OnTarget (February 26, 2007)
I. WHAT'S NEW?
Target Health - e*CRO
II. UIZ - (Fill In The Blanks)
Plant Steroid - Stigmasterol
III. HISTORY OF MEDICINE
Percy L. Julian (1899–1975;
Harvard
U.
, M.A., 1923; U.
Vienna
, Ph.D., 1931)
IV. CARDIOLOGY
On-Pump/Off-Pump CABG - No Difference in
Cognitive Function
V. IMMUNOLOGY
Vaccine Against CMV Reduces Stillbirths in Animals
VI. INFECTIOUS DISEASE
Dexamethasone and Tuberculous Meningitis
VII. REGULATORY AFFAIRS
Combination Products
VIII.
TARGET
HEALTH
I.
WHAT'S NEW
Target
Health - e*CRO
Target e*CRO, is committed to the development of web-based technology tools to
support clinical research. Our products include Target e*CRF (over 100 studies
to date with 2 NDA,1 PMA approved and 1 PMA
submitted), Target Document, Target Encoder and Target Patient Profiler.
All of our products are Part 11 compliant. We also represent 19 companies at
FDA, so regulatory compliance is key.
For more information, please contact Dr.
Jules T. Mitchel. Visit our Blog and Website.
II. QUIZ (Fill In The Blanks)
Plant Steroid - Stigmasterol
Stigmasterol is an unsaturated plant sterol occurring in the plant fats or
oils of soybean, calabar bean, wild yam, rapeseed, and in a number of medicinal herbs, including the
Chinese herbs, Mai men dong and American Ginseng. Stigmasterol is chemically similar to animal 1) ___. Stigmasterol is used as a 2) ___ in the manufacture of synthetic progesterone, a valuable
human hormone that plays an important physiological role in the regulatory and
tissue rebuilding mechanisms related to estrogen effects. Stigmasterol also acts as an intermediate in the biosynthesis of androgens, estrogens, and
corticoids. Research has indicated that 3) ___ may be useful in prevention of
certain cancers, including ovarian, prostate, breast and colon cancers. Studies
have also indicated that a diet high in phytoesterols may inhibit the absorption of cholesterol and lower serum cholesterol levels by
competing for 4) ___ absorption. Plant sterols and stanols represent a group of 5) ___ that are an essential constituent of cell membranes
in animals and plants. Cholesterol is actually a sterol of human cells, whereas phytosterols are produced by plants. The most common
plant sterols are sitosterol, campesterol,
and stigmasterol. Plant sterols, although
structurally similar to cholesterol, are not 6) ___ by the human body and are
very poorly absorbed. The specific plant sterols that are currently
incorporated into foods, supplements and drugs are extracted from soybean oil
and wild yams. Dr. Percy Julian did major research in plant steroids.
ANSWERS: 1) cholesterol;
2) precursor; 3) stigmasterol; 4) intestinal; 5)
compounds; 6) synthesized
III. HISTORY
OF MEDICINE
Percy L. Julian
(1899–1975; Harvard U., M.A., 1923; U. Vienna, Ph.D., 1931)
When Percy Lavon Julian,
whose grandfather was a slave, attended DePauw University in the early 1900s,
there were very few African American college students anywhere, and its Indiana
town was still segregated. Julian was not allowed to live in a college
dormitory and initially stayed in an off campus boarding house. Ultimately, he
took work firing the furnace and doing other odd jobs in a fraternity house
and, in return for his service, he was allowed to eat and sleep in the
basement. He graduated from DePauw in 1920, as Phi Beta Kappa
and the valedictorian. Julian, became an
American research chemist, and a pioneer in the chemical synthesis of medicinal
drugs from plants. He was the first to synthesize the natural product physostigmine. His chemical synthesis of human steroids
from plant steroid precursors would lay the foundation for the birth control
pill and cortisone. Dr. Julian isolated simple compounds in natural products.
He investigated how those compounds were naturally altered into chemicals
essential to life, including vitamins and hormones, and then attempted to
create the compounds artificially. As director of research of Glidden's Soya
Products Division in
Chicago
,
Dr. Julian attracted attention for synthesizing the drug physostigmine,
used to treat glaucoma. He refined a soya protein
that became the basis of Aero-Foam, a foam fire extinguisher used by the U.S.
Navy in World War II. He led research that resulted in quantity production of
the hormones progesterone (female) and testosterone (male) and of cortisone
drugs. In 1950, Julian was named "
Chicago
's
Man of the Year" in a Chicago Sun-Times poll. Tragically, his home was
bombed and burned when he moved to the all-white suburb of
Oak Park
. Eventually, he started his own
company, Julian Laboratories Inc., and competed against Syntex,
and testified before Congress to break their monopoly on synthesizing human
steroids from the Mexican yam. His efforts helped to reduce the cost of
synthetic steroids. During his lifetime, Julian received more than 130 chemical
patents. Julian was the second African American to receive a doctorate in
chemistry and was the first African American chemist inducted into the National
Academy of Sciences.
IV. CARDIOLOGY
On-Pump/Off-Pump CABG - No
Difference in Cognitive Function
Conventional
coronary artery bypass graft (CABG) surgery with use of cardiopulmonary bypass
(on-pump CABG) is associated with excellent long-term cardiac outcomes but also
with a high incidence of cognitive decline. The effect of avoiding
cardiopulmonary bypass (off-pump CABG) on long-term cognitive and cardiac
outcomes is unknown. As a result, a study published in the Journal of the
American Medical Association (2007;297:701-7080, was
performed to compare the effect of off-pump CABG and on-pump CABG surgery on
long-term cognitive and cardiac outcomes. The Octopus Study was a multicenter randomized controlled trial conducted in the
Netherlands
,
which enrolled 281 low-risk CABG patients between 1998 and 2000. Five years
after their surgery, surviving patients were invited for a follow-up
assessment. For the study, patients were randomly assigned to receive either
off-pump (n = 142) or on-pump (n = 139) CABG surgery. The main outcome measure
was cognitive status 5 years after surgery, determined by a psychologist
blinded to treatment allocation. Ten standardized validated neuropsychological
tests were used. Secondary measures were occurrence of cardiovascular events
(all-cause mortality, stroke, myocardial infarction, and coronary reintervention), anginal status,
and quality of life. After 5 years, 130 patients were alive in each group.
Cognitive outcomes could be determined in 123 and 117 patients in the off-pump
and on-pump groups, respectively. When using a standard definition of cognitive
decline (20% decline in performance in 20% of the neuropsychological test
variables), 62 (50.4%) of 123 in the off-pump group and 59 (50.4%) of 117 in
the on-pump group had cognitive decline. When a more conservative definition of
cognitive decline was used, 41 (33.3%) in the off-pump group and 41 (35.0%) in
the on-pump group had cognitive decline (absolute difference, –1.7%; P = .79).
Thirty off-pump patients (21.1%) and 25 on-pump patients (18.0%) experienced a
cardiovascular event (absolute difference, 3.1%; P = .55). No differences were
observed in anginal status or quality of life.
According to the authors, in low-risk patients undergoing CABG surgery,
avoiding the use of cardiopulmonary bypass had no effect on 5-year cognitive or
cardiac outcomes.
V. IMMUNOLOGY
Vaccine Against
CMV Reduces Stillbirths in Animals
The experimental
vaccine used in this study is called a vector vaccine. Vector
vaccines differs from traditional vaccines in that it uses an altered
virus to deliver one gene from the viral DNA to the animal's cells. The cells
then begin manufacturing the viral protein. Cells of the
immune system detect the viral protein and launch an attack against it.
In so doing, they learn to recognize CMV. The gene used in the
present experimental guinea pig CMV vaccine -- UL83, also called pp65 --
contains the information needed to make a protein involved in the infection
process. The virus used to make the vector vaccine (Venezuelan Equine
Encephalitis Virus) was altered by removing 40 percent of the virus' genes, to
prevent it from reproducing and infecting new hosts.
Cytomegalovirus virus (CMV) is a common viral infection related to the herpes
virus and often causes few or no symptoms. Every year, 0.5 to 2.5% of babies
born in the
United States
are infected with CMV. Estimates place the number of
U.S.
children born with CMV each
year at about 40,000, and there is no vaccine or treatment for pregnant women
who have the infection. In a 2000 report, the
Institute
of
Medicine
of the National Academy of Sciences listed as a top priority the development of
a vaccine to prevent cytomegalovirus during pregnancy. The virus is transmitted
to the fetus through the mother's placenta. About10-15% of babies with
congenital CMV have a long-term disability such as
mental retardation, cerebral palsy, and hearing loss. The infection could
potentially cause other developmental disabilities such as autism or attention
deficit disorder. The virus can also damage the placenta, leading to pregnancy
loss. CMV is present in bodily secretions and is spread through close personal
contact. The virus can enter through mucosal surfaces such as the mouth or
breaks in the skin. It can also be transmitted through nasal secretions and
blood transfusions, and people-to-people contact. Most adults will become
infected with CMV at some point during their lives. According to an article
published in The Journal of Infectious Diseases (2007;195:789-798),
an experimental vaccine has been developed that reduces stillbirths among
rodents born to mothers infected with CMV. For the study, female guinea pigs
given the CMV vaccine before becoming pregnant gave birth to fewer dead pups
and were less likely to transmit the infection to their offspring than were
female guinea pigs not receiving the vaccine. The vaccinated group (10 litters)
produced 28 live pups and 4 dead pups, a mortality rate of 13%. The control
group (8 litters), which received a vaccine for the flu, produced 9 live pups
and 12 dead pups, a mortality rate of 57 %. The surviving pups also weighed
more than the pups of mothers that had not received the CMV vaccination before
becoming pregnant. The vaccine greatly reduced the total amount of virus found
in the mothers' blood. The vaccine in the study was developed in collaboration
with researchers at AlphaVax, Inc.
VI. INFECTIOUS DISEASE
Dexamethasone and Tuberculous
Meningitis
Adjunctive dexamethasone increases survival from tuberculous meningitis, but
the underlying mechanism is unclear. As a result, a study published in Lancet
Neurology (2007;6:230-236) was performed to determine
the effect of dexamethasone on cerebral MRI changes
and their association with intracerebral inflammatory
responses and clinical outcome in adults treated for tuberculous meningitis. For the study, cerebral MRI was undertaken, when possible, at
diagnosis and after 60 days and 270 days of treatment in adults with tuberculous meningitis admitted to two hospitals in
Vietnam
.
Patients were randomly assigned either dexamethasone (n=24) or placebo (n=19) and received 9 months of treatment with standard
first-line antituberculosis drugs. Associations were
assessed between MRI findings, treatment allocation, and resolution of fever,
coma, cerebrospinal fluid inflammation, and neurological outcome. During the
study, 83 scans were done for 43 patients: 19 given placebo, 24 given dexamethasone. Basal meningeal enhancement (82%) and hydrocephalus (77%) were the most common presenting
findings. Fewer patients had hydrocephalus after 60 days of treatment with dexamethasone than after placebo treatment (p=0.217). Tuberculomas developed in 74% of patients during treatment
and in equal proportions in the treatment groups. Tuberculomas were associated with long-term fever, but not relapse or poor clinical outcome.
The basal ganglia were the most common site of infarction. However, the
proportion with infarction after 60 days was halved in the dexamethasone group (27% vs 58%, p=0•130). According to the
authors, dexamethasone may affect outcome from tuberculous meningitis by reducing hydrocephalus and
preventing infarction, and that the effect may have been under-estimated
because the most severe patients could not be scanned.
VII. 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.
Combination Products
Target Health
has worked on and is working on several combination drug-device (PMA Approved), drug/drug (NDA Approved) products.
Combination
products (i.e., drug-device, drug-biologic, and device-biologic
products) are increasingly incorporating cutting edge, novel technologies that
hold great promise for advancing patient care. For example, innovative drug
delivery devices have the potential to make treatments safer or more effective,
or more convenient or acceptable to patients. Drug-eluting cardiovascular stents have the potential to reduce the need for surgery by
preventing the restenosis that sometimes occurs following stent implantation. Drugs and biologics can be used in combination to potentially
enhance the safety and/or effectiveness of either product used alone. Biologics
are being incorporated into novel orthopedic implants to help facilitate the
regeneration of bone required to permanently stabilize the implants. Since
combination products involve components that would normally be regulated under
different types of regulatory authorities, and frequently by different FDA
Centers, they also raise challenging regulatory, policy, and review management
issues. A number of criticisms have been raised regarding FDA's regulation of
combination products. These include concerns about the consistency,
predictability, and transparency of the assignment process; issues related to
the management of the review process when two (or more) FDA Centers have review
responsibilities for a combination product; lack of clarity about the postmarket regulatory controls applicable to combination
products; and lack of clarity regarding certain Agency policies, such as when
applications to more than one Agency Center are needed. To address these
concerns, FDA's Office of Combination
Products (OCP) was established on Dec. 24, 2002, as required by the Medical
Device User Fee and Modernization Act of 2002 (MDUFMA).
The law gives the Office broad responsibilities covering the regulatory life
cycle of drug-device, drug-biologic, and
device-biologic combination products. However, the primary regulatory
responsibilities for, and oversight of, specific combination products will
remain in one of three product centers -- the Center for Drug Evaluation and
Research, the Center for Biologics Evaluation and Research, or the Center for
Devices and Radiological Health -- to which they are assigned.
For more information about
our expertise in Regulatory Affairs, please contact Dr. Jules T. Mitchel or Dr.
Glen Park.
VIII. 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.
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New York
,
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Ms Joyce Hays, CEO
