New Publication in International Clinical Trials Addresses Risk-Based Monitoring and Direct Data Entry

 

 

As part of Target Health’s commitment to the scientific literature and innovations in clinical trials, we are pleased to announce the publication of an original article, entitled Risk Based Monitoring – Time For Change. The study addresses the history of direct data entry in clinical trials, the current concept of risk based monitoring and results from a Phase 2 study that used both approaches. The article appears in International Clinical Trials (February 2012).

 

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

Action Potential

 

 

Nearly all cells from animals, plants and fungi function as batteries, in the sense that they maintain a voltage difference between the interior and the exterior of the 1) ___, with the interior being the negative pole of the battery. The voltage of a cell is usually measured in millivolts (mV), or thousandths of a 2) ___. A typical voltage for an animal cell is -70 mV?approximately one-fifteenth of a volt. Because cells are so small, voltages of this magnitude give rise to very strong electric forces within the cell membrane.

 

In the majority of cells, the 3) ___ changes very little over time. There are some types of cells, however, that are electrically active in the sense that their voltages fluctuate. In some of these, the voltages sometimes show very rapid up-and-down fluctuations that have a stereotyped form: These up-and-down cycles are known as action 4) ___. The durations of action potentials vary across a wide range. In 5) ___ cells of animals, the entire up-and-down cycle may take place in less than a thousandth of a second. In other types of cells, the cycle may last for several seconds.

 

The electrical properties of an 6) ___ cell are determined by the structure of the membrane that surrounds it. A cell membrane consists of a layer of lipid molecules with larger protein molecules embedded in it. The lipid layer is highly resistant to movement of electrically charged ions, so it functions mainly as an insulator. The large membrane-embedded molecules, in contrast, provide channels through which ions can pass across the membrane, and some of the large molecules are capable of actively moving specific types of ions from one side of the membrane to the 7) ___.

 

ANSWERS: 1) cell; 2) volt; 3) voltage; 4) potentials; 5) brain; 6) animal; 7) other

Luigi Aloisio Galvani

 

 Luigi Galvani: Italian physician famous for pioneering bioelectricity

 

 

Luigi Aloisio Galvani (September 9, 1737 – December 4, 1798) was an Italian physician and physicist who lived and died in Bologna. In 1791, he discovered that the muscles of dead frog’s legs twitched when struck by a spark. This was one of the first forays into the study of bioelectricity, a field that still today studies the electrical patterns and signals of the nervous system.

 

At the University of Bologna Galvani was appointed public lecturer in anatomy, and gained a reputation as a skilled though not eloquent teacher, chiefly from his researches on the organs of hearing and genitourinary tract of birds, as a comparative anatomist. He enunciated his celebrated theory of animal electricity in the treatise, De viribus electricitatis in motu musculari commentarius (“Commentary on the Force of Electricity on Muscular Motion”) published in the seventh volume of the proceedings of the Institute of Sciences at Bologna in 1791

 

Late 1780s diagram of Galvani’s experiment on frog legs

 

 

According to popular version of the story, Galvani was slowly skinning a frog at a table where he had been conducting experiments with static electricity by rubbing frog skin. Galvani’s assistant touched an exposed sciatic nerve of the frog with a metal scalpel, which picked up a charge. At that moment, they saw sparks and the dead frog’s leg kick as if in life. The observation made Galvani the first investigator to appreciate the relationship between electricity and animation – or life. This finding provided the basis for the new understanding that electrical energy (carried by ions), and not air or fluid as in earlier balloonist theories, is the impetus behind muscle movement. He is poorly credited with the discovery of bioelectricity.

 

Galvani called the term animal electricity to describe the force that activated the muscles of his specimens. Along with contemporaries, he regarded their activation as being generated by an electrical fluid that is carried to the muscles by the nerves. The phenomenon was dubbed galvanism, after Galvani, on the suggestion of his peer and sometime intellectual adversary Alessandro Volta. Today, the study of galvanic effects in biology is called electrophysiolog, with the term galvanism being used only in historical contexts.

 

Electrodes touch a frog, and the legs twitch into the upward position

 

 

Volta’s investigations led shortly to the invention of an early battery, but not by Galvani, who did not perceive electricity as separable from biology. Galvani did not see electricity as the essence of life, which he regarded vitalistically. Galvani believed that the animal electricity came from the muscle. Galvani’s associate Alessandro Volta, in opposition, reasoned that the animal electricity was a physical phenomenon caused by rubbing frog skin and not a metallic electricity.

While, as Galvani believed, all frogs contain electrical power, specifically toads. Frog cells and every toad cell has a cell potential, biological electricity has the same chemical underpinnings as the current between electrochemical cells, and thus can be recapitulated in a way outside the body, Volta’s intuition was correct. Volta, essentially, objected to Galvani’s conclusions about “animal electric fluid”, but the two scientists disagreed respectfully and Volta coined the term “galvanism” for a direct current of electricity produced by chemical action. Thus, owing to an argument between the two in regard to the source or cause of the electricity, Volta built the first battery in order to specifically disprove his associate’s theory. Volta’s pile, became known therefore as a voltaic profile.  A voltaic pile is a set of individual Galvanic cells placed in a series.  The voltaic pile was invented by Alessandro Volta in 1800.

 

A copper-zinc voltaic pile.

Gene Regulator in Brain’s Executive Hub Tracked Across Lifespan

 

 

According to an article published online in the American Journal of Human Genetics (2 February 2012), for the first time, the activity of an environmentally responsive regulatory mechanism that turns genes on and off in the brain’s executive hub has been tracked across the lifespan. Among key findings of the study by National Institutes of Health scientists: genes implicated in schizophrenia and autism turn out to be members of a select club of genes in which regulatory activity peaks during an environmentally-sensitive critical period in development. The mechanism, called DNA methylation, abruptly switches from off to on within the human brain’s prefrontal cortex during this pivotal transition from fetal to postnatal life. As methylation increases, gene expression slows down after birth.

 

Epigenetic mechanisms, like methylation, leave chemical instructions that tell genes what proteins to make — what kind of tissue to produce or what functions to activate. Although not part of our DNA, these instructions are inherited from our parents. But they are also influenced by environmental factors, allowing for change throughout the lifespan.

 

Developmental brain disorders may be traceable to altered methylation of genes early in life. For example, genes that code for the enzymes that carry out methylation have been implicated in schizophrenia. In the prenatal brain, these genes help to shape developing circuitry for learning, memory and other executive functions which become disturbed in the disorders.

 

“This new study reminds us that genetic sequence is only part of the story of development. Epigenetics links nurture and nature, showing us when and where the environment can influence how the genetic sequence is read,” said NIMH director Thomas R. Insel, M.D.

 

In a companion study published last October, expression of gene products in the PFC was traced across the lifespan. The current study instead examined methylation at 27,000 sites within PFC genes that regulate such expression. Both studies examined post-mortem brains of non-psychiatrically impaired individuals ranging in age from two weeks after conception to 80 years old.

 

In most cases, when chemicals called methyl groups attach to regulatory regions of genes, they silence them. Usually, the more methylation, the less gene expression. The study found that the overall level of PFC methylation is low prenatally when gene expression is highest and then switches direction at birth, increasing as gene expression plummets in early childhood. It then levels off as we grow older. But methylation in some genes shows an opposite trajectory. The study found that methylation is strongly influenced by gender, age and genetic variation. For example, methylation levels differed between males and females in 85% of X chromosome sites examined, which may help to explain geneder differences in disorders like autism and schizophrenia.

 

Different genes — and subsets of genes — methylate at different ages. Some of the suspect genes found to peak in methylation around birth code for enzymes, called methytransferases, that are over-expressed in people with schizophrenia and bipolar disorder. This process is influenced, in turn, by methylation in other genes, as well as by genetic variation. So genes associated with risk for such psychiatric disorders may influence gene expression through methylation in addition to inherited DNA.

 

Scientists worldwide can now mine a newly created online database of PFC lifespan DNA methylation from the study. The data are accessible to qualified researchers are available online. BrainCloud, is the web browser application developed by NIMH to interrogate the study data.

V. WOMENS HEALTH

Ulipristal Acetate vs. Placebo for Fibroid Treatment Before Surgery

 

An article published in the New England Journal of Medicine (2012;366:409-420), was perform to assess the efficacy and safety of oral ulipristal acetate for the treatment of symptomatic uterine fibroids before surgery

 

The study randomly assigned women with symptomatic fibroids, excessive uterine bleeding (a score of >100 on the pictorial blood-loss assessment chart, where higher numbers indicate more bleeding, and anemia (hemoglobin level of =10.2 g per deciliter) to receive treatment for up to 13 weeks with oral ulipristal acetate at a dose of 5 mg per day (96 women) or 10 mg per day (98 women) or to receive placebo (48 women). All patients received iron supplementation. The coprimary efficacy end points were control of uterine bleeding (PBAC score of <75) and reduction of fibroid volume at week 13, after which patients could undergo surgery.

 

Results showed that at 13 weeks, uterine bleeding was controlled in 91% of the women receiving 5 mg of ulipristal acetate, 92% of those receiving 10 mg of ulipristal acetate, and 19% of those receiving placebo (P<0.001 for the comparison of each dose of ulipristal acetate with placebo). The rates of amenorrhea were 73%, 82%, and 6%, respectively, with amenorrhea occurring within 10 days in the majority of patients receiving ulipristal acetate. The median changes in total fibroid volume were -21%, -12%, and +3% (P=0.002 for the comparison of 5 mg of ulipristal acetate with placebo, and P=0.006 for the comparison of 10 mg of ulipristal acetate with placebo).

 

Ulipristal acetate induced benign histologic endometrial changes that had resolved by 6 months after the end of therapy. Serious adverse events occurred in one patient during treatment with 10 mg of ulipristal acetate (uterine hemorrhage) and in one patient during receipt of placebo (fibroid protruding through the cervix). Headache and breast tenderness were the most common adverse events associated with ulipristal acetate but did not occur significantly more frequently than with placebo.

 

According to the authors, treatment with ulipristal acetate for 13 weeks effectively controlled excessive bleeding due to uterine fibroids and reduced the size of the fibroids.

Can Photographs in School Lunches Increase Vegetable Consumption

 

 

Can Photographs in Lunch Tray Compartments Increase Vegetable Consumption Among Children in Elementary School Cafeterias

 

To increase healthy eating among children, the US government has recommended providing more vegetables in school lunches, and schools are attempting to comply. However, children still consume insufficient amounts of vegetables. As a result, a study published online in the Journal of the American Medical Association (1 February 2012) was designed to increase vegetable consumption by placing photographs of vegetables in school lunch tray compartments.

 

For the study, vegetable consumption was compared on a control day (February 7, 2011) with an intervention day (May 9, 2011) in an elementary school (kindergarten through fifth grade) of approximately 800 students in Richfield, Minnesota. Cafeteria procedures were typical and the same meal was served on both days. Students helped themselves to preportioned servings of applesauce, orange slices, green beans, and carrots. Kitchen staff served the rest of the meal. On the intervention day (but not the control day), the authors placed photographs of carrots and green beans in tray compartments. After lunch, all the uneaten vegetables from the containers, tables, and floor were collected. Intervention and control days were compared using 2-sample tests of proportions (percentage taking each vegetable) or 2-sample mean comparisons (grams consumed).

 

Results showed that the intervention was associated with an increase in the percentage of students taking green beans from 6.3% to 14.8% (P < .001), and the percentage of students taking carrots from 11.6% to 36.8% (P < .001).

 

According to the authors, placing photographs in cafeteria lunch trays requires no special training and incurs minimal costs and labor (in this study, about $3 and 20 minutes per 100 trays), but was associated with an increase in vegetable consumption within the range of those found in more expensive interventions, including those that require multiple classroom sessions with trained instructors or parent involvement.

 

The number of students taking vegetables and the amounts consumed, however, remained low and did not yet meet government recommendations. In addition, these findings were obtained from just 2 days in 1 school, so further research is needed to assess how well the effects generalize to other settings and persist over time.

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

 

 

FDA Approves Kalydeco to Treat Rare Form of Cystic Fibrosis

 

 

Congratulations to our friends at Vertex for this breakthrough approval.

 

Cystic Fibrosis (CF) is a serious genetic disorder affecting the lungs and other organs that ultimately leads to an early death. It is caused by mutations (defects) in a gene that encodes for a protein called CFTR that regulates ion (such as chloride) and water transport in the body. The defect in chloride and water transport results in the formation of thick mucus that builds up in the lungs, digestive tract and other parts of the body leading to severe respiratory and digestive problems, as well as other complications such as infections and diabetes.

 

CF, which affects about 30,000 people in the United States, is the most common fatal genetic disease in the Caucasian population. About 4% of those with CF, or roughly 1,200 people, are believed to have the G551D mutation.

 

The FDA has approved Kalydeco (ivacaftor) for the treatment of a rare form of (CF) in patients ages 6 years and older who have the specific G551D mutation in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene. The FDA reviewed and approved Kalydeco in approximately three months under the agency’s priority review program that is designed to expedite the review of drugs. The priority review program uses a six-month review, instead of the standard 10 months, for drugs that may offer significant advances in treatment over available therapy.

 

Kalydeco was approved ahead of the drug’s April 18, 2012 prescription user fee goal date and is designated as an orphan drug, which identifies the disease as affecting fewer than 200,000 people in the United States.

 

In patients with the G551D mutation, Kalydeco, a pill taken two times a day with fat-containing food, helps the protein made by the CFTR gene function better and as a result, improves lung function and other aspects of CF such as increasing weight gain.

 

Two 48-week, placebo-controlled clinical studies involving 213 patients, one in patients ages 12 years and older and another in patients ages 6 years to 11 years, were used to evaluate the safety and efficacy of Kalydeco. In both studies, treatment with Kalydeco resulted in significant and sustained improvement in lung function.

 

Kalydeco is effective only in patients with CF who have the G551D mutation. It is not effective in CF patients with two copies of the F508 mutation in the CFTR gene, which is the most common mutation that results in CF. If a patient’s mutation status is not known, an FDA-cleared CF mutation test should be used to determine whether the G551D mutation is present.

 

The most common side effects of Kalydeco include upper respiratory tract infection, headache, stomach ache, rash, diarrhea, and dizziness.

 

Kalydeco is manufactured by Vertex Pharmaceuticals Inc. of Cambridge, Mass.

Target Health (www.targethealth.com) a full service e*CRO, is committed to serve the pharmaceutical community through knowledge, experience, technology and connectivity. Target Health strives to optimize the life cycle of drugs, biologics and devices with expertise, leadership, innovation and teamwork.

 

Target Health Inc. has fulltime staff dedicated to all aspects of Regulatory Affairs, Clinical Research, Biostatistics, Data Management, Strategic Planning and Drug and Device Development. Target Health is committed to the paperless clinical trial and has developed a full suite of eClinical Trial software including:

 

 

1) Target e*CRF® (EDC Made Simple)

2) Target e*CTMS™

3) Target Document®

4) Target Encoder®

5) Target e*Pharmacovigilance™

6) Target e*Monitoring™

7) Target Newsletter®

8) Target e*CTR™ (eSource, electronic medical record for clinical trials).

 

Target Health’s Pharmaceutical Advisory Dream Team assists companies in strategic planning from Discovery to Market Launch. Let us help you on your next project.

 

 

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