can be continued as needed throughout the entire intraoperative procedure to maintain NMB (no more than about 5% twitching compared to baseline). Suitable doses include administering to patients about 0.48 mg (cation-based) to about 3.6 mg / kg of RP2000 per kg of body weight. Other contemplated dosage ranges include about 0.48 mg / kg to about 3.0 mg / kg, about 0.48 mg / kg to about 2.4 mg / kg, about 0.48 mg / kg to about 1.8 mg / kg, about 0.48 mg / kg to about 1.0 mg / kg, about 0.64 mg / kg to about 3.0 mg / kg, about 0.80 mg / kg to about 3.0 mg / kg, about 0.96 mg / kg to about 1.8 mg / kg, and about 0.96 mg / kg to about 2.4 mg / kg of RP2000. Specific dosages include, but are not limited to, any dose therebetween, such as 0.64 mg / kg, 0.80 mg / kg, 0.96 mg / kg, 1.80 mg / kg, 2.4 mg / kg, 3.0 mg / kg, and 3.60 mg / kg of RP1000. Patients may be under IV anesthesia as described above.

[0044] In one or more embodiments, spontaneous recovery is achieved about 25% faster with RP2000 than with RP1000. For example, spontaneous recovery can be achieved within about 15 minutes after cessation of administration of RP2000. More preferably, spontaneous recovery is achieved within about 10 minutes, within about 7.5 minutes, or within about 5 minutes.

[0045] Without wishing to be bound by theory, it is believed that the predictability of spontaneous recovery from NMBAs can be derived from their metabolism in the human body, for example, by glutathione, which is readily available in the human body. This is unique to RP1000 and RP2000; other NMBAs undergo more complex degradation, which does not result in a predictable timetable for spontaneous recovery. Comparative metabolic studies have demonstrated that glutathione metabolic patterns may be unique to humans compared to other species, such as primates; therefore, data demonstrating that predictability of spontaneous recovery can be achieved in humans after administration of RP1000 was particularly encouraging. Furthermore, careful consideration is usually required when administering NMBAs to patients with disease conditions that may affect the degree of NMB and the breakdown of NMBAs in the body. Because RP1000 and RP1000 and RP2000 rely solely on glutathione for predictable breakdown, these agents can be used in a wide variety of populations, even in people with disease states or conditions that make the use of other NMBAs difficult.

[0046] Predicting spontaneous recovery from RP1000- and RP2000-induced NMB is provided by the methods disclosed herein, and advantageously, each of RP1000 and RP2000 is particularly responsive to its respective antagonists. Reversal drugs for RP1000 and RP2000 have been developed, which have been shown to inhibit ED 95Even at doses three times higher than the RP1000 dose, NMB caused by RP1000 can be effectively eliminated within minutes. Therefore, if a patient needs immediate recovery from NMB induced by RP1000 or RP2000 and the timing of natural recovery is inappropriate, an NMB antagonist can be administered to rapidly reverse NMB. Such agents include, but are not limited to, cysteine, glutathione, N-acetylcysteine, homocysteine, methionine, S-adenosyl-methionine, penicillamine, related cysteine ​​analogs, combinations thereof, or pharmaceutically acceptable salts thereof. The use of such antagonists is also disclosed in U.S. Patent No. 8,148,398, the disclosure of which is incorporated herein by reference. In some embodiments, the antagonist is cysteine. In other embodiments, the antagonist is cysteine ​​in combination with glutathione. In other embodiments, the antagonist is cysteine ​​or glutathione in combination with any of the other antagonists. For example, in some embodiments, a combination of cysteine ​​and glutathione is particularly effective.

[0047] RP1000 can be administered to a patient as a composition comprising RP1000. Similarly, RP2000 can be administered as a composition comprising RP2000. Compositions suitable for the methods disclosed herein include RP1000 or RP2000 and can be aqueous or non-aqueous solutions or mixtures, which can include bacteriostatic agents (e.g., benzyl alcohol), antioxidants, buffers, or other pharmaceutically acceptable additives (e.g., dextrose). The compositions can also include solvents such as alcohol, polyethylene glycol, dimethyl sulfoxide, or any mixture thereof.

[0048] RP1000 or RP2000 compositions can be administered to human patients under inhalation anesthesia in dosages such as those described above. For example, an appropriate amount of RP1000 to achieve NMB in an adult (150 lbs or 70 kg) is about 0.1 mg to about 14 mg, or in some embodiments, about 1 mg to about 14 mg, or in other embodiments, about 0.5 mg to about 14 mg, or in further embodiments, about 3.5 mg to about 14 mg. For heavier human patients, the dosage would be higher, e.g., up to about 18 mg for a 200 lb (90 kg) patient and up to about 23 mg for a 250 lb (114 kg) patient. Thus, a pharmaceutical parenteral formulation suitable for human administration may contain from about 0.1 mg / mL to about 50 mg / mL of RP1000 in solution, or multiples thereof in the case of multidose vials. Similar calculations can be made for the administration of RP2000, based on the above disclosure.

[0049] Another aspect of the present disclosure provides kits comprising, separately packaged, (a) RP1000 or RP2000 in an amount sufficient to relax or block skeletal muscle activity, and (b) instructions describing how to administer the RP1000 or RP2000 agent to a human patient. Optionally, the kit can further comprise (c) an RP1000 or RP2000 antagonist in an amount effective to reverse the effects of RP1000 or RP2000, respectively, in a human, and (d) instructions on how to use the antagonist to reverse the effects of the blocker in a human patient to which RP1000 or RP2000 has been administered. In such kits, RP1000 or RP2000 is provided in an aqueous or non-aqueous solution or mixture, which may contain a bacteriostatic agent (e.g., benzyl alcohol), an antioxidant, a buffer, or other pharmaceutically acceptable additives (e.g., dextrose). The composition may contain a solvent such as alcohol, polyethylene glycol, dimethyl sulfoxide, or any mixture thereof. Alternatively, RP1000 or RP2000 may be presented in the form of a lyophilized solid, optionally containing other solid components, for reconstitution with water (for injection) or dextrose solution or saline. Such preparations are usually presented in unit-dose forms such as ampoules or disposable syringes. They may also be presented in multi-dose forms, such as bottles from which appropriate amounts can be taken. All such preparations must be sterile.

[0050] Another aspect of the present invention includes a method for predicting spontaneous recovery in a patient receiving an NMBA, the method comprising the steps of subjecting the patient to TOF monitoring, thereby generating electronic data including twitch height measurements; transmitting the data to a data processing device programmed to compare the twitch height measurements with baseline measurements; initiating a predictive calculation at a first time, defined as the time at which a twitch height measurement greater than 5% of the baseline measurement is collected; and generating a predicted spontaneous recovery time for the patient's NMB by inputting that time into a pre-programmed formula based on the spontaneous recovery time described herein.

[0051] For example, for a patient under inhalation anesthesia receiving RP1000 at a dose of about 0.08 to about 0.14 mg / kg, the time to a specific twitch height above baseline can be calculated by Equation (1) based on the data in Figure 4, where T 回復 is the time to a specific twitch height (min), and H t is the specific twitch height. TIFF0007748737000003.tif7128

[0052] The predicted recovery time can then inform what actions should be taken regarding anesthesia administration and intraoperative duration to ensure the desired maintenance of NMB. For example, this calculation can alert if further NMBA administration is required within the intraoperative period or inform when anesthesia can be discontinued (as recovery from NMB must be achieved before recovery from anesthesia).

[0053] Equation 1 above relates to the use of RP1000 under inhalational anesthesia, however similar calculations can be made for RP1000 under IV anesthesia, as well as RP2000 under either type of anesthesia.

[0054] Various tests for measuring NMB are disclosed herein and described in further detail below.

[0055] Twitch height: A peripheral nerve stimulator was used for neuromuscular monitoring, applying a supramaximal stimulus to the ulnar nerve at the wrist via surface electrodes. After induction of anesthesia, twitch stimulation (0.10 Hz) was applied continuously for 15–20 min to establish a baseline twitch height. Twitch monitoring could continue during and after administration of NMBAs.

[0056] Train-of-Four twitch stimulation pattern ratio (TOFR): TOF delivers four supramaximal electrical impulses involving four equal-intensity twitches of the stimulated muscle. Twitch fade occurs when neuromuscular blockade increases. Comparing the fourth twitch (T4) to the first twitch (T1) yields the TOFR.

[0057] Whenever a numerical range with a lower and upper limit is disclosed, any numerical value falling within that range and any range encompassed therein is specifically disclosed. In particular, any numerical range disclosed herein (e.g., a range in the form of "about a to about b," or, equivalently, "about a to b," or, equivalently, "about a to b") should be understood to specify any numerical value or range encompassed within the broader range. It should also be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. As used herein, the term "about" means plus or minus 10% of the numerical value with which it is used. Thus, about 50% means within a range of 45% to 55%.

[0058] One or more exemplary embodiments are presented herein. For clarity, not all features of a physical implementation are described or shown in this application. It is understood that the development of physical embodiments of the present disclosure involves numerous implementation-specific decisions to achieve the developer's goals, which may vary from implementation to implementation, such as compliance with system-related, business-related, government-related, and other constraints. While the developer's efforts may be time-consuming, such efforts would nevertheless be routine for one of ordinary skill in the art having the benefit of this disclosure.

[0059] Thus, the present disclosure is well adapted to achieve the ends and advantages mentioned, as well as those inherent therein. The specific embodiments disclosed above are merely exemplary, as the disclosure may be modified and practiced in different but equivalent manners apparent to those skilled in the art having the benefit of the teachings herein. Moreover, no limitations are intended to the details of construction or design herein shown, other than as described in the following claims. It is therefore evident that the specific exemplary embodiments disclosed above may be altered, combined, or modified, and all such variations are considered within the scope and spirit of the present disclosure. The embodiments illustratively disclosed herein may suitably be practiced in the absence of elements not specifically disclosed herein and / or optional elements disclosed herein. [Example]

[0060] Example 1: Preclinical study results in rhesus monkeys A bolus dose of either RP2000 or RP1000 was administered to isoflurane-anesthetized rhesus monkeys to measure the ED1000 of the administered compound in rhesus monkeys. 95 The dose was 1 to 10 times the ED 95, RP1000 = 0.040 mg / kg; ED 95, RP2000 = 0.053 mg / kg). Twitch (0.15 Hz) and TOF (2 Hz × 2 s) were recorded throughout the 6–10 h experiment. The time to spontaneous recovery after bolus administration, characterized by recovery of twitches from 5% to 95% of baseline, was measured.

[0061] Separately, continuous infusions were administered (in separate subjects) for periods ranging from 20 to 180 minutes, and the time to spontaneous recovery of NMB, characterized by the return of twitches from 5% to 95% of baseline, after cessation of the infusion was measured. Table 1 below shows the data collected from these experiments. Figures 1 and 2 present the data graphically. TIFF0007748737000004.tif55146

[0062] Details of this experiment can be found in the abstract for poster number F1004 at the Annual Meeting of Anesthesiology in October 2019, the contents of which are incorporated herein by reference.

[0063] Example 2: Phase I Clinical Trial Results in Humans The abstract is available in the final supplement to the Journal of Anesthesia and Analgesia, May 2020 (Vol. 30, No. 5, pp. 73-74) and is incorporated herein by reference. Healthy male and female volunteers (n=34), aged 18-55 years, provided informed consent to an IRB-approved Phase I protocol. NMB was measured by mechanomyography during sevoflurane (0.5 MAC) / NO (70%) anesthesia. Each volunteer received a single IV bolus of RP1000.

[0064] Table 3 below provides various pharmacokinetic data for each dose tested. TIFF0007748737000005.tif100146AUC = area under the plasma concentration-time curve; CL = clearance; C max = maximum plasma concentration; SD = standard deviation; t 1 / 2 = terminal elimination half-life; T max =C max Time when V occurs ss = volume at steady state

[0065] Injection of RP1000 showed a rapid onset of action and a moderate duration of NMB effect. ED of 0.08 mg / kg 95 Doses were established under sevoflurane anesthesia, with the 0.14 mg / kg dose producing 100% twitch inhibition in all subjects. At doses less than 0.08 mg / kg, 100% twitch inhibition (n = 18) did not occur in any of the volunteers. However, 12 of 14 volunteers receiving doses of 0.08, 0.10, or 0.14 mg / kg developed 100% block: (n = 2 of 6 for 0.08 mg / kg, 6 of 6 for 0.10 mg / kg, and 4 of 4 for 0.14 mg / kg). 95At these doses, 95% T1 suppression was achieved in approximately 2 to 3 minutes, and maximum T1 suppression was achieved in approximately 3 to 5 minutes.

[0066] In all volunteers, TOF stimulation was applied to the ulnar nerve every 20 seconds during spontaneous recovery from 100% block; thumb responses were continuously monitored until TOF T1 recovered to 95% of baseline and TOFR reached 0.90. The total duration of block was calculated from injection until T1 recovered to 95% of baseline and TOFR reached 0.90. The 5-95% recovery interval during recovery from 100% block was measured. After data acquisition for all treatment groups was completed, the 5-95% recovery times obtained after administration of 0.08, 0.10, and 0.14 mg / kg were compared by ANOVA. Recovery data from the 12 volunteers who experienced 100% block were then combined to demonstrate a single composite recovery pattern. ANOVA was again performed to compare the composite recovery data (5-95% interval) with the corresponding intervals for the separate 0.08, 0.10, and 0.14 mg / kg treatment groups.

[0067] When spontaneous recovery was allowed, the mean time to 95% T1 recovery was approximately 45, 55, and 60 minutes for the 0.08 mg / kg, 0.10 mg / kg, and 0.14 mg / kg doses, respectively. The time to maximum T1 recovery was approximately 50 minutes for the 0.08 mg / kg dose and approximately 20 minutes longer (approximately 70 minutes) for the 0.10 mg / kg and 0.14 mg / kg doses. The mean time to T4:T1 > 0.9 was approximately 50, 70, and 80 minutes for the 0.08 mg / kg, 0.10 mg / kg, and 0.14 mg / kg doses, respectively. The mean time to 5% to 95% T1 recovery was similar (35-40 minutes) for the 0.1 mg / kg and 0.145 mg / kg doses, as shown in Table 2 below.

[0068] [Table 2]

[0069] Next, the recovery data for the 12 mixed group subjects were analyzed by linear regression. The regression included data from 5% to 95% recovery time. The slope of the mixed regression line was calculated. The results are summarized in Figures 3 and 4. Figure 3 shows the apparent parallelism of all recovery curves for the 0.08, 0.10, and 0.14 mg / kg groups and the mixed group. Both comparisons using duplicated ANOVAs showed no significant differences between the 0.08, 0.10, and 0.14 mg / kg groups; when the mixed group comparison was added, the differences remained nonsignificant: P = 0.58 and P = 0.76, respectively. Figure 4 shows the regression of the mixed recovery line from 5% twitch height to 25, 50, 75, and 95% twitch height against time for the 12 subjects who experienced 100% twitch block. This relationship is significant (P = 0.002). The slope of this line is 2.518.

[0070] ED of RP1000 under sevoflurane 95 Based on extrapolation and indirect comparisons from published human data comparing RP1000 (0.07 mg / kg-0.08 mg / kg) with other commercially available NMBAs, RP1000 is expected to have approximately two-thirds the potency of cisatracurium and four times the potency of rocuronium under volatile anesthesia. Furthermore, utilizing the same multiple comparisons, the duration of NMB is expected to be approximately 80%-85% of that of cisatracurium and approximately 60%-70% of that of rocuronium. Based on data from previously completed first-in-human trials and ED 95 Based on animal data regarding the onset of block at twice the dose, we found that the onset with RP1000 was faster than that achieved with cisatracurium but slightly slower than that of rocuronium.

[0071] Safety: In humans, administration of RP1000 at doses up to 0.14 mg / kg did not produce significant cardiopulmonary side effects or signs of histamine release. In general, doses of RP1000 ranging from 0.02 mg / kg to 0.14 mg / kg were generally well tolerated among healthy volunteers enrolled in this study.

[0072] Example 3: Metabolism of RP1000 and RP2000 Consistent with the observation of predictable recovery times, pharmacokinetic measurements revealed that elimination half-lives across this dose range were also consistent across all dose groups, at approximately 25-26 minutes.

[0073] Without wishing to be bound by theory, it is believed that the highly reproducible half-life is due to the degradation of RP1000 by cysteine ​​addition (e.g., by reaction with glutathione). Benefits of understanding the pharmacodynamics of RP1000 include, but are not limited to, the ability to easily predict the level of functional recovery in human patients. Furthermore, without wishing to be bound by theory, it is believed that RP2000 is degraded in the body via a pathway similar to that of RP1000, and therefore may be associated with a reduced risk of ED. 95 It is anticipated that spontaneous recovery in patients under inhalation anesthesia following administration of RP2000 at doses up to 2.5-3 times the normal dose will also be highly predictable, as the elimination half-life in this dose range depends on its degradation pathway. Accordingly, the present disclosure reflects this expectation.

[0074] Example 4 Healthy volunteers receive an infusion of up to 0.24 mg / kg of RP1000 administered IV over 10 minutes while the patient is under inhalation anesthesia, IV anesthesia, or a combination thereof. Doses may include 0.8 mg / kg, 0.10 mg / kg, 0.12 mg / kg, 0.14 mg / kg, 0.16 mg / kg, 0.18 mg / kg, 0.2 mg / kg, 0.22 mg / kg, or 0.24 mg / kg. The volume of distribution of the central compartment (V c ) and the rate constant (k eo ) is determined for each dose.

[0075] Example 5 Healthy volunteers receive a single IV bolus of RP1000 or two single boluses of RP1000. The bolus dose can be 0.02 mg / kg, 0.4 mg / kg, 0.8 mg / kg, 0.10 mg / kg, 0.14 mg / kg, 0.16 mg / kg, 0.18 mg / kg, or 0.2 mg / kg while the patient is under inhalation anesthesia, IV anesthesia, or a combination thereof. Doses can include 0.8 mg / kg, 0.10 mg / kg, 0.12 mg / kg, 0.14 mg / kg, 0.16 mg / kg, 0.18 mg / kg, 0.2 mg / kg, 0.22 mg / kg, or 0.24 mg / kg.

Claims

1. 1. A pharmaceutical composition for use in a method for inducing paralysis or neuromuscular blockade (NMB) and recovery therefrom, comprising a compound selected from RP2000 or RP1000, The method includes administering to an anesthetized human patient an effective amount of the compound; the effective amount of the compound RP2000 is 0.16 mg / kg to 0.60 mg / kg; the effective amount of the compound RP1000 is 0.15 mg / kg to 0.48 mg / kg; RP2000 is 4-(3-(((E)-4-(3-((1R)-6,7-dimethoxy-1-(4-methoxybenzyl)-2-methyl-1,2,3,4-tetrahydro-2-isoquinolin-2-ium-2-yl)propoxy)-4-oxobut-2-enoyl)oxy)propyl)-4-(3,4-dimethoxybenzyl)morpholin-4-ium, or a pharmaceutically acceptable salt thereof; RP1000 is (2S)-1-(3,4-dimethoxybenzyl)-2-(3-(((E)-4-(3-((1R,2S)-1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-2-ium-2-yl)propoxy)-4-oxobut-2-enoyl)oxy)propyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-2-ium, or a pharmaceutically acceptable salt thereof; recovery is brought about by cessation of administration of the compound and is characterized by a train of four (TOF) ratio measurement of at least about 0.90 in the human patient. Pharmaceutical compositions.

2. the compound is RP2000, and the method comprises: administering an effective amount of RP2000 to an anesthetized human patient; and causing spontaneous recovery from paralysis or neuromuscular blockade (NMB) in the absence of an RP2000 antagonist, wherein the spontaneous recovery is characterized by a measured TOF ratio of at least about 0.90 in a human patient. Inducing paralysis or NMB and recovery therefrom, 10. The pharmaceutical composition of claim 1.

3. 3. The pharmaceutical composition of claim 2, wherein the anesthesia is an inhalation anesthesia.

4. 3. The pharmaceutical composition of claim 2, wherein the anesthesia is IV anesthesia.

5. 5. The pharmaceutical composition of claim 4, wherein the effective amount of RP2000 is 0.48 mg / kg to 0.60 mg / kg.

6. the compound is RP1000, and the method comprises: administering an effective amount of RP1000 to an anesthetized human patient; and causing spontaneous recovery from paralysis or neuromuscular blockade (NMB) in the absence of an RP1000 antagonist, wherein the spontaneous recovery is characterized by a measured TOF ratio of at least about 0.90 in a human patient. Inducing paralysis or NMB and recovery therefrom, 10. The pharmaceutical composition of claim 1.

7. 7. The pharmaceutical composition of claim 6, wherein the anesthesia is an inhalation anesthesia.

8. 8. The pharmaceutical composition according to claim 6 or 7, wherein the effective amount of RP1000 is 0.24 mg / kg to 0.40 mg / kg.

9. 7. The pharmaceutical composition of claim 6, wherein the anesthesia is IV anesthesia.

10. (a) a compound in an amount sufficient to relax or block the activity of skeletal muscle; (b) any instructions explaining how to administer the compound to a human patient; and (c) optionally, an antagonist to the compound effective to reverse the effect of the compound in humans, and instructions on how to use the antagonist to reverse the effect of the blocker in a human patient to which the compound has been administered.

1. A kit for use in a method for inducing paralysis or neuromuscular blockade (NMB), comprising: the compound is selected from RP2000 or RP1000; the amount of compound RP2000 is 0.16 mg / kg to 0.60 mg / kg; the amount of compound RP1000 is 0.15 mg / kg to 0.48 mg / kg; RP2000 is 4-(3-(((E)-4-(3-((1R)-6,7-dimethoxy-1-(4-methoxybenzyl)-2-methyl-1,2,3,4-tetrahydro-2-isoquinolin-2-ium-2-yl)propoxy)-4-oxobut-2-enoyl)oxy)propyl)-4-(3,4-dimethoxybenzyl)morpholin-4-ium, or a pharmaceutically acceptable salt thereof; RP1000 is (2S)-1-(3,4-dimethoxybenzyl)-2-(3-(((E)-4-(3-((1R,2S)-1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-2-ium-2-yl)propoxy)-4-oxobut-2-enoyl)oxy)propyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-2-ium, or a pharmaceutically acceptable salt thereof; The kit.

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