OnTarget (January 15, 2007)
I. WHAT'S NEW?
New Publication to be Presented at ASCO
II.
QUIZ - (Fill In The Blanks)
Neanderthal DNA
III. HISTORY OF MEDICINE
Chemotherapy
IV. ONCOLOGY
Gene Signature For Outcome
Prediction in NSCLC
V. PEDIATRICS
Treatment of Takayasu Arteritis in Children
VI. NEUROLOGY
Depressive Symptoms and Risk of Stroke
VII. RHEUMATOLOGY
Folic
Acid Supplemetation Reduces Hearing Loss
VIII. REGULATORY AFFAIRS
Orphan Drugs
IX.
TARGET
HEALTH
I.
WHAT'S NEW
New
Publication to be Presented at ASCO
Target Health is pleased to announce coauthorship of
an abstract entitled, “Phase II Study of a Novel Micellar Paclitaxel Formulation for Treatment of Pancreatic
Cancer.” The abstract will be presented at the ASCO Multidisciplinary
Approaches to the Prevention, Diagnosis, and Therapy of GI Cancers meeting
(January 19-21, 2007, at the Orlando World Center Marriott). The study used
Target e*CRF® for data collection and data management. Target Health monitored
the study, performed the statistical analyses and wrote the study report. We
also represent this Asian company at FDA.
The abstract is authored by
Terry Plasse, MD (Target Health,
NY
,
NY
), Mark Rubin, MD
(Florida Cancer Specialists, Ft Myers, FL), Wasif Saif, MD (Yale University
School of Medicine,
New Haven
,
CT
),
Jose Figueroa, MD (
Arrington
Cancer
Center
,
Lubbock
,
Texas
)
and Robert Kerr, MD (
Southwest
Regional
Cancer
Center
,
Austin
,
TX
).
Please let us know if you
will be attending the meeting. For more information, please contact Dr.
Jules T. Mitchel.
II. QUIZ (Fill In The Blanks)
Neanderthal DNA
We know that Neanderthals and,
Cro-Magnon man overlapped in
Europe
for
thousands of years. Then 1) ___ arrived, and 30,000 years ago, Neanderthals
either died out or we interbred with them. Previously, scientists have looked
at Neanderthal 2) ___ DNA (mtDNA) because there is a
lot of it in fossils. But to really figure out if our ancestors mixed with
Neanderthals, we need to look at 3) ___ DNA, which is where the research has
now focused. New methods have become available that allow scientists to get DNA
from smaller, more fragmented samples. One company, called 454 Life Sciences,
separates out, all of the Neanderthal DNA contaminated with bacterial or 4) ___
DNA, with computers and fancy computer tools, using a process called 5) ___.
One groups' findings see a split from Neanderthals around 500,000 years ago,
just as the mtDNA suggested, showing that humans and
Neanderthal are around 99.5% the same. The similarity between any two random
people is 99.9%. And between a 6) ___ and a human is 98.7%. The second group's
data was consistent with male Neanderthals interbreeding with female
Cro-Magnon. This is just the sort of liaison that would be invisible in 7) ___.
A lot more nuclear DNA sequencing is needed to get a definitive answer. As more
and more DNA is 8) ___ from many different fossils, we should find out, soon,
if 21st Century humans have any Neanderthal DNA?
ANSWERS: 1) Homo Sapiens;
2) mitochondrial; 3) nuclear; 4) fungal; 5) metagenomics;
6) chimp; 7) mtDNA; 8) sequenced
III. HISTORY OF MEDICINE
Chemotherapy
Sidney Farber, a
pathologist at
Harvard
Medical
School
,
studied the effects of folic acid on leukemia patients. Folic acid, a vitamin
crucial for DNA metabolism, was discovered by Lucy Wills in 1937. Folic acid
seemed to stimulate the proliferation of acute lymphoblastic leukemia (ALL) cells when administered to children with this cancer. In one of
the first examples of rational drug design (rather than accidental discovery),
in collaboration with Harriett Kilte and Lederle Laboratories chemists, Farber synthesized folate analogues. These analogues, first aminopterin and then amethopterin (AKA methotrexate) were folic acid antagonists, and
blocked the function of folate-requiring enzymes.
When administered to children with ALL in the late 1940s, these agents became
the first drugs to induce remission in children with ALL. Remissions were
brief, but the principle was clear that antifolates could suppress proliferation of malignant cells, and could thereby re-establish
normal bone-marrow function. It is worth noting that Farber met resistance to
conducting his studies at a time when the commonly held medical belief was that
leukemia was incurable, and that the children should be allowed to die in
peace. Afterwards, Farber's 1948 report in the New England Journal of Medicine
was met with incredulity and ridicule. Remarkably, a decade later at the
National Cancer Institute, Roy Hertz and Min Chiu Li discovered that methotrexate treatment alone could cure choriocarcinoma (1958), a germ-cell malignancy that originates in trophoblastic cells of the placenta. This was the first solid tumor to be cured by
chemotherapy. edited by Alex Hays
IV. ONCOLOGY
Gene Signature For Outcome
Prediction in NSCLC
Current staging
methods are inadequate for predicting the outcome of treatment of
non–small-cell lung cancer (NSCLC). As a result, a study published in the New
England Journal of Medicine (2007; 356:11-20), was performed to develop a gene
signature that is closely associated with survival of patients with NSCLC. For
the study, computer-generated random numbers was used to assign 185 frozen
specimens for microarray analysis, real-time
reverse-transcriptase polymerase chain reaction (RT-PCR) analysis, or both.
Gene expression was then studied in frozen specimens of lung-cancer tissue from
125 randomly selected patients who had undergone surgical resection of NSCLC.
The association between the level of expression and survival was then evaluated
using risk scores and decision-tree analysis to develop a gene-expression model
for the prediction of the outcome of treatment of NSCLC. Results showed that 16
genes correlated with survival among patients with NSCLC were identified by
analyzing microarray data and risk scores. Five genes
(DUSP6, MMD, STAT1, ERBB3, and LCK) were then selected for RT-PCR and
decision-tree analysis. The five-gene signature was found to be an independent
predictor of relapse-free and overall survival. These data were then validated
with data from an independent cohort of 60 patients with NSCLC and with a set
of published microarray data from 86 patients with
NSCLC. The authors concluded that the five-gene signature is closely associated
with relapse-free and overall survival among patients with NSCLC.
V. PEDIATRICS
Treatment of Takayasu Arteritis in Children
Arteritis is a general term that refers to the inflammation of arteries, or blood vessels
(vasculitis), that carry blood away from the heart. Takayasu’s arteritis (TA) is an
uncommon form of vasculitis where inflammation
damages large and medium-sized blood vessels. The vessels most commonly
affected are the branches of the aorta (the main blood vessel that leaves the
heart), including the blood vessels that supply blood to the arms and travel
through the neck to provide blood to the brain. The aorta itself is also often
affected. According to an article published in the Journal of Pediatrics
(2007;150:72-76), a study was performed to evaluate a 7-year treatment protocol
for TA in children using cyclophosphamide (CYC)
induction and corticosteroids followed by methotrexate.
The study included six patients (4 girls, 2 boys) with an age range of 12 to 17
years. Patients were allocated to receive: 1) oral steroids and methotrexate (MTX) (12.5 mg/m2/week) if they had disease
limited to one side of the diaphragm only without pulmonary disease involvement
(n=2); and 2) oral steroids and oral CYC (maximum total dose 150 mg/kg)
followed by oral MTX for maintenance as above if the disease was more
widespread (n=4). Results to date showed that one patient died of pulmonary vasculitis during the first month of therapy. The remaining
three patients with involvement of both the thoracic and abdominal aorta and
branches received the second protocol for 12 to 18 months. All entered
remission. Aortic bypass, aortorenal bypass, balloon
dilatation, and unilateral nephrectomy were also
performed in these patients. According to the authors, this single-center
experience suggests that CYC induction and corticosteroids followed by MTX is
an effective and safe treatment for childhood TA.
VI. NEUROLOGY
Depressive Symptoms and Risk
of Stroke
For an interesting
article on the interaction of major depression and medical illness, see Medscape Today's article authored by Paul J. Perry, Ph.D.
Emerging evidence raises the
possibility of an association between depression and stroke risk. As a result,
a study published in the journal Stroke (2007;38:16-21),
was performed to examine whether depressive symptoms are associated with an
increased risk of cerebrovascular events. The
investigation was a prospective study conducted with 4,120 Framingham Heart
Study participants aged 29 to 100 years, with up to 8 years of follow-up. The
Center for Epidemiologic Studies Depression Scale was used to measure
depressive symptoms. Incident stroke and transient ischemic attack (TIA) events
were assessed by uniform diagnostic criteria. The association between
depressive symptoms and risk of stroke/TIA was analyzed with Cox
proportional-hazards models, after adjusting for traditional stroke risk
factors. Results showed that in participants <65 years, the risk of
developing stroke/TIA was 4.21 times greater (P=<0.001) in those with
symptoms of depression. After adjusting for components of the Framingham Stroke
Risk Profile (hazard ratio=3.43, P=0.002) and education (hazard ratio=4.89),
similar results were obtained. In subjects aged 65 and older, depressive
symptoms were not associated with an increased risk of stroke/TIA. Taking
antidepressant medications did not alter the risk associated with depressive
symptoms. According to the authors, depressive symptoms were an independent
risk factor for incident stroke/TIA in individuals <65 years, and that these
data suggest that identification of depressive symptoms at younger ages may
have an impact on the primary prevention of stroke.
VII. OTOLOGY
Folic Acid Supplemetation Reduces Hearing Loss
Age-related hearing loss
is a common chronic condition of elderly persons. Low folate status has been associated with poor hearing. As a result, a study published in
the Annals of Internal Medicine (2007;146:1-9) was
performed to determine whether folic acid supplementation slows age-related
hearing loss. The investigation was a double-blind, randomized, placebo-controlled
trial conducted from September 2000 to December 2004. For the study, 728 older
men and women in The Netherlands were recruited from municipal and blood bank
registries. All study participants at screening had to have plasma total homocysteine concentrations of 13 µmol/L or greater, and
serum and vitamin B12 concentrations of 200 pmol/L or
greater. Participants also had to have no middle ear dysfunction, no unilateral
hearing loss, or no pathologic ear conditions unrelated to aging. Treatment was
daily oral folic acid (800 µg) or placebo supplementation for 3 years. Study
measurements included 3-year change in hearing thresholds, assessed as the
average of the pure-tone air conduction thresholds of both ears of the low
(0.5-kHz, 1-kHz, and 2-kHz) and high (4-kHz, 6-kHz, and 8-kHz) frequencies.
Baseline median hearing thresholds were 11.7 dB (interquartile range, 7.5 to 17.5 dB) for low frequencies and 34.2 dB (interquartile range, 22.5 to 50.0 dB) for high frequencies. Sixteen participants (2%) were
lost to follow-up. After 3 years, thresholds of the low frequencies increased
by 1.0 dB in the folic acid group and by 1.7 dB in the placebo group
(difference, -0.7 dB, P = 0.020). Folic acid supplementation did not affect the
decline in hearing high frequencies. Limitations of the study were that the
strict criterion for participation on the basis of serum homocysteine concentrations limited extrapolation to the general population. Also, folic
acid fortification of food was prohibited in the
Netherlands
during the study, so baseline folate levels in
participants were about half of those found in the
U.S.
population. Nevertheless, it
was concluded that folic acid supplementation slowed the decline in hearing of
the speech frequencies associated with aging in a population from a country
without folic acid fortification of food.
VIII. REGULATORY AFFAIRS
TARGET HEALTH excels in
Regulatory Affairs and works closely with many of its clients performing all
FDA submissions. TARGET HEALTH receives daily updates of new developments at
FDA. Each week, highlights of what is going on at FDA are shared to assure that
new information is expeditiously made available.
Orphan Drugs
Target Health is
currently involved in 2 Orphan Drug Designation requests. To date, we have
submitted and have received, 6 Orphan Drug Designations on behalf of our
clients.
The Office of Orphan Products Development (OOPD) is dedicated to promoting the
development of products that demonstrate promise for the diagnosis and/or
treatment of rare diseases or conditions since 1982. OOPD interacts with the
medical and research communities, professional organizations, academia, and the
pharmaceutical industry, as well as rare disease groups. The OOPD administers
the major provisions of the Orphan Drug Act (ODA) which
provide incentives for sponsors to develop products for rare diseases. The ODA
has been very successful - more than 200 drugs and biological products for rare
diseases have been brought to market since 1983. In contrast, the decade prior
to 1983 saw fewer than ten such products come to market. In addition, the OOPD
administers the Orphan Products Grants
Program which provides funding for clinical research in rare diseases
For more information about
our expertise in Regulatory Affairs, please contact Dr. Jules T. Mitchel or Dr. Glen Park.
IX. TARGET HEALTH
TARGET HEALTH INC. (www.targethealth.com) is a full service e*CRO with full-time staff dedicated to all aspects of drug
and device development. Areas of expertise include Regulatory Affairs, comprising,
but not limited to, IND, IDE, NDA, PMA and 510(k) submissions, execution of
Clinical Trials, Project Management, Biostatistics and Data Management, Web
Trials, utilizing Target e*CRF®, our proprietary Internet-based Clinical Trial
System, and Medical Writing. TARGET HEALTH's Pharmaceutical Advisory Dream Team (PADT) assists companies in strategic
planning from Discovery to Market Launch. Let us help you on your next project.
TARGET HEALTH INC.
261 Madison Avenue
24th Floor
New York
,
NY
10016
Phone: (212) 681-2100; Fax (212) 681-2105
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Dr. Jules T. Mitchel, President
Ms Joyce Hays, CEO
