By Dr. N. Arulmozhi, MPT, PGDCR & PV, Drug Safety Associate
Circadian rhythms9 are physical, mental and behavioral changes that follow a roughly 24 hour cycle, responding primarily to light and darkness in an organism’s environment. They are found in most living things, including animals, plants and many tiny microbes. Circadian rhythms are produced by natural factors within the body, but they are also affected by signals from the environment. Light is the main cue9 influencing circadian rhythms, turning on or turning off genes that control an organism’s internal clocks.
Circadian rhythms can affect normal diurnal changes (6-PAGE 138-139), sleep-wake cycles, hormone release, body temperature and other important bodily functions.
The biological clocks 8 that control circadian rhythms are groupings of interacting molecules in cells throughout the body. Melatonin (5-PAGE 11) is a hormone secreted by the pineal gland in the brain. It helps regulate other hormones and maintains the body's circadian rhythm. A “master clock” in the brain coordinates all the body clocks so that they are in synch. The release of ACTH (4-PAGE 879) (adrenocorticotropin) by the pituitary gland at the base of the brain is driven by a third hormone that is activated by the body's master clock.
The “master clock” 9 that controls circadian rhythms consists of a group of nerve cells in the brain called the suprachiasmatic nucleus, or SCN. The SCN contains about 20,000 nerve cells and is located in the hypothalamus, an area of the brain just above where the optic nerves from the eyes cross.
AN UNKNOWN ELECTRICAL INSTABILITY IN THE HEART
A fundamental discovery (7-PAGE 18) by the research team led by Case Western Reserve University School of Medicine, United States, uncovers the first molecular evidence linking the body’s natural circadian rhythms to sudden cardiac death.
Ventricular arrhythmias (3-PAGE 10) or abnormal heart rhythms are the most common cause of sudden cardiac death. They occur most frequently in the morning walking hours (2-PAGE 674), followed by a smaller peak in the evening hours. Circadian rhythms are highest level in the morning and lowest level on going to bed at night. While scientists have observed this tendency for many years, prior to this breakthrough, the molecular basis for these daily patterns was unknown.
NEUROPHYSIOLOGY OF CIRCADIAN RHYTHM & STRESS (1-PAGE 4-157)
This discovery will be the first step towards new diagnostic tools and therapies to prevent or treat the occurrence of this fatal event. The research team discovered that a novel genetic factor, “Kruppel-like Factor 15” (KLF15) (7-PAGE NO 18), links the body’s natural circadian rhythm to, and regulates the heart’s electrical activity. A lack or excess of KLF15 causes a loss or disruption in the heart’s electrical cycle and greatly increases susceptibility to arrhythmias.
A lack of KLF15 seen in patients with heart failure, while its excess electrocardiography (ECG) changes such as those seen in patients with Brugada syndrome, a genetic heart rhythm disorder.
“This study identifies a hitherto unknown mechanism for electrical instability in the heart. It provides insight into day and night variation in arrhythmia susceptibility that has been known for many years”.
With this understanding, scientists can propose new patient treatments with the goal of reducing incidences of sudden cardiac death (7-PAGE NO 18). This landmark finding shows that circadian rhythms are an important factor in sudden cardiac death. In addition, it raises the possibility that additional factors may affect that occurrence of sudden cardiac death.
Sudden cardiac death due to electrical instability is the leading cause of death in the United States at 700 – 800 deaths per day(7-PAGE NO 18). It accounts for 10,460 (75.4%) of all 13,873 cardiac disease deaths in persons aged 35 - 44 years old in the U.S. When a person changes daily sleeping habits, the cycle changes accordingly (4-PAGE 880). Further studies are needed to examine the how additional components of the biological clock affect electrical instability in the heart.
- CHATERJEE C.C, “HUMAN PHYSIOLOGY”, 10th edition, 1988, Ashutosh Lithographic Company, Kolkata.
- DAVIDSON, “PRINCIPLES AND PRACTICE OF MEDICINE”, 7th edition, 1996, Churchil Livingstone, New York.
- DESMOND G.JULIAN, “CARDIOLOGY”, 7th edition, 1998, W.B.Saunders, Sydney.
- GUYTON & HALL, “TEXTBOOK OF MEDICAL PHYSIOLOGY”, 10th edition, 2001, W.B.Saunders, Singapore.
- JOHN WALTON, “BRAIN’S DISEASES OF THE NERVOUS SYSTEM”, 10th edition, Oxford university press, Oxford.
- LARRY G. SHAVER, “ESSENTIALS OF EXERCISE PHYSIOLOGY”, 5th edition, Surjeet Publications, Delhi.
- “THE HINDU”, Dated 23 Feb 2012, Bangalore.
By Teresa Ceseña, Ph.D., Manager, Medical Writing
Medical writers at Contract Research Organizations (CROs) are playing an increasingly prominent role in writing documents associated with bringing drugs to market - everything from pharmacology reports that summarize testing results for potential new drugs, to safety summaries in New Drug Applications (NDAs) submitted for approval by regulatory bodies. A day in the life of a medical writer consists of producing high quality documents in usually the shortest amount of time possible. Clients, that is, pharmaceutical companies and biotechs, may have a handle on producing and testing the drugs, but it’s the job of the medical writer to tie it up with a pretty bow - presentation is crucial!
With that said, there’s no such thing as a typical day for a medical writer. Every day brings something new. There are, however, some basic steps that most medical writing projects follow. A typical project may start off with a kick-off meeting. For large or complicated projects, an internal kick-off meeting should be the first step so that the entire internal medical writing team is on the same page when client introductions are made. An internal team meeting allows the team to prepare ahead of time in order to provide a united front when meeting with the client, which then gives that client confidence that the team understands the project.
For both the medical writers and the client, one of the most important steps is understanding expectations. Expectations should be laid out as much as possible before writing is even initiated. Such expectations include:
- How many drafts will there be?
- How much input will the client want to provide?
- How often will the client provide input?
- Is publishing included?
There are usually one or two draft deliverables, followed by a final deliverable document. For more straight-forward documents, such as study protocols or clinical study reports, comprehensive templates are usually provided. The client will provide source material, and the medical writer will add information into the corresponding sections. Of course, it’s not just a matter of cutting and pasting. Medical writing requires knowledge of regulatory requirements (for example, knowing what information is required in the efficacy section of a Clinical Overview), experience with client preferences (for agency submissions, client A prefers that all data is presented individually from all phase 1 studies, not just an overall, pooled phase 1 summary), and, yes, a bit of finesse.
It’s the job of the medical writer to “clean up” the deliverable, in other words, perform a spell check, read for fluidity, and adjust the formatting. If these “clean up” steps are not taken, this can prove distracting to the client, who in turn may not be able to focus on providing the necessary feedback on content. It’s like giving someone the most thoughtful present in the world, but doing a sloppy job with the wrapping paper. So, although something like formatting may seem trivial, when not done to the client’s satisfaction, it takes away from the perceived quality of the deliverable, which in turn may lead the client to infer that the content is less than satisfactory as well.
It’s also helpful to provide comment logs with drafts. This allows the writer to communicate exactly what input they need from the client in an organized fashion. By then adding client responses to the log, this can quickly clear up any misunderstood directives, if there are any, and it ensures that the team and the client are on the same page.
By the final draft, any feedback from the client should be integrated into the document. Before it is delivered, it should also go through quality control (QC). This is where the content is checked against sources, which can be anything from an email with wording provided by the client, to the number of adverse events provided in client table, to agreed upon responses in a comment log. Documentation is everything. Remember, if you don’t have proof of an information exchange, then it never really happened!
In the end, clients will come back to a CRO that have medical writers who consistently produce high quality documents in the promised time frame. You can have a quality document, but if it’s a week late, then it does the client no good. Time is money, especially when a company is trying to get a product to market. And the converse is also true - you can have a document done on time, but if it’s less than stellar, then the client may also be inclined to take their business elsewhere. With so many CROs out there, pharmaceutical companies and biotechs have their pick of medical writers to work with, so the key is to consistently produce quality documents in a timely fashion.