Target Health Presenting at the Biotech Showcase 2012 January 9-11

 

 

Target Health is pleased to announce that Dr. Jules T. Mitchel will be chairing a Regulatory Panel at the Biotech Showcase 2012, January 9-11, 2012 in San Francisco. Please let us know if you will be attending or in San Francisco concurrent with the JP Morgan Meeting.

 

The esteemed panelists include:

  1. Afia K. Asamoah – Senior Associate, Covington & Burling LLP; former Special Assistant to the Principal Deputy Commissioner, FDA
  2. Nancy Bradish Myers, JD – President and Founder, Catalyst Healthcare Consulting
  3. Michele Yelmene – President, QCRC Services

 

Panel Title: Getting a Drug Approved as the FDA Is Evolving

Location: Parc 55 Wyndham on Cyril Magnin Street

Date: Wednesday, January 11

Time: 8:00 – 8:55 am

Room: Level 4, Mission II

 

Abstract: The FDA recently kicked off an organization-wide Innovation Initiative, which promises to redouble the agency’s efforts to encourage innovations that will promote public health as well as strengthen the American economy. While the FDA has many critics calling for change and there is hope that this initiative will benefit not only patients but innovators and their investors as well, this does not obviate the need for companies with drugs in advanced stages of development to have a strategy to their drugs approved. This panel will share their thoughts on what to do and how do it even as this all important agency is going through change

 

For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website at www.targethealth.com

Nanotechnology May Speed Up Drug Testing

Santra and his team used semiconductor Qdots to create a new probe. (Credit: Image courtesy of University of Central Florida)

 

 

Testing the effectiveness of new pharmaceuticals may get faster thanks to a new technique incorporating quantum dots developed at the University of Central Florida.

 

Some drug 1) ___ can take a decade or more, but UCF associate professor Swadeshmukul Santra and his team have created an electronic quantum dots (Qdots) probe that “lights up” when a drug it is delivering attaches to cancer cells. The research appears online in this month’s Biomaterials. Using this technique, a researcher can use a microscope to see where and how much of the drug has been delivered because the probe emits a reddish color under special 2) ___ or via MRI because of its optical and magnetic components. As the drug testing continues, images can be taken over and over without any loss of optical or MRI signal. Researchers can then measure the size of the tumor and number of cancer 3) ___ that “light up” compared with the original untreated tumor. This provides a way to determine whether the drug is doing what it is supposed to be doing in the targeted areas. The technique is much easier than the current process of removing treated cancer 4) ___ and weighing them at regular intervals to determine the drug’s efficiency in an animal.

 

“Many people in my area have been studying this approach for years,” Santra said. “But we have now moved it into a live cell, not just in 5) ___ tubes.” Sudiptal Seal, the director of UCF’s NanoScience Technology Center and nanoscience scientist believes Santra’s research is significant. “This is indeed a major breakthrough in Qdot research,” Seal said. “This new diagnostic 6) ___ will certainly impact the field of nanomedicine.”

 

Santra and his team used semiconductor Qdots to create the probe. Because of their small 7) ___ and crystal-like structure, Qdots display unique optical and electronic properties when they get excited. These unique properties make them ideal for sustained and reliable imaging with special lights.

 

For this research funded by the National Science Foundation and National Institutes of Health, the UCF-led team used a superparamagnetic iron oxide nanoparticle core decorated with satellite CdS:Mn/ZnS Qdots which carried the cancer-fighting agent STAT3 inhibitor. The Qdot optical signal turned on when the 8) ___ bonded with the cancer cells. “The potential applications for drug testing specifically for 9) ___ research are immediate,” Santra said.

 

Santra has his own team of students and scientists at the UCF NanoScience Technology Center, which has been studying nanotechnology, quantum dots and their applications for years. The team focuses on the engineering of nanomaterials for bioimaging and sensing, 10) __ delivery and anti-microbial applications.

 

ANSWERS: 1) testing; 2) lighting; 3) cells; 4) tumors; 5) test; 6) tool; 7) size; 8) probe; 9) cancer; 10) drug

Metabolism

 

Santorio Santorio in his steelyard balance, from Ars de statica medicina, first published 1614

 

 

 

Metabolism, derived from the Greek “Metabolismos” for “change”, or “overthrow,” is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories. Catabolism breaks down organic matter, for example to harvest energy in cellular respiration. Anabolism uses energy to construct components of cells such as proteins and nucleic acids.

 

The history of the scientific study of metabolism spans several centuries and has moved from examining whole animals in early studies, to examining individual metabolic reactions in modern biochemistry. The first controlled experiments in human metabolism were published by Santorio Santorio in 1614 in his book Ars de statica medicina. In the book, Santorio describes how he weighed himself before and after eating, sleep, working, intimacy, fasting, drinking, and excreting. He found that most of the food he took in was lost through what he called “insensible perspiration.”

 

In these early studies, the mechanisms of these metabolic processes had not been identified and a vital force was thought to animate living tissue. In the 19th century, when studying the fermentation of sugar to alcohol by yeast, Louis Pasteur concluded that fermentation was catalyzed by substances within the yeast cells he called “ferments”. He wrote that “alcoholic fermentation is an act correlated with the life and organization of the yeast cells, not with the death or putrefaction of the cells.” This discovery, along with the publication by Friedrich Wohler in 1828 of the chemical synthesis of urea, notable for being the first organic compound prepared from wholly inorganic precursors, proved that the organic compounds and chemical reactions found in cells were no different in principle than any other part of chemistry.

 

It was the discovery of enzymes at the beginning of the 20th century by Eduard Buchner that separated the study of the chemical reactions of metabolism from the biological study of cells, and marked the beginnings of biochemistry. The mass of biochemical knowledge grew rapidly throughout the early 20th century. One of the most prolific of these modern biochemists was Hans Krebs who made huge contributions to the study of metabolism. He discovered the urea cycle and later, working with Hans Kornberg, the citric acid cycle and the glyoxylate cycle. Modern biochemical research has been greatly aided by the development of new techniques such as chromatography, X-ray diffraction, NMR spectroscopy, radioisotopic labeling, electron microscopy and molecular dynamics simulations. These techniques have allowed the discovery and detailed analysis of the many molecules and metabolic pathways in cells.

 

Glucose can exist in both a straight-chain and ring form.

 

 

The chemical reactions of metabolism are organized into metabolic pathways, in which one chemical is transformed through a series of steps into another chemical, by a sequence of enzymes. Enzymes are crucial to metabolism because they allow organisms to drive desirable reactions that require energy and will not occur by themselves, by coupling them to spontaneous reactions that release energy. As enzymes act as catalysts they allow these reactions to proceed quickly and efficiently. Enzymes also allow the regulation of metabolic pathways in response to changes in the cell’s environment or signals from other cells.

 

The metabolism of an organism determines which substances it will find nutritious and which it will find poisonous. For example, some prokaryotes use hydrogen sulfide as a nutrient, yet this gas is poisonous to animals. The speed of metabolism, the metabolic rate, influences how much food an organism will require, and also affects how it is able to obtain that food.

 

A striking feature of metabolism is the similarity of the basic metabolic pathways and components between even vastly different species. For example, the set of carboxylic acids that are best known as the intermediates in the citric acid cycle are present in all known organisms, being found in species as diverse as the unicellular bacteria Escherichia coli and huge multicellular organisms like elephants. These striking similarities in metabolic pathways are likely due to their early appearance in evolutionary history, and being retained because of their efficacy.

ONCOLOGY

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EGFR Expression as a Predictor of Survival for First-Line Chemotherapy Plus Cetuximab in Patients with Advanced Non-Small-Cell Lung Cancer

 

 

Findings from the phase 3 First-Line ErbituX in lung cancer (FLEX) study showed that the addition of cetuximab (Erbitux) to first-line chemotherapy significantly improved overall survival compared with chemotherapy alone (hazard ratio [HR] 0.871; p=0·044) in patients with advanced non-small-cell lung cancer (NSCLC). As a result, a study published in The Lancet Oncology (2012;13:33-42), was performed to define patients benefiting most from cetuximab by evaluating the association of tumor EGFR expression level with clinical outcome in FLEX study patients.

 

The study used prospectively collected tumor EGFR expression data to generate an immunohistochemistry score for FLEX study patients on a continuous scale of 0-300, and used response data to select an outcome-based discriminatory threshold immunohistochemistry score for EGFR expression of 200. Treatment outcome was analyzed in patients with low (immunohistochemistry score <200) and high (>200) tumor EGFR expression. The primary endpoint in the FLEX study was overall survival.

 

Tumor EGFR immunohistochemistry data were available for 1,121 of 1,125 (99.6%) patients from the FLEX study ITT population. High EGFR expression was scored as for 345 (31%) evaluable patients and low for 776 (69%) patients. For patients in the high EGFR expression group, overall survival was longer in the chemotherapy plus cetuximab group than in the chemotherapy alone group (median 12.0 months vs. 9·6 months p=0.011), with no meaningful increase in side-effects. There was no corresponding survival benefit for patients in the low EGFR expression group (median 9.8 months; p=0.88). A treatment interaction test assessing the difference in response for overall survival between the EGFR expression groups suggested a predictive value for EGFR expression (p=0.044).

 

According to the authors, high EGFR expression is a tumor biomarker that can predict survival benefit from the addition of cetuximab to first-line chemotherapy in patients with advanced NSCLC and that assessment of EGFR expression could offer a personalized treatment approach in this setting.

Bariatric Surgery and Long-term Cardiovascular Events

 

 

Obesity is a risk factor for cardiovascular events. Weight loss might protect against cardiovascular events, but solid evidence is lacking. As a result, a study published in the Journal of the American Medical Association (2012;307:56-65) was performed to study the association between bariatric surgery, weight loss, and cardiovascular events.

 

Data were derived from the Swedish Obese Subjects (SOS) study. The SOS is an ongoing, nonrandomized, prospective, controlled study conducted at 25 public surgical departments and 480 primary health care centers in Sweden of 2010 obese participants who underwent bariatric surgery and 2,037 contemporaneously matched obese controls who received usual care. Patients were recruited between September 1, 1987, and January 31, 2001. Date of analysis was December 31, 2009, with median follow-up of 14.7 years (range, 0-20 years). Inclusion criteria were age 37 to 60 years and a body mass index of at least 34 in men and at least 38 in women. Exclusion criteria were identical in surgery and control patients.

 

Surgery patients underwent gastric bypass (13.2%), banding (18.7%), or vertical banded gastroplasty (68.1%), and controls received usual care in the Swedish primary health care system. Physical and biochemical examinations and database cross-checks were undertaken at preplanned intervals. The primary outcome measure was total mortality with myocardial infarction and stroke as predefined secondary end points.

 

Results showed that bariatric surgery was associated with a reduced number of cardiovascular deaths (28 events among 2,010 patients in the surgery group vs. 49 events among 2,037 patients in the control group; P = .002). The number of total first time (fatal or nonfatal) cardiovascular events (myocardial infarction or stroke, whichever came first) was lower in the surgery group (199 events among 2010 patients) than in the control group (234 events among 2037 patients; P < .001).

 

The authors concluded that compared with usual care, bariatric surgery was associated with reduced number of cardiovascular deaths and lower incidence of cardiovascular events in obese adults.

Rotating Night Shift Work and Risk of Type 2 Diabetes

 

 

Rotating night shift work disrupts circadian rhythms and has been associated with obesity, metabolic syndrome, and glucose dysregulation. However, its association with type 2 diabetes remains unclear. As a result, a study published in PLoS Medicine (2011;8:e1001141)was performed to evaluate this association in two cohorts of US women.

 

The study followed 69,269 women aged 42–67 in Nurses’ Health Study I (NHS I, 1988–2008), and 107,915 women aged 25–42 in NHS II (1989–2007) without diabetes, cardiovascular disease, and cancer at baseline. At the baseline visit, study participants were asked how long they had worked rotating night shifts (defined as at least 3 nights/month in addition to days and evenings within the same month). This information was updated every 2-4 years in NHS II. Self-reported type 2 diabetes was confirmed by a validated supplementary questionnaire. During the study there were 6,165 (NHS I) and 3,961 (NHS II) incident type 2 diabetes cases documented during the 18–20 years of follow-up. Results showed that the duration of shift work was monotonically associated with an increased risk of type 2 diabetes in both cohorts. Compared with women who reported no shift work, the pooled hazard ratios for participants with 1-2, 3-9, 10-19, and >20 years of shift work were 1.05, 1.20, 1.40, and 1.58; p-value for trend <0.001), respectively. Further adjustment for updated body mass index attenuated the association, and the pooled hazard ratios were 1.03, 1.06, 1.10 and 1.24 (p-value for trend <0.001).

 

The authors conclude that an extended period of rotating night shift work is associated with an increased risk of type 2 diabetes in women, which appears to be partly mediated through body weight, and that screening and intervention strategies in rotating night shift workers are needed for prevention of diabetes.

TARGET HEALTH excels in Regulatory Affairs. Each week we highlight new information in this challenging area.

 

 

FDA Prohibits Certain Uses of Antimicrobial Drugs in Food-Producing Animals

 

 

Core structure of the cephalosporins

 

 

The cephalosporins are a class of β-lactam antibiotics originally derived from Acremonium, which was previously known as “Cephalosporium”.

Together with cephamycins they constitute a subgroup of β-lactam antibiotics called cephems.

Cephalosporins are indicated for the prophylaxis and treatment of infections caused by bacteria susceptible to this particular form of antibiotic. First-generation cephalosporins are active predominantly against Gram-positive bacteria, and successive generations have increased activity against Gram-negative bacteria (albeit often with reduced activity against Gram-positive organisms).

Cephalosporins are commonly used in humans to treat pneumonia as well as to treat skin and soft tissue infections. In addition, they are used in the treatment of pelvic inflammatory disease, diabetic foot infections, and urinary tract infections. If cephalosporins are not effective in treating these diseases, doctors may have to use drugs that are not as effective or that have greater side effects.

 

Antimicrobial drugs are important for treating disease in both humans and animals. This past week, FDA issued an order that prohibits certain uses of the cephalosporin class of antimicrobial drugs in cattle, swine, chickens and turkeys effective April 5, 2012. FDA is taking this action to preserve the effectiveness of cephalosporin drugs for treating disease in humans. Prohibiting these uses is intended to reduce the risk of cephalosporin resistance in certain bacterial pathogens. This new order takes into consideration the substantial public comment FDA received on a similar order that it issued in 2008, but revoked prior to implementation.

 

In its order, FDA is prohibiting what are called “extralabel” or unapproved uses of cephalosporins in cattle, swine, chickens and turkeys, the so-called major species of food-producing animals. Specifically, the prohibited uses include:

 

  • using cephalosporin drugs at unapproved dose levels, frequencies, durations, or routes of administration;
  • using cephalosporin drugs in cattle, swine, chickens or turkeys that are not approved for use in that species (e.g., cephalosporin drugs intended for humans or companion animals);
  • using cephalosporin drugs for disease prevention.

 

The order does not limit the use of cephapirin, an older cephalosporin drug that is not believed by FDA to contribute significantly to antimicrobial resistance. Veterinarians will still be able to use or prescribe cephalosporins for limited extra-label use in cattle, swine, chickens or turkeys as long as they follow the dose, frequency, duration, and route of administration that is on the label. Veterinarians may also use or prescribe cephalosporins for extralabel uses in minor species of food-producing animals such as ducks or rabbits.