TAG: "Drugs"

Study finds codeine often prescribed to children despite available alternatives


ERs using drug even with strong evidence of potentially harm, UCSF study finds.

Despite its potentially harmful effects in children, codeine continues to be prescribed in U.S. emergency rooms, according to new research from UCSF Benioff Children’s Hospital San Francisco.

As reported in the May issue of Pediatrics, solutions include changing provider prescription behaviors to promote the use of better alternatives to codeine, such as ibuprofen or hydrocodone.

“Despite strong evidence against the use of codeine in children, the drug continues to be prescribed to large numbers of them each year,” said Sunitha Kaiser, M.D., UCSF assistant clinical professor of pediatrics at UCSF Benioff Children’s Hospital San Francisco and lead author. “It can be prescribed in any clinical setting, so it is important to decrease codeine prescription to children in other settings such as clinics and hospitals, in addition to emergency rooms.”

Codeine is an opioid used to treat mild to moderate pain and suppress cough. Because of variability in how children process the drug, about a third receive no symptom relief from taking it, while up to one in 12 can accumulate toxic amounts causing breathing to slow down and possible death.

As a result, several national and international organizations advise against codeine use in children. Guidelines from the American Academy of Pediatrics (AAP) issued in 1997 and reaffirmed in 2006 warn of its potential dangers and lack of documented effectiveness in children with coughs and colds, and the American College of Chest Physicians 2006 guideline on treatment of pediatric cough also advises against the drug.

Until now it was unknown to what extent codeine was being prescribed to children in U.S. emergency rooms, where it can be prescribed for common complaints such as painful injuries and coughs and colds.

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Mutant protein in muscle linked to neuromuscular disorder


A new therapeutic target for Kennedy’s disease and a potential treatment.

Graphic of SBMA mouse model

Sometimes known as Kennedy’s disease, spinal and bulbar muscular atrophy (SBMA) is a rare inherited neuromuscular disorder characterized by slowly progressive muscle weakness and atrophy. Researchers have long considered it to be essentially an affliction of primary motor neurons – the cells in the spinal cord and brainstem that control muscle movement.

But in a new study published in today’s (April 16) online issue of Neuron, a team of scientists at the UC San Diego School of Medicine say novel mouse studies indicate that mutant protein levels in muscle cells, not motor neurons, are fundamentally involved in SBMA, suggesting an alternative and promising new avenue of treatment for a condition that is currently incurable.

SBMA is an X-linked recessive disease that affects only males, though females carrying the defective gene have a 50:50 chance of passing it along to a son. It belongs to a group of diseases, such as Huntington’s disease, in which a C-A-G DNA sequence is repeated too many times, resulting in a protein with too many glutamines (an amino acid), causing the diseased protein to misfold and produce harmful consequences for affected cells. Thus far, human clinical trials of treatments to protect against these repeat toxicities have failed.

In the new paper, a team led by principal investigator Albert La Spada, M.D., Ph.D., professor of pediatrics, cellular and molecular medicine, and neurosciences, and the associate director of the Institute for Genomic Medicine at UC San Diego, propose a different therapeutic target. After creating a new mouse model of SBMA, they discovered that skeletal muscle was the site of mutant protein toxicity and that measures which mitigated the protein’s influence in muscle suppressed symptoms of SBMA in treated mice, such as weight loss and progressive weakness, and increased survival.

In a related paper, published in today’s (April 16) online issue of Cell Reports, La Spada and colleagues describe a potential treatment for SBMA. Currently, there is none.

The scientists developed antisense oligonucleotides – sequences of synthesized genetic material – that suppressed androgen receptor (AR) gene expression in peripheral tissues, but not in the central nervous system. Mutations in the AR gene are the cause of SBMA, a discovery that La Spada made more than 20 years ago while a M.D.-Ph.D. student.

La Spada said that antisense therapy helped mice modeling SBMA to recover lost muscle weight and strength and extended survival.

“The main points of these papers is that we have identified both a genetic cure and a drug cure for SBMA – at least in mice. The goal now is to further develop and refine these ideas so that we can ultimately test them in people,” La Spada said.

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Cancer drugs block dementia-linked brain inflammation


Research represents novel approach to lessening impact of Alzheimer’s, Parkinson’s.

Kim Green, UC Irvine

A class of drugs developed to treat immune-related conditions and cancer – including one currently in clinical trials for glioblastoma and other tumors – eliminates neural inflammation associated with dementia-linked diseases and brain injuries, according to UC Irvine researchers.

In their study, assistant professor of neurobiology & behavior Kim Green and colleagues discovered that the drugs, which can be delivered orally, eradicated microglia, the primary immune cells of the brain. These cells exacerbate many neural diseases, including Alzheimer’s and Parkinson’s, as well as brain injury.

“Because microglia are implicated in most brain disorders, we feel we’ve found a novel and broadly applicable therapeutic approach,” Green said. “This study presents a new way to not just modulate inflammation in the brain but eliminate it completely, making this a breakthrough option for a range of neuroinflammatory diseases.”

The researchers focused on the impact of a class of drugs called CSF1R inhibitors on microglial function. In mouse models, they learned that inhibition led to the removal of virtually all microglia from the adult central nervous system with no ill effects or deficits in behavior or cognition. Because these cells contribute to most brain diseases – and can harm or kill neurons – the ability to eradicate them is a powerful advance in the treatment of neuroinflammation-linked disorders.

Green said his group tested several selective CSF1R inhibitors that are under investigation as cancer treatments and immune system modulators. Of these compounds, they found the most effective to be a drug called PLX3397, created by Plexxikon Inc., a Berkeley-based biotechnology company and member of the Daiichi Sankyo Group. PLX3397 is currently being evaluated in phase one and two clinical trials for multiple cancers, including glioblastoma, melanoma, breast cancer and leukemia.

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SSRI use during pregnancy associated with risk of autism in boys


Highest association found during first-trimester exposure for autism.

Irva Hertz-Picciotto, UC Davis

Prenatal exposure to selective serotonin reuptake inhibitors (SSRIs), medications frequently prescribed to treat depression, anxiety and other mental health disorders, is associated with a higher incidence of autism spectrum disorder (ASD) and developmental delays (DD) in male children, a study of nearly 1,000 mother-child pairs has found.

Published online today (April 14) in the journal Pediatrics, the study involved 966 mother-child pairs from the Childhood Autism Risks from Genetics and the Environment (CHARGE) study, a population-based, case-control study at the UC Davis MIND Institute led by professor Irva Hertz-Picciotto, chief of the Division of Environmental and Occupational Health in the UC Davis Department of Public Health Sciences.

“This study provides further evidence that in some children, prenatal exposure to SSRIs may influence their risk for developing an autism spectrum disorder,” Hertz-Picciotto said. “It also highlights the challenge for women and their physicians, to balance the risks vs. benefits from taking these medications, given that a mother’s underlying mental health conditions may also pose a risk to both herself and her child.”

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Drug doubles positive effect in hormone-receptor-positive breast cancer


UCLA researchers lead clinical study.

Richard Finn, UCLA

Breast cancer researchers from the Revlon/UCLA Women’s Cancer Research Program at UCLA’s Jonsson Comprehensive Cancer Center announced final clinical trial results this week that showed the amount of time patients were on treatment without their cancer worsening (called “progression-free survival”) was effectively doubled in women with advanced breast cancer who took the experimental drug palbociclib.

The results of the phase 2 clinical trial were announced at the American Association for Cancer Research annual meeting in San Diego.

Palbociclib (PD 0332991) is an investigational drug discovered and being developed by Pfizer Inc. The preclinical work testing palbociclib in a panel of human breast cancer cells growing in culture dishes showed very encouraging activity, specifically against estrogen-receptor–positive (ER+) cancer cells.

This led to a clinical study collaboration with Pfizer led by Dr. Richard Finn, associate professor of medicine at the Jonsson Cancer Center. The phase 1 study built on laboratory work from the Translational Oncology Research Laboratory, which is directed by Dr. Dennis Slamon, professor of medicine at the Jonsson Cancer Center and director of the Revlon/UCLA Women’s Cancer Research Program.

The preclinical observations were moved into a phase 1 clinical study led by Finn and Slamon at UCLA. The study was designed to determine the doses and initial safety results of combining palbociclib with letrozole, a commonly used drug for advanced ER+ breast cancer. Once the phase 1 study was completed, the phase 2 study was performed in 165 postmenopausal breast cancer patients with advanced ER+, HER2- disease.

“By combining the test drug, palbociclib, with the standard drug, letrozole, we demonstrated a dramatic and clinically meaningful effect on progression-free survival in women with ER+ advanced breast cancer,” Finn said. “We are gratified and excited that these results confirm the preclinical work we began at the Translational Laboratory.”

As the primary endpoint of the study, progression-free survival was 20.2 months for patients who received palbociclib plus letrozole, and 10.2 months for those who received letrozole only. The progression-free survival results indicated a 51 percent reduction in the risk of disease progression with the addition of palbociclib to letrozole.

“Our final results very much validate the Translational Laboratory approach,” Slamon said. “By identifying the effective treatment targets in the correct patients, we advance personalized cancer treatment that we hope will greatly improve outcomes for this group of women with breast cancer. These results are as exciting as the initial results we saw for trastuzumab (Herceptin) in HER2+ breast cancers but represent a new approach for women with advanced ER+ breast cancer. This group is different from the women with HER2+ breast cancer, and comprises approximately 60 percent of all advanced breast cancer patients, compared with 20 percent with HER2+ cancer.”

This Phase 2 clinical study was sponsored by Pfizer.

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New breast cancer results illustrate promise, potential of I-SPY 2 trial


Trial identifies breast cancer patients likely to benefit from experimental drug.

Laura Esserman, UC San Francisco

In an innovative clinical trial led by UC San Francisco, the experimental drug neratinib along with standard chemotherapy was found to be a beneficial treatment for some women with newly diagnosed, high-risk breast cancer.

Additionally, researchers learned that an algorithm used in the adaptive, randomized trial known as I-SPY 2 was highly effective at predicting the success of the treatment regimen in the patients who have HER2-positive/HR-negative disease.

The finding marks the second drug “graduation” within the I-SPY 2 trial model, which is designed to accelerate drug development and to reduce the costs of bringing safe and effective new drugs to market.

The phase 2 data was presented in San Diego at the annual meeting of the American Association for Cancer Research (AACR), a premier gathering of scientists presenting cutting edge cancer research.

Launched by UCSF in tandem with a private-public partnership, I-SPY 2 combines personalized medicine with a novel investigational design. Its goals are to improve the efficiency of clinical trials and to streamline the process for developing new drugs and regimens where they are most urgently needed.

“What is so exciting about the graduations is that we’re proving unconditionally that the standing trial mechanism can efficiently evaluate multiple drugs and identify the specific populations for which the agents are most effective,” said Laura Esserman, M.D., M.B.A., professor of surgery and director of the Carol Franc Buck Breast Care Center at the UCSF Helen Diller Family Comprehensive Cancer Center.

Esserman is the co-principal investigator of I-SPY 2, which is under way at 20 cancer research centers in the United States and Canada.

“We are testing the agents in high-risk patients at a time in their disease (primary breast cancer) when we are most likely to make a difference in survival,” Esserman said. “This was the promise of I-SPY 2. It’s what we’ve been waiting to see. As drugs move through the confirmation process, we should be able to accelerate availability of successful agents, see few failures in phase 3 cancer trials and have better options for women.”

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What about BOB?


Berkeley Lab proposal for an open biofoundry passes crucial first test.

BOB, the Berkeley Open Biofoundry, would be housed in the EmeryStation East building in Emeryville along with DOE’s Joint BioEnergy Institute.

Picture an industrial-sized manufacturing plant in which workers are turning out a valuable chemical product, say a pharmaceutical drug, or an exotic material such as a truly biodegradable plastic, or a clean-burning carbon-neutral transportation fuel. Now picture that plant as being void of smokestacks venting carbon dioxide into the atmosphere, or receptacles for the collecting of toxic, non-recyclable waste. This is the promise of biomanufacturing, in which biological organisms or systems are used to make desired molecules, and it has the potential to become one of the defining technologies of the 21st century.

A Berkeley Lab proposal submitted to the Defense Advanced Research Projects Agency (DARPA) for the establishment of a scientific center for biomanufacturing has passed a crucial first test. DARPA has awarded Berkeley Lab $1.5 million to proceed with a “Task Area 1” (TA1) design and study phase for what is being called “BOB” – for Berkeley Open Biofoundry. By providing the science and technology that will enable the engineering of biological systems to produce valuable chemical products on a commercial scale, BOB is conceived to do for biology what the Molecular Foundry does for nanomaterials.

“The idea behind BOB is to create a new type of user facility in which industrial, academic and government stakeholders will have access to engineered biological systems, including microbes, plants and tissues, at all stages of the engineering process, including design, building, testing and learning,” says Mary Maxon, the head of strategic planning and development for biosciences at Berkeley Lab who is spearheading this proposal along with Jay Keasling, Berkeley Lab’s associate lab director for biosciences. “BOB represents an important step along a pathway that will ultimately lead to a biomanufacturing center for excellence. This center of excellence is envisioned to be a Silicon Valley-style ecosystem of engineering for biology where designs and start-up systems are created but manufacturing is done elsewhere.”

Manufacturing is defined as the human transformation of materials from one form to another, more valuable form. Whereas many traditional manufacturing processes deplete natural resources and damage the environment, biomanufacturing can be both sustainable and environmentally benign. The primary challenges to biomanufacturing have been complexity and cost. Despite these challenges, biomanufacturing now accounts for more than $190 billion annually in U.S. revenues, with California, the birthplace of genetic engineering, accounting for roughly 22 percent of that figure.

“Biomanufacturing could be a significantly larger fraction of the U.S. economy if biology were easier and cheaper to engineer,” says Keasling, who provided a look into what biomanufacturing can offer with the engineering of a strain of yeast that can be used to produce artemisinin, the world’s most powerful anti-malaria drug. When exclusively produced from the wormwood plant, the supply of artemisinin was unreliable and its price too high for the people in developing nations who need it most. With the arrival of a microbial-based form of the drug, the supply has stabilized and the price has become affordable.

“The construction of the artemisinin-producing yeast required $25 million in funding and 150 person-years of work, typical of similar-sized bioengineering projects,” Keasling says. “New synthetic biology and computational technologies are needed to accelerate the development of productive biological systems and  reduce their costs, and industry needs access to them if traditional manufacturing is to be transformed by biomanufacturing.”

“Within the first five years of BOB, if it is fully funded by DARPA and corporate users, we will aim to speed the design time for developing desired biological systems so that it will be 50 times faster than it is today,” Maxon says. “We’ll also aim to make construction time five times faster than it is now and reduce costs by a factor of 20. The goal is to generate 350 molecules that currently can’t be manufactured with biological methods, including some that currently rely on petroleum sources and traditional manufacturing.”

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Daiichi Sankyo, UCSF announce collaboration in drug discovery research


They will focus on developing drugs and diagnostics for neurodegenerative diseases.

Daiichi Sankyo Co. Ltd. and UC San Franciscohave established a drug-discovery collaboration focused on developing novel therapeutics and molecular diagnostics for multiple neurodegenerative diseases.

Under the terms of the agreement, Daiichi Sankyo will provide its compound library to the UCSF Institute for Neurodegenerative Diseases (IND), and both parties will perform high-throughput compound screening and optimization together. The project will bring together the drug development capabilities of Daiichi Sankyo with the expertise of world-renowned neuroscientists at UCSF, in a collaborative effort to create multiple drug-discovery programs in debilitating disease areas such as Alzheimer’s, Parkinson’s, Creutzfeldt-Jakob disease and fronto-temporal dementias — all conditions for which there currently are no effective therapeutics available.

Daiichi Sankyo will provide research funding and milestone payments and royalties for successful clinical progression and commercialization of new products. Daiichi Sankyo will receive the option to enter into an exclusive license agreement to develop and commercialize promising compounds.

“This is a golden opportunity. These diseases require a big-picture approach, and that’s what Daiichi Sankyo is taking,” said Stanley Prusiner, M.D., who received the 1997 Nobel Prize in Physiology or Medicine for his discovery of prions, a new biological principle of infection. Prions are alternatively folded proteins that undergo replication — some prions perform critical cellular functions but others cause neurodegenerative diseases. Initially, Prusiner studied prions causing “mad cow” disease and Creutzfeldt-Jakob disease (CJD), but recently, he and many others have focused their work on other replicating, misfolded proteins— which Prusiner and others argue are prions—that are thought to cause the more common neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases.

“Alzheimer’s alone kills as many people every year as cancer does, but it only receives one-tenth of the funding that we dedicate to cancer research. This collaboration won’t fill that funding gap, but it will offer the tremendous value of Daiichi Sankyo’s scientific expertise to make progress on these diseases,” said Prusiner, UCSF professor of neurology and director of the IND.

“Daiichi Sankyo is committed to identifying potential new therapies to help fuel our passion to find medicines for the patients who need them. Using the compound screening technology at UCSF, along with their expertise in prion research, will give us an opportunity to explore the potential.  I am excited about this collaboration and look forward to seeing results of this partnership.” said Glenn Gormley, M.D., Ph.D., senior executive officer and global head of research and development, Daiichi Sankyo Co. Ltd.

Founded in 1999, the UCSF IND is one of the top academic laboratories focused on discovering causes and developing cures for neurodegenerative diseases. As the leader of the IND, which is based at UCSF and includes neuroscience research at several other UC campuses, Prusiner is committed to creating therapeutics and diagnostics that will halt neuronal diseases with his experience in prion research.

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Using light-heated water to deliver drugs


UC San Diego researchers use near-infrared light to warm water-infused particles.

In this schematic representation, a hydrated polymeric nanoparticle is exposed to near-infrared light. The NIR heats pockets of water inside the nanoparticle, causing the polymer soften and allowing encapsulated molecules to diffuse into the surrounding environment.

Researchers from the UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences, in collaboration with materials scientists, engineers and neurobiologists, have discovered a new mechanism for using light to activate drug-delivering nanoparticles and other targeted therapeutic substances inside the body.

This discovery represents a major innovation, said Adah Almutairi, Ph.D., associate professor and director of the joint UC San Diego-KACST Center of Excellence in Nanomedicine. Up to now, she said, only a handful of strategies using light-triggered release from nanoparticles have been reported.

The mechanism, described in today’s (April 1) online issue of ACS Nano, employs near-infrared (NIR) light from a low-power laser to heat pockets of water trapped within non-photo-responsive polymeric nanoparticles infused with drugs. The water pockets absorb the light energy as heat, which softens the encapsulating polymer and allows the drug to be released into the surrounding tissue. The process can be repeated multiple times, with precise control of the amount and dispersal of the drug.

“A key advantage of this mechanism is that it should be compatible with almost any polymer, even those that are commercially available,” said Mathieu Viger, a postdoctoral fellow in Almutairi’s laboratory and co-lead author of the study. “We’ve observed trapping of water within particles composed of all the biodegradable polymers we’ve so far tested.”

The method, noted Viger, could thus be easily adopted by many biological laboratories.

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Brain differences found in college-aged occasional drug users


UC San Diego findings point to potential biomarkers for early detection of at-risk youth.

Martin Paulus, UC San Diego

Researchers at the UC  San Diego School of Medicine have discovered impaired neuronal activity in the parts of the brain associated with anticipatory functioning among occasional 18- to 24-year-old users of stimulant drugs, such as cocaine, amphetamines and prescription drugs such as Adderall.

The brain differences, detected using functional magnetic resonance imaging (fMRI), are believed to represent an internal hard wiring that may make some people more prone to drug addiction later in life.

Among the study’s main implications is the possibility of being able to use brain activity patterns as a means of identifying at-risk youth long before they have any obvious outward signs of addictive behaviors.

The study is published in the March 26 issue of the Journal of Neuroscience.

“If you show me 100 college students and tell me which ones have taken stimulants a dozen times, I can tell you those students’ brains are different,” said Martin Paulus, M.D., professor of psychiatry and a co-senior author with Angela Yu, Ph.D., professor of cognitive science at UC San Diego. “Our study is telling us, it’s not ‘this is your brain on drugs,’ it’s ‘this is the brain that does drugs.’”

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Potential lung cancer vaccine shows renewed promise


Tecemotide a potential maintenance therapy to prolong survival, improve quality of life.

Michael DeGregorio, UC Davis

Researchers at UC Davis have found that the investigational cancer vaccine tecemotide, when administered with the chemotherapeutic cisplatin, boosted immune response and reduced the number of tumors in mice with lung cancer. The study also found that radiation treatments did not significantly impair the immune response. The paper was published on March 10 in the journal Cancer Immunology Research, an American Association for Cancer Research (AACR) publication.

Though tecemotide, also known as Stimuvax, has shown great potential at times, the recent Phase III trial found no overall survival benefit for patients with non-small cell lung cancer (NSCLC). However, further analysis showed one group of patients, who received concurrent chemotherapy and radiation followed by tecemotide, did benefit from the vaccine. As a result, tecemotide’s manufacturer, Merck KGaA, is sponsoring additional post-clinical animal and human studies, so far with good results.

“There aren’t any good options for patients with inoperable stage III lung cancer following mainline chemotherapies,” said UC Davis professor of medicine and lead author Michael DeGregorio. “We are looking at tecemotide as a potential maintenance therapy to prolong survival and improve quality of life.”

Tecemotide activates an immune response by targeting the protein MUC1, which is often overexpressed in lung, breast, prostate and other cancers. The vaccine stimulates production of interferon gamma and MUC1-targeted killer T-lymphocytes, which seek out and destroy MUC1 cancer cells.

The team, which included investigators from the UC Davis School of Veterinary Medicine and the Department of Radiation Oncology, wanted to know if cisplatin/tecemotide treatments, along with radiation therapy, could boost the immune response and alter lung cancer’s trajectory, stabilizing the disease.

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New therapeutic target discovered for Alzheimer’s disease


Drug candidate blocks production of disease-causing neurotoxins in mouse models.

Vivian Hook, UC San Diego

A team of scientists from the UC San Diego School of Medicine, the Medical University of South Carolina and San Diego-based American Life Science Pharmaceuticals Inc., report that cathepsin B gene knockout or its reduction by an enzyme inhibitor blocks creation of key neurotoxic pGlu-Aβ peptides linked to Alzheimer’s disease (AD). Moreover, the candidate inhibitor drug has been shown to be safe in humans.

The findings, based on AD mouse models and published online in the Journal of Alzheimer’s Disease, support continued development of cysteine protease inhibitors as a new drug target class for AD. “No other therapeutic program is investigating cysteine protease inhibitors for treating AD,” said collaborator Vivian Hook, Ph.D., professor in the UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences and in the UC San Diego School of Medicine.

Current AD drugs treat some symptoms of the devastating neurological disorder, but none actually slow its progress, prevent or cure it. No new AD drug has been approved in more than a decade.

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