(Complimentary Newsletter from Target Health Inc.)
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4 December 2006
I.
WHAT'S NEW?
Growth at Target Health
II.
QUIZ - (Fill In The Blanks)
Humpback Whales Have 'Human' Brain Cells
III. HISTORY OF MEDICINE
Ancient Dentistry – As Early As 9,000 Years Ago
IV. TECHNOLOGY
Use of Google as a Diagnostic Aid: Internet
Based Study
V. OPHTHALMOLOGY
Ranibizumab Plus Phototherapy in Macular Degeneration
VI. PEDIATRICS
Serotonin
Levels in SIDS
VII.
INFECTIOUS DISEASE
Episodic Treatment in HIV Not Efficacious
VIII. REGULATORY AFFAIRS
Pfizer Stops Major Lipitor Combination
Drug Program
IX.
Growth At
Target Health
Target Health is pleased to announce that we have taken a lease for additional
space. We are now on the 23rd and 24th floors at
For more information, please
contact Dr.
Jules T. Mitchel.
II. QUIZ (Fill In The Blanks)
Humpback Whales Have
'Human' Brain Cells
A type of cell called a 1) ___
neuron, found in the cerebral cortex, an area comparable to where they are seen
in humans and great 2) ___ has been discovered in the brains of humpback
whales. This type of brain cell has only previously been seen in humans, the
great apes, and other cetaceans such as dolphins. This might mean such whales
are more intelligent than they have been given credit for, and suggests the
basis for complex brains either evolved more than once, or has gone unused by
most species of animals. The finding may help explain some of the behaviors
seen in whales, such as intricate 3) ___ skills, the formation of alliances,
cooperation, cultural transmission and tool usage. Although the function of
spindle neurons is not well understood, they may be involved in 4) ___ --
learning, remembering and recognizing the world around oneself. Spindle cells
may be affected by Alzheimer's disease and other debilitating brain disorders
such as autism and 5) ___. Spindle neurons, were found in the same location in
toothed whales with the largest brains and they may be related to brain size.
Toothed whales such as 6) __ are generally considered more intelligent than
baleen whales. The humpbacks also had structures that resembled
"islands" in the cerebral cortex, also seen in some other mammals.
These islands may have evolved in order to promote fast and efficient
communication between neurons. Spindle neurons probably first appeared in the
common ancestor of hominids, humans and great apes about 7) ___ million years
ago. They are not seen in lesser apes or monkeys. In cetaceans they would have
evolved earlier, possibly as early as 8) ___ million years ago. Either the
spindle neurons were only kept in the animals with the largest brains or they
evolved several times independently. In spite of the relative scarcity of
information on many cetacean species, Sperm whales, killer whales, and
certainly humpback whales, exhibit complex social patterns that included
intricate communication skills, coalition-formation, cooperation, cultural
transmission and tool usage. It is thus likely that some of these abilities are
related to comparable histological complexity in brain organization in
cetaceans and in hominids.
ANSWERS: 1) spindle; 2)
apes; 3) communication; 4) cognition; 5) schizophrenia; 6) Orcas; 7) fifteen;
8) thirty
III. HISTORY OF MEDICINE
Ancient Dentistry
– As Early As 9,000 Years Ago
In 2001
archaeologists studying the remains of two men from
Use of Google as a Diagnostic
Aid: Internet Based Study
According to an
article published in the British Medical Journal (2006;333:1143-1145), a study
was performed to determine how often searching with Google (the most popular
search engine on the world wide web) leads doctors to the correct diagnosis.
The study was designed as an Internet-based study using Google to search for
diagnoses; researchers were blind to the correct diagnoses. The study used One
year's (2005) diagnostic cases published in the case records of the New England
Journal of Medicine. Twenty six cases were excluded. The main outcome measure
was % of correct diagnoses from Google searches (compared with the diagnoses as
published in the New England Journal of Medicine). Results showed that Google
searches revealed the correct diagnosis in 15 (58%, 95% confidence interval 38%
to 77%) cases. According to the authors, as Internet access becomes more
readily available in outpatient clinics and hospital wards, web based searching
may help doctors to diagnose difficult cases.
Ranibizumab Plus
Phototherapy in Macular Degeneration
According to an
article published in the Archives of Ophthalmology (2006;124:1532-1542), a
study was performed to investigate the safety and efficacy of intravitreal ranibizumab
(Genentech) treatment combined with verteporfin
photodynamic therapy (PDT) in patients with predominantly classic choroidal neovascularization
secondary to age-related macular degeneration. The investigation was a 2-year,
phase I/II, multicenter, randomized, single-masked,
controlled study, with patients receiving monthly ranibizumab
(0.5 mg) (n = 106) or sham (n = 56) injections. The PDT was performed 7 days
before initial ranibizumab or sham treatment and then
quarterly as needed. The main outcomes measures were the proportion of patients
losing fewer than 15 letters from baseline visual acuity at 12 months (primary
efficacy outcome) and the incidence and severity of adverse events. Results
showed that at 12 months, 90.5% of the ranibizumab-treated
patients and 67.9% of the control patients had lost fewer than 15 letters
(P<.001). The most frequent ranibizumab-associated
serious ocular adverse events were intraocular inflammation (11.4%) and endophthalmitis (1.9%; 4.8% if including presumed cases).
On average, patients with serious inflammation had better visual acuity
outcomes at 12 months than did controls. Key serious nonocular
adverse events included myocardial infarctions in the PDT-alone group (3.6%)
and cerebrovascular accidents in the ranibizumab-treated group (3.8%). According to the authors,
ranibizumab + PDT was more efficacious than PDT alone
for treating neovascular age-related macular
degeneration, and that although ranibizumab treatment
increased the risk of serious intraocular inflammation, affected patients, on
average, still experienced visual acuity benefit.
Serotonin Levels in SIDS
SIDS (sudden infant
death syndrome) is the sudden and unexpected death of an infant under 1 year of
age, which cannot be explained after a complete autopsy, an investigation of
the scene and circumstances of the death, and a review of the medical history
of the infant and his or her family. In previous studies, it was hypothesized
that abnormalities in the brainstem could make an infant susceptible to
situations in which they re-breathe their own exhaled breath, thus depriving
them of oxygen. The brainstem is that part of the brain that helps control
heart rate, breathing, blood pressure, temperature and arousal. This hypothesis
holds that certain infants may not be able to detect high carbon dioxide or low
oxygen levels during sleep, and do not wake up. According to an article
published in Journal of the American Medical Association (2006;296:2143-2144), infants who die of SIDS have abnormalities
in the brainstem. The abnormalities appeared to affect the brainstem's ability
to use and recycle serotonin, a brain chemical which also is used in a number
of other brain areas and plays a role in communications between brain cells.
Serotonin is most well known for its role in regulating mood, but it also plays
a role in regulating vital functions like breathing and blood pressure. For the
study, tissues were examined from the brainstems of 31 infants who died of SIDS
and 10 infants who died of other causes. Study results showed that brainstems
from SIDS infants contained more neurons that manufacture and use serotonin
than did the brainstems of the control infants. Although the brainstem tissue
from the SIDS infants contained more serotonin-using neurons, these
serotonin-using neurons appeared to contain fewer receptors for serotonin than
did the brainstems of control infants. There are at least 14 different subtypes
of serotonin receptor. In the present study, the infants' brainstem tissue was
tested for a serotonin receptor known as "subtype 1A." Tissue from
both the SIDS infants and the control infants contained roughly equal amounts
of a key brain protein, serotonin transporter protein. This protein recycles
serotonin, collecting the neurotransmitter from the surrounding spaces outside
the neuron and transporting it back into the neuron so it can be used again.
However, because the SIDS infants had proportionately more serotonin-using
neurons than did the control infants, they would also be expected to have more
serotonin transporter protein. So even though they had equal amounts of
serotonin transporter protein, the levels were nevertheless
reduced, relative to the increased number of serotonin-using neurons. For
this reason, the serotonin levels are unlikely to meet the needs of these
cells. According to the authors, based on the current study it was not possible
to determine how much serotonin the infants' brainstems contained when the
infants were alive. However, that the pattern of abnormalities i.e. more
serotonin neurons, an apparent reduction of serotonin 1A receptors, and
insufficient serotonin transporter, suggested that the level of serotonin
in the brainstems of SIDS infants was abnormal. The study also found that male
SIDS infants had fewer serotonin receptors than did either female SIDS infants
or control infants. The finding may provide insight into why SIDS affects
roughly twice as many males as females. The NICHD-sponsored Back to Sleep http://www.nichd.nih.gov/sids/ campaign urges parents
and caregivers to place infants to sleep on their backs, to reduce SIDS risk.
The campaign has reduced the number of SIDS deaths by about half since it began
in 1994.
Episodic
Treatment in HIV Not Efficacious
Despite declines in
morbidity and mortality with the use of combination antiretroviral therapy, its
effectiveness is limited by adverse events, problems with adherence, and
resistance of the human immunodeficiency virus (HIV). As a result, a study
published in the New England Journal of Medicine (2006;355:2283-2296)
was designed to evaluate the continuous use of antiretroviral therapy (the
viral suppression group) or the episodic use of antiretroviral therapy (the
drug conservation group). For the study, persons infected with HIV who had a
CD4+ cell count of more than 350 per mm3 were randomly assigned to either the
viral suppression group or the drug conservation group. Episodic use involved
the deferral of therapy until the CD4+ count decreased to less than 250/mm3 and
then the use of therapy until the CD4+ count increased to more than 350/mm3. The
primary end point was the development of an opportunistic disease or death from
any cause. An important secondary end point was major cardiovascular, renal, or
hepatic disease. A total of 5,472 participants (2,720 assigned to drug
conservation and 2,752 to viral suppression) were followed for an average of 16
months before the protocol was modified for the drug conservation group. At
baseline, the median and nadir CD4+ counts were 597/mm3 and 250/mm3,
respectively, and 71.7% of participants had plasma HIV RNA levels of 400 copies
or less per mL. Opportunistic disease or death from
any cause occurred in 120 participants (3.3 events per 100 person-years) in the
drug conservation group and 47 participants (1.3 per 100 person-years) in the
viral suppression group (hazard ratio for the drug conservation group vs. the
viral suppression group, 2.6; P<0.001). Hazard ratios for death from any
cause and for major cardiovascular, renal, and hepatic disease were 1.8
(P=0.007) and 1.7 (P=0.009), respectively. Adjustment for the latest CD4+ count
and HIV RNA level (as time-updated covariates) reduced the hazard ratio for the
primary end point from 2.6 to 1.5. According to the authors, episodic
antiretroviral therapy guided by the CD4+ count, significantly increased the risk
of opportunistic disease or death from any cause, as compared with continuous
antiretroviral therapy, largely as a consequence of lowering the CD4+ cell
count and increasing the viral load. The authors added that episodic
antiretroviral therapy does not reduce the risk of adverse events that have
been associated with antiretroviral therapy.
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.
Pfizer Stops Major Lipitor Combination Drug Program
Torceptrapib is a cholesteryl ester transfer protein
(CETP) inhibitor that prevents the transfer of cholesteryl
esters from HDL to very-low-density lipoprotein (VLDL), thus increasing HDL
levels. Atorvastatin (Lipitor)
is an HMG Co-A reductase inhibitor. Due to an
increased rate of death in patients receiving the combination of torceptrapib/atorvastatin compared to those receiving atorvastatin alone, on December 2, 2006, FDA was notified
that Pfizer will suspend a large, Phase 3 trial. As FDA does with all
such development programs, FDA assured that Pfizer had the appropriate
protections in place for patients participating in the drug’s development,
including informed consent, a Data Safety Monitoring Board (DSMB) for its
outcome study, and that the development program was done in a careful, stepwise
manner. For this trial, the DSMB was conducting a monthly analysis of mortality
data and a quarterly analysis of a number of outcomes including stroke, heart
attack, and revascularizations (e.g., coronary stents
or bypass surgery) to ensure the ongoing safety of patients in this trial. This
independent board notified Pfizer of the mortality finding early the morning of
December 2, 2006 and FDA was notified at 4:00 PM EST that evening that Pfizer
planned to halt this trial and the development program overall. FDA has fully
supported Pfizer's decision to suspend this trial. According to FDA, the system
of biomedical research monitoring was effective in this case, assuring that
once a certain signal was seen, the trial was halted. FDA will continue to work
with Pfizer and other sponsors developing molecules in this class of drugs to
ensure that appropriate protections are in place to identify any safety signals
as early in the development process as possible.
For more information
about our expertise in Regulatory Affairs, please contact Dr. Jules T. Mitchel or Dr. Glen Park.
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.
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