Tuesday, June 30, 2020

New treatment kills off infection that can be deadly to cystic fibrosis patients

A new treatment developed by researchers at Aston University and Birmingham Children's Hospital has been found to completely kill a bacterial infection that can be deadly to cystic fibrosis patients and other chronic lung conditions such as bronchiectasis.

The findings, which are published in the journal Scientific Reports, show that scientists from Aston University, Mycobacterial Research Group, combined doses of three antibiotics—amoxicillin and imipenem-relebactam and found it was 100% effective in killing off the infection which is usually extremely difficult to treat in patients with cystic fibrosis. The infection results in severe decline in lung function and sometimes death.
Amoxicillin.svg                               Imipenem.svg 
amoxicillin                                                                   Imipenem  \

Relebactam structure.svg Relebactam
Cystic fibrosis (CF) is a genetic condition affecting more than 10,000 people in the UK (Cystic Fibrosis Trust) and there are more than 70,000 people with the condition worldwide (Cystic Fibrosis Foundation). While bronchiectasis affects 210,000 people in the UK (British Lung Foundation).
Mycobacterium abscessus is a bacterial pathogen from the same family that causes tuberculosis, which causes serious lung infections in people (particularly children) with lung disorders, most notably cystic fibrosis. It is highly drug resistant. Currently patients are given a cocktail of antibiotics that cause serious side effects including severe hearing loss and often doesn't result in cure.
The researchers used samples of the pathogen taken from 16 infected cystic fibrosis patients and tested the new drug combination to discover how much was required to kill the bacteria. They found the amounts of amoxicillin-imipenem-relebactam required were low enough to be given safely to patients.
Until now Mycobacterium abscessus has been virtually impossible to eradicate in people with cystic fibrosis. It can also be deadly if the patient requires a lung transplant because they are not eligible for surgery if the infection is present.
In the UK, of the 10,000 people living with cystic fibrosis, Mycobacterium abscessus infects 13% of all patients with the condition. This new treatment is advantageous not only because it kills off the infection, but it does not have any side-effects on patients, thus ensuring their quality of life and greatly improving survival chances for infected CF patients.
Dr. Jonathan Cox, Lecturer in Microbiology, Aston University and leader of the team that discovered this new treatment said: "This new drug combination is a significant step forward for patients with cystic fibrosis that get infected with the deadly Mycobacterium abscessus bacteria. Our new drug combination is significantly less toxic than those currently used, and so far we have managed to kill every patient's bacterial isolate that we have received.
"This shows our drugs, when used in combination, are widely effective and could therefore make a huge difference to people whose treatment options are currently limited.
"Because amoxicillin is already widely available and imipenem-relebactam has just been approved for use by the Food and Drug Administration (FDA) in the US, these drugs are already available to clinicians. We therefore hope to start treating patients as soon as possible. "
The findings of this research will impact children being treated for the infection at Birmingham Children's Hospital—who part funded the research—but it can also be used nationally and further afield.
With more funding, the next stage of the research will be to test the treatment on more people with CF infected by this bacterium, comparing it to the antibiotics that are currently used.
Dr. Maya Desai, Consultant in Respiratory Paediatrics, Birmingham Children's Hospital added: "This exciting development will significantly impact on the care of CF patients globally. It has been possible only with close collaboration between Aston University and Birmingham Children's Hospital both from a clinical research and financial point of view."
Dr. Paula Sommer, Head of Research at the Cystic Fibrosis Trust said: "It's exciting that these lab-based studies investigating new antibiotic treatments for M. abscessus infection are showing such promise and adding to our expanding knowledge of this devastating bug.
"Mycobacterium abscessus also known as NTM, is the most feared  a person with cystic fibrosis can develop. Taking drugs to treat NTM can add to an already significant regime of daily treatments and take up to a year to clear infections. We look forward to a time when effective, short courses of treatment are available to treat NTM."


https://en.wikipedia.org/wiki/Imipenem                                                                                                      https://en.wikipedia.org/wiki/Relebactam


Saturday, June 27, 2020

Study: Antioxidant flavonol linked to lower risk of Alzheimer's dementia

In continuation of my update on kaempferol, myricetin and  quercetin



Skeletal formula of myricetin






People who eat or drink more foods with the antioxidant flavonol, which is found in nearly all fruits and vegetables as well as tea, may be less likely to develop Alzheimer's dementia years later, according to a study published in the January 29, 2020, online issue of Neurology, the medical journal of the American Academy of Neurology.

"More research is needed to confirm these results, but these are promising findings," said study author Thomas M. Holland, MD, of Rush University in Chicago. "Eating more fruits and vegetables and drinking more tea could be a fairly inexpensive and easy way for people to help stave off Alzheimer's . With the  increasing worldwide, any decrease in the number of people with this devastating disease, or even delaying it for a few years, could have an enormous benefit on ."
Flavonols are a type of flavonoid, a group of phytochemicals found in plant pigments known for its beneficial effects on health.
The study involved 921 people with an average age of 81 who did not have Alzheimer's dementia. The people filled out a questionnaire each year on how often they ate certain foods. They were also asked about other factors, such as their level of education, how much time they spent doing  and how much time they spent doing mentally engaging activities such as reading and playing games.
The people were tested yearly to see if they had developed Alzheimer's dementia. They were followed for an average of six years. The researchers used various tests to determine that 220 people developed Alzheimer's dementia during the study.
The people were divided into five groups based on how much flavonol they had in their diet. The average amount of flavonol intake in US adults is about 16 to 20 milligrams per day. In the study, the lowest group had intake of about 5.3 mg per day and the highest group consumed an average of 15.3 mg per day.
The study found that people in the highest group were 48 percent less likely to later develop Alzheimer's dementia than the people in the lowest group after adjusting for genetic predisposition and demographic and lifestyle factors. Of the 186 people in the highest group, 28 people, or 15 percent, developed Alzheimer's dementia, compared to 54 people, or 30 percent, of the 182 people in the lowest group.
The results were the same after researchers adjusted for other factors that could affect the risk of Alzheimer's dementia, such as, diabetes, previous heart attack, stroke and high blood pressure.
The study also broke the flavonols down into four types: isorhamnetin, kaempferol, myricetin and quercetin. The top food contributors for each category were: pears, olive oil, wine and tomato sauce for isorhamnetin; kale, beans, tea, spinach and broccoli for kaempferol; tea, wine, kale, oranges and tomatoes for myricetin; and tomatoes, kale, apples and tea for quercetin.
People who had high intake of isorhamnetin were 38 percent less likely to develop Alzheimer's. Those with high intake of kaempferol were 51 percent less likely to develop dementia. And those with high intake of myricetin were also 38 percent less likely to develop dementia. Quercetin was not tied to a lower risk of Alzheimer's dementia.
Holland noted that the study shows an association between dietary flavonols and Alzheimer's risk but does not prove that flavonols directly cause a reduction in disease risk.
Other limitations of the study are that the food frequency questionnaire, although valid, was self-reported, so people may not accurately remember what they eat, and the majority of participants were white people, so the results may not reflect the general population.

Friday, June 26, 2020

Elagolix Cuts Heavy Menstrual Bleeding in Women With Fibroids

In continuation of my update on elagolix

For women with uterine fibroids, elagolix with add-back hormonal therapy is associated with a reduction in heavy menstrual bleeding compared with placebo, according to a study published in the Jan. 23 issue of the New England Journal of Medicine.

William D. Schlaff, M.D., from Thomas Jefferson University in Philadelphia, and colleagues conducted two randomized, placebo-controlled phase 3 trials (Elaris Uterine Fibroids 1 and 2 [UF-1 and UF-2]) to assess the efficacy and safety of elagolix twice daily with hormonal add-back therapy to replace reduced levels of endogenous hormones. Overall, 412 women in UF-1 and 378 in UF-2 were randomly assigned in a 2:1:1 ratio to receive elagolix with add-back therapy, elagolix alone, or placebo. The primary end point was menstrual blood loss <80 mL in the final month of treatment and ≥50 percent reduction in menstrual blood loss from baseline to the final month.
The researchers found that in UF-1 and UF-2, the criteria for the primary end point were met by 68.5 percent of 206 and 76.5 percent of 189 women, respectively, who received elagolix plus add-back therapy, compared with 8.7 percent of 102 and 10 percent of 94 women, respectively, who received placebo. The primary end point was met by 84.1 percent of 104 women and 77 percent of 95 women in UF-1 and UF-2, respectively, who received elagolix alone. With add-back therapy, hypoestrogenic effects of elagolix were attenuated.
"In both trials reported here, the risk of heavy menstrual bleeding among premenopausal women with uterine fibroids was significantly lower among women who received elagolix," the authors write.
Several authors disclosed financial ties to biopharmaceutical companies, including AbbVie, which manufactures elagolix and funded the study.

Thursday, June 25, 2020

Naloxone Prescribing Increasing but Still Very Low

In continuation of my update on Naloxone

Naloxone prescribing has increased but is still very low among patients at risk for opioid overdose, according to a study recently published in the Journal of General Internal Medicine.

Lewei (Allison) Lin, M.D., from the University of Michigan in Ann Arbor, and colleagues compared adults who received opioids and naloxone from January 2014 to June 2017 to those who received opioids without naloxone using a U.S.-wide health insurance claims dataset. A total of 3,963 opioid+naloxone and 19,815 opioid-only patients were matched based on gender, age, month/year of opioid fill, and number of opioid claims.
The researchers found that high opioid daily dosage (50 to <90 morphine milligram equivalents [MME] and ≥90 MME versus <50 MME: adjusted odds ratios, 2.43 and 3.94, respectively), receiving concurrent benzodiazepines (adjusted odds ratio, 1.27), and having a diagnosis of opioid use disorder (adjusted odds ratio, 1.56) were key factors associated with naloxone fills. There was an increase in the percentage of patients receiving naloxone, but by the last six months of the study period, less than 2 percent of patients in any of the key overdose risk factor groups received naloxone.
"Increasing naloxone availability is one of the most promising interventions to reduce opioid overdose," the authors write. "These findings suggest there is substantial further work needed to increase naloxone for patients at risk for opioid overdose."
One author disclosed financial ties to the pharmaceutical industry.

Wednesday, June 24, 2020

Suvorexant May Improve Insomnia With Alzheimer Disease

In continuation of my update on Suvorexant

Suvorexant improves total sleep time (TST) in patients with probable Alzheimer disease (AD) dementia and insomnia, according to a study published online Jan. 15 in Alzheimer's & Dementia.

W. Joseph Herring, M.D., Ph.D., from Merck & Co., in Kenilworth, New Jersey, and colleagues randomly assigned patients with both probable AD dementia and insomnia to four weeks of suvorexant 10 mg (136 patients; could be increased to 20 mg based on clinical response) or placebo (141 patients). Overnight polysomnography in a sleep laboratory was used to assess TST.
The researchers found that at week 4, the mean improvement from baseline in TST was 73 minutes for the suvorexant group and 45 minutes for the placebo group. Patients taking suvorexant were twice as likely to show an improvement of ≥60 minutes in TST compared with those taking placebo. In suvorexant-treated patients, somnolence was reported by 4.2 percent of participants versus 1.4 percent of placebo-treated patients.
"Suvorexant did not appear to impair next-day cognitive or psychomotor performance as assessed by objective tests, although these assessments do not constitute a comprehensive assessment of cognition," the authors write.
Several authors disclosed financial ties to pharmaceutical companies, including Merck, which manufactures suvorexant and funded the study.


Tuesday, June 23, 2020

Fermented soy products linked to lower risk of death

In continuation of my update on the benefits of soy

Natto with Miso and Mayonnaise recipe main photo

Natto with Miso and Mayonnaise

A higher intake of fermented soy products, such as miso and natto, is associated with a lower risk of death, finds a study from Japan published by The BMJ today.
However, the researchers stress that the findings should be interpreted with caution as they may have been affected by unmeasured (confounding) factors.
In Asian countries, especially Japan, several types of  are widely consumed, such as natto (soybeans fermented with Bacillus subtilis), miso (soybeans fermented with Aspergillus oryzae), and tofu (soybean curd).
It is, however, still unclear whether different soy products, especially fermented soy products, are associated with specific health effects.
So a team of researchers in Japan set out to investigate the association between several types of soy products and death from any cause ("all cause mortality") and from cancer, total cardiovascular disease ( and ), respiratory disease, and injury.
They base their findings on 42,750 men and 50,165 women aged 45-74 years who were taking part in a study based in 11 of Japan's public health centre areas.
Participants filled in detailed questionnaires about their dietary habits, lifestyle, and health status. Deaths were identified from residential registries and  over a follow-up period of nearly 15 years.
The researchers found that a higher intake of fermented soy (natto and miso) was associated with a significantly lower (10%) risk of all cause mortality, but total soy product intake was not associated with all cause mortality.
Men and women who ate natto also had a lower risk of cardiovascular mortality than those who did not eat natto, but there was no association between soy intake and cancer related mortality.
These results persisted even after further adjusting for intake of vegetables, which was higher among those consuming larger portions of natto.
The authors point out that fermented soy products are richer in fibre, potassium and bioactive components than their non-fermented counterparts, which may help to explain their associations.
However, this is an observational study, so can't establish cause, and the researchers cannot rule out the possibility that some of the observed risk may be due to other unmeasured factors.
They conclude: "In this large prospective study conducted in Japan with a high rate of soy consumption, no significant association was found between intake of total soy products and all cause mortality. In contrast, a higher intake of fermented soy products (natto and miso) was associated with a lower risk of ."
Increasing evidence has suggested that fermented soy products are associated with health benefits, write researchers in a linked editorial. Whether people eat those products depends on their food culture, they say, but some countries already include soy and fermented soy products in their dietary guidelines.
Further studies are still required, however, "to refine our understanding of the health effects of fermented soy, and perhaps to inform the development of healthier and more palatable products," they conclude. "These efforts should be collaborative, including not only researchers but also policy makers and the food industry."

Saturday, June 20, 2020

Researchers uncover two-drug combo that halts the growth of cancer cells

Neratinib skeletal.svg                       EverolimusEverolimus.svg


In continuation of my update on Neratinib  and Everolimus

UT Southwestern Simmons Cancer Center researchers have discovered a two-drug combo that halts the growth of cancer cells that carry HER2 mutations.

The findings, published today in the journal Cancer Cell, were prompted by the observation that, after an initial response, patients with cancers harboring HER2  eventually develop resistance to a promising new  drug currently in clinical trials.
The scientists found that another drug, already on the market, counters that resistance and blocks the cancer, thereby providing the basis for a novel drug combination against cancers with mutations in the HER2 gene.
Dhivya Sudhan, Ph.D., a postdoctoral research fellow in the Harold C. Simmons Comprehensive Cancer Center, and collaborators evaluated data from a molecularly guided trial where patients with tumors with HER2 mutations were treated with the HER2 inhibitor neratinib. In this study, patients' cancers were sequenced as the disease progressed during treatment. Based on this analysis, Sudhan discovered in the laboratory that an effective way to offset eventual resistance to neratinib is with everolimus, a TORC1 inhibitor commonly used to treat other types of breast cancer.
"This finding may give clinicians an effective response to neratinib resistance. That could make a real difference for patients with breast, ovarian, lung, and other cancers harboring HER2 mutations," says Carlos L. Arteaga, M.D., Director of the Simmons Cancer Center at UT Southwestern and corresponding author of the study.
HER2 mutations have long been identified as a key driver in breast and other cancers. The authors of this study zeroed in on a signaling network driven by TORC1, which they showed is the pathway through which HER2-mutant cancers become neratinib-resistant.
"We consistently noted activation of TORC1 signaling as a mechanism of resistance to neratinib across different types of HER2-mutant cancers. Different cancer types used different strategies to escape neratinib, but they all converged on TORC1 signaling," Sudhan says.
In addition to studying tumor sequencing data from HER2-mutant cancer patients across the country who are in clinical trials for neratinib, Sudhan also studied neratinib-resistant cells and tumors that continue to live and grow in the laboratory.
The sequencing of the patients' cancer before and during the clinical trial showed that some patients already had a mutation that could activate the TORC1 pathway. Others would develop it eventually, but they could benefit from everolimus which is currently used as a TORC1 inhibitor to address the other roles TORC1 plays in cancer. Everolimus would allow the patient to continue benefiting from neratinib's inhibition of HER2.
Sudhan says the combination of neratinib and everolimus worked in cell lines, organoids established from patient-derived tumors, and in mice harboring HER2 mutant tumors. The next step will be testing this two-drug combo in humans.

Friday, June 19, 2020

Taking aim at gastric cancer: New approach to selective chemotherapy

A novel drug, named "FerriIridium," can simultaneously help diagnose and treat gastric cancer. The initially weakly active precursor (prodrug), based on an iridium-containing compound, is selectively activated only after reaching the interior of a tumor cell. This is possible because of the higher amount of iron present there, report scientists in the journal Angewandte Chemie. Selective activation reduces undesired side effects.

thumbnail image: Taking Aim at Gastric Cancer
Cells transport substances from their exterior to their interior by folding in small regions of their membrane and then binding them off (endocytosis). This is how FerriIridium enters target cells. The resulting vesicles then fuse with lysosomes. These cell organelles have an acidic environment that contains trivalent iron ions, Fe(III), and enzymes, with which they dismantle cell components that are no longer needed. In gastric cancer cells, the Fe(III) concentration within the lysosomes is significantly elevated.
Scientists working with Yu Chen and Hui Chao at Sun Yat-Sen University, Guangzhou, and Hunan University of Science and Technology, Xiangtan (China) made use of this feature. They equipped FerriIridium with a special functional group (the m-iminocatechol group) that selectively binds to Fe(III). When bound, the functional group is oxidized while the iron ions are reduced to Fe(II). Under the acidic conditions within the lysosomes, the FerriIridium is then split into two components: an iridium complex and a benzoquinone derivative.
This reaction mechanism has a threefold effect. First, Fe(II) ions can catalyze a reaction that produces highly reactive hydroxyl radicals. Second, benzoquinones are highly oxidizing. With certain cellular substances, such as NADPH, they form hydroxyquinones, which react with oxygen to produce radical oxygen species, as well as hydrogen peroxide, which in turn can react with Fe(II) to produce hydroxyl radicals. Benzoquinone compounds can also disrupt cellular respiration. The radicals destroy the lysosomes, releasing their contents. Third, the splitting of FerriIridium drastically increases both the phosphorescence and the toxicity of the iridium complex. The phosphorescence can be used to diagnose the tumor. Most importantly, however, the toxic iridium complex is absorbed by mitochondria, the "cellular power plants." It destroys them from the inside out by collapsing their membrane potential. Together, these effects lead to the death of the gastric cancer cells and shrinking of the tumors, as demonstrated by experiments on cell lines and mice.