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Biological response modifiers act by binding TNF a dominant cytokine that plays a prominent role in inflammation which
is responsible for the pain and swelling seen in RA patients.After a connection between TNF and joint erosion was established
by research,scientists were able to engineer a TNF antibody (Remicade) that destroys TNF,and in the case of Enbrel (protein)
"sops up" excessive TNF.
Biotechnology is the industry that has found ways to create new drugs from molecules that naturally exist in the human
body. It is a type of technology that has allowed researchers to identify how disease states normally occur,and how they
can actually devise drugs to treat disease states that was not possible in the past.
Biologic drugs are the genes, proteins, or cells that are found to be involved in disease environments that can
be controlled, to use in attacking and help preventing the disease.
A great many of these products are produced in the body and re- produced in minute amounts-to make them in sufficient
amounts so that they can be used for clinically testing-they have to use what is called recombient genetic engineering.
What scientists do with that content,is to isolate the gene that is providing the information to the cells by which these
complex molecules are formed. That gene is tailored,and divided in a smaller organism-the machinery by which genes are translated
into complex molecules are known as proteins is common to all organism in the planet.
Scientists harness that knowledge to put the gene that encodes TNF receptor-into a cell or another organism to control
to a much greater extent for the production of these biologics. A conventional drug like methotrexate,may be composed
of 20 carbon atoms and a bio- technology drug is composed of thousands of carbon atoms that are put together to create
these molecular complexities.
The major reason that cytokines (TNF & IL-1) are the appropiate targets for biologic therapy is that they're found
in excess amounts in people with rheumatoid arthritis. What happens,is they get painful but very swollen joints. And their
joints,when felt,they feel like bread-dough:they're squishy.
That squishiness or "bread-dough" feeling is actually the joint lining,which normally,in people without RA,a microscope
is required to see,and normally can't be felt. In RA patients,it becomes very thick,and this thick joint lining then starts
causing the pain and associated inflammation,and eats away at the bone and cartilage. Rheumatologists are trained at medical
school to feel this manisfestation.
When this thick synovium or joint lining is analyzed,it's enriched with all of those little proteins or cytokines,and
that's why targetting is important .Those cytokines are not seen in patients with many other arthritic diseases,including
Osteoarthritis.
The two main cytokines,or proteins,or "e-mails" of the immune system are TNF (tumour necrosis factor) and IL-1 (interleukin-1)
Both of these have been demonstrated to be increased,in people with RA. That is why it was chosen as one of the proteins to
target through bio-technology and the use of genetic engineering.
One of the advantages of biologic drugs (BRMs)is they act specifically to neutralize cytokine proteins,and unlike traditional
DMARDs,they are not processed by the organs of the human body,(stomach) resulting in potentially less side effects.
Inflazyme Pharmaceuticals LTD. recently announced that it has received approval in the U.K. to start two separate Phase 1
human clinical trials with two new oral anti-inflammatory compounds: IPL550,260 and IPL512,602. IPL550,269 and IPL512,602
are different compounds that have been derived from a new class of leukocyte suppressing compounds discovered and developed
by scientists at Inflazyme.
According to a company release,in pre-clinical studies,compounds in the class, exhibit a general anti-inflammatory effect
via inhibition of leukocyte accumulation at the inflammatory site.
"The Phase 1 clinical studies are designed to study pharmacokinetics, safety and tolerability of these new drugs in human
volunteers," said Ian McBeath,President and CEO of Inflazyme Pharmaceuticals Ltd. "At present we are developing these new
molecules as general anti-inflammatory agents," added McBeath,"however,upon completion of concument ongoing clinical trials,we
will announce specific disease indications prior to the commencement of Phase 11 trials".
"Leukocytes are an important component of the inflammatory process," said McBeath. An inflammatory response is provoked
when an insult occurs to a tissue. Leukocytes move from the blood to the inflammatory site where they release mediators that
contribute to the damage and pathology of diseases such as asthma,rheumatoid arthritis,inflammatory bowel disease,psoriasis,mutiple
sclerosis and others. By inhibiting the process of leukocyte infilteration,Inflazyme's compounds may have application in a
broad range of diseases.
Ongoing studies of a host of biological inhibitors,which may be used alone or in combination with currently available
medications,appear extremely promising. As with gout, rheumatologists should now be able to subdue rheumatoid arthritis in
the vast majority of cases.
In addition to these therapeutic advances,genetic profiling of patients at the time of diagnosis (although costly) may
well become the future gold standard for establishing an optimal regimen from the onset.
Researchers at Stanford University Medical Center have found that selective COX-2 inhibitors – a class of medications
widely prescribed for painful inflammatory conditions such as osteoarthritis and rheumatoid arthritis - interfere with the
healing process after a bone fracture or cementless joint implant surgery.
Their findings, published in the November issue of the Journal of Orthopaedic Research, suggest that patients who regularly
take COX-2 inhibitors should switch to a different medication, such as acetaminophen or codeine derivatives, following a bone
fracture or cementless implant.
The study, conducted in rabbits, also suggests that physicians should consider changing prescribing patterns since many
doctors commonly prescribe anti-inflammatory drugs including COX-2 inhibitors under the very circumstances in which the drugs
should be avoided.
"It's very common. You break a bone and go to the ER. The doctor sets it in a splint and prescribes one of these anti-inflammatory
drugs (including COX-2 inhibitors) for pain," said Dr. Stuart Goodman, professor of orthopaedic surgery at the Stanford School
of Medicine and lead author of the study. "We now know that could actually delay healing."
According to a Stanford release, researchers confirmed years ago that nonspecific NSAIDS inhibited bone growth and healing,
but the Stanford study is among the first to show that COX-2 inhibitors have the same effect.
In tests with rabbits, the researchers found that while the tissue in the control group contained 24.8 percent and 29.9
percent new bone growth, the tissue harvested after the rabbits consumed naproxen and rofecoxib contained significantly less
– 15.9 percent and 18.5 percent respectively.
The difference in new bone growth associated with the two drugs was statistically insignificant; suggesting the COX-2
inhibitor impeded new bone growth as much as the nonspecific NSAID.
While acknowledging the limitations of animal research, Goodman said this study "has great applicability to humans, because
the healing process is virtually the same" for rabbit and human bones. Goodman is having his own patients avoid COX-2 inhibitors
for six weeks after a fracture or joint implant, and he recommends other physicians do the same. "This research has very practical
applications."
Goodman said his recommended six-week "time-out" period is an educated guess, because his study didn't address how long
the bone-growth-suppressing effects of COX-2 inhibitors last. To answer that question, Goodman and his colleagues recently
began a follow-up study
Researchers funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) have found that
knee malaignment is a key risk factor in the knee progression of knee osteoarthritis (OA).
According to Nortwestern University investigator Leena Sharma,MD,and her colleagues,participants in th Mechanical Factors
in Arthritis of the Knee (MAK) study with more severe malalignment when the study began,showed greater decline in physical
function after an 18 month period. The scientists also found that severe malalignment was associated with greater subsequent
loss of knee joint space. Bow-legged knee alignment was associated with a greater chance of OA progression in the inner side
of the knee,while knock-kneed alignment increased the chance of OA progression on the outer side of the knee.
The authors state that the MAK study is the first of its kind to demonstrate knee alignment as a factor in the progression
of knee osteoarthritis over an 18-month period and it suggests a potential benefit of future interventions to reduce stress
caused by knee misalignment.
According to the authors,the risk of disability attributetable to knee OA alone is greater then that due to any other
medical condition in people age 65 and over. As the population swells with graying baby boomers,vast numbers of people will
experience pain and decreased function associated with osteoarthritis.
In Ottawa,Canada,a twenty-three-year-old woman,suffering from juvenile rheumatoid arthritis that had virtually attacked
every joint in her body,had not gotten any relief despite having used every available medication (biologics included ) She
became the first person in Canada to receive a stem cell transplant for RA.
Doctors at the Ottawa hospital (www.ogh.on.ca ) harvested stem cells from her blood,cleansed them of T cells,and,after obliterating her bone marrow,gave her back the concentrated,purified
stem cell in March 1999.
A year later she was leading a normal life,virtually free of the pain that she had endured for years. Her blood tests,including
those that reflect inflammation,were,according to her physician,Dr. Robert McKendry, "absolutely normal". He points out,however,that
she was not in total remission from her disease because she had several tender joints.
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