Methods for controlling and predicting recovery after nmba administration

Abstract

To provide methods of inducing paralysis or neuromuscular blockade (NMB) and recovery therefrom.SOLUTION: The methods comprise administering an effective amount of at least RP1000 or RP2000 to a human patient under anesthesia.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 093,179, filed on October 17, 2020, which is hereby incorporated by reference in its entirety.

[0002] Technical Field The present disclosure relates to neuromuscular blocking agents (NMBAs), and more specifically, to methods for predicting and controlling the natural recovery of a patient after administration of an NMBA to the patient.

Background Art

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

[0004] The most commonly used neuromuscular detection method is the measurement of TOF by electrical stimulation. In TOF, usually, four short (100 - 300 μs) current pulses (generally less than 70 mA) at 2 Hz, repeated every 10 - 20 seconds as electrical stimulation, are used. The resulting single twitches are measured and quantified for electromyogram response, force, acceleration, deflection, or another means. The first (T1 single twitch) and the last (T4 single twitch) are compared, and the level of NMB is estimated from these two ratios (TOFR). A series of stimuli are spaced 10 seconds or more apart (generally 20 seconds is used to provide a safety margin) to give a rest period for complete recovery of the steady state; if the stimuli are made faster, the evoked response becomes smaller. Other methods for monitoring the degree of NMB include single twitch (ST) measurement, double burst stimulation (DBS), and post-tetanic count (PTC).

[0005] However, even with careful monitoring, the use of NMBA (especially those characterized as long-acting) still frequently causes residual paralytic effects (postoperative residual curarization: PORC) during the postoperative period because the administered paralytic agent is incompletely converted to its inactive form at the neuromuscular junction. The safety of NMBA has been thoroughly scrutinized, debated, and is of utmost importance. Incomplete recovery (residual block) from NMBA after anesthesia and surgery remains a common problem in the post-anesthesia care unit and poses a threat to patient safety. The adverse effects of residual block include, but are not limited to, airway obstruction, hypoxic episodes, postoperative respiratory complications, intraoperative awareness, and unpleasant symptoms of muscle weakness.

[0006] Reversal of NMB can be achieved with a reversal agent, but the most common NMBA reversal agent, acetylcholinesterase inhibitor (AChEI), only antagonizes the paralytic agent. It does not accelerate the metabolism of NMBA. Therefore, even when using an NMBA reversal agent, residual curarization may still occur because the body metabolizes the reversal agent in the normal process. Furthermore, in current practice, anesthesiologists have to wait until the patient begins to recover from NMBA naturally before administering the antagonist. In many cases, this waiting time ranges from 30 minutes to 60 minutes or more.

[0007] Prediction and / or control of NMB recovery can be derived from government agency guidelines. For example, the FDA mandates the maximum allowable clinical duration of NMBA, which is measured as the time it takes to return to a single twitch height that is 25% higher than the baseline in a single twitch response test after administering a dose that is twice the 95% effective dose (ED 95 ).

[0008] What is needed is a simple method that not only induces but also brings about recovery from NMB in patients and reduces the occurrence of postoperative residual effects. Since compliance with intraoperative monitoring is not universal and is not always possible, this field would benefit from a method that provides a highly predictable NMBA recovery period in both the timing and extent of recovery. One such method is described below in this specification. SUMMARY OF THE INVENTION

[0009] Summary The present disclosure relates to a method for inducing and effecting natural recovery from NMB in a patient, the method comprising administering to the patient an effective amount of RP1000 or RP2000. This method provides a highly predictable NMBA recovery period in both the timing and extent of recovery. [INVENTION 1001] administering an effective amount of RP2000 to a human patient under anesthesia; and in the absence of an RP2000 antagonist, a stage that results in spontaneous recovery from paralysis or neuromuscular blockade (NMB), wherein the spontaneous recovery is characterized by a measured TOF ratio of at least about 0.90 in a human patient A method of inducing paralysis or NMB and recovery therefrom, comprising: [Inventive concept 1002] The method of inventive concept 1001, wherein the anesthesia is inhalation anesthesia [Inventive concept 1003] The method of inventive concept 1001 or 1002, wherein the effective amount of RP2000 is at least ED 95 for humans [Inventive concept 1004] The method of any one of inventive concepts 1001 to 1003, wherein the effective amount of RP2000 is at least 1.5 times the ED 95 for humans [Inventive concept 1005] The method of any one of inventive concepts 1001 to 1004, wherein the effective amount of RP2000 is at least 2 times the ED 95 for humans [Inventive concept 1006] The method of any one of inventive concepts 1001 to 1005, wherein the effective amount of RP2000 is from about 0.16 mg / kg to about 0.60 mg / kg [Inventive concept 1007] The method of any one of inventive concepts 1001 to 1006, wherein the spontaneous recovery is achieved within about 17 minutes after discontinuation of RP2000 administration [Inventive concept 1008] The method of any one of inventive concepts 1001 to 1007, wherein the spontaneous recovery is achieved within about 12 minutes after discontinuation of RP2000 administration [Inventive concept 1009] The method of any one of inventive concepts 1001 to 1008, wherein the spontaneous recovery is achieved within about 10 minutes after discontinuation of RP2000 administration [Inventive concept 1010] Any method of the present invention from 1001 to 1009, wherein an effective amount of RP2000 is sufficient to induce a single contraction height of about 5% or less of the baseline within 2 minutes after the start of administration. [The present invention 1011] Any method of the present invention from 1001 to 1010, wherein the anesthesia is IV anesthesia. [The present invention 1012] The effective amount of RP2000 is at least 3 times the ED 95 for humans, in the method of the present invention 1011. [The present invention 1013] The effective amount of RP2000 is at least 4 times the ED 95 for humans, in the method of the present invention 1011 or 1012. [The present invention 1014] The effective amount of RP2000 is at least 5 times the ED 95 for humans, in any method of the present invention from 1011 to 1013. [The present invention 1015] The effective amount of RP2000 is from about 0.48 mg / kg to about 2.00 mg / kg, in any method of the present invention from 1011 to 1014. [The present invention 1016] Any method of the present invention from 1011 to 1015, wherein the spontaneous recovery is further characterized by a single contraction height of at least 95% of the baseline in a human patient. [The present invention 1017] Any method of the present invention from 1011 to 1016, wherein the administration of RP2000 is performed parenterally. [The present invention 1018] (a) An amount of RP2000 sufficient to relax or block the activity of skeletal muscle; (b) Any instructions explaining how to administer the RP1000 drug to a human patient; and (c) Optionally, an RP2000 antagonist effective to reverse the effect of RP2000 in humans, and instructions on how to use the antagonist to reverse the effect of the blocker in a human patient to whom RP2000 has been administered A kit comprising. [The present invention 1019] 4-(3-(((E)-4-(3-((1R)-6,7-Dimethoxy-1-(4-methoxybenzyl)-2-methyl-1,2,3,4-tetrahydro-2-isoquinolinium-2-yl)propoxy)-4-oxobuta-2-enoyl)oxy)propyl)-4-(3,4-dimethoxybenzyl)morpholin-4-ium dichloride formulated into a dosage form suitable for administration at a dosage of about 0.08 mg / kg to about 0.60 mg / kg body weight. [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-isoquinolinium-2-yl)propoxy)-4-oxobuta-2-enoyl)oxy)propyl)-4-(3,4-dimethoxybenzyl)morpholin-4-ium or a pharmaceutically acceptable salt thereof and water. [Invention 1021] The pharmaceutical composition of Invention 1020 comprising 4-(3-(((E)-4-(3-((1R)-6,7-dimethoxy-1-(4-methoxybenzyl)-2-methyl-1,2,3,4-tetrahydro-2-isoquinolinium-2-yl)propoxy)-4-oxobuta-2-enoyl)oxy)propyl)-4-(3,4-dimethoxybenzyl)morpholin-4-ium dichloride. [Invention 1022] The pharmaceutical composition of Invention 1020 or 1021 further comprising a solvent selected from one or more of alcohol, polyethylene glycol, and dimethyl sulfoxide. [Invention 1023] The pharmaceutical composition according to any one of Inventions 1020 to 1022, wherein the dosage form is suitable for parenteral administration. [Invention 1024] Administering an effective amount of RP1000 to an anesthetized human patient; and In the absence of an RP1000 antagonist, effecting spontaneous recovery from paralysis or neuromuscular blockade (NMB), wherein the spontaneous recovery is characterized by a measured TOF ratio of at least about 0.90 in the human patient. A method for inducing paralysis or NMB and recovery therefrom. [Inventive Concept 1025] The method of Inventive Concept 1024, wherein the anesthesia is inhalation anesthesia. [Inventive Concept 1026] The effective amount of RP1000 is at least ED 95 for humans, in the method of Inventive Concept 1024 or 1025. [Inventive Concept 1027] The effective amount of RP1000 is at least 1.5 times ED 95 for humans, in any of the methods of Inventive Concepts 1024 to 1025. [Inventive Concept 1028] The effective amount of RP1000 is at least 2 times ED 95 for humans, in any of the methods of Inventive Concepts 1024 to 1027. [Inventive Concept 1029] The effective amount of RP1000 is about 0.08 mg / kg to about 0.2 mg / kg, in any of the methods of Inventive Concepts 1024 to 1028. [Inventive Concept 1030] The effective amount of RP1000 is about 0.08 mg / kg to about 0.16 mg / kg, in any of the methods of Inventive Concepts 1024 to 1028. [Inventive Concept 1031] In any of the methods of Inventive Concepts 1024 to 1030, the spontaneous recovery is achieved within about 50 minutes after discontinuation of the administration of RP1000. [Inventive Concept 1032] In any of the methods of Inventive Concepts 1024 to 1030, the spontaneous recovery is achieved within about 40 minutes after discontinuation of the administration of RP1000. [Inventive Concept 1033] In any of the methods of Inventive Concepts 1024 to 1030, the spontaneous recovery is achieved within about 30 minutes after discontinuation of the administration of RP1000. [Inventive Concept 1034] In any of the methods of Inventive Concepts 1024 to 1033, the effective amount of RP1000 is sufficient to induce a twitch height of about 5% or less of the baseline within 2 minutes after the start of administration. [Inventive Concept 1035] Any method according to any one of 1024 - 1034 of the present invention, wherein the intermediate recovery period is characterized by the transition from 25% of the single contraction height of the baseline measurement to 75% of the single contraction height of the baseline measurement in a human patient, and the recovery period has a duration of about 25 minutes or less. [The present invention 1036] The method of the present invention 1024, wherein the anesthesia is IV anesthesia. [The present invention 1037] The effective amount of RP1000 is at least 95 twice that of the ED for humans, for the method of the present invention 1036. [The present invention 1038] The effective amount of RP1000 is at least 95 three times that of the ED for humans, for the method of the present invention 1036 or 1037. [The present invention 1039] The effective amount of RP1000 is at least 95 four times that of the ED for humans, for any method according to any one of 1036 - 1038 of the present invention. [The present invention 1040] The effective amount of RP1000 is from about 0.24 mg / kg to about 0.48 mg / kg, for any method according to any one of 1036 - 1039 of the present invention. [The present invention 1041] Any method according to any one of 1036 - 1040 of the present invention, wherein the spontaneous recovery is further characterized by at least 95% of the single contraction height of the baseline in a human patient. [The present invention 1042] Any method according to any one of 1036 - 1041 of the present invention, wherein the administration of RP1000 is performed parenterally. [The present invention 1043] (a) RP1000 in an amount sufficient to relax or block the activity of skeletal muscle; (b) Any instructions explaining how to administer the RP1000 agent to a human patient; and (c) Optionally, an RP1000 antagonist effective to reverse the effect of RP1000 in humans, and instructions on how to use the antagonist to reverse the effect of the blocker in a human patient to whom RP1000 has been administered A kit comprising [Inventive concept 1044] (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-oxobuta-2-enoyl)oxy)propyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-2-ium or a pharmaceutically acceptable salt thereof, and water. A pharmaceutical composition [Inventive concept 1045] A pharmaceutical composition of Inventive concept 1044, 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-oxobuta-2-enoyl)oxy)propyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-2-ium dichloride [Inventive concept 1046] A pharmaceutical composition of Inventive concept 1044 or 1045, further comprising a solvent selected from one or more of alcohol, polyethylene glycol, and dimethyl sulfoxide [Inventive concept 1047] A pharmaceutical composition of any one of Inventive concepts 1044 to 1046, wherein the dosage form is suitable for parenteral administration [Inventive concept 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-oxobuta-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 [Inventive concept 1049] (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-oxobuta-2-enoyl)oxy)propyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-2-ium or a pharmaceutically acceptable salt thereof, and water, a pharmaceutical composition comprising the same. [Invention 1050] (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-oxobuta-2-enoyl)oxy)propyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-2-ium dichloride, a pharmaceutical composition of Invention 1049 comprising the same. [Invention 1051] A pharmaceutical composition of Invention 1049 or 1050, further comprising a solvent selected from one or more of alcohol, polyethylene glycol, and dimethyl sulfoxide. [Invention 1052] A pharmaceutical composition according to any one of Inventions 1049 to 1051, wherein the dosage form is suitable for parenteral administration. [Invention 1053] A method of inducing paralysis or neuromuscular blockade (NMB), comprising administering an effective amount of RP2000 to a human patient under anesthesia. [Invention 1054] The method of Invention 1052, further comprising a step of recovering from paralysis or NMB. [Invention 1055] The method of Invention 1053, wherein the recovery is characterized by a measured TOF ratio of at least about 0.90 in a human patient. [Invention 1056] A method of inducing paralysis or neuromuscular blockade (NMB) comprising the step of administering an effective amount of RP1000 to an anesthetized human patient. [Invention 1057] The method of Invention 1056, further comprising the step of recovering from paralysis or NMB. [Invention 1058] The method of Invention 1057, wherein said recovery is characterized by a measured TOF ratio of at least about 0.90 in a human patient.

Brief Description of the Drawings

[0010]

Figure 1

Figure 2

Figure 3

Figure 4

Modes for Carrying Out the Invention

[0011] Detailed Description Before describing the compositions and methods, it is to be understood that the scope of the present disclosure is not limited to the specific 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 aspects only and is not intended to limit the scope of the present 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. Any methods and materials similar or equivalent to those described herein may be used in the practice or testing of various aspects disclosed herein, but the preferred methods, apparatus, and materials are described herein. All publications mentioned herein are incorporated herein by reference with respect to the aspects they describe. No part of this specification should be construed as an admission that the present disclosure does not have the right to antedate such disclosure by virtue of prior invention.

[0012] In general medical procedures, patients may be administered various chemical agents to reduce discomfort and / or prevent movements that would interfere with the medical treatment. The patient is first administered an anesthetic agent to induce anesthesia. As used herein, anesthesia refers to a controlled temporary loss of sensation or consciousness induced for medical purposes (e.g., surgical procedures) and can be maintained over the intra - anesthetic period by continuous or intermittent administration of anesthetic agents.

[0013] Anesthesia can be administered by inhalation or intravenously. As used herein, inhalation anesthesia refers to anesthesia by the respiratory action of vapor from a volatile liquid or gaseous anesthetic agent into the patient's airway / trachea, unless otherwise indicated. Suitable inhalation agents include, but are not limited to, nitrous oxide (N2O), desflurane, sevoflurane, isoflurane, methoxyflurane, halothane, and any combination thereof. Those of ordinary skill in the art will be familiar with inhalation anesthetic agents and their methods of use.

[0014] As used herein, intravenous anesthesia, unless otherwise indicated, refers to the administration of a liquid anesthetic agent to one or more veins of a patient. Suitable intravenous anesthetic agents 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 anesthetic agents and their methods of use.

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

[0016] The administration of an anesthetic agent and the administration of an NMBA each involve an onset period that extends from the time the agent is first administered until the time the agent exerts its full effect. A medical procedure, such as a surgical operation, can be performed during the intraoperative period after the anesthetic agent and NMBA have exerted their full effects. After the medical procedure is completed, it is possible to discontinue the administration of the NMBA and the anesthetic agent, resulting in recovery therefrom. Similar to the onset period, the discontinuation of the anesthetic agent and the NMB agent involves a recovery period that extends from the time the anesthetic agent or NMB agent is first discontinued until the time the effect of the agent is fully reversed. At this point of full 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 - 1.00 can be measured. Recovery can be achieved regardless of the use or administration of an antagonist to NMBA. "Spontaneous recovery" as used herein 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 metrics may be used to characterize recovery and / or spontaneous recovery, such as, but not limited to, at least 95% of the single twitch height relative to baseline.

[0018] RP1000, also sometimes referred to by the aliases AV002 or CW002, is a non-depolarizing intermediate-duration NMBA as shown below. TIFF2025111498000001.tif85128

[0019] Chemically, RP1000 may be 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-oxobuta-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-described structure identified as RP1000 herein. The RP1000 shown above reflects the chloride salt form of RP1000, but RP1000 as used herein can also include other pharmaceutically acceptable salts thereof. RP1000 has been previously disclosed in U.S. Patent 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 with respect to the disclosure of the RP1000 (or AV002) compound, its method of preparation, its formulations, and methods of use. In preclinical trials using RP1000, 100% NMB has been confirmed within about 90 seconds after administration.

[0021] Another non-depolarizing NMBA is RP2000 (also known as "CW 1759-50"), which is a short-acting NMBA. TIFF2025111498000002.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-oxobuta-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-described structure identified as RP2000 herein. The RP2000 shown above reflects the chloride salt form of RP2000, but RP2000 as used herein can also include other pharmaceutically acceptable salts thereof.

[0023] Disclosed herein is a method for inducing and effecting spontaneous recovery from NMB in a patient, which comprises the step of 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 the timing and the extent of recovery. Using the method 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 recovery period from anesthetic agents, and / or the achievement of recovery from anesthetic agents. Further, since there is a substantially linear correlation between the time after discontinuation of administration and various measurement time points during the NMB recovery period (e.g., 5% single twitch, 10% single twitch, 25% single twitch, 50% single twitch, 75% single twitch, 95% single twitch (all compared to baseline)), the extent of recovery can be accurately predicted. This property of RP1000 enables a method of inducing NMB during anesthesia to gain the ability to minimize the time spent under NMB after surgery through accurate prediction of the recovery period. For example, the administration of NMB can be discontinued before the end of the intraoperative period, with the understanding that the surgical procedure can be completed by the time the patient begins to emerge from NMB blockade.

[0024] Accordingly, one aspect of the present disclosure is a method of inducing NMB, comprising administering RP1000 to a human patient under inhaled anesthesia in an amount effective to maintain a single twitch height that does not exceed about 5% above the baseline measurement, thereby inducing NMB in the human patient; and after a desired duration, discontinuing the administration of RP1000 to the patient, thereby effecting a natural recovery of the patient from NMB. An "effective amount" of a compound is a predetermined amount calculated to achieve a desired effect (e.g., the degree of NMB as measured by single twitch height). The "effective amount" of a compound for use in therapy is an amount of the compound in a formulation which, when administered as part of a desired dosing regimen (to a mammal such as a human), alleviates symptoms, improves the condition, or delays the onset of the medical condition, according to clinically acceptable criteria for the disease or condition to be treated or for cosmetic purposes, e.g., at a reasonable benefit / risk ratio applicable to any medical treatment. Optionally, NMB can be induced during the intraoperative period and / or during the anesthesia period.

[0025] In various embodiments, RP1000 can be administered to a human patient as a single dose or multiple doses, each dose comprising an amount of RP1000 that is about 1.0 to about 3.0 times the ED 95 (about 0.077 mg / kg) for humans. The dose can be administered as a single IV bolus dose, multiple IV bolus doses, or as a continuous IV infusion. A single bolus administration of RP1000 can be carried out over a period of about 5 seconds to about 15 seconds. Administration by this method can be continued as needed throughout the intraoperative procedure to maintain NMB (single twitch of about 5% or less compared to baseline). Alternatively, RP1000 can also be administered as a slow infusion over a period of about 1 minute to about 2 minutes, or as a slow continuous infusion, for example, over at least a portion of the intraoperative period.

[0026] As specific dosages, but not limited thereto, about 0.08 mg (based on the cation) to about 0.25 mg / kg of RP1000 per kg of body weight can be administered to the patient. Other assumed 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 any dosage therebetween, for example, 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, etc., but are not limited thereto. The patient can be under inhalational anesthesia such as, for example, nitrous oxide, desflurane, sevoflurane, isoflurane, methoxyflurane, or any combination thereof. The dosage of anesthesia can be any desired dosage, for example, 0.5 MAC, 0.75 MAC, 1.0 MAC, 1.25 MAC, or more. At higher anesthesia dosages, although it takes longer due to the deeper state of anesthesia, natural recovery is still expected to be predictable.

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

[0028] RP1000 has a relatively rapid onset period and provides an additional opportunity to minimize the time the patient is below NMB. Thus, optionally and additionally, administration of RP1000 to a patient within the period during anesthesia can result in a measurement of single twitch height in the patient that does not exceed about 5% above the baseline measurement within about 2 minutes, more preferably within about 90 seconds, after the start of administration.

[0029] The methods described herein include a stage that results in natural recovery from NMB without using an antagonist or reversal agent for NMBA. In one or more embodiments, natural recovery is achieved within about 50 minutes after discontinuation of administration of RP1000. More preferably, natural recovery is achieved within about 40 minutes, within about 30 minutes, or within about 25 minutes. Additional measurements, such as measuring at least 95% of single twitch height relative to baseline, can supplement the TOFR measurement.

[0030] RP2000 may also be used as an NMBA. Thus, another aspect of the disclosure is a method of inducing NMB, comprising administering RP2000 to a human patient under inhaled anesthesia in an amount effective to maintain a single twitch height that does not exceed about 5% above the baseline measurement, thereby inducing NMB in the human patient; and after a desired duration, discontinuing administration of RP2000 to the patient, thereby causing natural recovery of the patient from NMB. Optionally, NMB can be induced during the surgical period and / or during the anesthesia period.

[0031] In various embodiments, RP2000 can be administered to a human patient in a single dose or multiple doses, each dose being an ED for humans 95It contains RP2000 in an amount about 1.0 to about 3.0 times that of (about 0.077 mg / kg). The dosage may be administered by multiple IV bolus dosages or as a continuous IV infusion. The single bolus administration of RP1000 can be carried out over a period of about 5 seconds to about 15 seconds. Administration by this method can be continued as necessary throughout the intraoperative procedure to maintain NMB (single twitch about 5% or less compared to baseline). Alternatively, RP1000 can also be administered as a slow infusion over a period of about 1 minute to about 2 minutes or as a slow continuous infusion, for example, over at least a portion of the intraoperative period.

[0032] Since the duration of action of RP2000 is shorter than that of RP1000, the appropriate dosage of RP2000 will be about 2 to 3 times more than in the case of RP1000. For example, appropriate dosages of RP2000 can include, but are not limited to, administering from about 0.16 mg (based on the cation) to about 0.60 mg / kg of RP2000 per kg of patient body weight. Other contemplated dosage ranges include RP2000 of 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. Specific dosages can include any dosage in between, such as, for example, 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, but are not limited thereto. The patient can be under any of the above types of inhalation anesthesia.

[0033] Similar to RP1000, RP2000 has a relatively rapid onset period and provides an additional opportunity to minimize the time the patient is under NMB. Thus, optionally and additionally, administration of RP1000 to the patient during the intraoperative period can result in a measured value of single twitch height that does not exceed about 5% above the baseline measurement value in the patient within about 2 minutes, more preferably within about 90 seconds, after the start of administration.

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

[0035] Predictable spontaneous recovery from NMB represents a significant advantage over current methods of reversing NMB using NMBA antagonists, because these antagonists tend to be unpredictable and difficult to control. By inducing NMB with RP1000 or RP2000, the duration of NMB and the time at which infusion can be discontinued precisely determine the timing of spontaneous recovery. In this way, administration of NMBA antagonists can be completely avoided, and the time spent under NMB postoperatively can be reduced.

[0036] RP1000 has also been demonstrated to be safe. Whenever NMBA is used, there is a possibility that important autonomic functions such as respiration are blocked. In animal models (e.g., monkeys and cats), no adverse effects on the autonomic or cardiovascular systems were observed (see, for example, 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 resulted in a 20% decrease in mean arterial pressure and a 20% increase in heart rate. Furthermore, RP1000 was shown to have a low potential for bronchoconstriction or histamine release.

[0037] As described above, the natural recovery of patients from NMB using RP1000 and RP2000 under inhaled anesthesia is sufficiently predictable over a wide range of doses. However, inhaled anesthetics such as sevoflurane have been observed to potentially enhance NMB (see, for example, Ye, L., et al.; Int. J. Physicol. Pathophysiol Pharmacol; 2015 7(4), 172-177). Therefore, clinically, it is suggested that in patients under intravenous anesthesia such as propofol, lower doses of NMBA can be used compared to the doses required for the same level of NMB in patients during inhaled anesthesia. For example, a dose of about 0.08 mg / kg to about 0.25 mg / kg of RP1000 (or about 0.08 mg / kg to about 0.20 mg / kg) can be used in patients under inhaled anesthesia, but a dose of about 0.2 mg / kg to about 0.5 mg / kg may be required to achieve the same NMB effect when the same patient is under IV anesthesia.

[0038] Accordingly, another aspect of the present disclosure is a method of inducing NMB, comprising administering RP1000 to a human patient under IV anesthesia in an amount effective to maintain a single twitch height not exceeding about 5% above the baseline measurement, thereby inducing NMB in the human patient; and after a desired duration, discontinuing the administration of RP1000 to the patient, thereby effecting the natural recovery of the patient from NMB. Optionally, the NMB can be induced during the intraoperative period and / or during the anesthesia period.

[0039] In various embodiments, RP1000 is the ED for humans 95It can be administered to human patients in an amount about 3.0 to about 6.0 times that. The amount may be administered as a single IV bolus dose, multiple IV bolus doses, or as an IV continuous infusion. Administration of a single bolus of RP1000 can be carried out over a period of about 5 seconds to about 15 seconds. Administration by this method can be continued as necessary (e.g., throughout the intraoperative procedure) to maintain NMB (single twitch about 5% or less compared to baseline). Alternatively, RP1000 can also be administered as a slow infusion over a period of about 1 minute to about 2 minutes, or as a slow continuous infusion (e.g., over at least a portion of the intraoperative period).

[0040] Specific dosages include, but are not limited to, administering about 0.24 mg (based on the cation) to about 0.48 mg / kg of RP1000 per kg of patient body weight to the patient. Other contemplated dosage ranges include RP1000 of 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. Specific dosages include any dosage in between, such as, for example, 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, etc., but are not limited thereto. The patient can be under IV anesthesia, for example, with propofol, etomidate, ketamine, barbiturates (e.g., 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 inhaled anesthesia. For example, spontaneous recovery can be achieved within about 38 minutes after discontinuation of the 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 used to induce NMB during IV anesthesia. Thus, another aspect of the present disclosure is a method of inducing NMB, the method comprising administering RP2000 to a human patient under IV anesthesia in an amount effective to maintain a single twitch height that does not exceed about 5% above the baseline measurement, thereby inducing NMB in the human patient; and after a desired duration, discontinuing the administration of RP2000 to the patient, thereby effecting the patient's spontaneous recovery from NMB. Optionally, NMB can be induced during the intraoperative period and / or during the anesthesia period.

[0043] In various embodiments, RP2000 can be administered to a human patient in an amount about 3.0 to about 6.0 times the ED 95 for humans. The amount can be administered as a single IV bolus dose, multiple IV bolus doses, or as an IV continuous infusion. The bolus administration of RP2000 can be performed as a slow infusion over a period of about 5 seconds to about 15 seconds, or over a period of about 1 minute to about 2 minutes. Administration by this method can be continued throughout the intraoperative procedure, as needed, to maintain NMB (single twitch of about 5% or less compared to baseline). Suitable doses include administering to the patient from 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 doses include any dose therebetween, for example, RP1000 at 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, but are not limited thereto. The patient can be under IV anesthesia as described above.

[0044] In one or more embodiments, spontaneous recovery is achieved approximately 25% faster with RP2000 than with RP1000. For example, spontaneous recovery can be achieved within about 15 minutes after discontinuation of RP2000 administration. 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, the predictability of spontaneous recovery from NMBA is thought to be derivable from its metabolism in the human body, which is readily available in the human body, for example by glutathione. This is specific to RP1000 and RP2000, and other NMBA undergo more complex breakdown, so a predictable time table for spontaneous recovery cannot be obtained. Comparative metabolic studies have demonstrated that glutathione metabolic patterns can be specific to humans compared to other species such as primates; therefore, data showing that predictability of spontaneous recovery can be achieved in humans after administration of RP1000 was particularly reassuring. Furthermore, when administering NMBA to patients in disease states that can affect the degree of NMB and the breakdown of NMBA in the body, careful consideration is usually required. Since RP1000 as well as RP1000 and RP2000 simply rely on glutathione for predictable breakdown, these agents can be used in a wide variety of populations, even in people with medical conditions or states that make the use of other NMBA difficult.

[0046] Predicting spontaneous recovery from NMB induced by RP1000 and RP2000 is provided by the methods disclosed herein, but advantageously, each of RP1000 and RP2000 is particularly responsive to its respective antagonist. Reversal agents for RP1000 and RP2000 have been developed, and they have an ED 95Even when using a dose three times that amount, RP1000 can effectively remove the NMB caused by it within minutes. Therefore, when a patient needs to recover immediately from NMB induced by RP1000 or RP2000 and the timing of natural recovery is inappropriate, an NMB antagonist can be administered to rapidly reverse the 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 comprise RP1000 or RP2000 and may 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 composition may include solvents such as alcohol, polyethylene glycol, dimethyl sulfoxide, or any mixture thereof.

[0048] The composition of RP1000 or RP2000 can be administered to human patients under inhaled anesthesia at the dosages as described above. For example, in adults (150 pounds or 70 kg), the appropriate amount of RP1000 to obtain NMB 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 human patients with higher body weights, this dosage will be higher. For example, in a 200-pound (90 kg) patient, it can be up to about 18 mg, and in a 250-pound (114 kg) patient, it can be up to about 23 mg. Thus, a pharmaceutical parenteral formulation suitable for administration to humans contains about 0.1 mg / mL to about 50 mg / mL of RP1000 in solution, or may contain multiples thereof in the case of multi-dose vials. Similar calculations can be made for the administration of RP2000 based on the above disclosure.

[0049] Another aspect of the disclosure provides a kit comprising separately packaged (a) an amount of RP1000 or RP2000 sufficient to relax or block skeletal muscle activity and (b) instructions explaining how to administer the agent of RP1000 or RP2000 to a human patient. Optionally, the kit may further comprise (c) an antagonist of RP1000 or RP2000 in an amount effective to reverse the effects of RP1000 or RP2000, respectively, in humans, as needed, and (d) instructions on how to use the antagonist to reverse the effects of the blocking agent on a human patient to whom RP1000 or RP2000 has been administered. In such a kit, RP1000 or RP2000 is provided as 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 include 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 solids, for reconstitution with water (for injection) or a dextrose solution or saline. Such formulations are typically presented in unit dosage forms such as ampoules or disposable syringes. They may also be presented in multiple dosage forms such as bottles from which appropriate amounts can be withdrawn. All such formulations must be sterile.

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

[0051] For example, in the case of a patient under inhaled anesthesia who has been administered RP1000 at a dose of about 0.08 to about 0.14 mg / kg, the time to a specific single twitch height above baseline can be calculated by Equation (1) based on the data in Figure 4, where T 回復 is the time (minutes) to a specific single twitch height, and H t is the specific single twitch height. TIFF2025111498000003.tif7128

[0052] Thereafter, the predicted recovery time can inform what actions should be taken to ensure the desired maintenance of NMB with respect to the administration and intraoperative duration of anesthesia. For example, this calculation can warn whether additional NMBA administration is needed during the intraoperative period or inform when anesthesia can be discontinued (recovery from NMB needs to be achieved prior to recovery from anesthesia).

[0053] Although the above Equation 1 is related to the use of RP1000 under inhaled anesthesia, similar calculations can be performed for RP1000 under IV anesthesia and for RP2000 under any type of anesthesia.

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

[0055] Single twitch height: A peripheral nerve stimulator that applies a supramaximal stimulus to the ulnar nerve at the wrist via surface electrodes was used for neuromuscular monitoring. After induction of anesthesia, single twitch stimuli (0.10 Hz) were continuously applied for 15 - 20 minutes to establish the baseline single twitch height. Single twitch monitoring can also continue during and after administration of NMBA.

[0056] Train-of-Four twitch stimulation pattern ratio (TOFR): TOF provides four supramaximal electrical impulses that include four twitches of the same strength in the stimulated muscle. Twitch fade appears when neuromuscular blockade increases. The TOFR is obtained by comparing the fourth twitch (T4) with the first twitch (T1).

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

[0058] One or more exemplary aspects are presented herein. For clarity, not all features of the physical implementation are described or shown in this application. In developing the physical aspects of the present disclosure, it is understood that numerous implementation-specific decisions must be made to achieve the developer's goals, which vary from time to time depending on the implementation, such as compliance with system-related, business-related, government-related, and other constraints. Although the developer's efforts may be time-consuming, such efforts would still be routine work for those of ordinary skill in the art having the benefit of this disclosure.

[0059] Accordingly, the present disclosure is well adapted to attain the ends and advantages mentioned, as well as those inherent therein. The specific embodiments disclosed above are merely illustrative and the present disclosure can be modified and practiced in different but equivalent ways that will be apparent to those skilled in the art having the benefit of the teachings herein. Further, no limitation is intended with respect to the details of the structure or design shown herein other than as described in the following claims. Accordingly, it is evident that the specific exemplary embodiments disclosed above can be varied, combined, or modified and all such variations are considered to be within the scope and spirit of the present disclosure. The embodiments illustratively disclosed herein can be suitably practiced without the specific elements and / or optional elements specifically disclosed herein.

Example

[0060] Example 1: Preclinical test results in rhesus monkeys Either an RP2000 or RP1000 bolus dose was administered to rhesus monkeys under isoflurane anesthesia at a dose equal to 1 to 10 times the ED 95 in rhesus monkeys of the administered compound (ED 95, RP1000 = 0.040 mg / kg; ED 95, RP2000 = 0.053 mg / kg). During the 6 - 10 hour experiment, single twitches (0.15 Hz) and TOF (2 Hz × 2 s) were recorded. The time to spontaneous recovery after bolus administration, characterized by the recovery of single twitches from 5% to 95% of baseline, was measured.

[0061] Separately, a continuous infusion for 20 - 180 minutes was performed (on separate subjects), and after termination of the infusion, the time to spontaneous recovery of NMB, characterized by the recovery of single twitches from 5% to 95% of baseline, was measured. The data collected from these experiments are shown in Table 1 below. Figures 1 and 2 graphically represent this data. TIFF2025111498000004.tif55146

[0062] Details of this experiment can be found in the abstract regarding poster number F1004 at the General Assembly of the Anesthesia Academic Year in October 2019, the content of which is incorporated herein by reference.

[0063] Example 2: Phase I Clinical Trial Results in Humans The abstract is available in the final supplement of the Journal of Anesthesia and Analgesia, May 2020 (Volume 30, Issue 5, pages 73 - 74), which is incorporated herein by reference. Healthy volunteers (n = 34) aged 18 - 55 years of both genders gave informed consent to the Phase I protocol approved by the IRB. NMB was measured by mechanomyography during sevoflurane (0.5MAC) / N2O (70%) anesthesia. Each volunteer received a single IV bolus of RP1000.

[0064] The following Table 3 provides various pharmacokinetic data for each dose tested. TIFF2025111498000005.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 when it occurs; V ss = Volume at Steady State

[0065] The injection of RP1000 showed rapid onset of action and intermediate duration of the NMB effect. The ED of 0.08 mg / kg dose was established under sevoflurane anesthesia, and the dose of 0.14 mg / kg produced 100% single - twitch suppression in all subjects. At doses less than 0.08 mg / kg, 100% (n = 18) single - twitch suppression did not occur in any volunteer. However, 12 out of 14 volunteers who received doses of 0.08, 0.10, or 0.14 mg / kg developed 100% block: (2 out of 6 at 0.08 mg / kg, 6 out of 6 at 0.10 mg / kg, 4 out of 4 at 0.14 mg / kg). ED 95 95At the above dosages, 95% T1 suppression was achieved in approximately 2 - 3 minutes and maximum T1 suppression was achieved in approximately 3 - 5 minutes.

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

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

[0068]

Table 2

[0069] Next, the recovery data of the 12-person mixed group were analyzed by linear regression. The regression basically included data from 5 to 95% recovery times. 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 the recovery curves for the 0.08, 0.10, and 0.14 mg / kg groups and the mixed group. Both comparisons applying ANOVA twice showed no significant differences among the 0.08, 0.10, and 0.14 mg / kg groups; even when the comparison of the mixed group was added, the difference was still not significant: P = 0.58 and P = 0.76 respectively. Figure 4 shows the regression of the mixed recovery straight line from 5% single twitch height to 25, 50, 75, and 95% single twitch height against time for the 12 persons who exhibited 100% block of single twitch. This relationship is significant (P = 0.002). The slope of this straight line is 2.518.

[0070] ED of RP1000 under sevoflurane 95 (Based on extrapolation and indirect comparison from published human data comparing RP1000 (0.07 mg / kg - 0.08 mg / kg) with other commercially available NMBA, RP1000 is expected to have approximately two-thirds the potency of cisatracurium and four times the potency of rocuronium under volatile anesthesia. Furthermore, using the same multiple comparison, 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 the data from the first human trial completed previously and the animal data regarding the onset of block at twice the ED 95 it was found that the onset by RP1000 is faster than that achieved by cisatracurium but slightly slower than that of rocuronium.)

[0071] Safety. In humans, even when RP1000 was administered at a dose of up to 0.14 mg / kg, no serious cardiorespiratory side effects or signs of histamine release occurred. Generally, doses of RP1000 in the range of 0.02 mg / kg to 0.14 mg / kg showed generally good tolerance among the healthy volunteers enrolled in this study.

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

[0073] Without wishing to be bound by theory, the highly reproducible half-lives are thought to be due to the degradation of RP1000 by cysteine addition (e.g., by reaction with glutathione). Advantages afforded by the understanding of the pharmacodynamics of RP1000 include, but are not limited to, the ability to readily predict the level of functional recovery in human patients. Further, without wishing to be bound by theory, since RP2000 is degraded in the body via a similar pathway to RP1000, the spontaneous recovery of patients under inhaled anesthesia after administration of RP2000 at doses up to 2.5-3 times the ED 95 is also predicted to be highly predictable within this dose range since the elimination half-life depends on its degradation pathway. Accordingly, the present disclosure reflects this prediction.

[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 inhaled 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. The volume of distribution (V c ) of the central compartment and the rate constant (k eo ) representing the delay between plasma concentration and NMB are 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 inhaled anesthesia, IV anesthesia, or a combination thereof. The dose 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. administering an effective amount of RP2000 to a human patient under anesthesia; and in the absence of an RP2000 antagonist, effecting spontaneous recovery from paralysis or neuromuscular blockade (NMB), said spontaneous recovery being characterized by a measured TOF ratio of at least about 0.90 in the human patient A method of inducing paralysis or NMB and recovery therefrom.

2. The method of claim 1, wherein the anesthesia is inhaled anesthesia.

3. The effective amount of RP2000 is at least ED for humans 95 The method according to claim 1 or 2, wherein:

4. The effective amount of RP2000 is at least 1.5 times the ED 95 for humans, according to any one of claims 1 to 3.

5. The effective amount of RP2000 is at least twice the ED 95 for humans, according to any one of claims 1 to 4.

6. The method according to any one of claims 1 to 5, wherein the effective amount of RP2000 is from about 0.16 mg / kg to about 0.60 mg / kg.

7. The method according to any one of claims 1 to 6, wherein said spontaneous recovery is achieved within about 17 minutes after cessation of administration of RP2000.

8. The method according to any one of claims 1 to 7, wherein said spontaneous recovery is achieved within about 12 minutes after cessation of administration of RP2000.

9. The method according to any one of claims 1 to 8, wherein said spontaneous recovery is achieved within about 10 minutes after cessation of administration of RP2000.

10. The method according to any one of claims 1 to 9, 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.

11. The method according to any one of claims 1 to 10, wherein the anesthesia is IV anesthesia.

12. The effective amount of RP2000 is at least three times the ED 95 for humans, according to the method of claim 11.

13. The effective amount of RP2000 is at least 4 times the ED 95 for humans, according to the method of claim 11 or 12.

14. The effective amount of RP2000 is at least 5 times the ED 95 for humans, according to any one of claims 11 to 13.

15. The method according to any one of claims 11 to 14, wherein the effective amount of RP2000 is from about 0.48 mg / kg to about 2.00 mg / kg.

16. The method according to any one of claims 11 to 15, wherein said spontaneous recovery is further characterized by a twitch height of at least 95% of baseline in the human patient.

17. The method according to any one of claims 11 to 16, wherein the administration of RP2000 is by parenteral administration.

18. A kit comprising: (a) an amount of RP2000 sufficient to relax or block the activity of skeletal muscle; (b) any instructions explaining how to administer the RP1000 agent 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 said antagonist to reverse the effects of the blocking agent in a human patient to whom RP2000 has been administered.

19. A kit comprising: (a) an amount of RP2000 sufficient to relax or block the activity of skeletal muscle; (b) any instructions explaining how to administer the RP1000 agent 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 said antagonist to reverse the effects of the blocking agent in a human patient to whom RP2000 has been administered. A kit comprising: (a) an amount of RP2000 sufficient to relax or block the activity of skeletal muscle; (b) any instructions explaining how to administer the RP1000 agent 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 said antagonist to reverse the effects of the blocking agent in a human patient to whom RP2000 has been administered.

19. 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-oxobuta-2-enoyl)oxy)propyl)-4-(3,4-dimethoxybenzyl)morpholin-4-ium dichloride, formulated into a dosage form suitable for administration at a dosage of about 0.08 mg / kg to about 0.60 mg / kg body weight.

20. 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-oxobuta-2-enoyl)oxy)propyl)-4-(3,4-dimethoxybenzyl)morpholin-4-ium or a pharmaceutically acceptable salt thereof, and water.

21. The pharmaceutical composition according to claim 20, 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-oxobuta-2-enoyl)oxy)propyl)-4-(3,4-dimethoxybenzyl)morpholin-4-ium dichloride.

22. The pharmaceutical composition according to claim 20 or 21, further comprising a solvent selected from one or more of alcohol, polyethylene glycol, and dimethyl sulfoxide.

23. The pharmaceutical composition according to any one of claims 20 to 22, wherein the dosage form is suitable for parenteral administration.

24. Administering an effective amount of RP1000 to an anesthetized human patient; and In the absence of an RP1000 antagonist, effecting spontaneous recovery from paralysis or neuromuscular blockade (NMB), wherein the spontaneous recovery is characterized by a measured TOF ratio of at least about 0.90 in the human patient, A method of inducing paralysis or NMB and recovery therefrom.

25. The method according to claim 24, wherein the anesthesia is inhalation anesthesia.

26. An effective amount of RP1000 is at least ED for humans 95 The method according to claim 24 or 25, wherein:

27. The effective amount of RP1000 is at least 1.5 times the ED 95 for humans, according to any one of claims 24 to 25.

28. The effective amount of RP1000 is at least 2-fold of the ED 95 for humans, the method according to any one of claims 24 to 27.

29. The method according to any one of claims 24 to 28, wherein the effective amount of RP1000 is from about 0.08 mg / kg to about 0.2 mg / kg.

30. The method according to any one of claims 24 to 28, wherein the effective amount of RP1000 is from about 0.08 mg / kg to about 0.16 mg / kg.

31. The method according to any one of claims 24 to 30, wherein the spontaneous recovery is achieved within about 50 minutes after discontinuation of the administration of RP1000.

32. The method according to any one of claims 24 to 30, wherein the spontaneous recovery is achieved within about 40 minutes after discontinuation of the administration of RP1000.

33. The method according to any one of claims 24 to 30, wherein the spontaneous recovery is achieved within about 30 minutes after discontinuation of the administration of RP1000.

34. The method according to any one of claims 24 to 33, wherein the effective amount of RP1000 is sufficient to induce a twitch height of about 5% or less of the baseline within 2 minutes after the start of administration.

35. The method according to any one of claims 24 to 34, wherein the intermediate recovery period is characterized by the transition from a twitch height of 25% of the baseline measurement value to a twitch height of 75% of the baseline measurement value in a human patient, and the recovery period has a duration of about 25 minutes or less.

36. The method according to claim 24, wherein the anesthesia is IV anesthesia.

37. The effective amount of RP1000 is at least 2-fold of the ED 95 for humans, the method according to claim 36.

38. The method according to claim 36 or 37, wherein the effective amount of RP1000 is at least three times the ED 95 for humans.

39. The method according to any one of claims 36 to 38, wherein the effective amount of RP1000 is at least 4 times the ED 95 for humans.

40. The method according to any one of claims 36 to 39, wherein the effective amount of RP1000 is from about 0.24 mg / kg to about 0.48 mg / kg.

41. The method according to any one of claims 36 to 40, wherein the spontaneous recovery is further characterized by a twitch height of at least 95% of the baseline in a human patient.

42. The method according to any one of claims 36 to 41, wherein the administration of RP1000 is performed parenterally.

43. (a) RP1000 in an amount sufficient to relax or block the activity of skeletal muscle; (b) Any instructions explaining how to administer the RP1000 agent to a human patient; and (c) Optionally, an RP1000 antagonist effective to reverse the effect of RP1000 in humans, and instructions on how to use the antagonist to reverse the effect of the blocker in a human patient to whom RP1000 has been administered A kit comprising.

44. 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-oxobuta-2-enoyl)oxy)propyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-2-ium or a pharmaceutically acceptable salt thereof, and water. **Claim 45** The pharmaceutical composition according to claim 44, 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-oxobuta-2-enoyl)oxy)propyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-2-ium dichloride. **Claim 46** The pharmaceutical composition according to claim 44 or 45, further comprising a solvent selected from one or more of alcohol, polyethylene glycol, and dimethyl sulfoxide. **Claim 47** The pharmaceutical composition according to any one of claims 44 to 46, wherein the dosage form is suitable for parenteral administration. **Claim 48** (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-oxobuta-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. **Claim 49** 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-oxobuta-2-enoyl)oxy)propyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-2-ium or a pharmaceutically acceptable salt thereof and water.

50. The pharmaceutical composition according to claim 49, 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-oxobuta-2-enoyl)oxy)propyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-2-ium dichloride.

51. The pharmaceutical composition according to claim 49 or 50, further comprising a solvent selected from one or more of alcohol, polyethylene glycol, and dimethyl sulfoxide.

52. The pharmaceutical composition according to any one of claims 49 to 51, wherein the dosage form is suitable for parenteral administration.

53. A method of inducing paralysis or neuromuscular blockade (NMB) comprising administering an effective amount of RP2000 to a human patient under anesthesia.

54. The method according to claim 52, further comprising a step of recovering from paralysis or NMB.

55. The method according to claim 53, wherein the recovery is characterized by a measured TOF ratio of at least about 0.90 in a human patient.

56. A method of inducing paralysis or neuromuscular blockade (NMB) comprising administering an effective amount of RP1000 to a human patient under anesthesia.

57. The method according to claim 56, further comprising a step of recovering from paralysis or NMB.

58. The method according to claim 57, wherein the recovery is characterized by a measured TOF ratio of at least about 0.90 in a human patient.

Images