Target Health Presenting at the 15th Annual eClinical Integration Summit

 

Target Health is pleased to announce that Dr. Jules T. Mitchel, will be presenting at a panel during the 15th Annual eClinical Integration Summit, being held on September 19-21, at the Seaport Hotel and World Trade Center, Boston. The topic is: “FDA Perspective Surrounding eSource Guidance”. Darlene Kalinowski, Senior Manager Regional Clinical Operations at Bristol Myers Squibb will be chairing the session. Download the latest conference brochure to learn more. You may also want to download the latest event podcast from Craig Lipset, Head of Clinical Innovations for Worldwide R&D at Pfizer.

 

You may register for the event with Target Health’s special discount of 25% off the standard registration rate. Register online, call 888.670.8200, or email register@iirusa.com. Be sure to use Priority Code XP1609SPJM. This event is part of the Clinical Business Expo, a unique opportunity to network across the clinical development continuum as six events convene with over 200 leading expert speakers, 600+ executive attendees and 50 exhibitors. 

 

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, and if you like the weekly newsletter, ON TARGET, you’ll love the Blog.

Minor Ailments Linked to Alzheimer’s

 

Photo by: Ruth Fremson/Redux

 

 

Loose dentures, sinus congestion, skin problems increase dementia risk. As we age, those minor physical ailments – including sore feet, poorly fitting dentures and skin irritations – may turn out to be not so minor after all. A new study published in the journal Neurology (19 July 2011) has found that as problems not traditionally associated with brain health pile up, a person’s chance of developing 1) ___ increases.

 

“When a lot of small things go wrong, it can add up to an important 2) ___,” says Kenneth Rockwood, M.D., professor of medicine at Dalhousie University, Halifax, and an author of the study “Nontraditional Risk Factors Combine to Predict Alzheimer Disease and Dementia.” The 10-year study, launched in 1992, included more than 7,200 cognitively healthy 65-year-old Canadians who were asked questions regarding their overall health. While the questions included known risk factors for 3) ___, such as high blood pressure and diabetes, the thrust of the research was on 19 problems that seemingly have no connection with brain health – including vision and hearing, loose dentures, sinus congestion, arthritis, morning cough, and problems with the skin, stomach, kidneys or bowel.

 

While any healthy 65-year-old has an 18% chance of developing dementia in 10 years simply because they are aging, the study found that each health problem not traditionally associated with Alzheimer’s increased that risk by 3.2%. The risk accelerated as more and more conditions were added, jumping to 40% among those in the study who reported as many as 12 conditions. Since 4) ___ is a major risk factor for Alzheimer’s, Richard Lipton, M.D., professor and vice chairman of neurology at the Albert Einstein College of Medicine, says the study in a sense is identifying people who “age badly” – developing one ailment after another so their biological age exceeds their chronological age.

 

While taking care of minor ailments is likely to improve a person’s quality of 5) ___, Rockwood says, no one has yet proved that fixing one problem after another would necessarily reduce one’s risk for Alzheimer’s. His advice” “Don’t panic over one problem.” As much as bad things can add up, so can the good, he said, citing studies showing that 6) ___ as little as 30 minutes a day, three days a week “dramatically attenuated” risk factors for dementia.

 

ANSWERS: 1) dementia; 2) risk; 3) Alzheimer’s; 4) age; 5) life; 6) walking

DNA of Jesus-Era Shrouded Man in Jerusalem Reveals Earliest Case of Leprosy

 

Jerusalem at the Time of Jesus Christ

 

 

The DNA of a first-century shrouded man found in a tomb on the edge of the Old City of Jerusalem has revealed the earliest proven case of leprosy. The burial cave, which is known as the Tomb of the Shroud, is located in the lower Hinnom Valley and is part of a 1st century C.E. cemetery known as Akeldama or “Field of Blood’ (Matthew 27:3-8; Acts 1:19) – next to the area where Judas is said to have committed suicide. The tomb of the shrouded man is located next to the tomb of Annas, the high priest (6-15 C.E.), who was the father in law of Caiaphas, the high priest who was said to have betrayed Jesus to the Romans. It is thus thought that this shrouded man was either a priest or a member of the aristocracy. According to Prof. Gibson, the view from the tomb would have looked directly toward the Jewish Temple. Details of the research are published in the journal PLoS ONE.

 

The molecular investigation was undertaken by Prof. Mark Spigelman and Prof. Charles Greenblatt and of the Sanford F. Kuvin Center for the Study of Infectious and Tropical Diseases at the Hebrew University of Jerusalem, Prof. Carney Matheson and Ms. Kim Vernon of Lakehead University, Canada, Prof. Azriel Gorski of New Haven University and Dr. Helen Donoghue of University College London. The archaeological excavation was led by Prof. Shimon Gibson, Dr. Boaz Zissu and Prof. James Tabor on behalf of the Israel Antiquities Authority and the University of North Carolina at Charlotte.

 

No Second Burial

 

What is particularly rare about this tomb is that it was clear this man, which is dated by radiocarbon methods to 1-50 C.E., did not receive a secondary burial. Secondary burials were common practice at the time, where the bones were removed after a year and placed in an ossuary (a stone bone box). In this case, however, the entrance to this part of the tomb was completely sealed with plaster. Prof. Spigelman believes this is due to the fact that this man had suffered from leprosy and died of tuberculosis, as the DNA of both diseases was found in his bones.

 

Historically, disfiguring diseases – particularly leprosy – caused the afflicted individuals to be ostracized from their communities. However, a number of indications – the location and size of the tomb, the type of textiles used as shroud wrappings, and the clean state of the hair – suggest that the shrouded individual was a fairly affluent member of society in Jerusalem and that tuberculosis and leprosy may have crossed social boundaries in the first century C.E.

 

Disproves Turin Shroud?

 

This is also the first time fragments of a burial shroud have been found from the time of Jesus in Jerusalem. The shroud is very different to that of the Turin Shroud, hitherto assumed to be the one that was used to wrap the body of Jesus. Unlike the complex weave of the Turin Shroud, this is made up of a simple two-way weave, as the textiles historian Dr. Orit Shamir was able to show. Based on the assumption that this is representative of a typical burial shroud widely used at the time of Jesus, the researchers conclude that the Turin Shroud did not originate from Jesus-era Jerusalem. The excavation also found a clump of the shrouded man’s hair, which had been ritually cut prior to his burial. These are both unique discoveries because organic remains are hardly ever preserved in the Jerusalem area owing to high humidity levels in the ground.

 

Social Health in Antiquity

 

According to Prof. Spigelman and Prof. Greenblatt, the origins and development of leprosy are largely obscure. Leprosy in the Old Testament may well refer to skin rashes such as psoriasis. The leprosy known to us today was thought to have originated in India and brought over to the Near East and to Mediterranean countries in the Hellenistic period. The results from the first-century C.E. Tomb of the Shroud fill a vital gap in our knowledge of this disease. Furthermore, the new research has shown that molecular pathology clearly adds a new dimension to the archaeological exploration of disease in ancient times and provides us with a better understanding of the evolution, geographic distribution and epidemiology of disease and social health in antiquity.

 

The co-infection of both leprosy and tuberculosis here and in 30% of DNA remains in Israel and Europe from the ancient and modern period provided evidence for the postulate that the medieval plague of leprosy was eliminated by an increased level of tuberculosis in Europe as the area urbanized.

New Model of ALS is Based on Human Cells From Autopsied Tissue

 

The research reported in this article was funded, in part, by NIH’s National Institute of Neurological Disorders and Stroke (NINDS), including a $1.7 million stimulus grant made possible by the American Recovery and Reinvestment Act.

 

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a disease of the nerve cells in the brain and spinal cord that control voluntary muscle movement. About 90% of ALS cases are sporadic and 10% run in families. In ALS, nerve cells (neurons) waste away or die, and can no longer send messages to muscles. This eventually leads to muscle weakening, twitching, and an inability to move the arms, legs, and body. The condition slowly gets worse. When the muscles in the chest area stop working, it becomes hard or impossible to breathe on one’s own. ALS affects approximately 5 out of every 100,000 people worldwide. ALS is characterized by the death of motor neurons, which are muscle-controlling nerve cells in the spinal cord. As these neurons die, the body’s voluntary muscles weaken and waste away. Death within five years of diagnosis is common. Mutations in the superoxide dismutase1 (SOD1) gene are found in about one-fifth of people with familial ALS, and for decades, experts have theorized that the gene holds clues to sporadic ALS. The only approved treatment, riluzole, extends life expectancy by just a few months.

 

According to an article published online in Nature Biotechnology (10 August 2011), researchers funded by the NIH have developed a new model of ALS by isolating cells from patients’ spinal tissue within a few days after death. The study found that during the disease, cells called astrocytes become toxic to nerve cells – a result previously found in animal models but not in humans. The new model could now be used to investigate many more questions about ALS.

 

Laboratory mice carrying human SOD1 mutations develop signs of ALS as they age, and have been widely used to investigate the causes and potential treatments for the disease. Recent NIH-funded studies showed that astrocytes derived from these SOD1 mice are toxic to motor neurons. Astrocytes – lesser known than neurons and usually described as playing a supportive role – became prime suspects for killing neurons in ALS. At the same time, however, researchers have questioned whether SOD1 mice are useful – and whether SOD1 itself is relevant – for understanding sporadic ALS. Although dozens of potential therapies have shown promise in the mice, so far only riluzole has proven to help patients in clinical trials. Those results raised concerns that SOD1 might not be a factor in the majority of ALS cases after all.

 

For the study, the investigators obtained post-mortem spinal tissue from ALS patients through the National Disease Research Interchange (NDRI). This is a nonprofit organization supported by NIH, voluntary health organizations and corporate and individual sponsors that enables people to donate their tissues for use in research after death, and then delivers specific tissues to research labs. NDRI performed the autopsies in the ALS patients’ local communities and used couriers to fly the tissue samples to Columbus.

 

First, the researchers isolated neural progenitor cells from the tissue and coaxed these cells to become astrocytes. Neural progenitor cells are the parent lineage of neurons and astrocytes. Next, the team combined the patient-derived astrocytes with mouse motor neurons. At first, the motor neurons grew normally, but after four days, they began to degenerate. By five days, the number of motor neurons was reduced by about half, compared to motor neurons that had been grown with control astrocytes. Similar results were seen when the motor neurons were grown with astrocytes from a patient with familial ALS, or with a cell culture broth that had been conditioned by astrocytes from any of the ALS patients. This suggests the astrocytes are releasing one or more unknown substances that are toxic to motor neurons. The study also found that inflammatory responses may play a role in this toxicity. When 84 genes involved in inflammation were analyzed, it was found that 35-60% of the genes showed increased activity in ALS astrocytes compared to controls.

 

Further experiments revealed that the SOD1 plays a critical role in the toxicity. The investigators used a method called RNA interference to silence the SOD1 gene. RNA serves as an intermediary between genes and proteins, but in RNA interference, small RNA fragments are used to block a gene from making proteins. When the researchers used a virus to deliver such small RNAs to astrocytes affected by familial ALS, the astrocytes were no longer toxic to motor neurons. This method also suppressed toxicity in four of six astrocyte lines derived from people with sporadic ALS, supporting the idea that the SOD1 enzyme also has a role in sporadic cases.

 

The results also suggest the need for further investigation of SOD1 and astrocytes as targets for therapy. For example, drugs or small molecules, such as the RNA fragments tested in this study, might be used to reduce SOD1 function in astrocytes and suppress their toxicity.

ONCOLOGY

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Genetically Modified Serial Killer T-Cells Obliterate Tumors in Leukemia Patients

 

Chronic lymphocytic leukemia (CLL) is a type of cancer of the blood and bone marrow – the spongy tissue inside bones where blood cells are made. CLL typically progresses more slowly than other types of leukemia, thus the adjective “chronic“. The term “lymphocytic” in CLL comes from the cells affected by the disease – a group of white blood cells called lymphocytes, which help the body fight infection. CLL most commonly affects older adults. According to the National Cancer Institute, about 14,990 new cases of chronic lymphocytic leukemia (CLL) were diagnosed in 2010, and about 4,390 people died.

 

Tumor immunotherapy with T lymphocytes, which can recognize and destroy malignant cells, has been limited by the ability to isolate and expand T cells restricted to tumor-associated antigens. Chimeric antigen receptors (CARs) composed of antibody binding domains connected to domains that activate T cells could overcome tolerance by allowing T cells to respond to cell surface antigens; however, to date, lymphocytes engineered to express CARs have demonstrated minimal in vivo expansion and antitumor effects in clinical trials.

 

According to an article published in Science Translational Medicine (2011;3:p95), it was demonstrated that CAR T cells that target CD19 and contain a costimulatory domain from CD137 and the T cell receptor zeta chain have potent non-cross-resistant clinical activity after infusion in three of three patients treated with advanced chronic lymphocytic leukemia (CLL). The engineered T cells expanded >1000-fold in vivo, trafficked to bone marrow, and continued to express functional CARs at high levels for at least 6 months.

 

Evidence for on-target toxicity included B cell aplasia as well as decreased numbers of plasma cells and hypogammaglobulinemia. On average, each infused CAR-expressing T cell was calculated to eradicate at least 1,000 CLL cells. Furthermore, a CD19-specific immune response was demonstrated in the blood and bone marrow. Moreover, a portion of these cells persisted as memory CAR+ T cells and retained anti-CD19 effector functionality, indicating the potential of this major histocompatibility complex-independent approach for the effective treatment of B cell malignancies.

 

Two of the 3 patients were cancer- free in three weeks after being treated with genetically engineered versions of their own immune cells. The 3rd patient was in partial remission and has remained there for seven months. All of the patients had previously been treated with cancer drugs such as Biogen Idec Inc.’s and Roche Holding AG’s Rituxan, and Sanofi’s Campath.

 

According to the authors, the results may point to a new way to cure chronic lymphocytic leukemia. The only method for achieving remission is a bone marrow transplant, which carries a 20% death risk and offers a cure half the time.

Androgenetic Alopecia as an Early Marker of Benign Prostatic Hyperplasia

 

Androgenetic alopecia (AGA) is a common form of hair loss in both men and women. In men, this condition is also known as male-pattern baldness. Hair is lost in a well-defined pattern, beginning above both temples. Over time, the hairline recedes to form a characteristic “M” shape. Hair also thins at the crown (near the top of the head), often progressing to partial or complete baldness. The pattern of hair loss in women differs from male-pattern baldness. In women, the hair becomes thinner all over the head, and the hairline does not recede. AGA in women rarely leads to total baldness.

 

AGA in men has been associated with several other medical conditions including coronary heart disease and benign prostatic hypertrophy (BPH). Additionally, prostate cancer, disorders of insulin resistance (such as diabetes and obesity), and high blood pressure (hypertension) have been related to AGA. In women, AGA is associated with an increased risk of polycystic ovary syndrome (PCOS). PCOS is characterized by a hormonal imbalance that can lead to irregular menstruation, acne, excess body hair (hirsutism), and weight gain.

 

Both AGA and BPH are androgen-dependent entities that respond to the blocking of 5-alpha-reductase (i.e. the conversion of testosterone to dihydrotestosterone (DHT).

 

According to an article published online in the Journal of the American Academy of Dermatology (12 August 2011), a study was performed to determine whether prostatic volumes and urinary flow changes were higher in patients with early-onset AGA than in healthy control subjects.

 

The investigation was an observational case-control study of 87 men: 45 with early-onset AGA diagnosed in the dermatology department and 42 control subjects. End-point variables were prostatic volume, measured by transrectal ultrasound, and urinary flow, measured by urinary flowmetry. A hormone study was performed on all participants, and the International Prostate Symptom Score (IPSS) and International Index of Erectile Function (IIEF) score were determined.

 

Results showed that the groups did not significantly differ in mean age (cases, 52.7 years vs. control subjects, 49.8 years). Patients with AGA had significantly higher mean prostate volume (29.65 vs. 20.24 mL, P < 0.0001), International Prostate Symptom Score (4.93 vs 1.23, P < 0.0001), and prostate-specific antigen value (1.53 vs. 0.94 ng/mL, P < 0.0001) and significantly lower maximum urinary flow (14.5 vs 22.45 mL/s, P < 0.0001) versus control subjects. Binary logistic regression analysis showed a strong association between the presence of AGA and BPH after adjusting for age, urinary volume, urination time, IPSS, abdominal obesity, glucose levels, systolic blood pressure, insulin levels, fibrinogen, and C-reactive protein (odds ratio = 5.14; P = .041).

 

According to the authors, there is a relationship between the presence of AGA and prostate growth-associated urinary symptoms, likely attributable to their pathophysiological similarity, and that early-onset AGA may be an early marker of urinary/prostatic symptomatology. The authors added that future studies may clarify whether treatment of patients with AGA may benefit any concomitant BPH, which would be present at an earlier stage in its natural evolution.

Cancer Drug Shortages

 

FDA has a dedicated webpage to address drug shortages.

 

According to the New York Times (13 August 2011), oncologist Ezekiel Emanuel has warned about a shortage of older but curative cancer drugs. Of the 34 generic cancer drugs on the market, as of this month, 14 were in short supply. They include drugs that are the mainstay of treatment regimens used to cure leukemia, lymphoma and testicular cancer. The reason is that what are essentially government price controls on generic cancer drugs. If the laws of supply and demand were working properly, a drug shortage would cause a price rise that would induce other manufacturers to fill the gap. But such laws do not really apply to cancer drugs. The underlying reason for this is that cancer patients do not buy chemotherapy drugs from their local pharmacies the way they buy asthma inhalers or insulin. Instead, it is their oncologists who buy the drugs, administer them and then bill Medicare and insurance companies for the costs.

 

Historically, this “buy and bill” system was quite lucrative; drug companies charged Medicare and insurance companies inflated, essentially made-up “average wholesale prices.” The Medicare Prescription Drug, Improvement and Modernization Act of 2003 put an end to this arrangement. It required Medicare to pay the physicians who prescribed the drugs based on a drug’s actual average selling price, plus 6% for handling. And indirectly – because of the time it takes drug companies to compile actual sales data and the government to revise the average selling price – it restricted the price from increasing by more than 6% every six months.

 

The act had an unintended consequence. In the first two or three years after a cancer drug goes generic, its price can drop by as much as 90% as manufacturers compete for market share. But if a shortage develops, the drug’s price should be able to increase again to attract more manufacturers. Because the 2003 act effectively limits drug price increases, it prevents this from happening. The low profit margins mean that manufacturers face a hard choice: lose money producing a lifesaving drug or switch limited production capacity to a more lucrative drug.

 

The result is clear: in 2004 there were 58 new drug shortages, but by 2010 the number had steadily increased to 211, which include non-cancer drugs as well.

Target Health (www.targethealth.com) is a full service eCRO 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 (eCTD), IDE, NDA (eCTD), BLA (eCTD), PMA (eCopy) and 510(k) submissions, execution of Clinical Trials, Project Management, Biostatistics and Data Management, EDC utilizing Target e*CRF®, and Medical Writing.

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