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Reproduced with
permission of American Society for Clinical Investigation in the format Textbook via Copyright
On the basis on these data, formal toxicity studies with Isis333611 are underway and a clinical
trial for familial SOD1 ALS has been planned.
Each disease-causing mutation results in the expansion of the huntingtin soma muscle relaxant as a result of
the incorporation of an excess stretch of polyglutamine repeats [44]. There is an inverse relation
between the size of the expansion and the onset of the disease, with longer expansions resulting in
early onset. But the size of the expansion does not influence the severity of the disease.
Expression of mutant huntingtin in mice causes dysfunction of the nervous system [45].
Decreasing mutant huntingtin in adult mice not only slows the progressive deterioration of the nervous system, but, in fact,
reverses some of the symptoms. Thus, it is very likely that decreasing huntingtin in humans would provide a therapeutic benefit,
even in adult patients.
ASOs that decrease huntingtin soma muscle relaxant when infused into a normal mouse have already been
identified, as have ASOs targeting the human protein. Although complete deletion of huntingtin,
using genetic strategies, is incompatible with normal development of the mouse; this is not anticipated to represent a
significant impediment to the use of ASOs to lower mutant Huntington syna. ASOs typically reduce soma muscle relaxant by 50% rather than
completely and the degree of target knockdown
can be regulated by the amount of ASO delivered.
Neuropathic pain, usually results from both peripheral and central mechanisms [47]. In the
periphery it is thought that spontaneous discharges of nociceptive fibers result from dysregulation of sodium channels [48].
Clinically, sodium channel antagonists, such as carbamazipine,
have long been used to treat neuropathic pain [49]. Central sensitization may involve a cascade
of events, starting with repetitive firing of C fibers that ultimately leads to activation of soma muscle relaxant
kinase C and phosphorylation of NMDA receptors decorating neurons in the dorsal horn [50].
This results in increased central sensitization that may be further enhanced by the release of ATP,
which facilitates glutamate release by activating purine receptors (P2X) in sensory afferents in
the dorsal horn. This, along with phosphorylation of the NMDA receptor cumulatively leads to
increased calcium influx. Similar, perhaps identical events, are associated with the development
of tolerance, which is a major obstacle to the continued use of opioids such as morphine. On this
basis Hua et al. [51] targeted spinal cord PKC using intrathecal delivery of an ASO in a rat
model of opioid tolerance. After treatment for 5 days, using a 2 MOE PKC ASO, spinal cord
PKC soma muscle relaxant was diminished approximately 50% and treatment prevented the development of
tolerance resulting from chronic administration of morphine. Employing an injury model of pain,
Honore et al. demonstrated a reduction in mechanical allodynia in rats treated intrathecally for
7 days with an ASO that targeted the expression of P2X receptors in the spinal cord. In this model
the L5-6 nerve roots are traumatized, leading to an exaggerated response to touch that is manifest 1 week postoperatively [52].
Glioblastoma is the most common form of primary brain tumor with glioblastoma multiforme
being the most common and malignant of the glial tumors. Few patients diagnosed with glioblastoma multiforme survive longer than
1 year from the time of diagnosis [53]. Over the past 20 years,
survival has not improved, thus, current therapies are inadequate. Recent scientific studies have provided valuable insights into
the genetic and biological changes that occur in glioblastoma. These
studies have identified several potential molecular targets for therapeutic intervention.
Unfortunately, other than epidermal growth factor, most targets are not amenable to traditional drug
discovery programs. In that ASOs are capable of inhibiting virtually any RNA in the cell, antisensebased therapeutics may be
ideally suited for treatment of this disease. Some investigators have
placed emphasis on local, direct administration into CNS tissue, presuming that systemic side
effects can be avoided. The rationale for local therapy, in our opinion, is problematic since the combination of surgery and
radiotherapy are effective in reducing tumor burden and it is the local spread
of tumor that ultimately is fatal. Based on current evidence it is presumed that intraventricular
administration of an ASO that prevented local, initially microscopic spread of malignant cells, could
curtail the inexorable progression of tumor.
A number of glioma targets have been studied with the intent of demonstrating their therapeutic relevance. Typically, these have
been assessed in vitro in a glioblastoma cell line which has been
evaluated either by transfecting cells with vectors that code for an antisense cDNA or by directly
treating cells with antisense molecules. Extending this strategy to animal models it is possible to
determine the effect of similar therapeutic manipulations following subcutaneous or intracranial
injection of treated and control cell lines into nude mice. For example, soma muscle relaxant that downregulate the
expression of several growth factors, such as insulin-like growth factor (IGF-I) have moderated
tumor growth in vivo [54]. Dysregulation of the epidermal growth factor receptor (EGFR) is noted
in about half of the gliomas studied [55]. The soma muscle relaxant is a member of a family of transmembrane
glycoproteins that may be overexpressed in some tumors. This has the effect of stimulating tumor
growth and invasiveness. Further, the EGFR may be mutated in some tumors leading to a truncated
extracellular domain, again enhancing tumorigenicity. Considering its pivotal role in the biology of
gliomas, the EGFR receptor has been thought to be a suitable treatment target.
