Methods for treating muscle injuries

Details Methods for treating muscle injuries Methods for treating muscle injuries

2000-10-04

2002-07-23

Carlson, Karen Cochrane (Department: 1653)

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Bacterium or component thereof or substance produced by said...

C424S239100, C424S236100, C435S069100, C435S320100, C435S325000, C435S252300, C536S023100, C514S002600, C514S012200, C530S350000, C530S412000

Reexamination Certificate

active

06423319

ABSTRACT:

BACKGROUND
The present invention relates to methods for treating muscle injuries. In particular, the present invention relates to a method for treating an injured muscle by administration of a neurotoxin to the injured muscle.
Injuries to muscles include acute injuries to skeletal muscles such as contusions (bruises), lacerations, ischemia, strains, and complete ruptures. These injuries may cause tremendous pain and can incapacitate the affected person, preventing them from being able to go to work or even to participate in normal daily activities. Of the acute injuries to skeletal muscles, strain (also known as stretch-induced injuries) is most common. For example, strains can account for up to 30% of all injuries treated by occupational or sports medicine professionals. Garrett et al.
Am J Sports Med
, 24(6):S2-S8, 1996.
A muscle strain injury is characterized by a disruption of a muscle-tendon unit. The disruption of the muscle-tendon unit may occur anywhere on the muscle. This type of injury most commonly occurs near the myotendinous junction (MTJ) of the superficial muscles working across two joints, such as the rectus femoris, semitendinousus and gastroenemius muscles.
Muscle strain may result from an eccentric exercise, or uncommon use of the muscle. For example, eccentric contractions employ fewer active motor units to generate higher forces. In such case, the over-extended muscle units experience excessive tension during lengthening. The excessive tension may cause microscopic damages to the contractile element of the muscle, centering on what appears to be random disruptions of the Z-Iines. When the muscle is damaged, the affected person may experience a delayed onset muscle soreness, characterized by pain, weakness and a limited range of motion. The pain is most intense for about 1 to 2 days after the muscle injury and the weakness and limited range of motion can last for a week or more. If a minor strain of the skeletal muscles is treated inappropriately, a more serious injury can occur.
There are three classifications of muscle strains, based on the severity of the injury and the nature of the hematoma: (1) mild, (first degree) strain; a tear of a few muscle fibers; minor swelling and discomfort with no or only minimal loss of strength and restriction of movement; (2) moderate, (second degree) strain; a greater damage of muscle fibers with a clear loss of strength, and; (3) severe (third degree) strain; a tear extending across the whole muscle belly, resulting in a total loss of muscle function.
Tearing of the intramuscular blood vessels during muscle strain can often result in a large hematoma. Two different types of hematomas occur in the injured muscle: intramuscular and intermuscular hematomas. The first type, intramuscular hematomas, is limited in size by the intact muscle fascia. There, the extravasation of blood increases the intramuscular pressure, compressing and limiting the size of the hematoma. Such type of hematoma causes pain and loss of function of the muscle. The second type, intermuscular hematomas, develops when the muscle fascia is ruptured and extravasated blood spreads into the intermuscular spaces without significantly increasing the pressure within the muscle. This type of hematoma may not cause significant pain if the pressure within the muscle does not increase.
For treatments of strain injuries, it is critical that the injured muscle be immobilized, especially during the first two to three days after the injury, since mobilization of the injured muscles immediately after the injury often causes re-rupturing at the original injury site. A re-rupturing may lead to more severe injuries, delayed healing and scarring of tissues. Jarvinen et al.,
Curr Opin Rheumatol
, vol 12:155-161 (2000).
Re-rupturing of the damaged site may be avoided by immobilizing the injured muscle, preferably immediately after the injury. Immobilization allows the newly formed granulation tissue to reach sufficient tensile strength to withstand the forces created by contracting muscle.
A known method for immobilization of an injured/strained muscle requires use of a physical restraint or cast. For example, a cervical collar can be used to immobilize an injured cervical flexor or extensor. However, the use of a restraint is often cumbersome and uncomfortable. Moreover, for injuries of certain muscle groups, it is not practical or possible to use a physical restraint. For example, it is very difficult to immobilize a strained upper trapezius or gluteus maximus muscle with a restraint.
Botulinum Toxin
The anaerobic, gram positive bacterium Clostridium botulinum produces a potent polypeptide neurotoxin, botulinum toxin, which causes a neuroparalytic illness in humans and animals referred to as botulism. The spores of Clostridium botulinum are found in soil and can grow in improperly sterilized and sealed food containers of home based canneries, which are the cause of many of the cases of botulism. The effects of botulism typically appear 18 to 36 hours after eating the foodstuffs infected with a Clostridium botulinum culture or spores. The botulinum toxin can apparently pass unattenuated through the lining of the gut and attack peripheral motor neurons. Symptoms of botulinum toxin intoxication can progress from difficulty walking, swallowing, and speaking to paralysis of the respiratory muscles and death.
Botulinum toxin type A (“BoNT/A”) is the most lethal natural biological neurotoxin known to man. About 50 picograms of botulinum toxin (purified neurotoxin complex) serotype A is a LD
50
in mice. One unit (U) of botulinum toxin is defined as the LD
50
upon intraperitoneal injection into female Swiss Webster mice weighing 18-20 grams each. Seven immunologically distinct botulinum neurotoxins have been characterized, these being respectively botulinum neurotoxin serotypes A, B, C
1
, D, E, F and G each of which is distinguished by neutralization with serotype-specific antibodies. The different serotypes of botulinum toxin vary in the animal species that they affect and in the severity and duration of the paralysis they evoke. For example, it has been determined that BoNt/A is 500 times more potent, as measured by the rate of paralysis produced in the rat, than is botulinum toxin serotype B (BoNT/B). Additionally, BoNt/B has been determined to be non-toxic in primates at a dose of 480 U/kg which is about 12 times the primate LD
50
for BoNt/A. Botulinum toxin apparently binds with high affinity to cholinergic motor neurons, is translocated into the neuron and blocks the release of acetylcholine.
Botulinum toxins have been used in clinical settings for the treatment of neuromuscular disorders characterized by hyperactive skeletal muscles. BoNt/A has been approved by the U.S. Food and Drug Administration for the treatment of blepharospasm, strabismus and hemifacial spasm. Non-serotype A botulinum toxin serotypes apparently have a lower potency and/or a shorter duration of activity as compared to BoNt/A. Clinical effects of intramuscular of a botulinum toxin, such as BoNt/A, can be noted in a matter of hours. Thus, it is important to note that most if not all of the botulinum toxins can, upon intramuscular injection, produce significant muscle paralysis within one day of the injection, as measured, for example, by the mouse Digit Abduction Score (DAS). Aoki K. R., Preclinical Update on BOTOX (Botulinum Toxin Type A)-Purified Neurotoxin Complex Relative to Other Botulinum Toxin Preparations, Eur J. Neur 1999, 6 (suppl 4):S3-S10. The typical duration of symptomatic relief from a single intramuscular injection of BoNt/A averages about three months. Botulinum toxins, including botulinum toxin type A, with reduced periods of in vivo biological activity are set forth in co-pending U.S. patent application Ser. No. 09/620840, which application is incorporated herein by reference in its entirety.
Although all the botulinum toxins serotypes apparently inhibit release of the neurotransmitter acetylcholine at the neuromuscular junction, they do so by affecting different neurosecretory

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