Methods for the treatment of a traumatic central nervous system injury

Abstract

Methods of treating a subject with a traumatic central nervous system injury, more particularly, a traumatic brain injury, are provided. The methods comprise a therapy comprising a constant or a two-level dosing regime of progesterone. In one method, a subject in need thereof is administered at least one cycle of therapy, wherein the cycle of therapy comprises administering a therapeutically effective two-level intravenous dosing regime of progesterone. The two-level dosing regime comprises a first time period, wherein a higher hourly dose of progesterone is administered to the subject, followed by a second time period, wherein a lower hourly dose of progesterone is administered to the subject.

Description

FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0001] This invention was made with United States Government support under 1R01 N5 39097-01 A1 awarded by the National Institute of Neurological Disorders and Stroke (NIDS), National Institute of Health. The United States Government has certain rights in the invention.FIELD OF THE INVENTION

[0002] The invention relates to methods for treating a traumatic injury to the central nervous system.BACKGROUND OF THE INVENTION

[0003] Between 1.5 and 2 million Americans sustain a traumatic brain injury (TBI) each year (Anonymous, “Traumatic Brain Injury,”Center for Disease Control and Prevention, National Center for Injury Prevention and Control, 2003, Vol. 2003). In the U.S. it is estimated that TBI is responsible for 50,000 deaths and 100,000 hospitalizations annually (Anonymous, “Traumatic Brain Injury,”Center for Disease Control and Prevention, National Center for Injury Prevention and Control, 2003, Vol. 2003). Over 80,000 are disabled annually, appr...

Examples

example 1

[0076]As a first step in assessing the applicability of progesterone therapy in humans, we examined the effects of acute TBI and extracranial trauma on the pharmacokinetics of PG given by intravenous infusion. Multiple blood samples were obtained from 11 female and 21 male trauma patients receiving PG and 1 female and 3 male patients receiving placebo infusions for 72 h. Values for CSS, CL, t1 / 2 and Vd were obtained using AUC(0-72) and post-infusion blood samples. CSS values were 337±135 ng / mL, which were significantly lower than the target concentration of 45±100 ng / mL. The lower CSS is attributed to the CL, which was higher than anticipated. In addition, t1 / 2 was longer and Vd was higher than anticipated. There were no significant gender differences in any of these parameters. These changes are consistent with the hyperkinetic changes associated with critical injury. Our results demonstrate that stable PG concentrations can be rapidly achieved following TBI.

Methods

Patient Selecti...

example 2

[0095]A pilot phase II, randomized, double-blind, controlled trial of progesterone for the treatment of a traumatic brain injury was preformed. The administration protocol was carried out was described above in Example 1.

[0096]To determine if a therapeutic response was achieved, the following endpoints were monitored:

[0097]ICP reduction determined by calculating “therapeutic intensity level” (ICP-TIL);

[0098]duration of coma (injury to awaking);

[0099]mortality one-month post injury;

[0100]neurological outcome 1 month and 1 year post-injury, as determined by Glasgow outcome scale (GOS), Disability rating scale (DRS) and Galveston orientation and amnesia test (GOAT).

[0101]The preliminary evaluations are as follows. One hundred patients having moderate to severe TBI were enrolled in the study, which had a randomized block design 4:1 enrollment. Three days IV administration of progesterone [450+ / −mmol / L] in both males and females. The administration protocol and pharmaceutical composition...

example 3

[0104]We conducted a clinical trial to assess the safety of progesterone as a treatment for acute TBI. This phase II, randomized, double blind, placebo-controlled clinical trial was conducted at an urban, level I trauma center. 100 adults presenting within 11 hours of a blunt TBI with a Glasgow Coma Scale score of 4-12 were enrolled with proxy consent. Subjects were randomized on a 4:1 basis to progesterone versus placebo. Blinded observers closely monitored patients for the occurrence of adverse events, and initial functional outcomes were assessed 30 days post-injury. The primary safety outcome was difference in adverse event rates, including mortality. The primary measure of activity was dichotomized Glasgow outcome scale extended (GOSE) 30 days post injury. Seventy-seven patients received progesterone; 23 received placebo. The groups had very similar demographic and clinical characteristics. With the exception of mortality, the rate of adverse events was similar in both groups. ...

FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0001] This invention was made with United States Government support under 1R01 N5 39097-01 A1 awarded by the National Institute of Neurological Disorders and Stroke (NIDS), National Institute of Health. The United States Government has certain rights in the invention.FIELD OF THE INVENTION

[0002] The invention relates to methods for treating a traumatic injury to the central nervous system.BACKGROUND OF THE INVENTION

[0003] Between 1.5 and 2 million Americans sustain a traumatic brain injury (TBI) each year (Anonymous, “Traumatic Brain Injury,”Center for Disease Control and Prevention, National Center for Injury Prevention and Control, 2003, Vol. 2003). In the U.S. it is estimated that TBI is responsible for 50,000 deaths and 100,000 hospitalizations annually (Anonymous, “Traumatic Brain Injury,”Center for Disease Control and Prevention, National Center for Injury Prevention and Control, 2003, Vol. 2003). Over 80,000 are disabled annually, appr...

Examples

example 1

[0076]As a first step in assessing the applicability of progesterone therapy in humans, we examined the effects of acute TBI and extracranial trauma on the pharmacokinetics of PG given by intravenous infusion. Multiple blood samples were obtained from 11 female and 21 male trauma patients receiving PG and 1 female and 3 male patients receiving placebo infusions for 72 h. Values for CSS, CL, t1 / 2 and Vd were obtained using AUC(0-72) and post-infusion blood samples. CSS values were 337±135 ng / mL, which were significantly lower than the target concentration of 45±100 ng / mL. The lower CSS is attributed to the CL, which was higher than anticipated. In addition, t1 / 2 was longer and Vd was higher than anticipated. There were no significant gender differences in any of these parameters. These changes are consistent with the hyperkinetic changes associated with critical injury. Our results demonstrate that stable PG concentrations can be rapidly achieved following TBI.

Methods

Patient Selecti...

example 2

[0095]A pilot phase II, randomized, double-blind, controlled trial of progesterone for the treatment of a traumatic brain injury was preformed. The administration protocol was carried out was described above in Example 1.

[0096]To determine if a therapeutic response was achieved, the following endpoints were monitored:

[0097]ICP reduction determined by calculating “therapeutic intensity level” (ICP-TIL);

[0098]duration of coma (injury to awaking);

[0099]mortality one-month post injury;

[0100]neurological outcome 1 month and 1 year post-injury, as determined by Glasgow outcome scale (GOS), Disability rating scale (DRS) and Galveston orientation and amnesia test (GOAT).

[0101]The preliminary evaluations are as follows. One hundred patients having moderate to severe TBI were enrolled in the study, which had a randomized block design 4:1 enrollment. Three days IV administration of progesterone [450+ / −mmol / L] in both males and females. The administration protocol and pharmaceutical composition...

example 3

[0104]We conducted a clinical trial to assess the safety of progesterone as a treatment for acute TBI. This phase II, randomized, double blind, placebo-controlled clinical trial was conducted at an urban, level I trauma center. 100 adults presenting within 11 hours of a blunt TBI with a Glasgow Coma Scale score of 4-12 were enrolled with proxy consent. Subjects were randomized on a 4:1 basis to progesterone versus placebo. Blinded observers closely monitored patients for the occurrence of adverse events, and initial functional outcomes were assessed 30 days post-injury. The primary safety outcome was difference in adverse event rates, including mortality. The primary measure of activity was dichotomized Glasgow outcome scale extended (GOSE) 30 days post injury. Seventy-seven patients received progesterone; 23 received placebo. The groups had very similar demographic and clinical characteristics. With the exception of mortality, the rate of adverse events was similar in both groups. ...

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