Thursday, August 18, 2016

Soy shows promise as natural anti-microbial agent

In continuation of my update on soy

Soy isoflavones and peptides may inhibit the growth of microbial pathogens that cause food-borne illnesses, according to a new study from University of Guelph researchers.

Soybean derivatives are already a mainstay in food products, such as cooking oils, cheeses, ice cream, margarine, food spreads, canned foods and baked goods.
The use of soy isoflavones and peptides to reduce microbial contamination could benefit the food industry, which currently uses synthetic additives to protect foods, says engineering professor Suresh Neethirajan, director of the BioNano Laboratory.
U of G researchers used microfluidics and high-throughput screening to run millions of tests in a short period.
They found that soy can be a more effective antimicrobial agent than the current roster of synthetic chemicals.
The study is set to be published in the journal Biochemistry and Biophysics Reports this summer and is available online now.
"Heavy use of chemical antimicrobial agents has caused some strains of bacteria to become very resistant to them, rendering them ineffective for the most part," said Neethirajan.
"Soy peptides and isoflavones are biodegradable, environmentally friendly and non-toxic. The demand for new ways to combat microbes is huge, and our study suggests soy-based isoflavones and peptides could be part of the solution."
Neethirajan and his team found soy peptides and isoflavones limited growth of some bacteria, including Listeria and Pseudomonas pathogens.
"The really exciting thing about this study is that it shows promise in overcoming the issue of current antibiotics killing bacteria indiscriminately, whether they are pathogenic or beneficial. You need beneficial bacteria in your intestines to be able to properly process food," he said.
Peptides are part of proteins, and can act as hormones, hormone producers or neurotransmitters. Isoflavones act as hormones and control much of the biological activity on the cellular level.

Wednesday, August 17, 2016

New drug combination before surgery may improve outcomes in breast cancer patients

In continuation of my update on Paclitaxel 

Results from the I-SPY 2 trial show that giving patients with HER2-positive invasive breast cancer a combination of the drugs trastuzumab emtansine (T-DM1) and pertuzumab before surgery was more beneficial than the combination of paclitaxel plus trastuzumab. Previous studies have shown that a combination of T-DM1 and pertuzumab is safe and effective against advanced, metastatic HER2-positive breast cancer, but in the new results, investigators tested whether the combination would also be effective if given earlier in the course of treatment. Results of the study are presented by trial investigators from the Abramson Cancer Center at the University of Pennsylvania at the AACR Annual Meeting 2016, April 16-20.
In this latest phase of the I-SPY2 trial, investigators worked to determine whether T-DM1 plus pertuzumab could eradicate residual disease (known as pathological complete response, or pCR) for more patients if delivered before surgery to shrink cancer tumors compared with paclitaxel plus trastuzumab. They also examined whether this combination could meet that goal without the need for patients to receive paclitaxel.
"The combination of T-DM1 and pertuzumab substantially reduced the amount of residual disease in the breast tissue and lymph nodes for all subgroups of HER2-positive breast cancers compared with those in the control group," said lead author, Angela DeMichele, MD, MSCE, a professor of Medicine and Epidemiology at the Perelman School of Medicine at the University of Pennsylvania, who will present the findings. "Our results suggest a possible new treatment option for patients that can not only effectively shrink tumors in the breast, but potentially reduce the chance of the cancer coming back later. The results also show that by replacing older, non-targeted therapies with more effective and less-toxic new therapies, we have the potential to both improve outcomes and decrease side effects."
For the study, patients whose tumors were 2.5 cm or bigger were randomly assigned to 12 weekly cycles of paclitaxel plus trastuzumab (control) or T-DM1 plus pertuzumab (test). Following the initial test period, all patients received four cycles of the chemotherapies doxorubicin and cyclophosphamide, and surgery. Patients' tumors were then tested for one of three biomarker signatures: HER2-positive, HER2-positive and hormone receptor (HR)-positive, and HER2-positive and HR-negative.

New drug combination before surgery may improve outcomes in breast cancer patients: Results from the I-SPY 2 trial show that giving patients with HER2-positive invasive breast cancer a combination of the drugs trastuzumab emtansine (T-DM1) and pertuzumab before surgery was more beneficial than the combination of paclitaxel plus trastuzumab.

Tuesday, August 16, 2016

New clinical study to evaluate inexpensive drug to prevent type 1 diabetes


In continuation of my update on metformin

New trial aims to prevent type 1 diabetes
A clinical study evaluating a new hypothesis that an inexpensive drug with a simple treatment regimen can prevent type 1 diabetes will be launched in Dundee tomorrow.

The autoimmune diabetes Accelerator Prevention Trial (adAPT) is led by Professor Terence Wilkin, of the University of Exeter Medical School, with support from colleagues at the University of Dundee and NHS Tayside. It will be launched at Ninewells Hospital, Dundee, on Tuesday, 19th April.

Initial funding of $1.7 million is being provided by JDRF, the leading global organisation backing type 1 diabetes research. The study aims to contact all 6,400 families in Scotland affected by the condition, with a view to expanding into England at a later date. Children aged 5 to 16 who have a sibling or parent with type 1 diabetes will be invited for a blood test to establish whether they are at high risk of developing the disease. If so, they will be invited to take part in the trial.

Researchers will then examine the impact of administering metformin, the world's most commonly prescribed diabetes medicine, to young people in the high-risk category. If successful, the large-scale trial could explain why the incidence of type 1 diabetes has risen five-fold in the last 40 years, and provide a means of preventing it.

Researchers have previously hypothesised that type 1 diabetes is an autoimmune disease caused by a faulty immune system which attacks and destroys insulin-producing beta cells in the pancreas. Clinical trials have tried drugs that supress the immune system to attempt to subdue the attack, but the results have so far been disappointing.

The Accelerator Prevention Trial is the first to test an alternative explanation for type 1 diabetes, and is based on the accelerator hypothesis, proposed in 2001 by Professor Wilkin.

This hypothesis theorises that autoimmunity occurs as a response to damaged beta cells. It believes that beta cells, stressed by being made to work too hard in a modern environment, send out signals that switch on the immune system. adAPT will test whether metformin, which is known to protect the beta cells from stress, can stop the immune response that goes on to destroy them.

Professor Wilkin said, "We still have no means of preventing type 1 diabetes, which, at all ages, results from insufficient insulin. We all lose beta cells over the course of our lives, but most of us have enough for normal function.

"However, if the rate of beta cell loss is accelerated, type 1 diabetes develops, and the faster the loss, the younger the onset of the condition. The accelerator hypothesis talks of fast and slow type 1 diabetes - beta cell loss which progresses at different rates in different people, and appears at different ages as a result."

Monday, August 15, 2016

Experimental treatment shrinks rare pediatric tumor by 90%

Image result for loxo-101 structure In continuation of my update on LOXO-101

When a baby's life was threatened by a rare pediatric cancer that would not respond to surgery or chemotherapy, doctors at Nemours Children's Hospital rapidly, successfully shrank the tumor by 90 percent using an experimental treatment, according to a new study published online in Pediatric Blood and Cancer. The now-20-month-old girl achieved the remarkable improvement by receiving a drug called LOXO-101 that was being tested on adults, researchers reported.

"Most infants and children with infantile fibrosarcoma (IFS) can be cured through surgery and chemotherapy. When our patient's disease progressed in spite of these treatments, we had to investigate new options that could target the disease," said Dr. Ramamoorthy Nagasubramanian M.D., lead author of the manuscript, division chief of pediatric hematology-oncology at Nemours Children's Hospital. "The dramatic reduction in tumor size shows early but promising evidence of the potential for LOXO-101 to provide significant benefit for pediatric patients with NTRK gene fusions."

Nemours' oncology team operated on the girl at 6 months to remove a large tumor located in the neck and face. The tumor did not respond to standard chemotherapy and relapsed after extensive surgery. Genetic testing confirmed an ETV6-NTRK3 gene fusion, which is frequently found in IFS. At the time, LOXO-101 was in a Phase 1 multi-center basket trial in adults. Working with Nemours, Loxo Oncology, Inc., a biopharmaceutical company developing highly selective medicines for patients with genetically defined cancers, was able to expand the trial to children and enroll her.

Friday, August 12, 2016

Scientists develop new drug for life-threatening lung disease treatment

Researchers are developing a new drug to treat life-threatening lung damage and breathing problems in people with severe infections like pneumonia, those undergoing certain cancer treatments and premature infants with underdeveloped, injury prone lungs.

Scientists at Cincinnati Children's Hospital Medical Center report April 19 in Science Signaling that a transcription factor called FOXF1 activates several biological processes that promote recovery from acute lung injury. Two laboratories at Cincinnati Children's are developing a pharmacologic compound that in mouse models stimulates FOXF1 and promotes repair after lung injury.

"Besides toxic insults from some cancer treatments, acute lung injury can be a major medical problem for people who get infectious diseases like flu, pneumonia or Ebola because of pathogens that target the lung," said Vladimir Kalinichenko, MD, PhD, co-senior author and a physician and researcher in the Divisions of Pulmonary Biology and Developmental Biology at Cincinnati Children's. "A small molecule compound we developed efficiently stabilizes the FOXF1 protein in cell cultures and mouse lungs, and it shows promise in inhibiting lung inflammation and protecting experimental mice from lung injury."

Along with co-senior author Tanya Kalin, MD, PhD, in the Cincinnati Children's Perinatal Institute, the research team learned that loss of FOXF1 in lung endothelial cells of mice caused them to die from respiratory problems, pulmonary edema (fluid in the lungs) and lung inflammation. This happens when endothelial cells that line blood vessels in the lung can no longer provide a protective barrier between the external environment and the body's circulatory system.

Thursday, August 11, 2016

Frontline nilotinib supported for newly diagnosed CP-CML


Long-term results from the ENESTnd trial indicate a favourable risk-benefit profile for frontline use of nilotinib in patients within 6 months of chronic phase-chronic myeloid leukaemia (CP-CML) diagnosis.

"Throughout the study, nilotinib has demonstrated several benefits over imatinib in surrogate endpoints of therapeutic efficacy, such as higher rates of response and lower rates of disease progression, death due to advanced CML and treatment-emergent BCR-ABL mutations", the researchers report in Leukemia.

"The risk of AEs [adverse events] (regardless of AE type) appears to be similar with nilotinib and imatinib; however, each TKI [tyrosine kinase inhibitor] is associated with different types of AEs, including a higher risk of CVEs [cardiovascular events] with nilotinib vs imatinib."

By 5 years, 77.0% of the 282 patients randomly assigned to receive nilotinib 300 mg twice daily and 77.2% of the 281 using nilotinib 400 mg twice daily achieved a major molecular response (BCR-ABL ≤0.1% on the International Scale [BCR-ABLIS]) compared with 60.4% of the 283 patients given imatinib 400 mg once daily.

Deep molecular responses by 5 years were also more common with nilotinib 300 mg and 400 mg than with imatinib, with rates of MR4 (BCR-ABLIS ≤0.01%) of 65.6%, 63.0% and 41.7%, respectively. The corresponding rates for MR4.5 (BCR-ABLIS ≤0.0032%) were 53.5%, 52.3% and 31.4%.

And estimated 5-year progression-free survival was 92.2%, 95.8% and 91.0% for the nilotinib 300 mg and 400 mg groups and the imatinib group, respectively. Overall survival at 5 years was estimated to be 93.7%, 96.2% and 91.7%, respectively.

Wednesday, August 10, 2016

Antidepressant Wellbutrin linked to long-term modest weight loss

Group Health researchers have found that bupropion (marketed as Wellbutrin) is the only antidepressant that tends to be linked to long-term modest weight loss.

Skeletal formula of bupropion

Previously, Group Health researchers showed a two-way street between depression and body weight: People with depression are more likely to be overweight, and vice versa. These researchers also found that most antidepressant medications have been linked to weight gain.

Prior research on antidepressants and weight change was limited to one year or shorter. But many people take antidepressants--the most commonly prescribed medications in the United States--for longer than a year. So for up to two years the new study followed more than 5,000 Group Health patients who started taking an antidepressant. TheJournal of Clinical Medicine published it: "Long-Term Weight Change after Initiating Second-Generation Antidepressants."

"Our study suggests that bupropion is the best initial choice of antidepressant for the vast majority of Americans who have depression and are overweight or obese," said study leader David Arterburn, MD, MPH. He's a senior investigator at Group Health Research Institute (GHRI), a Group Health physician, and an affiliate associate professor in the University of Washington (UW) School of Medicine's Department of Medicine. But in some cases, an overweight or obese patient has reasons why bupropion is not for them--like a history of seizure disorder--and it would be better for them to choose a different treatment option.

Tuesday, August 9, 2016

Novel combination of cancer drugs can have therapeutic impact on diffuse large B-cell lymphoma

In continuation of my update on carfilzomibJQ1 and ABT 199

New research from Roswell Park Cancer Institute (RPCI) shows that promising cancer drugs used in combination can have significant therapeutic impact on a particularly aggressive subtype of diffuse large B-cell lymphoma (DH-DLBCL) in preclinical studies. The researchers will present their findings at the American Association for Cancer Research (AACR) Annual Meeting 2016, to be held April 16-20 in New Orleans.

Priyank Patel, MD, a fellow in the Department of Medicine at Roswell Park, is the first author and Francisco Hernandez-Ilizaliturri, MD, Clinical Chief of the Institute's Lymphoma/Myeloma Service, is the senior author of "Investigating novel targeted therapies for double hit diffuse large B-cell lymphoma (DH-DLBCL)" (abstract 3038), which will be presented on Tuesday, April 19, at 8 a.m. CDT.

Diffuse large B-cell lymphoma, the most common type of non-Hodgkin lymphoma, is an aggressive form of lymphoma. This research team reviewed a database of 650 patients with diffuse large B-cell lymphoma, identifying 36 patients whose tumors had two or more aberrant genes. Patients with mutations of the c-MYC, BCL2 and/or BCL6 genes — a subtype known as "double-hit lymphoma" — have especially have poor outcomes when treated with standard chemotherapy. The scientists evaluated the effectiveness of three novel anticancer drug candidates that targeted those proteins. In preclinical studies, the therapeutic agents ABT-199, JQ-1 and carfilzomib induced cell death in a dose- and time-dependent manner. Significant synergistic activity was observed when researchers combined ABT199 with carfilzomib and, to a lesser extent, with JQ1 in cancer cell lines.

"Increasing knowledge of genetics and molecular pathways has helped us identify a subgroup of patients who harbor aggressive aberrant gene mutations. Understanding the mechanisms of action and clarifying how these potential therapies work to inhibit cancer cell growth may result in improved outcomes for patients diagnosed with this aggressive type of lymphoma," says Dr. Hernandez-Ilizaliturri.

Carfilzomib.svg Carfilzomib JQ1.svg  JQ1 Venetoclax.svg ABT-199

Novel combination of cancer drugs can have therapeutic impact on diffuse large B-cell lymphoma: New research from Roswell Park Cancer Institute shows that promising cancer drugs used in combination can have significant therapeutic impact on a particularly aggressive subtype of diffuse large B-cell lymphoma (DH-DLBCL) in preclinical studies. The researchers will present their findings at the American Association for Cancer Research (AACR) Annual Meeting 2016, to be held April 16-20 in New Orleans.

Monday, August 8, 2016

Potential first-in-class treatment is well-tolerated in patients with chronic hepatitis B: Phase 1 study shows the investigational capsid assembly inhibitor NVR 3-778 combined with pegylated interferon reduces levels of hepatitis B more than NVR 3-778 alone.

New data presented today confirms that a novel first-in-class treatment for Hepatitis B, called NVR 3-778, is well-tolerated and can reduce levels of the virus' genetic material in the body when combined with pegylated interferon after four weeks of treatment. The updated Phase 1b trial results were presented today at The International Liver CongressTM 2016 in Barcelona, Spain.
NVR 3-778 is a first-in-class HBV capsid assembly inhibitor which modulates the function of the core protein. This protein plays an essential role in viral replication and persistence of the virus.
Approximately 14 million people within the World Health Organization European region are chronically infected with Hepatitis B.1 There are several medicines that are effective at suppressing the virus over many years, slowing down damage to the liver, and allowing the body to repair itself.2 However, it is unusual for these treatments to clear the virus permanently.3
"Previous Phase 1 results with NVR 3-778 have shown reduction in HBV viral load," said Dr Man-Fung Yuen of Queen Mary Hospital, University of Hong Kong, and lead author of the study. "It is promising to see that the combination of NVR 3-778 with pegylated interferon produces responses that are greater than those seen with either monotherapy."
The international Phase 1b study was conducted in 64 patients who had not previously received any treatment for Hepatitis B. There were six dosing cohorts in the study: 100mg daily, 200mg daily, 400mg daily, 600mg twice a day, or 600mg twice a day combined with pegylated interferon, and finally pegylated interferon combined with placebo. Treatment was given for a total of 28 days.
The results demonstrated that NVR 3-778 was well tolerated in all cohorts with no discontinuations. Most adverse events were mild and not attributed to the study drug. Dose-related reductions in HBV DNA were observed, the largest of which was in the NVR 3-778 and pegylated interferon combination (1.97 log IU/mL). Using NVR 3-778 alone, the HBV DNA reduction was 1.72 log10 in the 600 mg BD group, and in the pegylated interferon alone group the HBV DNA reduction was 1.06 log10. Study results also indicated early reductions in levels of HBeAg (a sign that the virus is actively replicating in the body and that the infection is worse) across all groups, which were greatest in the NVR 3-778 group.
"The results from this study are certainly interesting and promising for the treatment of patients with Hepatitis B,'" said Professor Frank Tacke, EASL Governing Board member. "The medical community is always on the look-out for treatments which can cure this condition, as opposed to simply suppressing the replication of the virus. More research is needed to confirm whether NVR 3-778 could really change the treatment paradigm."

Friday, August 5, 2016

Once-a-day epilepsy drug may prevent seizures as well as twice-a-day drug

In continuation of my update on Carbamazepine (CBZ)

A new study suggests that an epilepsy drug that can be taken once a day may control seizures as well as a drug that must be taken twice a day, according to a preliminary study released today that will be presented at the American Academy of Neurology's 68th Annual Meeting in Vancouver, Canada, April 15 to 21, 2016.

The study compared the once-a-day drug eslicarbazepine acetate to the twice-daily drug carbamazepine for people newly diagnosed with partial seizures, which start in one area of the brain.
"Seizure control is crucial," said study author Elinor Ben-Menachem, MD, of Gothenburg University in Gothenburg, Sweden, and a member of the American Academy of Neurology. "A once-a-day drug may help people stick to their medication schedule." For the study, 815 people newly diagnosed with partial seizures received either eslicarbazepine or carbamazepine for about six months. Participants started the study at the lowest of three dosing levels. Those who had a seizure at the lowest level were then moved up to the second dosing level. If they had another seizure, they received the highest dosing level.
A total of 71 percent of those taking eslicarbazepine and 76 percent of those taking carbamazepine were seizure-free after six months. After one year, 65 percent of those taking the once-daily drug were seizure-free compared to 70 percent of those taking the twice-daily drug.
The study was what is called a non-inferiority study, which is designed to show that a new treatment is not clinically worse than an existing treatment. According to the study design, eslicarbazepine would be considered "non-inferior" if the difference in seizure-free rate between the two drugs was 12 percent or lower. At six months, the difference was 4 percent. At one year, the difference was 5 percent.
"Memory issues, fatigue, or a complicated medication schedule can all interfere with a person taking their seizure-control medications on a regular basis so having a once-daily option for patients, especially when they are newly diagnosed and still learning to manage the disease, may be beneficial," said Ben-Menachem. "The hope is that these results may also give doctors more options to better tailor treatments for people with epilepsy."

Once-a-day epilepsy drug may prevent seizures as well as twice-a-day drug

Thursday, August 4, 2016

LOXO-101 drug shows efficacy with tumor regression in varied types of genetically defined cancer


 A phase I study of the drug LOXO-101 appears to significantly reduce tumors in patients with varied types of genetically defined cancer, according to a study led by The University of Texas MD Anderson Cancer Center.

The results of the study, which followed patients with unique proteins called tropomyosin receptor kinase fusions (TRKs), were presented at the American Association for Cancer Research's annual meeting held April 16-20 in New Orleans.

"We saw efficacy with significant tumor regression in all six TRK fusion patients enrolled in the study," said David Hong, M.D., associate professor of Investigational Cancer Therapeutics. "We were surprised by the fact that the study demonstrated efficacy in every one of the TRK fusion-positive patients."

Out of 43 patients enrolled in the study, the six with TRK gene fusions had tumors representing cancers such as sarcoma, thyroid, salivary gland, gastrointestinal and non-small cell lung. Five demonstrated partial responses to LOXO-101 and the sixth recorded a 17 percent tumor regression. All six of these patients remain on study, with the longest out past one year and all of them into at least their seventh cycle. A seventh patient with a TRK gene fusion more recently enrolled for the study.

"We are currently enrolling all solid tumor types with TRK fusions for a phase II trial," said Hong. "Over time, we anticipate that the list of tumor types will continue to grow. In published literature, TRK fusions have been found in nearly every tumor type. The phase II study is important not only for generating additional data about LOXO-101 in patients with TRK fusion cancer, but we anticipate it will further broaden the range of tumor types that we've tested thus far."

The phase I study revealed that LOXO-101 has been well tolerated at various once-daily and twice-daily doses. Common side effects included fatigue, constipation, and dizziness. The planned phase II trial, which will include only patients tested positive for TRK gene fusions, will use a dosage of 100 mg twice daily, for patients who responded previously.
Hong believes comprehensive genomic profiling is key to further unlocking information about TRK gene fusions.

"It's fundamentally important that we adopt comprehensive genomic profiling as a field," he said. "In the case of this Phase I trial, many of the TRK fusion patients were detected as part of genomic testing, and I am encouraged to see that labs around the world are increasingly including TRK fusions in their routine testing menu."

New triple drug combination shows promise in hepatitis C infected patients: High sustained virologic response achieved with sofosbuvir/velpatasvir and GS-9857, even in patients unsuccessfuly treated with direct-acting antivirals

New data presented today at The International Liver Congress™ 2016 in Barcelona, Spain, demonstrates a high sustained virologic response (SVR) at 12 weeks from the all-oral combination of sofosbuvir/velpatasvir and experimental compound GS-9857 in patients with the Hepatitis C virus (HCV).
ChemSpider 2D Image | velpatasvir | C49H54N8O8 velpatasvir   Sofosbuvir structure.svgSofosbuvir[

This triple combination treatment was generally safe and effective, even in patients who had been unsuccessfully treated with direct acting antivirals (DAAs, medicines which have been used to treat and cure almost all patients with HCV). The study showed that 99% of patients with HCV genotype 1, 2, 3, 4 and 6 who had previously received treatment, achieved SVR 12 weeks after treatment using this triple combination.
Hepatitis C is a virus carried via the blood, which infects and damages the liver.1 HCV infects liver cells, resulting in inflammation and fibrosis.1 In chronic HCV cases, such symptoms may continue to increase and result in liver cirrhosis, scarring of the liver.1 Despite the high overall SVR rate achieved with currently approved DAA therapies, approximately 5% of patients treated with DAAs will not be cured.2 According to the study authors, for this small proportion of patients who are not cured, retreatment options are significantly limited.
"Our study demonstrates that for HCV patients whose prior treatment has failed with the use of DAAs, this triple combination provides a high rate of sustained virologic response across HCV genotypes," said Dr Eric Lawitz, Clinical Professor of Medicine at the University of Texas Health Science Center, San Antonio and lead author of the study. "Furthermore, the study indicates that the treatment combination is generally safe and well tolerated by patients, providing a promising alternative for HCV sufferers who have limited re-treatment options."
Two global, open-label Phase 2 studies were conducted among chronic HCV-infected patients that had failed prior HCV treatment. Genotype 1 HCV-infected patients enrolled in the study had previously been treated with an NS5A-inhibitor or multiple classes of DAAs, and genotype 2-6 HCV-infected patients had previously been treated with pegylated-interferon (Peg-IFN) plus ribavarin and/or any DAA. All patients received the triple combination of sofosbuvir/velpatasvir plus GS-9857 for 12 weeks. Frequently reported adverse events (AEs) were headache, fatigue, diarrhea and nausea; most were mild or moderate in severity.
"Having offered promising results, this three drug combination is being further evaluated in Phase 3 trials as a single tablet regimen in DAA-experienced patients," said Professor Laurent Castera, EASL Secretary General.
Additional study results
A total of 128 patients were treated: 75% were male, 82% were white, 73% with non-CC IL28B genotypes, and 48% with cirrhosis. 49% of patients had genotype 1, 16% had genotype 2, 27% had genotype 3, 5% had genotype 4 and 2% had genotype 6.
Overall, 27% of patients had been previously treated with NS5A-inhibitors, 52% had been previously treated with other DAAs, and 21% had failed interferon-based treatment without a DAA. Baseline resistance-associated variants (RAVs) were detected in 60% of patients (20% with RAVs to NS5A-inhibitors and 23% with RAVs to multiple classes).
The most commonly reported AEs (>10%) were headache, fatigue, diarrhea, and nausea; most were mild or moderate in severity. One patient (<1%) experienced a serious AE of gastroenteritis (<1%) and 1 patient discontinued treatment early due to an AE of gastritis at Week 9 and achieved SVR12; both AEs were not considered related to the study drugs. No clinically significant laboratory abnormalities were observed

Wednesday, August 3, 2016

Experimental drug guadecitabine found safe in patients with colorectal cancer: Combination with standard chemotherapy shows promise in overcoming treatment resistance

In continuation of my update on guadecitabine (SGI-110)


In a small, phase I clinical trial, Johns Hopkins Kimmel Cancer Center researchers say they show for the first time that the experimental drug guadecitabine (SGI-110) is safe in combination with the chemotherapy drug irinotecan and may overcome resistance to irinotecan in patients with metastatic colorectal cancer. Results of the study are expected to be presented April 17 at the American Association for Cancer Research (AACR) Annual Meeting 2016 in New Orleans (abstract CT017).
Guadecitabine works to reverse a so-called epigenetic change in cancer cells known as methylation, which may alter genetic activity in cells in a way that can block the action of tumor-suppressing genes, pushing cells to become cancerous and resistant to therapy. By reversing this change in cancer cells, the drug restores cancer cells' vulnerability to drugs such as irinotecan.
The clinical trial included 22 patients with metastatic colorectal cancer who had been treated previously with irinotecan and whose disease was progressing. The patients were divided into four groups, each receiving different doses of guadecitabine in combination with irinotecan, over an average period of four months.
During the study, 15 patients had at least one imaging scan to retest the extent and location of their cancers -- with 12 patients experiencing stable disease -- for more than the four-month period, on average, and one patient experiencing a partial response to the treatment (measured as at least a 30 percent reduction in the size of the tumors.)
Although the study's main purpose was to test the safety rather than the effectiveness of guadecitabine doses, "we were very happy to see some patients who benefited from the combination of the therapies for many months to more than a year," says Nilofer Azad, M.D., professor of oncology at the Johns Hopkins University School of Medicine.
The study also showed signs that guadecitabine reduced methylation among the cancer cells. "We did see that giving a higher dose of the drug seemed to produce a better methylation response among patients," says Valerie Lee, M.D., a fellow at the Johns Hopkins Kimmel Cancer Center. "However, it seemed that patients were responding at all levels of the drug."
Among the side effects of the combined treatment, 16 patients experienced neutropenia, a low count of the infection-fighting white blood cells called neutrophils; five patients with neutropenia had fevers; three patients became anemic; and two patients developed thrombocytopenia, a lowered count of blood-clotting platelets. Other side effects included diarrhea (three patients), fatigue (two patients) and dehydration (two patients). There was one death during the study, possibly resulting from febrile neutropenia caused by the treatment.
The current study was based on previous studies in the laboratory of Nita Ahuja, M.D., director of the Sarcoma and Peritoneal Surface Malignancy Program and professor of surgery at the Johns Hopkins University School of Medicine, which showed that guadecitabine limited the growth of colorectal cancer cell lines when combined with irinotecan, says Azad.
The drug combination is being tested in an ongoing phase II clinical trial (NCT01896856) in a larger group of metastatic colorectal cancer patients at multiple institutions to determine the effectiveness of the dual therapy compared with chemotherapy regimens that do not include guadecitabine, says Azad.
Scientists leading the new study will also look for biomarkers in patients that could help determine which of them are most likely to benefit from guadecitabine and irinotecan. Lee says the research team will measure the amount of methylation in patients' cells when they begin their treatment and the presence of genes associated with irinotecan resistance, among other possible biomarkers.
In 2015, there were more than 130,000 people in the U.S. diagnosed with colon cancers. Five-year survival rates among people with localized colon cancers are more than 90 percent, but they are only 20 percent in those with metastatic cancer.
Guadecitabine is an experimental drug that has not been approved for use by the U.S. Food and Drug Administration. It is manufactured by Astex Pharmaceuticals, a supporter of the Johns Hopkins-led study. The research was also supported by the Van Andel Research Institute SU2C/AACR Epigenetics Dream Team.
Other scientists who contributed to the research include Judy Wang, Anup Sharma, Zachary Kerner, Stephen Baylin, Ellen Lilly, and Thomas Brown from Johns Hopkins; Anthony El Khoueiry from the University of Southern California; Henk Verheul and Elske Gootjes from Vrije Universiteit in the Netherlands; and Peter Jones from the Van Andel Research Institute.

Tuesday, August 2, 2016

Study demonstrates therapeutic potential of SOD-mimetic compound M40403 against Parkinson disease

Parkinson disease is a debilitating and incurable neurodegenerative disorder, affecting approximately 1-2% of people over sixty-five years old. Oxidative damage is considered to play a central role in the progression of Parkinson disease and strong evidence links chronic exposure to the pesticide paraquat with the incidence of the disease, most probably through the generation of oxidative damage.

In this work we demonstrated in human SH-SY5Y neuroblastoma cells the beneficial role of superoxide dismutase (SOD) enzymes against paraquat-induced toxicity, as well as the therapeutic potential of the SOD-mimetic compound M40403.

Having verified the beneficial effects of superoxide dismutation in cells, we then evaluated the effects using Drosophila melanogaster as in vivo model. Besides protecting against the oxidative damage induced by paraquat treatment, our data demonstrated that in Drosophila M40403 was able to compensate for the loss of endogenous SOD enzymes, acting both at a cytosolic and mitochondrial level. Because previous clinical trials have indicated that the M40403 molecule is well tolerated in humans, this study may have important implication for the treatment of Parkinson disease.

Study demonstrates therapeutic potential of SOD-mimetic compound M40403 against Parkinson disease: Parkinson disease is a debilitating and incurable neurodegenerative disorder, affecting approximately 1-2% of people over sixty-five years old. Oxidative damage is considered to play a central role in the progression of Parkinson disease and strong evidence links chronic exposure to the pesticide paraquat with the incidence of the disease, most probably through the generation of oxidative damage.

Monday, August 1, 2016

Cyclodextrin dissolves cholesterol crystals, reduces atherosclerotic plaques

In continuation of my update of cyclodextrin

Cardiovascular disease from atherosclerosis is one of the most common causes of death worldwide. Inflammation plays a crucial role in atherosclerosis and cholesterol crystals are considered to be early triggers in the development of the disease.

An international team has now found that cyclodextrin dissolves cholesterol crystals and reduces atherosclerotic plaques. This is a promising therapeutic approach for treating atherosclerosis. Their find was published in Science Translational Medicine.

Cyclodextrin works by reprogramming macrophages so that they do not cause such a strong inflammatory response in blood vessels that contain cholesterol crystals. The cyclodextrin also dissolves cholesterol crystals so that the cholesterol can be excreted from the body in urine. The result is prevention of plaque formation and even atherosclerotic plaque reduction in mice. Furthermore, when researchers used cyclodextrin to treat biopsies of plaques from human carotid arteries, they found similar results.

The study points to cholesterol crystals as a target for treatment of atherosclerosis, meaning that using cyclodextrin to dissolve the crystals could affect how the disease is treated.

The original idea for the test of cyclodextrin came from Chris Hempel, an American mother whose twin daughters are affected by a rare illness called Niemann-Pick Type C disease, in which cholesterol accumulates in the body. The children are being treated with cyclodextrin with promising results.

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Cyclodextrin dissolves cholesterol crystals, reduces atherosclerotic plaques: Cardiovascular disease from atherosclerosis is one of the most common causes of death worldwide. Inflammation plays a crucial role in atherosclerosis and cholesterol crystals are considered to be early triggers in the development of the disease.