Breast Cancer Drug Promising in Phase 3 Trial

 For women with advanced breast cancer who carry the BRCA1 and BRCA2 gene mutations, an experimental drug could improve survival, a new study suggests.

The BRCA mutations are linked with a greater risk for aggressive breast and ovarian cancer. The drug, talazoparib, works by blocking an enzyme called poly ADP ribose polymerase (PARP), thus preventing cancer cells from killing healthy ones.

In a phase 3 trial of 431 women, funded by the drug's maker, those who received talazoparib lived longer without their cancer progressing than women treated with standard chemotherapy by an average of three months, researchers found.

"For women with metastatic breast cancer and a BRCA mutation, PARP inhibitors may be considered for their treatment," said lead researcher Dr. Jennifer Litton, an associate professor of breast medical oncology at the University of Texas M.D. Anderson Cancer Center in Houston.

When it's functioning properly, BRCA actually helps repair damaged DNA and prevents tumors, but when BRCA1 and BRCA2 go awry, they encourage breast cancers.

PARP inhibitors such as talazoparib appear to interfere with the function of mutated BRCA in breast cells, causing them to die rather replicate.

In addition, several ongoing studies are looking at combinations with PARP inhibitors "to try to expand who may benefit or lengthen how long they may work," Litton said.The trial results are preliminary, as talazoparib has not yet been approved by the U.S. Food and Drug Administration.

In January, the FDA approved the first PARP inhibitor, Lynparza, to treat BRCA-mutated breast cancer.

Similar drugs have already been used to treat advanced, BRCA-mutated ovarian cancer, according to the agency.

In the current trial, the women who were randomly selected to receive talazoparib had a higher response rate to treatment than women who received standard chemotherapy: 63 percent versus 27 percent, the researchers found.

The drug does have side effects. Among women receiving talazoparib, 55 percent had blood disorders, mostly anemia, compared with 38 percent of those receiving standard chemotherapy.

In addition, 32 percent of the women receiving talazoparib had other side effects, compared with 38 percent of those on standard chemotherapy.

Oncologist Dr. Marisa Weiss is the founder and chief medical officer of Breastcancer.org. "Smart medicines like this PARP inhibitor work better than traditional chemo in women with HER2-negative metastatic disease and a BRCA1/2 genetic mutation," she said.

This targeted form of treatment takes advantage of a weakness in the BRCA gene to further cripple the cancer cell's ability to repair itself, grow and spread, said Weiss, who was not involved with the study.

Normal cells are mostly spared. As a result, more cancer cells are killed with fewer side effects, Weiss said.

"Most importantly, patients themselves have reported a better experience with less hair loss and improved quality of life," she said.

Weiss advises women with advanced breast cancer to have genetic testing.

"In both my clinical practice and within the online support community, we advise women with metastatic breast cancer to get genetic testing upon diagnosis, in order to get the best care first," she said.

The trial was funded by drug maker Pfizer, and the results were published Aug. 15 in the New England Journal of Medicine.

https://www.nejm.org/doi/full/10.1056/NEJMoa1802905

Ref : https://en.wikipedia.org/wiki/Talazoparib

Nusinersen (Spinraza) for Spinal Muscular Atrophy May Help Older Children

 A drug used to treat a rare and deadly muscle-wasting disease in children still improves muscle control even if treatment begins at a later age, a new study found.

Spinal muscular atrophy (SMA) is a leading genetic cause of death in infants worldwide. It attacks nerve cells in the spinal cord, leading to muscle weakness, which can affect breathing, swallowing, walking and head control.

SMA type 1 is the most common and severe form of the disease. It starts before 6 months of age, with infants never gaining the ability to sit up. The median survival rate is eight to 14 months. That means half have shorter lives, half longer.

Previous studies focused on children 7 months old or younger.

This new study included 33 children, ages 8 months to 8 years, with SMA type 1. They were given an injection of the drug nusinersen (Spinraza) into the spinal canal.

The drug increases production of a protein essential for motor neurons in the spinal cord to survive. It was approved by the U.S. Food and Drug Administration in December 2016, and is the first and only approved treatment for all types of SMA.

Six months after the injection, all 33 children had significant muscle control improvements, even the oldest, the researchers reported.

Five patients, ranging from 18 months to 4 years of age when they got their first injection, were able to sit up without support for the first time.

The study was published Aug. 29 in the online issue of the journal Neurology.

"This study is exciting because we found participants had motor function improvement six months after receiving treatment, even an 8-year-old participant," study author Dr. Laurent Servais said in a journal news release.

Servais is a pediatric neurologist at Pitie-Salpetriere Hospital in Paris, France, and Citadelle Hospital in Liege, Belgium.

"The overall response was to the same extent as that in the previously studied younger population," he noted.

"Spinal muscular atrophy type 1 is a devastating disease, and it is encouraging to see that nusinersen may also help people who are at a later stage in the disease process," Servais said.

More research is needed, he said, to find out if genetic factors affect differences in patients' response to treatment.

Ref : https://en.wikipedia.org/wiki/Nusinersen

Unapproved Drug, Ibudilast, Slows Brain Shrinkage in Progressive MS

A drug that has long been used in Japan for asthma may slow down brain shrinkage in people with progressive multiple sclerosis, a preliminary trial has found.

The study, published Aug. 30 in the New England Journal of Medicine, tested an oral drug called ibudilast. It is not approved in the United States, but has been used for years in Japan as a treatment for asthma and for vertigo in stroke survivors.

Researchers found that the drug slowed brain shrinkage by 48 percent when compared with an inactive placebo among patients with progressive MS.

Multiple sclerosis is a neurological disorder caused by a misguided immune system attack on the protective sheath around nerve fibers in the spine and brain. Depending on where the damage occurs, symptoms include vision problems, muscle weakness, numbness, and difficulty with balance and coordination.

Most people with MS are initially diagnosed with the "relapsing-remitting" form, meaning that their symptoms flare up for a time and then ease.

Patients in this trial had progressive MS, where the disease steadily worsens without periods of recovery.

And while more than a dozen drugs are available to manage relapsing MS, there are few options for progressive forms of the disease, said Dr. Robert Fox, lead researcher on the new study.

In general, the drugs for relapsing MS do not work for people with progressive forms, said Fox, a neurologist at the Cleveland Clinic.

The biology of progressive MS, Fox explained, seems to be "fundamentally different." Inflammation drives relapsing MS, while the progressive forms seem to be driven by degeneration of nerve cells in the brain, following damage from the inflammatory phase.

Ibudilast can suppress inflammation, and it was first tested against relapsing MS -- where it failed to prevent relapses. But, Fox said, the drug did slow brain shrinkage (atrophy). And that led researchers to suspect it might help patients with progressive MS.

Fox and his colleagues recruited 255 patients with progressive MS from 28 U.S. medical centers. Patients were randomly assigned to take either ibudilast or placebo pills every day for 96 weeks.

In the end, patients on the drug showed, on average, 48 percent less atrophy in their brain tissue.

The big question, Fox said, is whether that will slow patients' progression to disability.

"This is a proof-of-concept," he said. "We've shown that this slows brain atrophy. We haven't shown that it slows clinical progression."

Longer-term studies are needed to prove that. For now, Fox stressed, "this drug is not available in the U.S., and it will be some time before it is."

Bruce Bebo is executive vice president of research for the National Multiple Sclerosis Society -- which partly funded the trial.

Bebo called the findings a "milestone," but cautioned that the drug will have to show benefits against the disease's course, and not only brain shrinkage."Those clinical benefits take a longer time to measure," he said. For patients and families, though, this is one more positive step against progressive MS, he added."This is one of a number of trials testing new therapies for progressive MS," Bebo said. "It's only a matter of time before we'll have more and better treatments."Ibudilast did have side effects: 92 percent of patients in the trial reported "adverse events," though 88 percent of placebo patients did, too. Headaches and gastrointestinal symptoms -- like abdominal pain and nausea -- were the main problems tied to the drug.In addition, 9 percent of ibudilast patients developed depression, compared to 3 percent of placebo patients.Fox said, "That's something we'll want to watch very carefully going forward."But overall, only 8 percent of ibudilast patients withdrew from the study because of a side effect. That suggests the drug was well-tolerated, Fox said.

There are two forms of progressive MS: secondary, which develops after an initial diagnosis of relapsing MS; and primary, which means it progressively worsens from the start, with no periods of remission.

About half of Americans with MS have a progressive form of the disease, according to Bebo.

Yet, Fox said, they've been "underserved" when it comes to research into new treatments."Progressive MS has been the forgotten child," Fox said. "I think this study can provide them with another chapter of hope."

FDA Approves Merck’s Pifeltro (doravirine) for the Treatment of HIV-1 in Appropriate Patients

Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has approved Pifeltro (doravirine, 100 mg), a new non-nucleoside reverse transcriptase inhibitor (NNRTI) to be administered in combination with other antiretroviral medicines. Pifeltro is indicated for the treatment of HIV-1 infection in adult patients with no prior antiretroviral treatment experience, and is administered orally once daily with or without food. Pifeltro does not cure HIV-1 infection or AIDS.

The FDA also approved Delstrigo, a once-daily fixed-dose combination tablet of doravirine (100 mg), lamivudine (3TC, 300 mg) and tenofovir disoproxil fumarate (TDF, 300 mg).

Pifeltro is contraindicated when co-administered with drugs that are strong cytochrome P450 (CYP)3A enzyme inducers as significant decreases in doravirine plasma concentrations may occur, which may decrease the effectiveness of Pifeltro.

FDA Approves Merck’s Pifeltro (doravirine) for the Treatment of HIV-1 in Appropriate Patients

Merck,  known as MSD outside the United States and Canada,  announced that the U.S. Food and Drug Administration (FDA) has approved Pifeltro (doravirine, 100 mg), a new non-nucleoside reverse transcriptase inhibitor (NNRTI) to be administered in combination with other antiretroviral medicines. Pifeltro is indicated for the treatment of HIV-1 infection in adult patients with no prior antiretroviral treatment experience, and is administered orally once daily with or without food. Pifeltro does not cure HIV-1 infection or AIDS.

The FDA also approved Delstrigo, a once-daily fixed-dose combination tablet of doravirine (100 mg), lamivudine (3TC, 300 mg) and tenofovir disoproxil fumarate (TDF, 300 mg).

Pifeltro is contraindicated when co-administered with drugs that are strong cytochrome P450 (CYP)3A enzyme inducers as significant decreases in doravirine plasma concentrations may occur, which may decrease the effectiveness of Pifeltro.

FDA Approves Merck’s Delstrigo (doravirine/lamivudine/tenofovir disoproxil fumarate) for the Treatment of HIV-1 in Appropriate Patients

In continuation of my update on Lamivudine and Tenofovir


    




doravirine                                 Lamivudine                                             Tenofovir

Merck  known as MSD outside the United States and Canada, announced that the U.S. Food and Drug Administration (FDA) has approved Delstrigo, a once-daily fixed-dose combination tablet of doravirine (100 mg), lamivudine (3TC, 300 mg) and tenofovir disoproxil fumarate (TDF, 300 mg) for the treatment of HIV-1 infection in adult patients with no prior antiretroviral treatment experience. Delstrigo is administered orally once daily with or without food. Delstrigo contains a boxed warning regarding post-treatment acute exacerbation of hepatitis B (HBV) infection. Delstrigo does not cure HIV-1 infection or AIDS.

The FDA also approved Pifeltro (doravirine, 100 mg), the new non-nucleoside reverse transcriptase inhibitor (NNRTI) contained in Delstrigo, for administration in combination with other antiretroviral medicines.

Delstrigo is contraindicated when co-administered with drugs that are strong cytochrome P450 (CYP)3A enzyme inducers as significant decreases in doravirine plasma concentrations may occur, which may decrease the effectiveness of Delstrigo. Delstrigo is contraindicated in patients with a previous hypersensitivity reaction to 3TC. For more information, see “Selected Safety Information” below.

Immune reconstitution syndrome can occur, including the occurrence of autoimmune disorders with variable time to onset, which may necessitate further evaluation and treatment. Renal impairment, including cases of acute renal failure and Fanconi syndrome, have been reported with the use of TDF. Delstrigo should be avoided with concurrent or recent use of a nephrotoxic agent, as cases of acute renal failure after initiation of high-dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs) have been reported in patients with risk factors for renal dysfunction who appeared stable on TDF.

Data Supporting the Approval of Delstrigo (doravirine 100 mg/3TC 300 mg/TDF 300 mg)

The FDA approvals of Delstrigo and Pifeltro are based on findings from the pivotal, randomized, multicenter, double-blind, active controlled Phase 3 trials, DRIVE-AHEAD and DRIVE-FORWARD, evaluating the efficacy and safety of Delstrigo and Pifeltro, respectively, in participants infected with HIV-1 with no antiretroviral treatment history.

FDA Approves Merck’s Delstrigo (doravirine/lamivudine/tenofovir disoproxil fumarate) for the Treatment of HIV-1 in Appropriate Patients

In continuation of my update on Imbruvica (ibrutinib)

The Janssen Pharmaceutical Companies of Johnson & Johnson today announced the U.S. Food and Drug Administration (FDA) approval of Imbruvica (ibrutinib) in combination with rituximab for the treatment of Waldenström’s macroglobulinemia (WM), a rare blood cancer.[1] The approval expands the label for Imbruvica in WM beyond its current approved use as a monotherapy to include combination use with rituximab. This approval represents the first approved non-chemotherapy combination option for the treatment of WM. Imbruvica first received FDA approval in WM as a monotherapy in January 2015 via the Breakthrough Therapy Designation pathway, making it the first FDA-approved therapy for the disease. The expanded label marks the ninth FDA approval for Imbruvica since 2013. Imbruvica is a first-in-class Bruton's tyrosine kinase (BTK) inhibitor jointly developed and commercialized by Janssen Biotech, Inc. and Pharmacyclics LLC, an AbbVie company.

The combination of Imbruvica and rituximab provides health care professionals with a new treatment option for patients living with this serious blood cancer,” said Dr. Lia Palomba, hematologist-oncologist at Memorial Sloan-Kettering Cancer Center, New York, and iNNOVATE study investigator. “Before Imbruvica, there were no FDA-approved treatment options for patients with Waldenström’s macroglobulinemia, a disease first acknowledged nearly 75 years ago. Today, Imbruvica continues to provide an important therapeutic approach in the treatment of this complex disease.”

This approval is based on results from the randomized, double-blind, placebo-controlled iNNOVATE study (PCYC-1127), the largest Phase 3 study of a non-chemotherapy combination in WM patients. The iNNOVATE study evaluated Imbruvica in combination with rituximab versus placebo plus rituximab in 150 patients with either relapsed/refractory (r/r) disease or previously untreated WM. At a median follow up of 26.5 months, a significant improvement in the Independent Review Committee (IRC)-assessed primary endpoint of progression-free survival (PFS) was seen with Imbruvica plus rituximab when compared with placebo plus rituximab (30-month PFS rates were 82% vs. 28%, respectively). Patients in the Imbruvica plus rituximab treatment arm experienced an 80% reduction in relative risk of disease progression or death compared with patients treated with placebo plus rituximab (hazard ratio=0.20; confidence interval, 0.11-0.38, p<0.0001). The data were presented in an oral session at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, selected for Best of ASCO 2018 Meetings, and simultaneously published in The New England Journal of Medicine.

“Results from iNNOVATE showed significant improvement in progression-free survival at 30 months and demonstrated the superiority of Imbruvica plus rituximab over rituximab monotherapy in Waldenström's macroglobulinemia,” said Meletios A. Dimopoulos, M.D., Professor and Chairman of the Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Athens, Greece, and iNNOVATE lead study investigator. “Based on these results, Imbruvica in combination with rituximab may be considered as a first- and second-line option for appropriate people diagnosed and living with WM.”

“The clinical data generated for Imbruvica plus rituximab in the treatment of Waldenström’s macroglobulinemia offers physicians evidence to consider this combination regimen for newly-diagnosed patients. Today’s approval represents an important milestone for people living with this rare and incurable blood cancer who have limited FDA-approved treatment options,” said Andree Amelsberg, M.D., Vice President of Oncology Medical Affairs at Janssen Scientific Affairs, LLC. “We remain dedicated to a comprehensive clinical development program to explore the full potential of Imbruvica, including in combination with other therapies.”

Warnings and Precautions remain the same: hemorrhage, infections, cytopenias, cardiac arrhythmias, hypertension, second primary malignancies, tumor lysis syndrome, and embryo-fetal toxicity. The most common adverse reactions (occurring in 20% or more of patients) of all grades in patients treated with Imbruvica plus rituximab in the iNNOVATE study were bruising (37%), musculoskeletal pain (35%), hemorrhage (32%), diarrhea (28%), rash (24%), arthralgia (24%), nausea (21%), and hypertension (20%). Grade 3 or 4 infusion-related reactions were observed in 1% of patients treated with Imbruvica plus rituximab.

The recommended dose of Imbruvica for WM is 420 mg orally once daily until disease progression or unacceptable toxicity as a single agent or in combination with rituximab. When administering Imbruvica in combination with rituximab, consider administering Imbruvica prior to rituximab when given on the same day.

Ref : https://en.wikipedia.org/wiki/Ibrutinib

Sunovion receives Complete Response Letter from FDA for dasotraline NDA

Sunovion Pharmaceuticals Inc. (Sunovion) today announced that the U.S. Food and Drug Administration (FDA) issued a Complete Response Letter for the New Drug Application (NDA) for dasotraline, a novel dual-acting dopamine and norepinephrine reuptake inhibitor (DNRI), for the treatment of attention-deficit hyperactivity disorder (ADHD).

Upon completion of their review, the FDA determined that they cannot approve the dasotraline NDA for the treatment of ADHD in its current form. The Agency indicated that additional clinical data are needed to further evaluate the efficacy and tolerability of dasotraline for the treatment of ADHD. Sunovion plans to meet with the FDA to discuss their comments and determine next steps.

Dasotraline was evaluated in approximately 2,500 children and adults with ADHD in multiple placebo-controlled safety and efficacy studies, as well as two long-term safety studies.

"While we are disappointed with the FDA's decision, we remain confident in the future of dasotraline," said Antony Loebel, M.D., Executive Vice President and Chief Medical Officer at Sunovion, Head of Global Clinical Development for Sumitomo Dainippon Pharma Group. "We plan to discuss next steps for the dasotraline ADHD program with the FDA as soon as possible."

Dasotraline is also being studied for the treatment of moderate to severe binge eating disorder (BED) in adults in the U.S. Data from two positive pivotal studies will support an expected marketing application submission to the FDA for dasotraline to treat BED in FY2018.​

Ref : https://news.sunovion.com/press-release/fda-issues-complete-response-letter-new-drug-application-dasotraline-treatment-adhd

https://en.wikipedia.org/wiki/Dasotraline

Ketamine’s role in treatment of depression: Study

In continuation of my update on Ketamine

The anaesthetic drug Ketamine has been shown to be beneficial in some cases of depression and suicidal ideation which have typically failed to respond to other standard antidepressant medications. A new study has explored the actual workings of ketamine in depression and found that the drug can act on the same receptors as opioid pain relievers.

The latest study was published in the American Journal of Psychiatry.

For this the researchers from the Stanford’s Neurosciences Institute included 12 volunteers at first. These cases were all of treatment-resistant depression.

The participants were all given infusion of Ketamine. In addition some were administered naltrexone and others normal saline infusion. Naltrexone is a drug that can block the effects of opioids.

Results showed that those on ketamine and saline combination found relief from their depressive symptoms quickly compared to those on ketamine and naltrexone combination. In fact those on ketamine and saline placebo reported at least a 90 percent reduction in their symptoms within the first three days of the infusion.

No such improvement was seen among those on ketamine and naltrexone. This proved that when the opioid actions are blocked, the ketamine cannot function as an antidepressant. Both groups faced certain side effects of ketamine such as an “out-of-the-body” experience, dysphoric feelings, tripping etc. This also showed that the antidepressant action of Ketamine was separate from its usual actions, which were seen in all participants in either group.

The initial trial plan was to include 30 patients. Due to the dramatic improvement seen in one group and no changes in the other, the team decided to stop the trial prematurely. This was to spare patients useless treatment.

Ketamine has been in news recently due to its unexplored potential as an antidepressant. If proven, researchers believe, this could impact depression research significantly. Ketamine has gathered interest mainly because it does not change the brain chemistry unlike other antidepressants. Co-author Boris Heifets, a clinical assistant professor of anesthesiology, perioperative and pain medicine at Stanford explained that ketamine blocks the brain’s receptors for glutamate. Glutamate is an important neurotransmitter in the brain. Many researchers have thought that glutamate could be the key zone where ketamine acts as an antidepressant. Heifets added that ketamine is not a simple drug and has varied targets which could be responsible for its antidepressant activities. A lot of money has been spent on developing agents that could work on the glutamate receptors and try to mimic ketamine’s antidepressant actions.

This study shows that the approach is incorrect and glutamates are not the target lead author Nolan Williams explained. Co-senior study author Dr. Alan Schatzberg, a professor of psychiatry and behavioral sciences at Stanford explained that the ketamine was not working as “everyone thought it was working.”

Heifets noted that ketamine is a drug of abuse (called “Special K” in party circuits) that has been in use for a long time and there is an abuse potential of this drug acting on the opioid receptors to provide such effects. He warned that this abuse potential should be kept in mind before ketamine comes into the market as an antidepressant.

However the whole team agrees that this new study shows how ketamine can help patients who have intractable depression. New drugs could be developed in the same lines they explain. These drugs could possibly activate the opioid receptors without having abuse potential they add. Williams added that ketamine has been seen to provide relief of symptoms in other mental ailments such as obsessive compulsive disorders and now is the time to explore if opioids play a role in these diseases as well.

Mark George, a professor of psychiatry, radiology and neuroscience at the Medical University of South Carolina in an editorial accompanying the article wrote that this study is a small one and so should be confirmed in larger trials before conclusions could be drawn.

Ref : https://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2018.18020138

https://en.wikipedia.org/wiki/Ketamine

Eat one avocado per day for six months and get paid, weight loss study

In continuation of my update on Avocado

A latest weight loss study from the Loma Linda University is looking for participants to consume avocados for them and get paid for it too. The study is to be called, “The Habitual Diet and Avocado Trial.”

Joan Sabaté, MD, PhD, lead author and director of the university's Center for Nutrition, Lifestyle and Disease Prevention, said in an online statement, “The study will examine whether eating one avocado per day reduces visceral adipose fat in the abdomen.” The team is calling out to men and women over the age of 25 years who have waist measurements of 40 and 35 inches or more respectively. The rules add that all participants must be willing to “eat one avocado per day for six months or eat only two avocados per month for the same period”. Pregnant and breastfeeding women and those who are planning to get pregnant would not be included in the study.

The rules for participating in the study state that the participants would be divided into two groups –

• The test group would be “given 16 avocados every two weeks and required to eat one avocado per day throughout the six-month study.”
• The control group on the other hand, “will be required to eat no more than two avocados per month during the same period.”

During the course of the study, all participants would be given free health screening and MRI scans and they would need to need each month with their dietician. Participants of both groups would be paid $300 each on completion of the study. They, in addition would be given 24 avocados.

Avocados are known to be rich in fats that are good for the heart. They can help control cholesterol and promote health. However some studies have contradicted the value of avocados in daily diet. Loma Linda University statement reads, “Since avocados contain the highest fat content of any fruit, it seems illogical to think they might actually help people lose their belly fat.” This study would examine if consuming one avocado per day can help reduce the abdominal fat.

At present the study is calling for 1000 participants from not only the Loma Linda University but also from the Tufts University, Penn State University and the University of California, Los Angeles. These would recruit 250 more participants each for the study. Once the study is complete, the data from the participants would be analyzed by the Wake Forest University.

Ref : https://hhd.psu.edu/nutrition/research/research-labs-and-initiatives/cardiometabolic-nutrition-research-lab/avocado-study

Low carbohydrate diet can increase risk of premature death, finds study

Low carbohydrate diets are unsafe and should be avoided, according to a large study presented today at ESC Congress 2018.

Study author Professor Maciej Banach, of the Medical University of Lodz, Poland, said: "We found that people who consumed a low carbohydrate diet were at greater risk of premature death. Risks were also increased for individual causes of death including coronary heart disease, stroke, and cancer. These diets should be avoided."

Obesity is a major health issue worldwide and raises the risk of several chronic conditions, including cardiovascular disease, hypertension, type 2 diabetes, and cancer. Different diets have been suggested for weight loss, such as diets low in carbohydrates and high in protein and fat. The long-term safety of these diets is controversial, with previous studies reporting conflicting results of their influence on the risk of cardiovascular disease, cancer, and death.

This study prospectively examined the relationship between low carbohydrate diets, all-cause death, and deaths from coronary heart disease, cerebrovascular disease (including stroke), and cancer in a nationally representative sample of 24,825 participants of the US National Health and Nutrition Examination Survey (NHANES) during 1999 to 2010. Compared to participants with the highest carbohydrate consumption, those with the lowest intake had a 32% higher risk of all-cause death over an average 6.4-year follow-up. In addition, risks of death from coronary heart disease, cerebrovascular disease, and cancer were increased by 51%, 50%, and 35%, respectively.

The results were confirmed in a meta-analysis of seven prospective cohort studies with 447,506 participants and an average follow-up 15.6 years, which found 15%, 13%, and 8% increased risks in total, cardiovascular, and cancer mortality with low (compared to high) carbohydrate diets (see figure for total mortality).

Professor Banach said: "Low carbohydrate diets might be useful in the short term to lose weight, lower blood pressure, and improve blood glucose control, but our study suggests that in the long-term they are linked with an increased risk of death from any cause, and deaths due to cardiovascular disease, cerebrovascular disease, and cancer."

Participants in the NHANES study had an average age of 47.6 years, and 51% were women. They were divided into quartiles based on the usual percentage of carbohydrates in their diet. The risks of all-cause and cause-specific death over an average 6.4-year follow-up rose with each fall in carbohydrate intake (see table), and remained significant after adjusting for all available factors that might have influenced the association (model 2 in the table).

The researchers also examined the link between all-cause death and low carbohydrate diets for obese (body mass index [BMI] 30 kg/m2 or greater) and non-obese (BMI under 30 kg/m2) participants in two age groups (55 years and older versus under 55) and found that the link was strongest in the non-obese older participants.

Low carbohydrate diet can increase risk of premature death, finds study

Overdose risk increases five-fold with concurrent opioid and benzodiazepine use

In continuation of my update on benzodiazepine

In the first 90 days of concurrent opioid and benzodiazepine use, the risk of opioid-related overdose increases five-fold compared to opioid-only use among Medicare recipients, according to a new study from the University of Pittsburgh School of Pharmacy, published today in JAMA Network Open.

The U.S. Centers for Disease Control and Prevention recommends against concurrent use of opioids and benzodiazepines, but nearly a quarter of Medicare recipients who are prescribed opioids also fill prescriptions for benzodiazepines. Both drugs have sedative effects.

"Patients who must be prescribed both an opioid and a benzodiazepine should be closely monitored by health care professionals due to an increased risk for overdose, particularly in the early days of this medication regimen," said Inmaculada Hernandez, Pharm.D., Ph.D., assistant professor at Pitt's School of Pharmacy and the study's lead author. "Moving forward, policy interventions should focus on preventing concurrent exposure instead of simply reducing the length of time patients use both drugs."

Hernandez and her team used 2013-2014 Medicare Part D data to assess how the duration of simultaneous exposure to the two types of drugs impacts the risk of overdose. Beneficiaries not being treated for cancer who filled at least one opioid prescription during that year were included in the analysis, which ultimately looked at more than 71,000 beneficiaries who averaged 66.5 years of age.

Patients were divided into two groups, those with a supply of only opioids the day before an overdose, and those with an opioid and benzodiazepine supply. The second group was then divided into four subgroups based on the cumulative number of days with overlapping opioid and benzodiazepine supplies.

For patients who did not have an overdose event in the first 90 days of concurrent use, overdose risk in the next 90 days decreased from five-fold to less than double, which is still elevated compared to opioid-only use. After 180 days of concurrent use, the risk of overdose was no higher than the risk for opioid-only use.

Results were adjusted to account for patient demographics, health insurance factors, clinical characteristics, and the number of unique clinicians who prescribed opioids or benzodiazepines to the patients.

Hernandez and her team also found that a beneficiary's risk of concurrent opioid and benzodiazepine use and of overdose increased with the numbers of opioid and benzodiazepine prescribers. In other words, the more clinicians prescribing medications to a beneficiary, the higher the risk of that beneficiary overdosing.

"These findings demonstrate that fragmented care plays a role in the inappropriate use of opioids, and having multiple prescribers who are not in communication increases the risk for overdose," said Yuting Zhang, Ph.D., director, Pharmaceutical Economics Research Group, Health Policy and Management, Pitt Graduate School of Public Health, and the study's senior author. "Prescription monitoring programs and policy interventions can help curb this problem and reduce risk for patients."

Overdose risk increases five-fold with concurrent opioid and benzodiazepine use

Clinical trial: Promising drug slows brain shrinkage in progressive MS patients

A promising drug slowed brain shrinkage in progressive multiple sclerosis (MS) by nearly half, according to new research led by Cleveland Clinic. Very limited therapies are currently available for this disabling form of the disease.

The definitive results of the phase 2 trial – published in the New England Journal of Medicine– showed that the drug ibudilast decreased progression of brain atrophy in progressive MS patients by 48 percent versus placebo. The two-year SPRINT-MS study was conducted at 28 sites with 255 patients.

"These findings are significant for patients with progressive MS," said Robert Fox, M.D., the study's principal investigator and vice-chair for research in Cleveland Clinic's Neurological Institute. "Our hope is that the benefit of ibudilast in slowing brain shrinkage will also translate to decreased progression of associated physical disabilities in a future phase 3 trial."

Progressive MS is associated with gradual worsening of symptoms and increasing disability. It commonly follows relapsing-remitting MS, for which there are more than a dozen approved treatments. However, none of these therapies has consistently demonstrated efficacy in slowing disability progression in patients with progressive MS, particularly those without evidence for active inflammation.

Ibudilast, an oral drug with activity on several biologic pathways with potential relevance to progressive MS, was approved in Japan in 1989 for use in asthma and stroke. It is also being studied in the U.S. for potential treatment of amyotrophic lateral sclerosis (ALS) and drug addiction.

Additionally, the SPRINT-MS study demonstrated the utility of advanced imaging in clinical trials to measure the impact of therapies on brain health. The potential application of imaging-based outcome measures may extend beyond progressive MS to other neurodegenerative disorders as well.

"There is a significant need for new treatment options to effectively delay disability progression for patients with progressive MS," said Dr. Fox. "We are hopeful these findings will help us develop more therapies for progressive MS, and do so more rapidly and efficiently."

The research, which paves the way for phase 3 testing, also determined that ibudilast is relatively safe and well tolerated. The drug has received fast-track designation from the U.S. Food & Drug Administration.

"Although a larger study is needed to confirm these findings, this promising study brings people with progressive MS, who currently do not have many treatment options, one step closer to a potential therapy," said Robin Conwit, M.D., program director at the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.

The study was conducted by the Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT), which is sponsored by NINDS. The research was supported by NINDS, National Multiple Sclerosis Society and MediciNova.

"These results are a promising step toward a potential new therapy for people living with progressive forms of MS, for whom there are few treatment options," said Bruce Bebo, Ph.D., Executive Vice President, Research, National MS Society. "It is gratifying to see our investments in progressive MS starting to pay off."

Ref : https://en.wikipedia.org/wiki/Ibudilast

Drug used for chest pain does not decrease chance of first occurrence of ventricular arrhythmias

A clinical trial of more than 1,000 patients with implantable cardioverter defibrillators (ICDs) found that the drug ranolazine (commonly used to treat chest pain; brand name Ranexa®) was safe but didn't significantly decrease the likelihood of the first occurrence of ventricular tachycardia, ventricular fibrillation or death in this high-risk population. The study was published recently in JACC, the Journal of the American College of Cardiology.

Researchers at the University of Rochester Medical Center launched the National Institutes of Health-sponsored trial in 2011 after previous studies suggested ranolazine might cut the incidence of arrhythmias. A limited number of anti-arrhythmic therapies have been developed and tested over the past 25 years, leaving doctors and patients with older treatment options that often come with substantial side effects.

The trial, which was conducted at 95 centers in the United States and Canada, did reveal a bright spot for ranolazine: the drug lowered the number of recurring episodes of ventricular tachycardia, a fast, abnormal heart rate that begins in the ventricles (lower chambers of the heart) and can cause dizziness, lightheadedness, palpitations or loss of consciousness. The results suggest that there could be a potential role for ranolazine in patients with ICDs who can't tolerate other drugs or aren't eligible for ablation, a procedure that attempts to correct faulty heart rhythms.

"This drug is already on the market to treat chest pain, and while it didn't provide the revolutionary results we had hoped for, I think there's a place for it in the toolbox of treatments for select patients," said Wojciech Zareba, M.D., Ph.D., lead study author and professor of Cardiology at the University of Rochester Medical Center. "Ventricular tachycardia is the most common arrhythmia that individuals with ICDs experience. This drug could be an option for patients who haven't had success with other therapies."

The double-blind, placebo-controlled randomized trial included 1,012 individuals with cardiomyopathy, a disease of the heart muscle that makes it difficult for the heart to pump blood throughout the body. All participants had ICDs and were at high risk for ventricular tachycardia (VT) and ventricular fibrillation (VF), irregular heart rhythms that are associated with increased hospitalizations and death.

The average age of participants was 64 years and 18 percent were women. Half received 1,000 mg of ranolazine orally twice daily and half received a placebo pill. Approximately 34 percent of patients who took ranolazine experienced ventricular tachycardia, ventricular fibrillation or death, compared to 39 percent of individuals in the placebo group. Though the number in the ranolazine group was lower, the difference between groups was not large enough to be considered "significant" or meaningful.

Upon further analysis, the researchers found that the risk for recurrent ventricular tachycardia was 30 percent lower in patients randomized to receive ranolazine compared with placebo.

Mehmet Aktas, M.D., associate professor of Cardiology and a member of the UR Medicine Heart & Vascular team enrolled 20 patients at the University of Rochester Medical Center.

"Through this trial we learned that ranalozine can be administered safely in patients with life threatening abnormal heart rhythms and that it can be given concomitantly with other commonly used antiarrhythmic drugs," said Aktas. "This trial provides clinicians with one more treatment option for patients who have recurrent lethal arrhythmias, which is huge given that this is a very sick population for which we often have limited therapies."

A major limitation of the study was that nearly half of the study participants discontinued the study drugs (both ranolazine and placebo).

The trial, dubbed RAID (Ranolazine in High-Risk Implantable Cardioverter-Defibrillator Patients), was funded with a $9.5 million grant from the National Heart, Lung and Blood Institute at the National Institutes of Health. Gilead Sciences, Inc., the biopharmaceutical company that markets ranolazine, donated the drug and placebo needed for the trial.

Ref : http://www.onlinejacc.org/content/72/6/646
https://en.wikipedia.org/wiki/Ranolazine

Drug used to treat amoebic dysentery may block journey of rabies virus in nerves

In continuation of my update on Emetine

To successfully infect its host, the rabies virus must move from the nerve ending to the nerve cell body where it can replicate.

In a study published July 20 in the journal PLoS Pathogens, researchers from Princeton University reveal that the rabies virus moves differently compared to other neuron-invading viruses and that its journey can be blocked by a drug commonly used to treat amoebic dysentery.

Most viruses only infect the nervous system accidentally when the immune system is compromised. But some "neurotropic" viruses have evolved to target neurons as part of their normal infectious cycle. The rabies virus, for example, is transmitted when an infected animal bites into a host's muscle. It then spreads into the end terminals of motor neurons innervating the muscle and travels along the neurons' long axon fibers to the neuronal cell bodies. From there, the virus can spread throughout the central nervous system and into the salivary glands, where it can be readily transmitted to other hosts. Though rabies infections in humans are rare in the United States, the virus kills more than 59,000 people annually, according to the Centers for Disease Control and Prevention.

Alpha herpesviruses, such as herpes simplex viruses, also enter peripheral nerve terminals and move along axons to the neuronal cell body, where they can lie dormant for the life of the host.

"Transport to the neuronal cell body is not a passive process, but an active one relying on the neuron's own motor proteins and microtubule tracks," said Lynn Enquist, Princeton's Henry L. Hillman Professor in Molecular Biology, a professor of molecular biology and the Princeton Neuroscience Institute, and the study's senior author. "Virus particles must engage this machinery for efficient transport in axons, otherwise infection cannot start."

Enquist and colleagues previously found that alpha herpesviruses engage the neuronal transport machinery by stimulating protein synthesis at infected nerve terminals. Viral transport to the cell body can therefore be blocked by drugs that inhibit protein synthesis, as well as by cellular antiviral proteins called interferons.

In the current study, Enquist and colleagues investigated how the rabies virus engages the neuronal transport machinery. The researchers infected neurons with a virulent strain of the virus tagged with a red fluorescent protein, allowing the researchers to observe viral transport in real time by live-cell fluorescence microscopy.

The study was led by Margaret MacGibeny, who earned her Ph.D. in 2018, and associate research scholar Orkide Koyuncu, at Princeton, with contributions from research associate Christoph Wirblich and Matthias Schnell, professor and chair of microbiology and immunology at Thomas Jefferson University.

In contrast to alpha herpesvirus infections, the team found that interferons had no effect on rabies virus transport, perhaps because, until it reaches the neuronal cell body, the rabies virus hides out inside cellular structures called endosomes.

"We also couldn't detect increased protein synthesis in axons upon rabies virus infection," MacGibeny said. "But, to our surprise, we saw that a protein synthesis inhibitor called emetine efficiently blocked rabies virus transport to the cell body."

Emetine had no effect on the transport of endosomes devoid of the rabies virus. But endosomes carrying the virus were either completely immobilized, or were only able to move short distances at slower-than-normal speeds.

Other protein synthesis inhibitors did not block rabies virus transport, however, suggesting that emetine works by inhibiting a different process in infected neurons.

"Emetine has been used to treat amoebic dysentery," Koyuncu said. "In the laboratory it is widely used to inhibit protein synthesis but there are recent reports indicating that emetine has anti-viral effects that are independent of protein synthesis inhibition. Our study shows that this drug can inhibit rabies virus invasion of the nervous system through a novel mechanism that hasn't been reported before."

"The manuscript by MacGibeny et al. both advances and complicates our understanding of how neurotropic viruses make their way from the axon terminus to the cell body," said Professor Glenn Rall, an expert in neurotropic virus infections at Fox Chase Cancer Center, who was not involved in the study. "Revealing variations in the axonal transport of neurotropic viruses, coupled with intriguing insights into new roles for well-known drugs, has both mechanistic and clinical implications for these life-threatening infections.

"Our next step is to figure out how emetine disrupts rabies virus transport in axons," Enquist says. "Does it inhibit cell signaling pathways after rabies virus entry, or does it directly block the recruitment of motor proteins to virus-carrying endosomes?"

Ref : https://molbio.princeton.edu/news/enquist-lab-researchers-uncover-new-details-rabies-virus-movement