More Efficient Access to ClinicalTrials.gov and EudraCT

Our colleagues at The Larvol Group have launched Larvol Sigma, a free pharmaceutical intelligence online resource developed to enable more efficient access to clinicaltrials.gov and EudraCT. With a database containing over 5,000 drugs and more than 150,000 drug trials across all major indications, Larvol Sigma is designed to meet the specific needs of investigators, researchers and industry professionals. The Larvol Group will be hosting a live Webinar to demonstrate the new platform’s capabilities on July 30, 2013 at 9am PDT.

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.

Blood Pressure

What would the great William Harvey, a 17th century physician at Saint Bartholomew’s Hospital, London, which was founded in 1123, say about some new research there into blood pressure. High blood pressure is often called the silent 1) ___ because it greatly increases the risk of heart disease and stroke and yet many of us don’t realize we have it.

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A small trial of a new technique to control blood 2) ___ has shown promising results reported in the Lancet medical journal. Barts and the London NHS Trust was one of about two dozen centers around the world which took part. The procedure takes about an hour and involves inserting a tube into the renal artery and zapping the nerves with radio-frequency energy. This interrupts messages from the kidney to the 3) ___ which can escalate blood pressure. In a trial of 100 patients, most of those who had the procedure had substantially lower blood pressure after six months. The average 4) ___ pressure for the treatment group was 178/97 mmHg. Six months after treatment, it had dropped to 146/86 mmHg, a substantial fall.

What the investigators cannot explain is why 1 in 10 patients who underwent the procedure did not show any 5) ___ in blood pressure. Far bigger, longer trials will be needed before doctors will know whether the technique will give them a new weapon in treating 6) ___. Dr Mel Lobo, a hypertension expert at Barts Hospital, believes the procedure may have the potential to save thousands of lives a year among patients who don’t respond well to a range of 7) ___.

We very rarely expect to see big drops in blood pressure – more than 10mm of mercury – with further changes in medication. So, to be able to drop somebody’s blood pressure by this much as a result of a relatively simple quick procedure (and no new 8) ___) is of ground-breaking importance.

ANSWERS: 1) killer; 2) pressure; 3) brain; 4) blood; 5) reduction; 6) hypertension; 7) medicines; 8) drug

Circulation:
Michael Servetus (1509-1553) Predated William Harvey (1578-1657)

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Michael Servetus (1509-1553)

 

 

Michael Servetus, a Spanish theologian, physician, cartographer, and Renaissance humanist, was the first European to correctly describe the function of pulmonary circulation. In parallel, Servetus participated in the Protestant Reformation, and later developed a nontrinitarian Christology. As a result, he was condemned by Catholics and Protestants alike, and burnt at the stake in Geneva as a heretic by order of the Protestant Geneva governing council. Widespread aversion to Servetus’s death influenced the birth, in Europe, of the idea of religious tolerance.

While Servetus was the first European to describe the function of pulmonary circulation, his achievement was not widely recognized at the time, for a few reasons. One was that the description appeared in a theological treatise, Christianismi Restitutio, not in a book on medicine. However, the sections in which he refers to anatomy and medicines demonstrate an amazing understanding of the body and treatments. Most copies of the book were burned shortly after its publication in 1553 because of persecution of Servetus by religious authorities. Three copies survived, but these remained hidden for decades. In passage V, Servetus recounts his discovery that the blood of the pulmonary circulation flows from the heart to the lungs (rather than air in the lungs flowing to the heart as had been thought). His discovery was based on the color of the blood, the size and location of the different ventricles, and the fact that the pulmonary vein was extremely large, which suggested that it performed intensive and transcendent exchange. However, Servetus does not talk just about cardiology. In the same passage, from page 169 to 178, he also talks of the brain, the cerebellum, the meninges, the nerves, the eye, the tympanum, the rete mirabile, etc., demonstrating a great knowledge of anatomy. In some other sections of this work he also talks of medical products.

He published several books which dealt with medicine and pharmacology, such as his Syruporum universia ratio (Complete Explanation of the Syrups), which became a very famous work. After an interval, Servetus returned to Paris to study medicine in 1536. In Paris, his teachers included Sylvius, Fernel and Johann Winter von Andernach, who hailed him with Andrea Vesalius as his most able assistant in dissections. During these years he wrote his Manuscript of the Complutense, an unpublished compendium of his medical ideas. Servetus taught mathematics and astrology while he studied medicine.

The ancestors of the father of Servetus came from the hamlet of Serveto, in the Aragonese Pyrenees. His father was a notary of Christian ancestors from the lower nobility (infanzon), who worked at the nearby Monastery of Santa Maria de Sigena. Servetus had two brothers, one was a Catholic priest, Juan, another was a notary, Pedro. Although Servetus declared during his trial in Geneva that his parents were “Christians of ancient race”, and that he never had any communication with Jews, his maternal line actually descended from the Zaportas (or Çaportas), a wealthy and socially relevant Jewish converso family from the Barbastro and Monzon areas in Aragon. This was confirmed by a notarial protocol published in 1999.

Servetus was gifted in languages and studied Latin and Greek under the instruction of Dominican friars. He also had a knowledge of Hebrew, a language he could have learnt from his converso relatives. At the age of fifteen, Michael Servetus entered the service of a Franciscan friar by the name of Juan de Quintana Michael Servetus later attended the University of Toulouse in 1526 where he studied law. Servetus could have had access to forbidden religious books, some of them may be Protestant, while he was studying in this city.

Friar Quintana became Charles V’s confessor in 1530, and Servetus joined him in the imperial retinue as his page or secretary. Servetus travelled through Italy and Germany, and attended Charles’ coronation as Holy Roman Emperor in Bologna. He was outraged by the pomp and luxury displayed by the Pope and his retinue, and decided to follow the path of reformation. It is not known when Servetus left the imperial entourage, but in October 1530 he visited Johannes Oecolampadius in Basel, staying there for about ten months, and probably supporting himself as a proofreader for a local printer. By this time he was already spreading his theological beliefs. Two months later, in July 1531, Servetus published De Trinitatis Erroribus (On the Errors of the Trinity). The next year he published the work Dialogorum de Trinitate (Dialogues on the Trinity) and the supplementary work De Iustitia Regni Christi (On the Justice of Christ’s Reign) in the same volume. After the persecution of the Inquisition, Servetus assumed the name “Michel de Villeneuve” while he was staying in France.

In 1553 Michael Servetus published yet another religious work with further anti-trinitarian views. It was entitled Christianismi Restitutio (The Restoration of Christianity), a work that sharply rejected the idea of predestination as the idea that God condemned souls to Hell regardless of worth or merit. God, insisted Servetus, condemns no one who does not condemn himself through thought, word or deed. This work also includes the first published description of the pulmonary circulation.

To John Calvin, the French theologian, who had written his summary of Christian doctrine Institutio Christianae Religionis (Institutes of the Christian Religion), Servetus’ latest book was an attack on Calvin’s personally held theories regarding Christian belief, theories that he put forth as “established Christian doctrine”. Calvin sent a copy of his own book as his reply. Servetus promptly returned it, thoroughly annotated with critical observations. Calvin wrote to Servetus, “I neither hate you nor despise you; nor do I wish to persecute you; but I would be as hard as iron when I behold you insulting sound doctrine with so great audacity.” In time their correspondence grew more heated until Calvin ended it. Servetus sent Calvin several more letters, to which Calvin took offense. Thus, Calvin’s antagonism against Servetus seems to have been based not simply on his views but also on Servetus’s tone, which he considered inappropriate. Calvin revealed the intentions of his offended pride when writing to his friend William Farel on 13 February 1546: “Servetus has just sent me a long volume of his ravings. If I consent he will come here, but I will not give my word; for if he comes here, if my authority is worth anything, I will never permit him to depart alive.”

On 16 February 1553, Michael Servetus while in Vienne, was denounced as a heretic by Guillaume de Trie, a rich merchant who had taken refuge in Geneva, and a very good friend of Calvin, in a letter sent to a cousin, Antoine Arneys, who was living in Lyon. On behalf of the French inquisitor Matthieu Ory, Michael Servetus and Balthasard Arnollet, the printer of Christianismi Restitutio, were questioned, but they denied all charges and were released for lack of evidence. Arneys was asked by Ory to write back to De Trie, demanding proof. On 26 March 1553, the letters sent by Michel to Calvin and some manuscript pages of Christianismi Restitutio were forwarded to Lyon by De Trie. On 4 April 1553 Michael de Villanueva was arrested by Roman Catholic authorities, and imprisoned in Vienne. Servetus escaped from prison three days later. On 17 June, Michel de Villeneuve was convicted of heresy, “thanks to the 17 letters sent by John Calvin, preacher in Geneva” and sentenced to be burned with his books. An effigy and his books were burned in his absence.

Meaning to flee to Italy, Servetus inexplicably stopped in Geneva, where Calvin and his Reformers had denounced him. On 13 August, he attended a sermon by Calvin at Geneva. He was arrested after the service and again imprisoned. All his property was confiscated.

An offensive question, asked at Michel de Villeneuve’s trial, was “whether he did not know that his doctrine was pernicious, considering that he favors Jews and Turks, by making excuses for them, and if he has not studied the Koran in order to disprove and controvert the doctrine and religion that the Christian churches hold, together with other profane books, from which people ought to abstain in matters of religion, according to the doctrine of St. Paul.”

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Born in Folkestone, Kent, England, William Harvey, a 17th-century British physician, was the physician to two consecutive kings, studied blood circulation, and his Anatomical Exercise on the Motion of the Heart and Blood in Animals (1628) recorded his findings. Though Harvey understood that the heart pumped blood into the circulatory system, he had no knowledge of the influence of oxygen in the blood nor knowledge of the existence of capillaries.

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Image of veins from Harvey’s Exercitatio Anatomica de Motu Cordis et Sanguinis in Animalibus

 

William Harvey is famous for his idea on blood being pumped around the body by the heart. However, credit and important influence has to be given to Michael Servetus’ Christianismi Restitutio, in which Servetus discovered and documented how the circulatory system worked, but his work at the time was lost when he was burned at the stake with many of his books. Harvey found this work of Servetus (Restitutio) a century later. Harvey travelled all over Europe doing research. Most of his research was done in Italy where he went to the Venerable English College in Rome.

A hospital in Ashford, Kent is named after Harvey. He went to The King’s School, Canterbury, then Ganville and Caius College, Cambridge. He then went to University of Padua where he graduated in 1602. When he returned to England he married Elizabeth Browne, the daughter of Elizabeth I’s royal physician. He became a doctor at St. Bartholomew’s Hospital in London from 1609 until 1643.

Harvey announced his discoveries about the circulatory system in 1616. He wrote a book (Exercitatio Anatomica de Motu Cordis et sanguinis in Animalibuson) about it in 1628. He said that blood was pumped around the body in a closed system. Blood was pumped by the heart through the body before coming back to the heart to repeat the process. This went against what was believed at the time to be true. William Harvey was an English physician who was the first to describe correctly and in detail the circulation and properties

The Roman doctor, Galen believed that there were two systems in the body dealing with blood. It was thought at the time that the dark red blood in veins came from the liver and the bright red blood in arteries came from the heart. It was believed that the liver and heart made the blood and it was used up by the body parts it was pumped to.

Harvey’s ideas came from dissecting human bodies. Harvey found that the liver would have to make 540 pounds of blood every hour for Galen to be right. This showed him that the blood was not being used up. It was being reused by the body. He said blood flowed through the heart in two loops. One loop went to the lungs and got oxygen. The other loop went to the organs and body tissue giving them the oxygen. He said the heart was just a pump that pumped blood around the body.

Pay Attention, the US Population is Changing

According to the federal government’s annual statistical report on the well-being of the nation’s children and youth, the number of children living in the US declined slightly, as did the percentage of the US population who are children,. The percentage of children living in the United States who are Asian, non-Hispanic increased, as did the percentage of children who are of two or more races, and the percentage of children who are Hispanic. The percentages of children who are white, non-Hispanic, and black, non-Hispanic also declined.

It is projected that by 2050, about half of the American population ages under 17 will be be composed of children who are Hispanic, Asian, or of two or more races. The report projected that, among children under age 17, 36% will be Hispanic (up from 24% in 2012); 6% will be Asian (up from 5% in 2012); and 7% will be of two or more races (up from 4% in 2012).”

These and other findings are described in America’s Children: Key National Indicators of Well-Being, 2013. The report was compiled by the Federal Interagency Forum on Child and Family Statistics, which includes participants from 22 federal agencies as well as partners in several private research organizations. The forum fosters coordination, collaboration, and integration of federal efforts to collect and report data on children and families.

The report, the 16th in an ongoing series, presents key indicators of children’s wellbeing in seven domains: family and social environment, economic circumstances, health care, physical environment and safety, behavior, education, and health.

Among the findings in this year’s report:

1. A drop for the fifth straight year in the percentage of infants born preterm, from 12.8% in 2006 to 11.7 in 2011.

2. A drop in the percentage of children ages 4-11 with any detectable blood cotinine level, a measure for recent exposure to secondhand smoke, from 53% in the years 2007 and 2008 to 42% in 2009 and 2010).

3. A drop in births to adolescents, from 17 per 1,000 girls ages 15 to 17 in 2009 to 15 per 1,000 in 2011 (preliminary data).

4. A drop in the percentage of births to unmarried women ages 15 to 44, from 40.8% in 2010 to 40.7% in 2011.

5. A rise in the percentage of male and female 12th graders who reported binge drinking1. consuming five or more alcoholic beverages in a row in the past two weeks1. from 22% in 2011 to 24% in 2012.

6. A drop in the percentage of children from birth to 17 years of age living with two married parents, from 65% in 2010 to 64% in 2011.

7. A drop in the percentage of children from birth to 17 years with no usual source of health care, from 5% in 2010 to 4% in 2011.

8. A rise in the percentage of households with children from birth to 17 years that reported housing that costs more than 30% of household income, crowding, and/or physically inadequate housing, from 45% in 2009 to 46% in 2011.

9. A rise in the percentage of children from birth to 17 years of age living with at least one parent employed year round full time, from 71% in 2010 to 73% in 2011.

10. A drop in the percentage of children ages 5-17 with untreated dental caries (cavities or tooth decay) over the past decade, from 23% in 1999 – 2004 to 14% in 2009 – 2010.

11. A rise in the percentage of children ages 5-17 with a dental visit in the past year from 85% in 2010 to 87% in 2011.

The percentage of youth ages 12-17 who had a major depressive episode was unchanged in the previous year (8.2% in 2010 and 2011). However, this figure was lower than the 2004 high of 9%. The report notes that adolescent depression can affect school and work performance, impair peer and family relationships, and exacerbate other health conditions, such as asthma and obesity.

The Healthy Eating Index score, a measure of overall dietary quality did not differ significantly from recent years. For children ages 2-17, total scores ranged between 47 and 50% in 2003-2004, 2005-2006, and 2007-2008. The report noted that the diet quality of children and adolescents fell considerably short of recommendations.

“Poor eating patterns can lead to childhood obesity and contribute to chronic diseases starting in childhood, such as type 2 diabetes, and those that emerge throughout the life cycle, such as cardiovascular disease,” the report stated.

The report added that the diet quality of children and adolescents would be improved by an increase in vegetables, especially dark greens and beans, replacing refined grains with whole grains, substituting seafood for some meat and poultry, and decreasing the intake of sodium, solid fats, and added sugars.

This year’s report includes a special feature on the kindergarten year, described as a pivotal marker for children’s development. Three and a half million children entered kindergarten for the first time in the fall of 2010. On average, girls received higher scores than boys on kindergarten entry assessments in reading and approaches to learning. There were no differences between girls and boys in mathematics and science.

The special feature was based on data from the Early Childhood Longitudinal Study, Kindergarten Class of 2010-2011 (ECLS-K:2011), conducted by the National Center for Education Statistics. The report noted that the ECLS-K:2011 will follow the children’s progress through the fifth grade, providing information on how the children’s development may be shaped by such factors as child care, home educational environment, teachers’ instructional practices, and class size.

Air Pollution and Lung Cancer Incidence in Europe

Ambient air pollution is suspected to cause lung cancer. As a result, a study published online in The Lancet Oncology (10 July 2013) was performed to assess the association between long-term exposure to ambient air pollution and lung cancer incidence in European populations.

This prospective analysis of data obtained by the European Study of Cohorts for Air Pollution Effects (ESCAPE) used data from 17 cohort studies based in nine European countries. Baseline addresses were geocoded and air pollution was assessed by land-use regression models for particulate matter (PM) with diameter of less than 10um (PM10), less than 2.5 um (PM2.5), and between 2.5 and 10um (PMcoarse), soot (PM2.5absorbance), nitrogen oxides, and two traffic indicators. Cox regression models with adjustment for potential confounders were used for cohort-specific analyses and random effects models for meta-analyses.

Results showed that the 312,944 cohort members contributed 4,013,131 person-years at risk. During follow-up (mean 12.8 years), 2,095 incident lung cancer cases were diagnosed. The meta-analyses showed a statistically significant association between risk for lung cancer and PM10 (hazard ratio [HR] 1.22/10 ug/m3). For PM2.5 the HR was 1.18/5 ug/m3. The same increments of PM10 and PM2.5 were associated with HRs for adenocarcinomas of the lung of 1.51 and 1.55, respectively. An increase in road traffic of 4,000 vehicle-km/day within 100m of the residence was associated with an HR for lung cancer of 1.09. The results showed no association between lung cancer and nitrogen oxides concentration or traffic intensity on the nearest street per 5,000 vehicles per day)

According to the authors, particulate matter air pollution contributes to lung cancer incidence in Europe.

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

 

FDA Approves New Treatment For a Type of Late-Stage Lung Cancer: Companion Test Also Approved to Identify Appropriate Patients

 

Lung cancer is the leading cause of cancer-related death among men and women. According to the National Cancer Institute, an estimated 228,190 Americans will be diagnosed with lung cancer, and 159,480 will die from the disease this year. About 85% of lung cancers are NSCLC, making it the most common type of lung cancer. EGFR gene mutations are present in about 10% of NSCLC, with the majority of these gene mutations expressing EGFR exon 19 deletions or exon 21 L858R substitution.

The FDA approved Gilotrif (afatinib) for patients with late stage (metastatic) non-small cell lung cancer (NSCLC) whose tumors express specific types of epidermal growth factor receptor (EGFR) gene mutations. Gilotrif is a tyrosine kinase inhibitor that blocks proteins that promote the development of cancerous cells. It is intended for patients whose tumors express the EGFR exon 19 deletions or exon 21 L858R substitution gene mutations. Gilotrif is being approved concurrently with the therascreen EGFR RGQ PCR Kit, a companion diagnostic that helps determine if a patient’s lung cancer cells express the EGFR mutations.

According to FDA, this approval further illustrates how a greater understanding of the underlying molecular pathways of a disease, together with companion diagnostic tests, can lead to the development of targeted treatments. In May, the FDA approved Tarceva (erlotinib) for first-line treatment of patients with NSCLC. Tarceva’s new indication was approved concurrently with the cobas EGFR Mutation Test, a companion diagnostic to identify patients with tumors having the EGFR gene mutations.

The FDA’s approval of the therascreen EGFR RGQ PCR Kit is based on data from the clinical study used to support Gilotrif’s approval. Tumor samples from NSCLC participants in the clinical trial helped to validate the test’s use for detecting EGFR mutations in this patient population.

Gilotrif’s safety and effectiveness were established in a clinical study of 345 participants with metastatic NSCLC whose tumors harbored EGFR mutations. Participants were randomly assigned to receive Gilotrif or up to six cycles of the chemotherapy drugs pemetrexed and cisplatin. Results showed that subjects receiving Gilotrif had a delay in tumor growth (progression-free survival) that was 4.2 months later than those receiving chemotherapy. However, there was no statistically significant difference in overall survival.

Common side effects of Gilotrif include diarrhea, skin breakouts that resemble acne, dry skin, itching (pruritus), inflammation of the mouth, skin infection around the nails (paronychia), decreased appetite, decreased weight, inflammation of the bladder (cystitis), nose bleed, runny nose, fever, eye inflammation and low potassium levels in the blood (hypokalemia). Serious side effects include diarrhea that can result in kidney failure and severe dehydration, severe rash, lung inflammation and liver toxicity.

The FDA reviewed Gilotrif under its priority review program, which provides an expedited review for drugs that may provide safe and effective therapy when no satisfactory alternative therapy exists, or offer significant improvement compared to marketed products.

Gilotrif is marketed by Ridgefield, Conn.-based Boehringer Ingelheim Pharmaceuticals, Inc. The therascreen EGFR RGQ PCR Kit is manufactured by QIAGEN Manchester Ltd., based in the United Kingdom. The cobas EGFR Mutation Test is manufactured by the Roche Molecular Systems in Pleasanton, Calif., and Tarceva is co-marketed by California-based Genentech, a member of the Roche Group, and OSI Pharmaceuticals of Farmingdale, N.Y.

Spinach/Endive Salad with Strawberries, Feta, Pecans and Poppy/Sesame Seed Dressing

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Nothing says summer, like a beautiful salad and this recipe is a beauty!

 

Ingredients

Salad

1 lb. fresh spinach leaves, stems removed, washed and dried (get all sand out)
2 cups fresh strawberries, hulled and halved
1 endive, cut leaves diagonally
1 cup Feta, crumbled
1 cup pecans, toasted then cut in half (not tiny pieces)
3/4 cup Salad Dressing (recipe follows)

Salad Dressing Ingredients

1/4 cup vegetable or olive oil
1/4 cup cider vinegar
1/4 to 1/2 cup sugar substitute, (taste & add more if needed)
1/2 onion, chopped well
1 garlic clove, juiced
2 Tablespoons sesame seeds
1 Tablespoon poppy seeds
1 teaspoon turmeric

Salad Dressing Directions (Makes approximately 3/4 cup)

Place the oil, vinegar, 1/4 cup of sugar substitute, the onion, garlic juice, turmeric, sesame seeds and poppy seeds, in a food processor and mix until homogenized. Taste and add additional sugar if needed. Use right away or store in the refrigerator, as needed or overnight.

Final Salad Directions

1. Wash spinach two or more times, to get all grit out
2. Separate endive leaves and rinse
3. Put spinach & endive leaves in ice water to perk up
4. Make the dressing and refrigerate
5. Toast the pecans in pan, stirring constantly, to prevent burning
6. Dry spinach leaves and tear apart
7. Dry endive leaves and cut strips (not too small) on diagonal

Place the spinach, endive, feta, pecans and strawberries in a large salad bowl. When you’re ready to sit down, just before eating, pour on the dressing and toss gently to mix. Serve right away.

This recipe is quick, easy and delicious. One caution: when it comes to adding the dressing, go very slowly. You’ll see that a little goes a long way. So, add a little, then toss and check to see that all the ingredients have been covered with the dressing. You should end up with some leftover dressing.

The salad is beautiful because of the colors (guests will love it) and the interesting juxtaposition of flavors. It’s easy to devour for lunch, brunch, snack and dinner. You can serve it alone with crackers (I like flax-snax crackers that I get on Amazon.com . . . pizza flavor), or it goes extremely well with some simple poached fish and your favorite veggie side dish. We had icy Chardonnay and, yes, my dear husband was the guinea pig, yet again. He said, “This is your best ever!” I urge readers to give this salad recipe a try. You won’t be disappointed.

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Enjoy!