Method of Dosing a Pain Therapeutic

Abstract

A method for minimizing tachycardia in a subject treated for pain and experiencing tachycardia after being treated with the compound having the structure:

##STR00001##

An effective amount of the compound is administered to a subject, where the effective amount treats pain and minimizes tachycardia in said subject experiencing tachycardia after being administered said compound.

Claims

1. A method for minimizing tachycardia in a subject treated for pain with the compound CMX-020, comprising administering to a subject experiencing tachycardia during pain treatment an effective amount of the compound CMX-020, wherein said effective amount treats pain and minimizes tachycardia in said subject.

2. The method of claim 1, wherein said compound CMX-020 is a dosage form in an intravenous solution.

3. The method of claim 1, wherein said compound CMX-020 is intravenously administered to said subject.

4. The method of claim 1, wherein the compound CMX-020 is administered at about 0.02 mg/kg to about 0.32 mg/kg over about 15 to about 30 minutes to the subject.

5. The method of claim 1, wherein the compound CMX-020 is administered at about 0.04 mg/kg to about 0.24 mg/kg over about 15 to about 30 minutes to the subject.

6. The method of claim 1, wherein the compound CMX-020 is administered at about 0.16 mg/kg to about 0.32 mg/kg over about 15 to about 30 minutes to the subject.

7. The method of claim 1, wherein the compound CMX-020 is administered at about 0.02 mg/kg over about 15 to about 30 minutes to the subject.

8. The method of claim 1, wherein the compound CMX-020 is administered at about 0.04 mg/kg over about 15 to about 30 minutes to the subject.

9. The method of claim 1, wherein the compound CMX-020 is administered at about 0.08 mg/kg over about 15 to about 30 minutes to the subject.

10. The method of claim 1, wherein the compound CMX-020 is administered at about 0.16 mg/kg over about 15 to about 30 minutes to the subject.

11. The method of claim 1, wherein the compound CMX-020 is administered at about 0.24 mg/kg over about 15 to about 30 minutes to the subject.

12. The method of claim 1, wherein said effective amount of the compound CMX-020 is administered to the subject at a rate over about 30 minutes to achieve a plasma concentration of CMX-020 of about 1420 ng/ml to about 1525 ng/ml in the subject.

13. The method of claim 12, wherein said effective amount of the compound CMX-020 is administered to the subject at a steady rate.

14. The method of claim 13, wherein said steady rate is about 0.48 mg/kg/hr to about 0.64 mg/kg/hr.

15. The method of claim 12, wherein the plasma concentration of CMX-020 is maintained by steady rate of administration in the subject for at least about 6 hours.

16. A compound having the structure ##STR00003## for use in minimizing tachycardia in a subject experiencing tachycardia after being administered said compound for treatment of pain.

17. A compound having the structure ##STR00004## for use in a method according to claim 1.

18. An intravenous solution comprising an effective amount of a compound having the structure ##STR00005## for use in minimizing tachycardia in a subject experiencing tachycardia as a result of being administered said intravenous solution for treatment of pain.

19. An intravenous solution comprising an effective amount of a compound having the structure ##STR00006## for use in a method according to claim 1.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0018] Before the present materials and methods are described, it is understood that this invention is not limited to the particular methodology, protocols, materials, and reagents described, as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention which will be limited only by the appended claims.

[0019] It must be noted that as used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural reference unless the context clearly dictates otherwise. As well, the terms “a” (or “an”), “one or more” and “at least one” can be used interchangeably herein. It is also to be noted that the terms “comprising”, “including”, and “having” can be used interchangeably.

[0020] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described.

[0021] The disclosed compound formulas and structures can in some cases vary between neutral, acid, and/or basic salt forms, depending on the surrounding environment, and such forms may be used interchangeably herein. As a non-limiting example, a primary amine moiety on a compound may be interchangeably designated as −NH.sub.2 or as NH.sub.3.sup.+. Furthermore, a given compound may have equivalent resonance structures, which may be used interchangeably herein.

[0022] All publications and patents specifically mentioned herein are incorporated by reference for all purposes including describing and disclosing the chemicals, cell lines, vectors, animals, instruments, statistical analysis and methodologies which are reported in the publications which might be used in connection with the invention. All references cited in this specification are to be taken as indicative of the level of skill in the art. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

[0023] As used herein, the term “administering” refers to bringing a subject, tissue, organ or cells in contact with the compound CMX-020 as described in this disclosure. In certain embodiments, the present invention encompasses administering the compounds useful in the present invention to a patient or subject. A “subject,” “patient” and “individual,” used equivalently herein, refers to a mammal, preferably a human.

[0024] As used herein, the terms “effective amount” and “therapeutically effective amount” refer to the quantity of active therapeutic agents sufficient to yield a desired therapeutic response without undue adverse side effects such as toxicity, irritation, or allergic response. The specific “effective amount” will, obviously, vary with such factors as the particular condition being treated, the physical condition of the patient, the duration of the treatment, the nature of concurrent therapy (if any), and the specific formulations employed. In this case, an amount would be deemed therapeutically effective if it results in an analgesic effective in the subject to provide a safe method of pain treatment. The optimum effective amounts can be readily determined by one of ordinary skill in the art using routine experimentation.

[0025] An “effective amount” includes administering CMX-020 at about 0.02 mg/kg to about 0.32 mg/kg, at about 0.04 mg/kg to about 0.24 mg/kg, or at about 0.16 mg/kg to about 0.32 mg/kg over about 15 to about 30 minutes to the subject. In still yet another “effective amount” of CMX-020 includes administering CMX-020 at about 0.02 mg/kg, at about 0.04 mg/kg, at about 0.08 mg/kg, at about 0.16 mg/kg, or about 0.24 mg/kg over about 15 to about 30 minutes to the subject. An effective amount of the compound CMX-020 is a plasma concentration of CMX-020 of about 1420 ng/ml to about 1525 ng/ml in the subject when CMX-020 is administered to a subject at a steady rate over about 30 minutes.

[0026] The disclosure also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. It is also envisioned that the compounds of the present invention may be incorporated into transdermal patches designed to deliver the appropriate amount of the drug in a continuous fashion.

[0027] For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutically acceptable carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture for a compound of the present invention, or a pharmaceutically acceptable salt thereof When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be easily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. The tablets or pills can be coated or otherwise compounded to provide a dosage affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which, serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

[0028] The liquid forms in which the compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium caboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

[0029] The following examples are, of course, offered for illustrative purposes only, and are not intended to limit the scope of the present invention in any way. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and the following examples and fall within the scope of the appended claims.

EXAMPLES

Example 1: Safely Evaluation

[0030] Tachycardia was the most common adverse event (AE) in this study, reported in 5 of 48 subjects (10%) following active treatment and in no subjects following placebo; all of the treatment-emergent AEs (TEAEs) of tachycardia were deemed related to study treatment. Tachycardia was only reported in subjects who received CMX-020, and only at the three highest doses (0.32 mg/kg and 0.24 mg/kg 15 minutes infusion and 0.32 mg/kg 30 minute infusion).

[0031] The Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventative Vaccine Clinical Trials criteria for tachycardia are defined as follows:

[0032] Mild (Grade 1): 101-116 bpm

[0033] Moderate (Grade 2): 117-130 bpm

[0034] Severe (Grade 3): >130 bpm

[0035] In this study, tachycardia was dose limiting at a level >130 bpm. The tachycardia TEAEs in this study are summarized in Table 1.

TABLE-US-00001 TABLE 1 Tachycardia TEAEs with Time to Down-Grade to “Mild” Subject TEAE Peak Time to Down-Grade Cohort Number Coding Pulse to “Mild” 5 0033 Moderate* 138 bpm 15 min 5 0036 Mild 110 bpm — 6 0045 Moderate* 156 bpm 10 min 6 0048 Mild 109 bpm — 8 0057 Mild 110 bpm — *“Moderate” because short-lived in a hospital setting

[0036] There were two TEAEs of tachycardia that occurred in Cohort 5 and Cohort 6 that were dose-limiting (>130 bpm). As shown in the table above, these TEAEs decreased in severity to “mild” within 15 minutes, and 10 minutes, respectively.

[0037] There were 3 subjects with vital signs measurements assessed as clinically significant as follows:

[0038] Subject 0033 (CMX-020 0.32 mg/kg 15-minute infusion) had a peak heart rate of 138 bpm at 16 minutes following the start of treatment administration, assessed as abnormal clinically significant. This subject's heart rate decreased to 113 bpm 15 minutes following the peak heart rate, when it was assessed as not clinically significant. This event was reported as a TEAE of tachycardia (moderate, probably related).

[0039] Subject 0036 (CMX-020 0.32 mg/kg 15-minute infusion) had a peak heart rate of 110 bpm 16 minutes following the start of dose administration, assessed as abnormal clinically significant. This subject's heart rate decreased to 101 bpm 15 minutes following the start of treatment administration, when it was assessed as not clinically significant. This event was reported as a TEAE of tachycardia (mild, probably related).

[0040] Subject 0045 (CMX-020 0.24 mg/kg 15-minute infusion) had an elevated heart rate (156 bpm) at 11 minutes following the start of dose administration, assessed as abnormal clinically significant. This subject's heart rate decreased to 109 bpm 10 minutes following the start of treatment administration, when it was assessed as not clinically significant. This event was reported as a TEAE of tachycardia (moderate, probably related). Study treatment was discontinued in this subject following 6.5 mL of a 10 mL infusion (total dose received 0.156 mg/kg). The subject was very anxious prior to, and during, CMX-020 administration.

[0041] Vital signs measurements associated with TEAEs were as follows:

[0042] Subject 0048 (CMX-020 0.24 mg/kg 15-minute infusion) reported a TEAE of tachycardia (mild, probably related) 11 minutes following start of treatment administration. This subject's heart rate peaked at 109 bpm 16 minutes following start of treatment administration. This subject's heart rate decreased to 103 bpm 15 minutes following the peak heart rate.

[0043] Subject 0057 (CMX-020 0.32 mg/kg 30-minute infusion) reported a TEAE of tachycardia (mild, probably related) 16 minutes following start of treatment administration. This subject's heart rate peaked at 110 bpm 20 minutes following start of treatment administration. This subject's heart rate decreased to 97 bpm 20 minutes following the peak heart rate.

[0044] There were a higher number of elevated heart rate assessed as clinically significant in the CMX-020 0.32 mg/kg 15-minute infusion group and CMX-020 0.24 mg/kg 15-minute infusion group compared with the other CMX-020 dose levels and compared with subjects who received placebo. Among cohorts 5 and 6 with 15-minute infusions, the peak in elevated heart rate occurred between 11-16 minutes following the start of treatment administration. Among cohorts 7 and 8 with 30-minute infusions, the peak in elevated heart rate occurred at approximately 30 minutes.

[0045] While this invention has been described in conjunction with the various exemplary embodiments outlined above, various alternatives, modifications, variations, improvements and/or substantial equivalents, whether known or that are or may be presently unforeseen, may become apparent to those having at least ordinary skill in the art. Accordingly, the exemplary embodiments according to this invention, as set forth above, are intended to be illustrative, not limiting. Various changes may be made without departing from the spirit and scope of the invention. Therefore, the invention is intended to embrace all known or later-developed alternatives, modifications, variations, improvements, and/or substantial equivalents (including enantiomers) of these exemplary embodiments. All technical publications, patents and published patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

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