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16 January 2006
I.
WHAT'S NEW?
DIA Annual
Meeting - Data Standards Presentation
II. QUIZ
(Fill In The Blanks)
Taiwan
Boasts Of Transgenic Pig As It Eyes Stem Cell Research
III.
HISTORY OF MEDICINE
The First
Isolated Antibiotic
IV. ENDOCRINOLOGY
New Diabetes Gene Identified
V. CARDIOLOGY
Biomarkers and Coronary Heart Disease
VI. NEUROLOGY
High-Sensitivity C-Reactive Protein and Stroke Risk
VII. PSYCHIATRY
Depression - SSRI Treatment in the "Real World"
VIII. FDA
New Guidance - Exploratory IND's
IX. Target Health Inc.
DIA Annual
Meeting - Data Standards Presentation
Target Health is
pleased to announce that Dr. Jules T. Mitchel will be presenting at the 2006
Annual DIA Meeting in Philadelphia. The session, entitled “Evolution of
Standards: Opportunities, Benefits and Challenges,” is being chaired by David A
Olagunju, Director, Global B&SR Standards, Novartis Pharma Corporation, and
will take place on Tuesday, June 20, 2006 at 10:30 AM. Please let us know if
you will be attending the annual meeting and please stop by at our
booth. For more information about this program, please contact Dr.
Jules T. Mitchel.
Taiwan Boasts Of Transgenic
Pig As It Eyes Stem Cell Research
A research team,
based in Taipei, Taiwan, which is home to the world's first transgenic glowing
1) ___, has successfully bred 2) ___ green pigs, that researchers hope will
boost Taiwan's stem cell research. Transgenic means: an organism whose 3) ___
has been modified by introduction of novel 4) ___. By injecting pig embryos
with jelly fish DNA which causes fluorescence, a research team at National
Taiwan University has managed to breed three male transgenic pigs. These are
the only pigs in the world that are green from 6) ___ out. Even their hearts
and internal organs are green. These transgenic pigs, will be used to study 7)
___ diseases, and will help researchers monitor and trace changes of 8) ___
during development. In 2003, a Taiwan company began selling the world's first
genetically 9) ___ fish, sparking protests by environmentalists who said the
fluorescent green fish posed a threat to the earth's 10) ___.
Answers: 1) fish; 2)
fluorescent; 3) genome; 4) DNA; 5) DNA; 6) inside; 7) human; 8) tissue; 9)
engineered; 10) ecosystem
The First Isolated
Antibiotic
One of the earliest areas of
scientific exploration in the field of antibiotics was whether harmless
bacteria could treat diseases caused by pathogenic strains of bacteria.
By the late 19th century there were a few notable breakthroughs. In 1877,
Louis Pasteur showed that the bacterial disease anthrax, which can cause
respiratory failure, could be rendered harmless in animals with the injection
of soil bacteria. In 1887, Rudolf Emmerich showed that the intestinal infection
cholera was prevented in animals that had been previously infected with the
streptococcus bacterium and then injected with the cholera bacillus. While
these experiments showed that bacteria could treat disease, it was not until a
year later, in 1888, that the German scientist E. de Freudenreich isolated an
actual product from a bacterium that had antibacterial properties.
Freudenreich found that the blue pigment released in culture by the bacterium Bacillus
pyocyaneus arrested the growth of other bacteria in the cell culture.
Experimental results showed that pyocyanase, the product isolated from B.
pyocyaneus, could kill a multitude of disease-causing bacteria. While
pyocyanase is the first antibiotic discovered, it unfortunately proved toxic
and unstable, and thus, could not be developed into an effective drug.
New Diabetes Gene
Identified
Dysfunction of
the exocrine pancreas is observed in diabetes, but links between concurrent
exocrine and endocrine pancreatic disease and contributing genetic factors are poorly
characterized. As a result, a study, published in Nature Genetics
(2006;38:54-62), evaluated two families with diabetes and exocrine pancreatic
dysfunction by genetic, physiological and in vitro functional studies. A
genome-wide screen in Family 1 linked diabetes to chromosome 9q34 (maximal lod
score 5.07). Fecal elastase deficiency, as a marker of exocrine pancreatic
dysfunction, refined the critical chromosomal region to 1.16 Mb (maximal lod
score 11.6). In this region, a single-base deletion was identified in the
variable number of tandem repeats (VNTR)-containing exon 11 of the carboxyl
ester lipase (CEL) gene. This gene is a major component of pancreatic juice and
responsible for the duodenal hydrolysis of cholesterol esters. Screening
subjects with maturity-onset diabetes in children, the study identified a
second family with another single-base deletion in CEL, with a similar
phenotype with beta-cell failure and pancreatic exocrine disease. The in vitro
catalytic activities of wild-type and mutant CEL protein were comparable. The
mutant enzyme was, however, less stable and secreted at a lower rate.
Furthermore, some evidence was found for an association between common
insertions in the CEL VNTR and exocrine dysfunction in a group of 182 unrelated
subjects with diabetes (odds ratio 4.2 (1.6, 11.5)). According to the authors,
the findings link diabetes to the disrupted function of a lipase in the
pancreatic acinar cells and that mutations in the gene encoding carboxyl ester
lipase (CEL), cause beta cell dysfunction and early-onset diabetes. As this
gene is expressed in the exocrine, and not the endocrine, pancreas, its
identification challenges many of our preconceived ideas about the causes of
beta cell dysfunction in diabetes.
Biomarkers and Coronary
Heart Disease
Apolipoprotein B (apoB) plasma
levels reflect the concentration of the proatherogenic lipoproteins very
low-density lipoprotein and low-density lipoprotein (LDL), whereas
non–high-density lipoprotein cholesterol (non–HDL-C) levels reflect the
concentration of cholesterol transported by these particles. As a result, a
study published in Circulation (2005;112:3375-3383), was performed to compare
apoB, non–HDL-C, LDL cholesterol (LDL-C), and other lipid markers as predictors
of coronary heart disease (CHD). The study was a nested case-control study
among 18,225 participants in the Health Professionals Follow-up Study. Results
showed that among men who were free of diagnosed cardiovascular disease at the
time of blood collection, 266 had nonfatal myocardial infarction or fatal CHD
during 6 years of follow-up. Through the use of risk set sampling, control
subjects were selected at a 2:1 ratio and matched with regard to age, date of
blood collection, and smoking status. After adjustment for matching factors,
the relative risk of CHD in the highest quintile compared with the lowest
quintile was 2.76 for non–HDL-C, 3.01 for apoB, 1.81 for LDL-C, 0.31 for
HDL-C, 2.41 for triglycerides (all P trend <0.001), and 1.42 (P trend =0.19)
for lipoprotein(a). When non–HDL-C and LDL-C were mutually adjusted, only
non–HDL-C was predictive of CHD. When non–HDL-C and apoB were mutually
adjusted, only apoB was predictive; the relative risk was 4.18 (P trend =0.02)
for apoB compared with 0.70 (P trend =0.72) for non–HDL-C. Triglycerides added
significant information to non–HDL-C but not to apoB for CHD risk prediction.
It was concluded that although non–HDL-C and apoB were both strong predictors
of CHD in this male cohort, more so than LDL-C, the findings support the
concept that the plasma concentration of atherogenic lipoprotein particles
measured by apoB is more predictive in development of CHD than the cholesterol
carried by these particles, measured by non–HDL-C.
High-Sensitivity C-Reactive
Protein and Stroke Risk
The role of high-sensitivity
C-reactive protein (hsCRP) in the development of stroke is not clearly
understood. As a result, a study published in Stroke (2006;37: 27-32), was
performed to investigate the relationship between serum hsCRP levels and stroke
occurrence in a general Japanese population. The study evaluated 2,692 subjects
>40 years of age for 12 years. The relative risks and 95% CIs for ischemic
and hemorrhagic stroke occurrence were calculated according to the hsCRP
quintiles. Results showed that during the follow-up, 129 first-ever ischemic
and 59 hemorrhagic strokes occurred. In men, the age-adjusted incidence of
ischemic stroke significantly increased with elevated serum hsCRP levels; the
difference between the first and fifth quintiles was statistically significant
(1.4 versus 6.6 per 1000 person-years; P=0.02). This association remained
significant even after adjustment for other confounding factors, such as age,
systolic blood pressure, ECG abnormalities, diabetes, body mass index, total
cholesterol, high-density lipoprotein cholesterol, smoking habits, alcohol
intake, and regular exercise (adjusted relative risks, 3.11; P=0.04). However,
such associations were not observed for ischemic stroke in women or in hemorrhagic
stroke in either gender. Among male subjects who were both in the fifth hsCRP
level and had hypertension, diabetes, obesity, hypercholesterolemia, or a
smoking habit, the risk of ischemic stroke was extremely increased, even after
adjustment for other risk factors. It was concluded that elevated serum hsCRP
levels are an independent risk factor for future ischemic stroke in Japanese
men and that the coexistence of a high hsCRP level with another risk factor
extremely increases the risk of ischemic stroke.
Depression - SSRI Treatment
in the "Real World"
Selective serotonin reuptake
inhibitors (SSRIs) are widely used to treat depression, but the rates, timing,
and baseline predictors of remission in "real world" patients have
not been established. As a result, a study published in the American Journal of
Psychiatry (2006;163:28-40), was performed to evaluate the effectiveness of
citalopram, an SSRI, using measurement-based care in actual practice, and to
identify predictors of symptom remission in outpatients with major depressive
disorder. The clinical study included outpatients with major depressive
disorder who were treated in 23 psychiatric and 18 primary care "real
world" settings. The patients received flexible doses of citalopram for up
to 14 weeks. The clinicians were assisted by a clinical research coordinator in
the application of measurement-based care, which included the routine
measurement of symptoms and side effects at each treatment visit, and the use
of a treatment manual that described when and how to modify medication doses
based on these measures. Remission was defined as an exit score of <7 on the
17-item Hamilton Depression Rating Scale (HAM-D) (primary outcome) or a score
of <5 on the 16-item Quick Inventory of Depressive Symptomatology,
Self-Report (QIDS-SR) (secondary outcome). Response was defined as a reduction
of >50% in baseline QIDS-SR score. Baseline data indicated that nearly 80%
of the 2,876 outpatients in the analyzed sample had chronic or recurrent major
depression, and most also had a number of comorbid general medical and
psychiatric conditions. The mean exit citalopram dose was 41.8 mg/day.
Remission rates were 28% (HAM-D) and 33% (QIDS-SR). The response rate was 47%
(QIDS-SR). Patients in primary and psychiatric care settings did not differ in
remission or response rates. A substantial portion of participants who achieved
either response or remission at study exit did so at or after 8 weeks of
treatment. Participants who were Caucasian, female, employed, or had higher
levels of education or income had higher HAM-D remission rates; longer index
episodes, more concurrent psychiatric disorders (especially anxiety disorders
or drug abuse), more general medical disorders, and lower baseline function and
quality of life were associated with lower HAM-D remission rates. According to
the authors, The response and remission rates, in this highly generalizable
sample with substantial axis I and axis III comorbidity, closely resemble those
seen in 8-week efficacy trials. The systematic use of easily implemented
measurement-based care procedures may have assisted in achieving these results.
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.
New Guidance - Exploratory IND's
The FDA has announced steps to advance the earliest phases of
clinical research in the development of innovative medical treatments.
FDA’s goal is to improve the process for bringing safe and effective drugs for
potentially serious and life-threatening diseases, such as cancer, heart disease
and neurological disorders, to the market. In guidance documents released
today, Exploratory IND
Studies and INDs-Approaches to Complying with CGMP During Phase 1, the FDA
lays out specific approaches for researchers who are planning to conduct very
early clinical studies in people and offers approaches for performing
appropriate safety testing and producing small amounts of drugs safely.
In line with the aims of FDA’s Critical Path Initiative to modernize the drug
development process, the goals of these changes are to make drug development
more efficient. The Exploratory IND Studies guidance should facilitate very
early exploratory scientific studies in people before the standard safety studies
(phase 1) begin. Because only small amounts of drugs are used in these
early studies, they represent fewer potential risks for people in these trials.
In this guidance, FDA makes recommendations about safety testing,
manufacturing, and clinical approaches that can be used in these very early
studies. The guidance explains how medical researchers can take full
advantage of the flexibility built into existing regulations in the amount of
data needed when asking the FDA’s permission to proceed with such a study,
enabling more rapid delivery of innovative products to patients. In a related
draft guidance, INDs-Approaches
to Complying with CGMP During Phase 1, the FDA outlines a suggested approach
to complying with current good manufacturing practice (CGMP) requirements for
drugs intended for use solely in phase 1 studies. Using this
approach, FDA formally recognizes specific standards for the manufacture of
small amounts of drug product for phase 1 studies and formulating an approach
to cGMP compliance that is appropriate for the particular stage of drug
development. The documents released today are part of FDA’s commitment to
modernize existing CGMP regulations to streamline clinical development. These
efforts are part of the Agency’s Critical Path Initiative, launched
in March 2004. The goal of the Critical Path Initiative is to reduce
the time and resources expended on candidate products that are unlikely to
succeed, by creating new tools to distinguish earlier in the process those
candidates that hold promise.
For copies of the Guidances and 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 fulltime 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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