The World Congress of Basic and Clinical Pharmacology

 

Our friend and colleague Bernd Rosenkranz, MD PhD, FFPM, moved to South Africa from Berlin awhile back and is now Professor and Head, Division of Clinical Pharmacology Department of Medicine, University of Stellenbosch, Tygerberg, Cape Town, South Africa. We worked with Bernd when has was at Jerrini AG and collaborated on their program in Hereditary Angioedema. The product is now marketed by Shire. Bernd told us about The World Congress of Basic and Clinical Pharmacology being held in South Africa this year so we would like to share the following:

 

The world’s leading pharmacologists are coming to South Africa in July 2014. The World Congress of Basic and Clinical Pharmacology (WCP2014) takes place in Africa for the first time and the five-day global forum will balance the latest scientific discoveries together with important pharmacological fundamentals. This is a unique opportunity to stay abreast of the latest industry developments and gain valuable insight into the African health sectors. Visit http://www.wcp2014.org/ to find out how you can participate in this high profile platform of scientific excellence.

 

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View of Cape Town from the Sea – Courtesy Carolyn Ackerman – Scatterlings Conference and Events

 

 

ON TARGET is the newsletter of Target Health Inc., a NYC-based contract research organization (CRO), providing strategic planning, regulatory affairs, clinical research, data management, biostatistics, medical writing and software services, including the paperless clinical trial, to the pharmaceutical and device industries.

 

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.

 

Joyce Hays, Founder and Chief Editor of On Target

Jules Mitchel, Editor

Vanessa Hays, Editorial Contributor

Tears

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Anatomy of lacrimation, showing:

a) Lacrimal gland

b) Superior lacrimal punctum

c) Superior lacrimal canal

d) Lacrimal sac

e) Inferior lacrimal punctum

f) Inferior lacrimal canal

g) Nasolacrimal canal

 

Lacrimation, or lachrymation, (from Latin lacrima, meaning “tear“) is the secretion of tears, which serve to clean and lubricate the eyes. Strong emotions such as sorrow, elation, awe and pleasure, as well as irritation of the eyes, laughing, and yawning may lead to an excess production of 1) ___, or weeping. In humans, the tear film coating the eye, known as the precorneal film, has three distinct layers, from the most outer surface:

 

 

Name Container(s) Secretors Functions
Lipid layer Oils Meibomian glands (or tarsal glands) Coats the aqueous layer, provides a hydrophobic barrier that envelopes tears and prevents their spilling onto the cheek. These glands are found among the tarsal plates. Thus, the tear fluid deposits between the eye proper and oil barriers of the lids.
Aqueous layer Water and other substances such as proteins (e.g., lipocalin, lactoferrin, lysozyme, and lacritin) Lacrimal gland Promotes spreading of the tear film, the control of infectious agents and osmotic regulation.
Mucous layer Mucins Conjunctival goblet cells Coats the cornea, provides a hydrophobic layer and allows for even distribution of the tear film.

 

 

Having a thin tear film may prevent one’s ability to wear 2) ___ lenses, as the amount of oxygen needed is higher than normal, and contact lenses stop oxygen from entering the eye. Eyes with thin tear film will dry out while wearing contact lenses. Special eye drops are available for contact lens wearers. Certain types of contact lenses are designed to let more oxygen through to the eye. The lacrimal glands secrete lacrimal fluid, which flows through the main excretory ducts into the space between the eyeball and lids. When the eyes blink, the lacrimal fluid is spread across the surface of the eye. Lacrimal fluid gathers in the lacrimal lake, and is drawn into the puncta by capillary action, then flows through the lacrimal canaliculi at the inner corner of the eyelids entering the lacrimal sac, then on to the nasolacrimal duct, and finally into the 3) ___cavity. An excess of tears, as with strong emotion, can thus cause the nose to run.

 

There are three very basic types of tears:

 

 

Category Description
Basal tears In healthy mammalian eyes, the cornea is continually kept wet and nourished by basal tears. They lubricate the eye, and help to keep it clear of dust. Tear fluid contains water, mucin, lipids, lysozyme, lactoferrin, lipocalin, lacritin, immunoglobulins, glucose, urea, sodium, and potassium. Some of the substances in lacrimal fluid (such as lysozyme) fight against bacterial infection as a part of the immune system. Lysozyme does this by dissolving a layer in the outer coating, called peptidoglycan, of certain bacteria. It is a typical body fluid with a salt content similar to blood plasma. Usually, in a 24-hour period, 0.75 to 1.1 grams (0.03-0.04 ounce avoirdupois) of tears is secreted; this rate slows with 4) ___.
Reflex tears The second type of tears results from irritation of the eye by foreign particles, or from the presence of irritant substances such as onion vapors, tear gas, or pepper spray in the eye’s environment, including the cornea, conjunctiva, or nasal mucosa, which trigger TRP channels in the ophthalmic 5) ___. It can also occur with bright light and hot or peppery stimuli to the tongue and mouth. It is also linked with vomiting, coughing and yawning. These reflex tears attempt to wash out irritants that may have come into contact with the eye.

The third category, in general, referred to as crying or weeping, is increased lacrimation due to strong emotional stress, pleasure, anger, suffering, mourning, or physical pain. This practice is not restricted to negative emotions; many people cry when extremely happy such as during times of intense humor and laughter. In humans, emotional tears can be accompanied by reddening of the face and sobbing ? cough-like, convulsive breathing, sometimes involving spasms of the whole upper body. Tears brought about by emotions have a different chemical make-up than those for lubrication; emotional tears contain more of the protein-based hormones prolactin, adrenocorticotropic hormone, and leucine enkephalin (a natural painkiller) than basal or reflex tears. The limbic system is involved in production of basic emotional drives, such as anger, fear, etc. The 6) ___ system, to be specific, the hypothalamus, also has a degree of control over the autonomic system. The parasympathetic branch of the autonomic nervous system controls the lacrimal glands via the neurotransmitter acetylcholine through both the nicotinic and muscarinic receptors. When these receptors are activated, the lacrimal gland is stimulated to produce tears.

Crying or weeping (psychic tears)  

 

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A toddler producing tears due to emotional stress or pain

 

 

The trigeminal V1 (fifth cranial) nerve bears the sensory pathway of the tear reflexes. When the trigeminal nerve is cut, tears from reflexes will stop, but not emotional tears. Likewise, application of cocaine to the surface of the eye, due to its paralyzing effect on the sensory nerve endings, inhibits the reflex even under exposure to strong tear gases. The motor pathway is autonomic (involuntary), and, in general, uses the pathway of the facial (seventh) nerve in the parasympathetic division. In parasympathetic imitators (such as acetylcholine), more tears are produced, and an anticholinergic drug like atropine inhibits tear production. A newborn infant has insufficient development of nervous control, so s/he “cries without weeping.“ If lacrimal gland malfunctions or is damaged (e.g. by surgery), but does not cause any severe drying of the cornea, it is not a serious matter, for the accessory glands are enough for general secretion. In reflex situations, copious tears are produced mainly in emergencies.

 

Quality of vision is affected by the stability of the tear film.

“Crocodile tears syndrome“ is an uncommon consequence of nerve regeneration subsequent to Bell’s palsy or other damage to the facial nerve in which efferent fibers from the superior salivary nucleus become improperly connected to nerve axons projecting to the lacrimal 7) ___, causing one to shed tears (lacrimate) during salivation while smelling foods or eating. It is presumed that one would also salivate while crying due to the inverse improper connection of the lacrimal nucleus to the salivary glands, but this would be less noticeable.

 

Keratoconjunctivitis sicca, known as dry eye, is a very common disorder of the tear film. However, sufferers can experience watering of the 8) ___, which is in fact a response to irritation caused by the original tear film deficiency. Lack of Meibomian gland secretion can mean the tears are not enveloped in a hydrophobic film coat, leading to tears spilling onto the face. Familial dysautonomia is a genetic condition that can be associated with a lack of overflow tears (alacrima) during emotional crying.

 

In nearly all cultures, crying is seen as a specific act associated with tears trickling down the cheeks and accompanied by characteristic sobbing sounds. Emotional triggers are most often sadness and grief, but crying can also be triggered by anger, happiness, fear, laughter or humor, frustration, remorse, or other strong, intense emotions. In many cultures, crying is associated with babies and children. Some cultures consider crying to be undignified and infantile, casting aspersions on those who cry publicly, except if it is due to the 9) ___ of a close friend or relative. In most cultures, it is more socially acceptable for women and children to cry than men. In some Latin regions, crying among men is acceptable.

 

Some modern therapy movements such as Re-evaluation Counseling teach that crying is beneficial to health and mental well-being, encouraging it positively. An insincere display of grief or dishonest remorse is sometimes called crocodile tears in reference to an Ancient Greek anecdote that crocodiles would pretend to weep while luring or devouring their prey. In addition, in medical terms, someone is said to have 10) ___tears syndrome as an uncommon consequence of recovery from Bell’s palsy, in which faulty regeneration of the facial nerve causes sufferers to shed tears while eating.

 

In a research study conducted by the Weizmann Institute of Science in Rehovot, Israel, emotional tears from women have been found to reduce arousal in 11) ___. Also, emotional tears are made up of a different chemical component than those evoked by eye irritants and can relay chemical messages to others. The change in libido could be attributed to a drop in testosterone provoked by the tear chemicals, reducing 12) ___. In the animal world, it has been found that some blind mole rats rub tears all over their bodies as a strategy to keep aggressive mole rats away.

 

Tear composition varies from tear types. Mainly, tears are composed of water, salts, antibodies and lysozymes (antibacterial enzymes). According to a discovery by Dr. William H. Frey II, a bio-chemist from St. Paul Ramsey medical center in Minnesota, the composition of tears caused by emotion differs from that of tears as a reaction to irritations, such as onion fumes, dust or allergy. Emotional tears are composed of more protein-based hormones, such as prolactin, andrenocorticotropic, and leucine enkephalin (a natural pain killer), which is suggested to be the mechanism behind the experience of crying from emotion making an individual feel better.

 

Lacrimosa (Requiem) – Wolfgang Amadeus Mozart (lyrics)

(can you listen without shedding a tear?)

 

ANSWERS: 1) tears; 2) contact; 3) nasal; 4) age; 5) nerve; 6) limbic; 7) glands; 8) eyes; 9) death; 10) Crocodile; 11) men; 12) aggression

William H. Frey II, PhD, and Biological Role of Emotional Tears

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Although Charles Darwin, the father of evolutionary theory, thought the crying process itself relieved suffering, he regarded emotional tears as an incidental and purposeless secretion. “This is not an easy view for me to accept,“ Dr. Frey said in an interview here. “Darwin himself showed that evolution doesn’t favor purposeless processes.“ The only other theory of emotional crying, offered by the anthropologist Ashley Montagu, saw tears as a means of lubricating upper respiratory passages that would otherwise be dried out by sobbing. Yet, Dr. Frey pointed out, “Most crying episodes are not associated with sobbing, and sobbing, when it occurs, doesn’t always come before the tears. Also, people who exercise vigorously breathe a lot but without crying.“ Understanding why people cry, Dr. Frey said, is especially important because “in our society men in particular are discouraged from crying. If crying reduced the effect of stress, by suppressing tears we may be increasing our susceptibility to stress-related disorders.“

 

To gain a better understanding of the role crying plays in human life, Dr. Frey studied “normal“ crying behavior in adult men and women. The several hundred emotionally healthy volunteers were asked to keep a complete record of any tears they shed over the course of a month. As might be predicted, the women in the study reported crying on an average five times more often than the men -five times a month versus approximately once a month. Furthermore, a much higher percentage of men than women did not cry at all in the course of the month. Forty-five percent of the men, but only 6% of the women, shed no emotional tears in the 30-day study. There was also a wide range in crying frequency. Some women did not cry at all and other women cried nearly every day. “These were all normal people without any psychological problems,“ Dr. Frey said. Women reported feeling a “lump in their throat“ when they cried much more often than men did. Women shed flowing tears in about half their crying episodes, but in only 29% of the male episodes did tears actually flow. In the rest, the eyes welled up with tears but the tears were not shed.

 

“Not only do men cry less often than women but their crying is also less obvious,“ Dr. Frey remarked. Sobbing occurred in only 14% of the women’s crying episodes and 10% of the men’s. More men than women said they were able to stop themselves from crying, and many women said they could make themselves cry without an external cause by thinking sad thoughts. Although men cry less often than women, when they do cry, the crying episodes last as long as a woman’s -about six minutes on the average, Dr. Frey’s study showed. Dr. Frey also explored the relationship between personality and crying behavior and, to his surprise, found absolutely no correlation between various personality characteristics and the frequency of crying. For example, no higher crying frequency was found among people who scored high on scales of stress, alienation, impulsiveness, social distance and social impotence. On average, those who showed some evidence of current depression cried more often, but other depressed people did not cry at all. Nor was any genetic factor revealed in studies of crying behavior among identical and fraternal twins. “This tells us crying frequency is environmentally determined,“ Dr. Frey concluded. The most frequent triggers of crying episodes were interpersonal relations – such as arguments – and watching a movie or television. Accordingly, Dr. Frey said, the peak time for crying was between 7 and 10 P.M. “when people are most likely to be with their significant others and to watch TV or a movie.“

 

Sadness was the emotion most often associated with crying episodes, accounting for nearly half the total. One in five crying episodes was provoked by happiness, one in 10 by anger, one in 15 by sympathy, one in 20 by anxiety and one in 30 by fear. Eighty-five percent of the women and 73% of the men said they felt better after crying. If Dr. Frey’s theory about the purpose of emotional tears is substantiated by further studies, he said, it bodes ill for societal admonitions like “big boys don’t cry“ and such comforting words as “now, now, don’t cry.“ “We should comfort people without telling them to stop crying,“ Dr. Frey observed. “They do stop crying when they’re comforted.“

 

While the eyes of all mammals are moistened and soothed by tears, only human beings shed tears in response to emotional stress. Although this fact has been known for hundreds, if not thousands, of years, science has until recently shed little light on the reasons for this uniquely human behavior. In fact, notes Dr. William H. Frey, until last week no study had ever been reported of how often and under what circumstances adults cry. Dr. Frey, a self-appointed student of “psychogenic lacrimation,“ as he calls emotionally induced tears, decided many years ago that it was time to find out why people cry. His theory, for which there is now some indirect evidence, is that tears help to relieve stress by ridding the body of potentially harmful stress-induced chemicals. Dr. Frey, a biochemist, is director of the Psychiatry Research Laboratories at St. Paul-Ramsey Medical Center here. Thus far he has shown that emotionally induced tears have a higher protein content than tears produced in response to eye irritation, such as that caused by a cut onion. And while he has not yet been able to do the costly analyses needed to determine the identity and levels of stress-related chemicals in human tears, at least one new report suggests that people with stress-related illnesses cry less than their healthy counterparts.

 

Dr. Margaret Crepeau of Marquette University College of Nursing studied 100 men and women with stress-related disorders – 50 with ulcers, 50 with colitis, an inflammation of the colon. She compared them to 50 healthy persons of similar age and life circumstances. As she reported to the American Psychological Association meeting last week in Washington, those with the two stress-related disorders were more likely than the healthy people to regard crying as a sign of weakness or loss of control. And, according to their own reports, those who were ill were less likely to cry in a variety of situations. “What now needs to be done is a study of the actual crying behavior of people with stress-related illnesses,“ Dr. Frey remarked. “People say they feel better after crying, and our data show this is so,“ he continued. He also noted that children with a rare inherited disease called familial dysautonomia show two characteristics that may be related: They cry without tears and they have a highly exaggerated reaction to mild stress.

 

“Crying is an exocrine process,“ Dr. Frey explained, “that is, a process in which a substance comes out of the body. Other exocrine processes, like exhaling, urinating, defecating and sweating, release toxic substances from the body. There’s every reason to think crying does the same, releasing chemicals that the body produces in response to stress.“ Dr. Frey sees such research as a route to understanding the biochemical basis of emotion and changes in emotional states. He said, “If we can measure the body’s specific excretion in response to stress, it may be a clue to the biochemical changes involved in sadness and joy. By measuring what comes out of the body in response to emotion, we may find out what is happening in the brain.“

 

QUESTION: Is it true that women’s tears contain an enzyme that can be released only by crying, meaning they are quicker to cry under emotional stress?

 

ANSWER: A large body of historical research has attributed the difference in men’s and women’s crying habits to social pressures. But one prominent tear researcher, William H. Frey II, who theorized three decades ago that crying had a stress-relieving excretory function, thinks there is a hormonal difference at work as well.

 

Both men and women have more of certain chemicals in the tears they shed because of emotional reasons, as opposed to those shed in response to physical stimuli, like onion fumes. Among these substances are the hormones prolactin (associated with milk production) and adrenocorticotropic hormone (ACTH), and the neurotransmitter leucine enkephalin, all of which are released when the body is under stress.

 

The author of “Crying: The Mystery of Tears“ (Winston, 1985), Dr. Frey speculates that because women’s tears show significantly higher levels of prolactin between the ages of 15 and 30, the difference could be associated with frequent tears, to excrete the excess. It has also been suggested that prolactin itself stimulates tears in both genders.

TCGA Bladder Cancer Study Reveals Potential Drug Targets

 

Approximately 72,000 new cases of bladder cancer will be diagnosed in the United States in 2014 and is estimated to cause more than 15,000 deaths. Tobacco is a major risk factor for bladder cancer; more than 70% of the cases analyzed in this study occurred in former or current smokers.

 

The Cancer Genome Atlas (TCGA) Research Network is a collaboration jointly supported and managed by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI), both parts of the National Institutes of Health. According to a study published online in Nature (29 January 2014), investigators with the TCGA Research Network have identified new potential therapeutic targets for a major form of bladder cancer, including important genes and pathways that are disrupted in the disease. The study examined bladder cancer that invades the muscle of the bladder, the deadliest form of the disease. The current standard treatments for muscle-invasive bladder cancer include surgery and radiation combined with chemotherapy. There are no recognized second-line therapies — second choices for treatments when the initial therapy does not work — and no approved targeted agents for this type of bladder cancer. The authors also discovered that, at the molecular level, some subtypes of bladder cancer — also known as urothelial carcinoma — resemble subtypes of breast, head and neck and lung cancers, suggesting similar routes of development.

 

The study analyzed DNA, RNA and protein data generated from the study of 131 muscle-invasive bladder cancer from patients who had not yet been treated with chemotherapy. The authors found recurrent mutations in 32 genes, including nine that were not previously known to be significantly mutated. They discovered mutations in the TP53 gene in nearly half of the tumor samples, and mutations and other aberrations in the RTK/RAS pathway (which is commonly affected in cancers) in 44% of tumors. TP53 makes the p53 tumor suppressor protein, which helps regulate cell division. RTK/RAS is involved in regulating cell growth and development.

 

The authors also showed that genes that regulate chromatin — a combination of DNA and protein within a cell’s nucleus that determines how genes are expressed — were more frequently mutated in bladder cancer than in any other common cancer studied to date. These findings suggest the possibility of developing therapies to target alterations in chromatin remodeling.

 

Overall, the authors identified potential drug targets in 69% of the tumors evaluated. They found frequent mutations in the ERBB2, or HER2, gene. The authors also identified recurring mutations as well as fusions involving other genes such as FGFR3 and in the PI3-kinase/AKT/mTOR pathway, which help control cell division and growth and for which targeted drugs already exist.

 

Because the HER2 gene and its encoded protein, HER2 — which affects cell growth and development — are implicated in a significant portion of breast cancers, scientists would like to find out if new agents under development against breast cancer can also be effective in treating subsets of bladder cancer patients.

 

The authors also uncovered a potential viral connection to bladder cancer. It is known that animal papilloma viruses can cause bladder cancer. In a small number of cases, DNA from viruses — notably, from HPV16, a form of the virus responsible for cervical cancer — was found in bladder tumors. This suggests that viral infection can contribute to bladder cancer development.

NCI Launches Trial to Assess the Utility of Genetic Sequencing to Improve Patient Outcomes

 

Very few types of tumors have just one mutated gene that triggers cancer progression. Once a gene is mutated, it can lead to the activation of multiple pathways, resulting in disease progression and potentially requiring multiple interventions.

 

A pilot trial to assess whether assigning treatment based on specific gene mutations can provide benefit to patients with metastatic solid tumors is being launched this month by the National Cancer Institute (NCI), part of the National Institutes of Health. The Molecular Profiling based Assignment of Cancer Therapeutics, or M-PACT, trial is one of the first to use a randomized trial design to assess if assigning treatment based on genetic screening can improve the rate and duration of response in patients with advanced solid tumors. A trial in which patients are randomly assigned to various treatment options is the gold-standard method for determining which treatment option is best.

 

The study hopes that, in addition to the knowledge gained from the trial about assigning therapy based on results of genetic sequencing of tumors, this trial could identify patient sub-groups that are likely to benefit from certain treatments and result in new treatments being developed quickly for some cancers. This could ultimately lead to smaller, more definitive clinical trials, which would be helpful to clinicians and patients in terms of cost and time.

 

The M-PACT trial is designed to determine whether people with specific mutations that have been demonstrated in laboratory systems to affect drug effectiveness will benefit from a specifically chosen targeted intervention and if these interventions lead to better outcomes. Ater screening hundreds of people, 180 patients with advanced refractory solid tumors (those resistant to standard therapy) will be enrolled based on their genetic profile. During the screening process, samples of the tumors will be genetically sequenced to look for a total of 391 different mutations in 20 genes that are known to affect the utility of targeted therapies. If mutations of interest are detected, using a molecular sequencing protocol for tumor biopsy samples evaluated by the U.S. FDA, those patients will be enrolled in the trial and randomly assigned to one of two treatment arms to receive one of the four treatment regimens that are part of this study.

 

To ensure that patients receive the best treatment already known to provide benefit, patients with specific tumor types should have received certain therapies prior to being enrolled in NCI’s M-PACT. For instance:

 

1. Patients with melanoma whose tumors have mutations in the V600E region of the BRAF gene should have received and progressed on a specific BRAF inhibitor therapy to be eligible for NCI’s M-PACT trial.

2. Patients with lung cancer should have had their tumors tested for the presence of EGFR and ALK gene mutations, and, if mutations were detected, they should have received and progressed on therapies targeting EGFR or ALK, respectively.

 

Patients with all types of solid tumors will be considered for trial eligibility. For the randomization, patients will be assigned to Arm A (they will receive a treatment regimen prospectively identified to target their specific mutation or relevant pathway) or Arm B (they will receive a treatment regimen not prospectively identified to target their specific mutation or relevant pathway). Patients in Arm B will have the option to cross over to Arm A to receive therapy identified to target their specific mutation or relevant pathway if their disease progresses on their initial study treatment. As of January 2014, the study is open for patient accrual. Clinicians hope that they can rapidly enroll patients and report results of their findings by 2017.

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

 

FDA Approves First Treatment for Non-24 hour Sleep-Wake Disorder in Blind Individuals

 

Although most people who are totally blind still can perceive light well enough to prevent Non-24-hour sleep-wake disorder (non-24), there may be as many as 100,000 individuals in the United States with this condition who can’t perceive enough light to establish a normal night sleep schedule.

 

Non-24 is a chronic circadian rhythm sleep disorder, classified within Chapter VI, Diseases of the Nervous System, in the ICD-10. It is defined as a “complaint of insomnia or excessive sleepiness related to abnormal synchronization between the 24-hour light-dark cycle and the endogenous circadian rhythms of sleep and wake propensity.“ Symptoms result when the non-entrained (free-running) endogenous circadian rhythm drifts out of alignment with the desired or conventional sleep-wake schedule. However, the sleep pattern can be quite variable; some individuals adopt a sleep pattern that is congruent with their free-running circadian clock, shifting their sleep times (usually later), thereby minimizing their sleep symptoms but suffering major social and occupational consequences. The majority of patients with non-24 are totally blind, and the failure of entrainment is explained by an absence of photic input to the circadian clock. However, the disorder can also occur in sighted people for reasons that are not well understood. Non-24 can occur at any age.

 

Though often referred to as non-24, it is also known by the following terms:

1. Free running disorder (FRD)

2. Hypernychthemeral disorder

3. Circadian rhythm sleep disorder – free-running type

4. Circadian rhythm sleep disorder – nonentrained type

5. Non-24-hour circadian rhythm disorder

 

The FDA has approved Hetlioz (tasimelteon), a melatonin receptor agonist, to treat non-24 in totally blind individuals. This is the first FDA approval of a treatment for the disorder. Those with non-24 may have difficulty falling asleep or staying asleep, and may wake up groggy or feeling as if they need more rest. People with non-24 may find their sleep patterns reversed — needing to sleep during the day and to be awake at night.

 

The effectiveness of Hetlioz was evaluated in 104 participants in two clinical trials of totally blind individuals with non-24 disorder. In the trials, treatment with Hetlioz resulted in significant improvement compared to placebo (inactive pill), both in increasing nighttime sleep and decreasing daytime sleep duration. In clinical trials, the most common side effects reported by patients treated with Hetlioz were headache, elevated liver enzymes (alanine aminotransferase) in the blood, nightmares or unusual dreams, disturbed night’s sleep, upper respiratory or urinary tract infection, and drowsiness. Hetlioz can impair activities that require complete mental alertness and should be taken at the same time every night before bedtime and activities should be limited after taking the drug.

 

Hetlioz was reviewed under priority review. Priority review provides for an expedited review of drugs that treat serious conditions and have the potential to provide significant improvement in safety or effectiveness of the treatment, diagnosis, or prevention of such serious conditions. Hetlioz also received orphan-product designation by the FDA because it is intended to treat a rare disease or condition.

 

Hetlioz is manufactured by Vanda Pharmaceuticals, Inc. of Washington, D.C.

Roasted Cauliflower with Tomatoes and Goat Cheese

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Just out of the oven and smelling so-o good

 

This cauliflower recipe was tried out two times, before offering it to our readers. The second time we added more garlic, turmeric and goat cheese. Not only do the fragrant spices and herbs add to the veggie mixture in the bottom of the casserole, but the juxtaposition of the creamy goat cheese topping, to the spicy veggies is what makes this recipe special.

 

 

Ingredients

1 head of cauliflower
Salt and freshly ground pepper to taste
3 Tablespoons extra virgin olive oil
1 red onion, cut in half, slice halves, thinly with a mandolin
6 garlic cloves, minced
1 teaspoon fresh thyme leaves
1 teaspoon fresh parsley, chopped
1 (14.8 oz can) CENTO chopped tomatoes in juice
1/8 teaspoon cinnamon
1 teaspoon turmeric
1/2 teaspoon coriander seeds, lightly toasted and coarsely ground
2 eggs
1 cup soft goat cheese (save 2 Tablespoons for topping)
2 to 3 teaspoon chopped chives (save a few to sprinkle on top)

 

Directions

1. Preheat oven to 450 degrees. Line a baking sheet with foil.

2. Cut away the bottom of the cauliflower stem, if it’s hard and thick, and trim off leaves. Cut cauliflower into 1/3 inch thick slices, letting the florets on the edges fall off. Toss all of it, including the bits that have fallen away, with 2 Tablespoons of the olive oil, pinch salt, and pinch black pepper. Place on baking sheet in one layer.

3. Roast for 15 to 20 minutes, stirring and turning after 8 minutes, until the slices are tender and golden brown. Remove from oven and cut large slices into smaller pieces. Put into a large bowl. Turn oven down to 375 degrees.

4. Oil a 2-quart baking dish. Heat remaining oil over medium heat in a medium pan and add onion. Cook, stirring, about 5 minutes. Add pinch of salt (optional), garlic and thyme and continue to cook, stirring, until garlic is fragrant, 30 seconds to a minute. Add tomatoes, cinnamon, ground coriander seeds, parsley, turmeric and pinch black pepper and bring to simmer. Cook, stirring often, over medium-low heat, for 10 to 15 minutes, until the tomato mixture has cooked down and sauce is fragrant. Taste and adjust seasoning to your taste.

 

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Cooking onions, garlic, spices and tomatoes together

 

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Adding the tomato mixture to the cauliflower

5. Add tomato mixture, to bowl with the cauliflower and stir everything together. Scrape into prepared baking dish.

 

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Beat eggs and goat cheese together

6. Set aside 2 Tablespoons of the goat cheese. Beat eggs, then add the remaining cheese and beat together until smooth. Pour over cauliflower mixture, making sure to scrape out every last bit with a rubber spatula. Dot top with small pieces of the remaining goat cheese and sprinkle on chives.

 

7. Bake 30 minutes, until top begins to turn golden brown. Remove from oven, let it set, then dig in.

 

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About to go into the oven

 

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Ready to gobble up the cauliflower/tomato gratin, along with a wonderfully fresh and crunchy tossed salad, basmati rice, California sauvignon blanc in our leopard wine glasses with fresh fruit and cheese for dessert.

 

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This is all that was left, Friday night

 

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Bon appetit!

Life is good!