Multiple-component pharmaceutical formulations and methods for their use in treating neuropathology and neurodegeneration caused by traumatic injury

Abstract

Novel two-component formulations, procedures and methods for use in treating neuropathology and neurodegeneration incident to trauma are provided. Two-component formulations of the invention comprise biologically active forms of at least one neurosteroid or neuroactive steroid, such as progesterone or synthetic progestin, and at least one anti-epileptic or anticonvulsant, such as pregabalin. The provided formulations are configured or adapted to prevent or reduce the incidence and severity of neurological damage caused by trauma. Formulations, procedures and methods of the invention advantageously effect both neuroprotective actions to prevent or reduce secondary injuries, and neurotrophic actions to repair and restore cells and tissues affected by the trauma, and are especially useful in treating neurological trauma, such as those caused by sports injuries, chemical weapons, vehicle collisions and improvised explosive devices in combat.

Description

RELATED APPLICATION AND PRIORITY[0001]This Utility patent application claims the priority and benefit of commonly owned U.S. Provisional Patent Application Ser. No. 61 / 750,745 of James L. Henry, as filed 9 Jan. 2013, and as entitled “Formulations, Methods And Procedures For Reducing Or Preventing The Development Or The Risk Of Development Of Neuropathology As A Result Of Traumatic Injury” which provisional patent application is hereby incorporated by reference in its entirety into the present patent application. Also hereby incorporated by reference in their entireties are each of the references cited herein, as well as those cited in Provisional Patent Application Ser. No. 61 / 750,745.FIELD OF THE INVENTION[0002]The presently disclosed invention, and the many particular embodiments of the invention, relate to multiple-component formulations, the use of such formulations, and to methods, procedures and combinations thereof to prevent, eliminate, or reduce, or to reduce the risk of, t...

AI Technical Summary

Problems solved by technology

Trauma to neural tissue often leads to injury, dysfunction or death of cells and tissues, and thus to numerous adverse health conditions and disabilities.

The direct, or “primary,” damage (such as physical disruption) is not salvageable once it has developed.

In stark contrast, trauma to neural tissue, such as nerves, nerve cells or any of the neural support cells or neural support tissues, often results in adverse health conditions or outcomes that persist for days, weeks or permanently.

Effective control of the balance of restorative and degenerative processes following trauma to neural tissue has proven to be difficult.

It is noteworthy that this balance is often skewed toward the degenerative outcomes in neural tissue, such as cell or tissue death, and thus to permanent dysfunction and disability.

Standard medical and therapeutic systems and processes have shown little effectiveness in addressing these negative outcomes.

As one example, injury-induced loss of glial cells or loss of glial function has been reported to have a negative outcome on injured neurons.

Brain injury is a major public health issue, inter alia, because it is a leading cause of disability.

As another example, therapeutic radiation also can lead to brain injury; white matter necrosis has been shown to occur at doses of >60Gy, leading to functional deficits including impairments in memory, attention and executive function, with profound effects on quality of life.

Whether the numbers are large, as in the case of battlefield brain injury, or small, as with falls in the elderly, brain injury can be devastating and life-changing to the individual.

Whether the numbers are large, as in the case of stroke, or small, as in the case of embolism from transcatheter aortic valve implantation, cerebral ischemia can have devastating and life-changing outcomes for the individual.

Whether the numbers are large, as in the case of vehicular accidents, or small, as in the case of many of the unreported cases, spinal cord injury can have a damaging and life-changing outcome for the individual.

As examples, chemotherapy and radiation therapy can lead to dysfunction and even cell death of neurons in the gastrointestinal tract.

Secondary injury to the enteric nervous system can have disabling and life-changing effects on the individual victim.

Neuropathology or neuropathy of peripheral nerves results in a myriad of adverse health conditions and disability.

Neuropathic pain is perhaps the best documented, largely because of the enormous impact of chronic neuropathic pain on individuals and the fact that it tends to be refractory to medical treatment.

However, other outcomes of secondary injury to peripheral nerves can be similarly devastating, including, in terms of sensory disturbance, numbness, dysesthesia (an unpleasant abnormal sensation, whether spontaneous or evoked), paresthesia (an abnormal sensation, such as tingling, whether spontaneous or evoked), hypoesthesia (decreased sensitivity to stimulation, including the special senses) and loss of proprioception (contributing to altered gait and to falls).

In terms of motor control, peripheral neuropathy can lead to weakness, loss of movement, loss of corrective motor control and loss of muscle mass.

In addition to any physical damage, trauma also compromises the normal supply of oxygen and glucose to the nervous system.

In turn, this causes a loss of ionic balance.

Nerve cells do not store alternate sources of energy for cellular metabolism and therefore intracellular stores of adenosine triphosphate (ATP), the source of cellular energy, become rapidly depleted.

Endothelial cells comprise the walls of the vasculature and their death can lead to subsequent loss of integrity of vessel wall, infiltration of degradative chemicals and immune cells into neural tissue, as well as bleeding into the extravascular space.

In particular, the excitatory amino acid transmitter, glutamate, is released at toxic levels, creating excitotoxicity.

Oxidative and nitrative stress are linked to activation of poly(ADP-ribose)polymerase, which, at high levels, impairs anaerobic glycolysis and mitochondrial respiration, leading to further exhaustion of ATP, energy failure and cell death.

Much of the neuropathology and neurodegeneration that are allowed to develop after the first few days may be refractory to any later medical treatment.