Stroke prevention drug combo shows promise, study says

In continuation of my update on clopidogrel  and aspirin

If you've had a minor stroke or a transient ischemic stroke (TIA), taking the clot-preventing drug clopidogrel along with aspirin may lower your risk of having a major stroke within the next 90 days, according to new research published in The New England Journal of Medicine.

An international study of 4,881 adults in 10 countries who either had a minor stroke or a TIA showed that people who took clopidogrel plus aspirin had a 25 percent lower risk of a major stroke, heart attack or death from blood clots within the three months after the first incident, compared with those who took aspirin alone.

clopidogrel          aspirin

"The study gives us solid evidence that we can use this drug combination to prevent strokes in the highest-risk people, but not without some risk of bleeding," said lead author Clay Johnston, M.D., Ph.D., dean and professor of neurology at Dell Medical School at The University of Texas at Austin.

Both minor stroke and TIA are warning signs that a person has a 3 to 15 percent chance of having a more severe stroke within the next three months. Minor stroke is one that results in mild, nondisabling symptoms. TIA, often called a warning stroke or mini-stroke, is caused by a temporary blockage in a blood vessel to the brain that often dissolves or dislodges on its own to stop symptoms. More than a third of U.S. adults have had TIA symptoms, according to the American Stroke Association.

The study also showed a small increase in the risk of hemorrhage in the clopidogrel-aspirin group compared with the aspirin alone group. For every 1,000 patients treated with the combination, an extra five major bleeds would be expected but with 15 fewer strokes and other major ischemic events. Because the bleeding events are generally reversible, the overall benefit outweighs the risk for most patients, Johnston said.

"Of the 33 major hemorrhages that occurred in these 4,881 patients, more than half involved the gastrointestinal tract, and none of them was fatal. These largely preventable or treatable bleeding complications of the treatment have to be balanced against the benefit of avoiding disabling strokes," said co-author J. Donald Easton, M.D., professor of neurology at the University of California, San Francisco School of Medicine.

One previous trial in this area showed that clopidogrel plus aspirin was effective in lowering risks but did not find the risk of hemorrhage.

"The results of this large international trial, when added to the results of previous research, provide evidence to support the use of clopidogrel plus aspirin for 90 days among patients with minor ischemic stroke and high-risk TIA treated within 12 hours," said Ralph Sacco, M.D., M.S., professor of neurology at Miller School of Medicine at the University of Miami. "This trial is likely to change practice since most clinicians and patients are usually willing to accept the increased risk of hemorrhage to offset the disabling impact of a stroke."

The research was part of the Platelet-Oriented Inhibition in New TIA and minor ischemic stroke (POINT) trial—a randomized, double-blind, placebo-controlled trial conducted between May 2010 and December 2017. It included patient information from 269 sites in 10 countries throughout North America, Europe and Australia. Patients were included if they had a minor stroke or a transient ischemic stroke and were at high risk of having a major stroke.

"It's likely we will see more patients who have had a TIA or a minor stroke receiving the combination of clopidogrel and aspirin in the future," Johnston said. "If you've suffered from a minor stroke or TIA, it's important to see a physician immediately, even in the emergency room, to ensure you're taking steps to avoid a potentially debilitating stroke later on," he said. "There are several tests that need to be done right away to determine the cause of the event and to make sure the best treatments are started as soon as possible."

Clopidogrel, known by the brand name Plavix, is a platelet inhibitor commonly prescribed to people who have peripheral artery disease or who have had a recent heart attack or stroke to prevent future cardiac or stroke events.

Ref : https://www.nejm.org/doi/full/10.1056/NEJMoa1800410

Hyaluronan combined with exercise versus exercise alone to relieve knee arthritis

A study at Hospital for Special Surgery (HSS) aims to determine if a hyaluronic acid treatment combined with an exercise program helps patients with knee arthritis more than exercise alone.

Hyaluronic acid is a gel-like solution that acts as a lubricant and shock absorber in the knee joint. Researchers will be studying Hymovis, an FDA-approved hyaluronic acid product that's administered in two injections in the knee joint given one week apart.

"Research shows that certain exercise programs can benefit people with knee arthritis. However, not all patients obtain sufficient pain relief through exercise," explains Sabrina Strickland, MD, an orthopedic surgeon and lead investigator at HSS. "The new study, which will take place at hospitals around the country including HSS, is designed to enroll a relatively young, active population of people with knee osteoarthritis. It will be interesting to see the results, as hyaluronic acid injections are typically used for an older patient population."

Study participants will be divided into two groups. One group will receive two hyaluronic acid injections combined with a physical exercise program of at least eight weeks. The other group will be provided with an exercise program alone, also to last eight weeks. All patients will receive a diary to record their activity and progress. They will see the physician for follow-up visits three months and six months after enrollment.

The initial doctor exam, x-rays, hyaluronic acid injections, exercise program, and follow-up visits will all be provided free of charge to study participants. Patients who have failed to obtain sufficient pain relief from the exercise program alone at the three-month follow-up will have the option of receiving the hyaluronic acid injections.

Dr. Andreas Gomoll, an orthopedic surgeon at HSS, is also involved in the study, which is open to individuals from 21 to 55 years of age. To qualify, patients must have experienced persistent knee pain lasting at least three months prior to the initial screening; lead an active lifestyle (play a sport or train at least two to three times per week); receive a diagnosis of knee osteoarthritis confirmed by an X-ray; and meet a number of additional requirements.

Single-tablet HIV treatment shows better outcomes over multi-tablet regimen

In continuation of my update on "teofovir"

HIV patients on a single-tablet daily regimen had better treatment retention and viral suppression than patients taking multiple pills, in a study by a Michael E. DeBakey Veterans Affairs Medical Center researcher and his colleagues.

The results were published in the Feb. 25, 2018, issue of AIDS Care.

HIV, or human immunodeficiency virus, weakens the human immune system. It increases the risk of catching other common infections and conditions that don't usually affect people with stronger immune systems. As the infection progresses, it can lead to AIDS (acquired immunodeficiency syndrome). If untreated, the average survival time with HIV is 9 to 11 years.

In 2016, more than 28,000 veterans with HIV received care from VA.

HIV care has come a long way in recent years. Combination antiretroviral therapy was introduced in the 1990s. This treatment led to significant reductions in deaths due to HIV infection. However, these early treatments were not without their downsides. Early therapy involved complex regimens involving up to a dozen pills each day.

Newer treatment regimens are typically taken only once per day. Once-daily regimens are the new standard for HIV care. Having to take medicine only once per day decreases pill burden, which could improve patients' quality of life and treatment adherence. Some of the newest regimens require only a single daily pill.

While studies have shown that patients prefer a single-tablet regimen, not much research has been done on whether a single pill results in better treatment outcomes than a multiple-tablet regimen. Some of the common multiple-tablet regimens are becoming available in generic versions, meaning they will be less expensive. Insurance companies may insist on these regimens if they are cheaper than a single tablet.

To test whether one treatment approach was better, the research team studied more than 1,000 patients at a non-VA Texas clinic who were just beginning HIV treatment. They looked at 622 patients on a single-tablet regimen and 406 on a multi-tablet regimen, all taken once daily.

While both regimens were based around the drug teofovir (below structure), they did not include the exact same combination of medicines. The multi-tablet regimen also contained an antiretroviral HIV drug class called boosted protease inhibitors, and the single-tablet regimen contained a different class called non-nucleoside reverse transcriptase inhibitors.

After following the patients for a year, the researchers found that the single-tablet regimen compared favorably with the multi-tablet regimen. They measured three aspects of treatment: adherence, retention, and HIV suppression.

Treatment adherence means that patients took their medicine more than 80 percent of the time, based on prescription fills. Interestingly, the two regimens had similar rates of adherence. So that factor alone would not explain the apparent edge for the single-tablet group.

To show retention in care, patients had to visit their doctors for viral load measurements at least twice, at least three months apart, during the first year. Eighty-one percent of the single-tablet group showed retention, compared with 73 percent of the multi-tablet group.

HIV suppression was defined as a viral load in the blood of less than 400 copies per milliliter. In the single-tablet group, 84 percent had viral suppression after the first year. In the multi-tablet group, 78 percent showed suppression.

While the results suggest that single-tablet regimens may lead to better clinical outcomes, more research is needed. Dr. Thomas P. Giordano, a researcher at the Michael E. DeBakey VA Medical Center in Houston and corresponding author on the study, explained that it is not yet entirely clear why the single-pill regimen appears to work better.

"There were not differences in adherence as we could measure it via pharmacy refill dates, which suggests that maybe the single-tablet regimens are more efficacious," he said. "It could also be that the persons who got the multi-tablet regimens had more barriers to care and that is why they did more poorly." He says more studies will be needed to help tease out the differences in the types of medications being used versus the effect of pill burden.

Future research will also need to focus on which treatment is more cost-effective, since single-pill regimens may prove to be more expensive.

Natural antioxidant bilirubin may improve cardiovascular health

Bilirubin, a yellow-orange pigment, is formed after the breakdown of red blood cells and is eliminated by the liver. It's not only a sign of a bruise, it may provide cardiovascular benefits, according to a large-scale epidemiology study.

A recent analysis of health data from almost 100,000 veterans, both with and without HIV infection, found that within normal ranges, higher levels of bilirubin in the blood were associated with lower rates of heart failure, heart attack and stroke.

The results are published in the Journal of the American Heart Association.

Several studies have suggested that bilirubin may have beneficial effects, by acting as an antioxidant or interfering with atherosclerosis. The data from the veterans adds to this evidence, and specifically looks at people living with HIV and at an anti-HIV drug, atazanavir, known to elevate bilirubin. The researchers did not see an independent effect of atazanavir on cardiovascular risk.

Even if well-controlled by antiretroviral drugs, HIV infection has negative effects on cardiovascular health, says lead author Vincent Marconi, MD.

"We initially wanted to see if bilirubin and cardiovascular disease had a different relationship in people who were HIV positive, compared to HIV negative," says Marconi, professor of medicine and global health at Emory University School of Medicine and Rollins School of Public Health. He is also director of infectious disease research at the Atlanta Veterans Affairs Medical Center.

Study authors include VACS principal investigator Amy Justice, MD, Ph.D. from Yale, Matt Freiberg, MD and others from Vanderbilt, Jeff Lennox, MD from Emory and additional investigators from Vanderbilt, Boston University, Penn, Pitt, UCLA and Baylor.

Marconi and his colleagues examined data from the Veterans Aging Cohort Study, a nationwide look at HIV infection, supported by the National Institutes of Health. VACS data included 31,418 HIV-positive and 66,987 HIV-negative veterans, almost all men and 48 percent African American. Their age was an average of 48 years.

The researchers divided study participants into four groups according to their bilirubin levels.

Higher levels of bilirubin meant lower risk of heart attack, heart failure or stroke. The group with the highest level of bilirubin had 76 percent of the risk for combined cardiovascular events as the group with the lowest level, with effects seen even in people without liver disease.

"Large increases in bilirubin were not required to see an effect on CVD risk reduction," Marconi says. "Most of the change happened well within the normal physiologic range and specifically from the first to the second quartile."

Atazanavir is a HIV protease inhibitor, and is designed to stop HIV from processing itself. It has a side effect on an enzyme in human cells that is necessary for the recycling of bilirubin. There are some indications that the drug itself has negative effects, balancing out the benefits of bilirubin, Marconi adds.

The authors conclude:

This work provides epidemiologic rationale for future studies to investigate how the antioxidant effect of bilirubin could be harnessed to reduce chronic disease morbidity risk. Future studies should explore the use of bilirubin as a biomarker for other inflammation‐mediated conditions and all‐cause mortality...

More at : http://jaha.ahajournals.org/content/7/10/e007792

Finasteride does not increase risk of prostate cancer death

Twenty five years after it opened for enrollment, the landmark Prostate Cancer Prevention Trial has delivered a final verdict. Finasteride, a common hormone-blocking drug, reduces mens' risk of getting prostate cancer without increasing their risk of dying from the disease. Initial study findings suggested there may be a link between use of the drug and a more lethal form of prostate cancer, but long-term follow-up shows that is not true.

Dr. Ian Thompson, Jr., principal investigator of SWOG's Prostate Cancer Prevention Trial, or PCPT, will deliver the findings May 19 at the Journal of Urology Lecture at the 2018 Annual American Urological Association Meeting in San Francisco. The meeting is the largest gathering of urologists in the world.

"What we can now say is that finasteride not only significantly reduces a man's risk of prostate cancer, it is safe to use based on very long-term follow-up in our study," said Thompson. "In PCPT, we found no increased risk of prostate cancer death in men who took finasteride compared with men who did not. These results are transformational. Prostate cancer is the most common cancer diagnosed in American men, and we have found an inexpensive, effective drug that can prevent it. I'm pleased to report that we've answered the questions and closed the book."

Thompson is chair of SWOG's genitourinary cancer committee, overseeing development of all urologic cancer studies for the federally-funded cancer clinical trials group, and serves as president of CHRISTUS Santa Rosa Hospital—Medical Center in San Antonio, Texas and as emeritus professor at the University of Texas Health Science Center. Thompson led SWOG's landmark PCPT. He and his team set out to determine whether finasteride, a drug used to treat symptoms of prostate enlargement as well as male pattern baldness, would prevent prostate cancer in men over the age of 55. At the time, scientists and doctors knew that prostate cancers were hormonally sensitive, and finasteride, the first 5-alpha-reductase inhibitor, which targets and blocks the action of androgens like testosterone, became available to test.

The PCPT randomized 18,882 men from 1993 to 1997 to finasteride or a placebo—making it one of the largest cancer prevention trials ever mounted. The trial intervention was stopped in 2003 when investigators found a significant, positive result: finasteride reduced prostate cancer risk by 25 percent. But the study also showed that finasteride produced a small increase in the number of high-grade prostate cancers—a negative finding that resulted in a "black box" warning posted by the U.S. Food and Drug Administration on prescription drug labels to flag potentially disabling or life-threatening side effects.

Subsequent SWOG analyses of PCPT data revealed unexpected benefits of finasteride. It improved detection of prostate cancer in screening tests and biopsies, and also improved detection of high-grade cancers. Additional analysis also revealed that men enrolled in the study lived about the same amount of time—regardless of whether they took finasteride or the placebo. Still, despite evidence of the benefits of finasteride, the label warning had an impact. Few men today take the generic drug to lower their cancer risk.

As most deaths from prostate cancer are caused by high-grade cancers, years of PCPT findings still left a critical question unanswered: Would the increased number of high-grade cancers detected in the PCPT years ago result in more prostate cancer deaths over time?

Thompson and his team went back to the study and matched participants to the National Death Index, a centralized database of death record information managed by the U.S. Centers for Disease Control and Prevention. This analysis allowed researchers to determine if a trial participant had died and to determine the cause of death. With almost 300,000 person-years of follow-up and a median follow-up of 18.4 years, they found 42 deaths due to prostate cancer on the finasteride arm and 56 on placebo. Thus, there was no statistically significant increased risk of prostate cancer death with finasteride.

"This discovery could benefit tens of thousands of men each year in the United States by identifying a drug that can safely and effectively prevent prostate cancer," Thompson said. "Treatment for the disease is costly and can have serious side effects, such as impotence and urinary incontinence. My hope is that the visionary decision of our National Cancer Institute colleagues to conduct this study, and the scientific evidence it produced these last 25 years, will provide a lasting benefit for patients."

Ovarian cancer drug shows promise in pancreatic cancer patients with BRCA mutation

In continuation of my update on Rucaparib

A targeted therapy that has shown its power in fighting ovarian cancer in women including those with BRCA1 and BRCA2 mutations may also help patients with aggressive pancreatic cancer who harbor these mutations and have few or no other treatment options. An international team of researchers led by the Perelman School of Medicine and the Basser Center for BRCA at the University of Pennsylvania reported their findings this week in JCO Precision Oncology.

The drug, PARP inhibitor rucaparib, which was approved by the U.S. Food and Drug Administration (FDA) last month for the treatment of women with ovarian cancer who have recurrent disease or received prior therapies, showed its clinical benefit in previously treated pancreatic patients with BRCA mutations in a phase II clinical trial. Of the 19 patients treated, four had responses and two additional patients had stable disease.

"These results not only point us in a new treatment direction to further investigate for patients with pancreatic cancers, but it also reinforces the clinical significance of the BRCA genes beyond ovarian and breast cancer and the utility of PARP inhibitors in other cancers," said Susan M. Domchek, MD, executive director of the Basser Center for BRCA at the Abramson Cancer Center of the University of Pennsylvania.

PARP—poly (ADP-ribose) polymerase—is an enzyme used by healthy cells to repair themselves. However, cancer cells also use PARP to repair DNA damage, thus extending their growth and possible lethality. Preliminary results from the study, which included patients from seven centers around the globe, were presented at the annual meeting of the American Society of Clinical Oncology in 2016. These latest findings represent the full study.

Pancreatic cancer, which is often caught in later, more aggressive stages, is projected to become the second leading cause of cancer death by 2020, emphasizing the need for a larger and more effective arsenal of treatments to combat the disease. Only about 32 percent of patients respond to a first line of chemotherapy, and less than 20 percent who don't respond to a first line of chemotherapy end up responding to a second.

This underscores the importance of looking outside of chemotherapy options, the authors said, particularly in patients with targetable mutations, like BRCA.

Importantly, Domchek said, none of the patients who benefited from rucaparib had tumors that had progressed on a prior platinum-based chemotherapy, suggesting a potential role for rucaparib as an earlier treatment for patients whose tumors are not resistant to such treatments.

Rucaparib is a PARP inhibitor shown to be an effective therapy in ovarian cancers with BRCA 1/2 mutations. In 2016, the drug was approved by the FDA for women with BRCA-associated ovarian cancer who received two or more prior chemotherapies. And in April 2018, the approval was extended to women with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are having a complete or partial response to platinum-based chemotherapies.

The success of rucaparib in ovarian cancers is what prompted the clinical study in pancreatic patients with the same mutation. About nine percent of pancreatic patients have BRCA/2 mutation associated pancreatic cancer.

Overall, a clinical benefit was observed in 32 percent of patients (6/19) treated with rucaparib, and 45 percent in patients (4/9) who had received only one prior chemotherapy for locally advanced or metastatic disease. Nine patients had progressive disease, and three were not evaluable for response. The objective confirmed response rate, the primary endpoint for the study, was 16 percent (3/19).

The trial included 11 men and eight women, with a median age of 57. Twenty-one percent of the patients had BRCA1mutation-associated pancreatic cancer, while 79 percent were associated with BRCA2 mutations.

"Consideration should be given to use of this therapy for treatment of patients whose tumors have not progressed on prior platinum therapy," the authors wrote. "Future studies should focus on better understand the sequencing of PARP inhibitor treatment and potential maintenance therapy, as well as potential predictors of resistance to therapy."

Antibacterial in your toothpaste may combat severe lung disease

In continuation of my update on Triclosan

A common antibacterial substance found in toothpaste may combat life-threatening diseases such as cystic fibrosis, or CF, when combined with an already FDA-approved drug.

Michigan State University researchers have found that when triclosan, a substance that reduces or prevents bacteria from growing, is combined with an antibiotic called tobramycin, it kills the cells that protect the CF bacteria, known as Pseudomonas aeruginosa, by up to 99.9 percent.

CF is a common genetic disease with one in every 2,500 to 3,500 people diagnosed with it at an early age. It results in a thick mucus in the lungs, which becomes a magnet for bacteria.

These bacteria are notoriously difficult to kill because they are protected by a slimy barrier known as a biofilm, which allows the disease to thrive even when treated with antibiotics.

"The problem that we're really tackling is finding ways to kill these biofilms," said Chris Waters, lead author of the study and a microbiology professor.

According to Waters, there are many common biofilm-related infections that people get such as ear infections and swollen, painful gums caused by gingivitis. But more serious, potentially fatal diseases join the ranks of CF including endocarditis, or inflammation of the heart, as well as infections from artificial hip and pacemaker implants.

The research is published in the journal Antimicrobial Agents and Chemotherapy.

Waters and his co-authors, Michael Maiden and Alessandra Hunt, grew 6,000 biofilms in petri dishes, added in tobramycin along with many different compounds, to see what worked better at killing the bacteria. Twenty-five potential compounds were effective, but one stood out.

"It's well known that triclosan, when used by itself, isn't effective at killing Pseudomonas aeruginosa," Hunt said, a post-doctoral associate of microbiology and molecular genetics. "But when I saw it listed as a possible compound to use with tobramycin, I was intrigued. We found triclosan was the one that worked every time."

Triclosan has been used for more than 40 years in soaps, makeup and other commercial products because of its antibacterial properties. Recently, the FDA ruled to limit its use in soaps and hand sanitizers due to insufficient data on its increased effectiveness and concern that it was being overused. Clear evidence has shown, though, that its use in toothpaste is safe and highly effective in fighting gingivitis, and it is still approved for use.

"Limiting its use is the right thing to do," Maiden said, a graduate student in medicine. "The key is to avoid creating resistance to a substance so when it's found in numerous products, the chances of that happening increase."

Tobramycin  (below structure) is currently the most widely used treatment for CF, but it typically doesn't clear the lungs of infection, Waters said. Patients typically inhale the drug, yet find themselves chronically infected their whole lives, eventually needing a lung transplant.

"Most transplants aren't a viable option though for these patients and those who do have a transplant see a 50 percent failure rate within five years," he said. "The other issue is that tobramycin can be toxic itself."

Known side effects from the drug include kidney toxicity and hearing loss.

"Our triclosan finding gives doctors another potential option and allows them to use significantly less of the tobramycin in treatment, potentially reducing its use by 100 times," Hunt said.

Within the next year, Waters and his colleagues will begin testing the effectiveness of the combination therapy on mice with hopes of it heading to a human trial soon after since both drugs are already FDA approved.

Just brushing your teeth with toothpaste that has triclosan won't help to treat lung infections though, Maiden said.

"We're working to get this potential therapy approved so we can provide a new treatment option for CF patients, as well as treat other biofilm infections that are now untreatable. We think this can save lives."

Old drug provides promising new avenue for treatment of MND

In continuation of my update on ebselen

An international study led by biochemists at the University of Liverpool has shown that the drug-molecule ebselen can correct many of the toxic characteristics of a protein that causes some cases of hereditary motor neurone disease (MND).

MND is an incurable, progressive disease that attacks the nerves controlling movement so muscles no longer work. MND affects about 5000 people in the UK at any one time and present treatment options have only a modest effect in improving the patient's quality of life.

Inherited MND is a rare form of the disease (5-10% of total cases) that runs in families. Around 20% of hereditary MND cases are caused by mutations in a gene which codes for a protein called SOD1. When the SOD1 gene is mutated, the protein assembly process malfunctions and steps are missed out. This makes the SOD1 protein structurally unstable leading to formation of protein 'clumps' in the motor neurones, causing them to die.

In a paper published in Nature Communications, scientists from the Universities of Liverpool (UK), Florence (Italy) and Wollongong (Australia) used state-of-the-art crystallography, mass-spectrometry and in-cell NMR technologies to search for a drug molecule which could 'correct' the SOD1 assembly line.

They found that ebselen, a drug which was discovered in the 1980s and has been investigated as a potential treatment for a variety of nervous system disorders, can effectively restore several important steps in the SOD1 assembly process including folding, dimerization and zinc binding.

Dr. Gareth Wright, an MND researcher at the University of Liverpool, said: "This discovery has the potential to prevent the accumulation of SOD1 into the large aggregates we see within the motor neurons of effected individuals. If we can stop that, we might be able to stop the neurons dying."

Professor Samar Hasnain, a structural biologist at the University of Liverpool, added: "The next step is to test ebselen in settings more accurately resembling human neuronal cells and optimising it so that it can become useful as a drug for motor neuron disease."

Commenting on the study, Dr Brian Dickie, Director of Research Development at the Motor Neurone Disease Association, said: "A causal link between the SOD1 gene and certain forms of hereditary motor neuron disease was established a quarter of a century ago. It is very encouraging to see new therapeutic strategies starting to emerge from the considerable advances in scientific understanding that have occurred in recent years."

FDA approves non-opioid treatment for opioid withdrawal

Lucemyra, an oral selective alpha 2-adrenergic receptor agonist, limits the body's output of norepinephrine, the hormone believed to play a role in symptoms of opioid withdrawal, the FDA said.

The safety and efficacy of Lucemyra was validated in two randomized, double-blind, placebo-controlled clinical trials of 866 adults who were physically dependent on opioids and undergoing abrupt opioid discontinuation. Compared to placebo, Short Opiate Withdrawal Scale of Gossop scores were found to be lower for patients treated with Lucemyra, and more patients finished the treatment in the Lucemyra group versus the placebo group.

The agency stressed that Lucemyra is not specifically approved for Opioid Use Disorder, and the drug's use shouldn't extend beyond 14 days. Lucemyra's side effects could include hypotension, bradycardia, sleepiness, and dizziness. Less common reactions could include fainting and abnormal heart rhythms. The drug has not been evaluated in people under age 17, the FDA said. The agency added that it's requiring 15 additional studies in both people and animals to evaluate factors such as longer-term use and the drug's effects on the liver.

Sustained use of oxymetazoline cream efficacious for rosacea

In continuation of my update on oxymetazoline

Zoe Diana Draelos, M.D., from Dermatology Consulting Services in High Point, Tenn., and colleagues examined the long-term safety (one year) and efficacy of oxymetazoline cream 1.0 percent in 440 patients with rosacea with moderate-to-severe persistent facial erythema. Assessments were conducted at three and six hours after the dose on day one, and at weeks four, 26, and 52.

The researchers found that 8.2 percent of patients reported treatment-emergent adverse events (TEAEs), the most common were application site dermatitis, paresthesia, pain, and pruritus. The rate of discontinuation mostly due to application-site TEAEs was 3.2 percent. There was no clinically meaningful skin blanching, inflammatory lesions, or telangiectasia. At week 52, a 2-grade or greater composite improvement from baseline in both Clinician Erythema Assessment and Subject Self-Assessment three and six hours after a dose was seen in 36.7 and 43.4 percent of patients, respectively. Following treatment cessation, less than 1 percent of patients experienced a rebound effect.

"This long-term study demonstrated sustained safety, tolerability, and efficacy of oxymetazoline for moderate-to-severe persistent erythema of rosacea," the authors write.Zoe Diana Draelos, M.D., from Dermatology Consulting Services in High Point, Tenn., and colleagues examined the long-term safety (one year) and efficacy of oxymetazoline cream 1.0 percent in 440 patients with rosacea with moderate-to-severe persistent facial erythema. Assessments were conducted at three and six hours after the dose on day one, and at weeks four, 26, and 52.

The researchers found that 8.2 percent of patients reported treatment-emergent adverse events (TEAEs), the most common were application site dermatitis, paresthesia, pain, and pruritus. The rate of discontinuation mostly due to application-site TEAEs was 3.2 percent. There was no clinically meaningful skin blanching, inflammatory lesions, or telangiectasia. At week 52, a 2-grade or greater composite improvement from baseline in both Clinician Erythema Assessment and Subject Self-Assessment three and six hours after a dose was seen in 36.7 and 43.4 percent of patients, respectively. Following treatment cessation, less than 1 percent of patients experienced a rebound effect.

"This long-term study demonstrated sustained safety, tolerability, and efficacy of oxymetazoline for moderate-to-severe persistent erythema of rosacea," the authors write.

New diabetes drug may help people with obesity lose weight

In continuation of my update on semaglutide

A compound that mimics a naturally occurring hormone that regulates appetite may help people who have obesity but not diabetes to lose weight, a new study suggests. The research will be presented Sunday, March 18, at ENDO 2018, the Endocrine Society's 100th annual meeting in Chicago, Ill

The compound, semaglutide, has a chemical structure that is very similar to the hormone glucagon-like peptide 1 (GLP-1), which regulates both insulin secretion and appetite. In December, the U.S. Food and Drug Administration approved the semaglutide injection Ozempic as a once-weekly adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

"This randomized study of weight loss induced with semaglutide in people with obesity but without diabetes has shown the highest weight reductions yet seen for any pharmaceutical intervention," said lead author Patrick M. O'Neil, Ph.D., Director of the Weight Management Center and Professor of Psychiatry and Behavioral Sciences at the Medical University of South Carolina in Charleston, S.C.

The new study included 957 participants, 35 percent of whom were male. All participants had a body mass index (BMI) of at least 30, but did not have diabetes. They were randomly assigned to seven different groups. Five groups received different doses of semaglutide (between 0.05 mg and 0.4 mg) via injection once daily; a sixth group received a placebo, and a seventh group received 3 mg of the diabetes drug liraglutide. All participants received monthly diet and exercise counseling.

After one year, all participants receiving semaglutide had lost significantly more weight than those receiving placebo. The higher the dose participants received, the greater their average weight loss. Participants who received 0.05 mg of semaglutide daily lost an average of 6.0 percent of their body weight; the 0.1 mg group lost an average of 8.6 percent; the 0.3 mg group lost an average of 11.2 percent; and those receiving a daily dose of 0.4 mg lost an average of 13.8 percent. Those receiving liraglutide lost an average of 7.8 percent of their body weight, while those in the placebo group lost only 2.3 percent on average.

Sixty five percent of participants who received 0.4 mg of semaglutide per day lost at least 10 percent of their body weight, compared with 10 percent of those in the placebo group and 34 percent of the liraglutide group.

The most common adverse events in those taking semaglutide were mild/moderate nausea, as seen previously with GLP-1 receptor agonists.

https://www.endocrine.org/news-room/2018/new-diabetes-drug-may-help-people-with-obesity-lose-weight

Drug used to treat daytime sleepiness does not appear to improve driving in those with sleep apnea

 Armodafinil

 In "Does Armodafinil Improve Driving Task Performance and Weight Loss in Sleep Apnea? A Randomized Trial," Nathaniel Marshall, Ph.D., and his colleagues at the Woolcock Institute for Medical Research, University of Sydney, report on their study of armodafinil, which has been approved by the U.S. Food and Drug Administration to treat excessive daytime sleepiness due to OSA, narcolepsy and other conditions.

The researchers found that armodafinil did not improve the driving performance of those with OSA after six months of use, the study's primary outcome. Nor did those taking the drug report less daytime sleepiness than those receiving a placebo, as measured by the Epworth Sleepiness Scale and the Functional Outcomes of Sleep Questionnaire.

In the study, 113 participants (ages 18 to 70) were randomly assigned to either receive 150 mg of armodafinil daily or a placebo. Participants had moderate to severe OSA, were moderately obese and did not use continuous positive airway pressure (CPAP) or an oral appliance that advances their lower jaw. Both therapies treat OSA by preventing the pauses in breathing that occur in OSA when the back of the throat collapses.

All participants were also randomly assigned to one of two popular diets in Australia: the Australian Guide to Healthy Eating diet, which is similar to the American Dietary Guidelines "Choose My Plate," or a low-glycemic index, high-protein diet. Driving ability was assessed during a simulated 90-minute drive.

According to Dr. Marshall, a clinical trials epidemiologist, about half of patients seen in sleep clinics fall into the category of having sleep apnea and abdominal obesity but being unable to tolerate CPAP or an oral appliance. "My clinical colleagues and I call these patients the 'forgotten patients,'" he said. "We felt we needed to help our patients lose weight to address their metabolic risks over the longer term whilst addressing their sleepiness and neurocognitive dysfunction immediately with armodafinil."

He added that sporadic reports indicate that patients using armodafinil and its cousin modafinil to improve wakefulness experienced weight loss, so he and his coauthors wanted to test whether the drugs might increase the success of a deliberate weight loss program.

 modafinil

In the current study, armodafinil did, in fact, have a positive effect on body mass. Participants on the drug lost more body fat on either of the diets, which appeared to reduce weight equally well, than those who received the placebo. At six months, those in the armodafinil arm of the study lost an average of 6.4 pounds more body fat than those receiving the placebo. The researchers said that some of this additional weight loss may be due to the increased activity levels of those receiving the drug, as measured by an activity tracker. Importantly, the authors noted that armodafinil did not appear to increase blood pressure.

Armodafinil also appeared to improve driving ability after three months. The researchers speculate that those taking armodafinil learned their simulated driving tasks faster than those receiving the placebo because by six months there was no difference between the two groups. Even with the improvements that came with practice, the authors noted that, on average, driving ability among these participants with untreated OSA was two standard deviations worse than healthy people without OSA.

Novartis Drug Tasigna Approved by FDA to Treat Children with Rare Form of Leukemia

In continuation of my update on Nilotinib

Novartis announced today that the US Food and Drug Administration (FDA) expanded the indication for Tasigna (nilotinib) to include treatment of first- and second-line pediatric patients one year of age or older with Philadelphia chromosome-positive chronic myeloid leukemia in the chronic phase (Ph+ CML-CP)

In the United States, Tasigna is now indicated for the treatment of adult and pediatric patients one year of age or older with newly diagnosed Ph+ CML-CP. Tasigna is also indicated for the treatment of pediatric patients one year of age or older with Ph+ CML-CP resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy, as well as adult patients with Ph+ CML in chronic phase and accelerated phase, resistant or intolerant to prior therapy that included imatinib.

This approval is the latest in a series of regulatory milestones that broadens the understanding and clinical use of Tasigna.

CML is a type of blood cancer where the body produces malignant white blood cells. Almost all patients with CML have an abnormality known as the "Philadelphia chromosome," which produces a protein called BCR-ABL. This protein aids the proliferation of malignant white blood cells in affected patients. Worldwide, CML accounts for approximately 3% of newly diagnosed childhood leukemia[1].

"Novartis' commitment to people living with CML is reinforced by today's FDA approval of Tasigna in children," said Liz Barrett, CEO, Novartis Oncology. "This expanded use, along with the other recent global regulatory Tasigna milestones, underscores our dedication to reimagining medicine and addressing the needs for people with CML, including children with this cancer."

The new indications, granted under the FDA's Priority Review designation, are based on two studies evaluating the efficacy and safety of nilotinib in pediatric patients (two years to less than 18 years of age) with Ph+ CML-CP. A total of 69 Ph+ CML-CP pediatric patients, either newly diagnosed (first-line) or who were resistant or intolerant to prior TKI therapy (second-line), received nilotinib[2]. In newly diagnosed pediatric patients, the major molecular response (MMR; BCR ABL/ABL <=0.1% International Scale [IS]) rate was 60.0% (95% confidence interval [CI]: 38.7, 78.9) at 12 cycles, with 15 patients achieving MMR[2]. The cumulative MMR rate among newly diagnosed pediatric patients was 64.0% by cycle 12, and the median time to first MMR was 5.6 months (range: 2.7 to 16.6). In pediatric patients with resistance or intolerance to prior TKI therapy, the MMR rate was 40.9% (95% CI: 26.3, 56.8) at 12 cycles, with 18 patients being in MMR[2]. The cumulative MMR rate among pediatric patients with resistance or intolerance was 47.7% by cycle 12, and the median time to first MMR was 2.8 months (range: 0.0 to 11.3)[2].

Adverse reactions observed in these pediatric studies were generally consistent with those observed in adults, except for laboratory abnormalities of hyperbilirubinemia (Grade 3/4: 13%)-a condition where there is too much bilirubin in the blood-and transaminase elevation (AST Grade 3/4: 1%, ALT Grade 3/4: 9%), which were reported at a higher frequency than in adult patients. One resistant or intolerant pediatric CML patient progressed to advance phase/blast crisis (AP/BC) after about 10 months on treatment.

Oral drug reduces venous thromboembolism recurrence among cancer patients

In continuation of my update on  rivaroxaban

Research from the University of Warwick indicates that taking a tablet a day can help treat cancer patients of a potentially deadly condition.

People with cancer have an increased risk of developing blood clots, with roughly one in five experiencing venous thromboembolism (VTE) - either deep vein thrombosis (DVT) or pulmonary embolism (PE). Blood clots in the deep veins of the leg may travel to the lungs causing a pulmonary embolism. These two conditions are referred to as VTE - a dangerous and potentially deadly medical condition of which there are 10 million cases worldwide.

Current international guidelines recommend cancer patients are injected with an anticoagulant (a low molecular weight heparin) to treat and prevent recurrence of VTE. However, new results from a large pilot trial run at the University's Warwick Medical School called 'select-d' suggest that a daily tablet could be a beneficial alternative for treating VTE in selected patients.

Research led by Professor Annie Young of Warwick Medical School found that prescribing the oral drug rivaroxaban (Xarelto) significantly reduced venous thromboembolism recurrence among patients with cancer and VTE. She said: "Clinicians were already adopting the oral drug into practice for non-cancer patients and now they have data from this study to indicate that this form of treatment is an alternative option for many cancer patients who have a clot."

 

Although there are many causes and risk factors for VTE, cancer patients are particularly at risk due to a combination of factors such as immobility (if in bed poorly), pancreatic and gastric tumours, and chemotherapy. Because VTE can be life-threatening, blood thinners are used to shrink existing clots and prevent others from forming.

The 'select-d' trial enrolled 406 patients who had cancer and VTE; most (69 percent) were receiving cancer treatment (typically chemotherapy) at the time of their VTE. Half were randomly assigned to receive low-molecular-weight heparin (dalteparin) and half were given the oral drug rivaroxaban. After six months of treatment, the VTE recurrence rate was four percent among those taking the tablet and 11 percent in those receiving dalteparin.

The results for secondary outcomes were mixed. In patients receiving rivaroxaban, there were around the same percentage of major bleeding events (6%) as those receiving dalteparin (4%) but a marked and significant increase in clinically relevant non-major bleeds (13%) with rivaroxaban compared to those having low molecular weight heparin (4%). The reason for increased bleeding is not known, it may be because rivaroxaban is more 'potent'.

Professor Young added: "We now need to be sitting down with each one of our cancer patients with VTE, discussing their preference alongside looking at all their clinical details including whether the cancer lesion is still there, what other medications are being taken and what other conditions the patient has so that we can choose the optimal VTE treatment for each patient."

Osteoporosis drug may be cardioprotective in hip fracture patients

In continuation of my update on alendronate

The osteoporosis drug alendronate was linked with a reduced risk of cardiovascular death, heart attack, and stroke in a Journal of Bone and Mineral Research study of patients with hip fractures. The association was seen for up to 10 years after fracture.

In the study, patients newly diagnosed with hip fracture from 2005 through 2013 were followed until late 2016. Among 34,991 patients, 4602 (13%) received osteoporosis treatment during follow-up.

Alendronate was associated with 67% and 45% lower risks of one-year cardiovascular death and heart attack, respectively. It was associated with an 18% reduced risk of stroke within five years and a 17% reduced risk of stroke within 10 years. Protective effects were not evident for other classes of osteoporosis treatments.

"It is well established that there is a world-wide crisis in the treatment of osteoporosis, due to patients' awareness of the extremely rare side effects," said senior author Dr. Ching-Lung Cheung, of the University of Hong Kong. "Our findings show that alendronate is potentially cardioprotective in hip fracture patients.

Therefore, physicians should consider prescribing alendronate or other nitrogen-containing bisphosphonates to hip fracture patients soon after their fracture, and patients should also have good compliance with alendronate treatment, as this is not only good for your bones, but also your heart."

In addition to clinical management, the study also has important implications in clinical trial design of anti-osteoporosis medications. The US Food and Drug Administration recently requested more data before reaching a decision on whether to approve the osteoporosis drug romosozumab, due to excess cardiovascular adverse events in the romosozumab arm compared with the alendronate arm. "In light of these important deliberations, our results suggest that such differences in cardiovascular adverse events could be potentially related to a protective association of alendronate, rather than an increase in cardiovascular adverse events related to romosozumab use, said Dr. Cheung."

 Ref : http://newsroom.wiley.com/press-release/osteoporosis-drug-may-benefit-heart-health

Osteoporosis drug may be cardioprotective in hip fracture patients