Testing Alzheimer’s Drugs…Controlled clinical trials are our best way to determine the effectiveness of drugs in large groups of people. But how do we know which drugs to test? In the treatment of Alzheimer’s disease, several large clinical trials have failed because the drugs being tested did not prove effective in blocking the formation of amyloid beta (A-beta), a protein that builds to unhealthy levels and forms brain plaques in Alzheimer’s patients.

    A new measurement technique called stable isotope-linked kinetics (SILK) is helping researchers identify which drugs to test. “Bringing a new Alzheimer’s disease drug into clinical trials from tests in animal models has always been challenging,” says study director Dr. Randall Bateman, a Washington University neurologist who treats patients at Barnes-Jewish Hospital. “We haven’t had a way to quickly and accurately assess the drug’s effects, and that meant there always had to be some degree of educated guesswork when it came to setting the optimal dosage for humans. SILK should help eliminate much of that guesswork.”

    With Alzheimer’s disease, in particular, Randall notes, time is of the essence in getting drugs to market. But well done clinical studies can take months. The SILK test takes about 36 hours and is too high-powered to use in large groups, but in small-group pretesting, it can be used to determine which among several promising drugs should be tested and at which dosage level, helping to steer studies in a more useful direction. In a small, double-blind study of 20 healthy volunteers, participants were given either an Alzheimer’s drug or a placebo. At the start of the SILK test, they were connected to an intravenous drip of a slightly altered form of an amino acid that is a component of A-beta. The results showed a drop in A-beta production, with the highest dose of the Alzheimer’s drug causing 84 percent reduction in A-beta formation. With the new technique, they were able to track both the A-beta production and clearance rates over time.

    The drug, LY450139, is made by Eli Lilly and Company and is now in phase 3 human trials, targeting 1,500 Alzheimer’s patients at multiple locations. The goal of the study is to see if this drug slows the progression of the disease. Thanks to the SILK test and the small previous trial, researchers feel more confident that the drug is safe and will have a useful effect.

Assisted In Vitro

    In vitro fertilization (IVF) can be scary and expensive for women who have trouble conceiving. To that end, a recent study looked at the IVF technique of ‘assisted hatching’ to see whether the costs were worth it.

    Before implanting itself in the uterus, an embryo must emerge from an outer layer through a process called ‘hatching.’ In some women, this outer layer or shell appears to harden, especially as they age, making it potentially harder for the embryo to implant. 

    In assisted hatching, the physician uses a delicate procedure to open that shell so it can more easily break loose and attach to the wall of the uterus. This practice has been widely used by IVF practitioners since the ‘90s, but few studies have measured the effect on pregnancy rates. “Because assisted hatching adds to the cost of IVF, and theoretically increases the risk due to extra handling of the embryo, we decided to conduct a prospective randomized trial to determine if it really increases pregnancy rates in women under the age of 38,” explains Dr. Randall Odem,  professor of obstetrics and gynecology and senior author of the study. “It’s not a good idea medically to do something unless it has proven helpful.”

    Odem says that in the world of IVF, there is a higher rate of identical twins. They don’t know exactly why, but one possibility is that the mechanical assistance with hatching may encourage the embryo to divide. If there isn’t a corresponding increase in pregnancy rates, hatching may not be a good idea.

    Between April 2004 and March 2007, women who underwent IVF were offered enrollment in the study. If they were selected for assisted hatching, the additional cost was covered by a Barnes-Jewish Foundation grant that funded the study. Women who did not become pregnant during the first cycle of IVF and elected to have a second cycle were crossed over to the other study group. “We are very grateful that women have enough faith in studies to participate. It’s an investment in future health care and can affect practices all over the world,” Odem notes.

    The study showed that assisted hatching did not affect pregnancy rates in women younger than 38. That work has been published in the Journal of Fertility and Sterility, and mirrors the results found in a similar study. “Because of this work, other centers have decreased their rate of assisted hatching,” Odem says, “and the American Society for Reproductive Medicine, which issues policy guidelines, is looking at papers for constructing assisted hatching guidelines.”   

Depression Differences

    The brain is made up of many systems that control our behavior. Imaging techniques such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) have helped us map the brain to see areas that change with activity. For instance, we move our hand and the motor cortex area shows activity. When we’re doing something, we turn on a different system of the brain, although in reality it is on all the time, just ‘running in the background,’ to use computer-speak.

    Neuroscientists at Washington University School of Medicine have demonstrated that certain brain regions, known collectively as the ‘default mode network,’ behave differently in depressed people. The default network is normally active when we’re daydreaming. It shuts down when we focus on a specific task. But what researchers have found is that it stays active in depressed people, even when they concentrate on specific tasks.

    Says senior investigator Dr. Marcus Raichle, “It came to our attention about 10 years ago that while some regions become more active during a task, some parts of the brain decrease their activity, and that was unexpected. Now we’ve identified several areas of the brain that seem to work together as a default system, one that’s on when we’re idle, but gets out of our way when we are focused,except in depressed people. This system seems to focus on the relationships, memories, and activities that are important to us personally, that are all about us. They are involved in how we see ourselves. When non-depressed people focus outwardly, that self-reference retreats into the background. When we think about depression, the symptoms involve highly self-referential depressive thoughts. Knowing the locations in the brain involved in this default system gives us some ideas for treatment, whether it’s behavioral therapy, deep-brain stimulation, or medication.”

    Raichle says if a particular therapy reduces depressive symptoms, neurologists can use imaging to see how the treatment is affecting the default system or if some other area in the brain is involved. “There has been research on how this default system is developed,” he says. “We know it is not operational in newborns and only partially developed by age 6. The strengths and connections develop as we age. Can we work backward and identify people predisposed to depression? The identification of this collection of brain areas never before viewed together has caught the interest of clinicians and researchers across the world. Hopefully, it will lead to more effective treatments for depression, a devastating and costly disease.”

Calculating Bleeding Risk

    When a person has a heart attack, choosing the appropriate treatment is critical. Complicating this, however, is the fact that each patient is different. One may have a high risk of ischemia, or damage to the heart caused by lack of oxygen. In that case, blood thinners can break up clots and reduce that risk. Another patient may have a high risk of bleeding, making anticoagulants or cardiac catheterizations more hazardous. Time is of the essence, so how does a doctor quickly decide?

    “Until now, there hasn’t been a simple tool applicable to the general population that can predict the risk of bleeding before patients are treated for a heart attack,” says Dr. Richard Bach, a Washington University cardiologist and director of the Cardiac Intensive Care Unit at Barnes-Jewish Hospital. Several years ago, a registry was designed to examine medical practice and identify how patients fare with various treatments. “The important value of this registry, called the CRUSADE Quality Improvement Initiative, is that it applies to real-world patients, and all data has been collected as patients entered the hospital.” Because of this large database of heart attack patients, researchers have been able to identify treatment outcomes and the measurements that are most indicative of their risk for ischemia or bleeding.

    What they found out is that with eight quickly obtainable basic tests or facts in hand…gender, heart rate, blood pressure, hematocrit (concentration of red blood cells), creatinine clearance (measurement of kidney function), diabetes, peripheral artery disease or stroke, and congestive heart failure, physicians can estimate the risk of bleeding in a patient having a heart attack. The bleeding risk score calculator assigns points to each factor so that the total score coincides with the risk of bleeding in the patients in the CRUSADE registry. “We worked it out on 70,000 cases and validated it with another 20,000. These eight factors were confirmed as being predictive; and the calculator is very user-friendly. All these factors can be determined before the doctor has to make those big decisions in a heart attack case: whether to apply conservative treatment or something more interventional.”

    Physicians can use this information, too. A patient with low risk of heart damage but high risk of bleeding might need more judicious medication use. In patients with low bleeding risk but high risk of ischemic heart damage, the doctor can be more assertive. “Physicians use this as a tool for decision-making, but it’s part of a multifaceted risk stratification,” Bach says. “When both risks are high, physicians have to use great care. However, we also wouldn’t want them to withhold beneficial treatments.”   

Sleep Clears Brain

    We’ve known for some time that one of the functions of sleep is to promote long-term memories. A new study with fruit flies shows that it also helps reduce the number of synapses, to clear room in the brain for new learning. The critical question for researchers is how many synapses (the junctions at which nerve cells communicate) are modified by sleep. Specialists in the field believe that the creation of these new synapses is one way the brain solidifies memories and learning, but making more and more synapses can’t go on indefinitely. “There are a number of reasons the brain can’t indefinitely add synapses, including the capacity of the skull,” says senior author Paul Shaw, Ph.D., assistant professor of neurobiology at Washington University School of Medicine.

    The reason fruit flies were used in the research is that many aspects of fly sleep are similar to sleep in humans. For example, both flies and humans deprived of sleep one day will try to make up for the loss by sleeping more the next. While we know sleep is a promoter of learning, three years ago, Shaw found that learning also increases the need for sleep, in the fruit fly. Scientists found that flies raised in a busy social environment slept two to three hours longer than flies raised in isolation. When the flies slept, the number of new synapses formed during social enrichment decreased. In sleep-deprived flies, that decline did not occur.

    Shaw likens the need to trim synapses to trying to tune in on a radio station. As you move around the dial, you have some static and some song. The idea of losing synapses is to get rid of the static noise. Clearing those out is also good for trying to find certain memories. “It’s like your e-mail inbox: If you don’t clear out the junk, you can’t find the important messages.”

    Though scientists have been studying sleep a long time, they still don’t know its main function. No single theory has universal agreement. “We know when we sleep our metabolic rate decreases, so one use might be energy conservation,” Shaw says. “We also know that chronic sleep deprivation creates health problems such as metabolic syndrome, diabetes and obesity. There is also general agreement that memory consolidation occurs during sleep, whether at night or during naps. It’s good for cognition and decreases the incidence of cardiac disease.”

    This study with fruit flies was the first one to show a decrease in synapses as a sleep function. “The bottom line is, we spend a lot of our time sleeping,” Shaw says. “We are trying to identify those functions most important for public health.”

Asthma Coaches

    Sometimes, what a parent of a sick child needs most is a good coach. A new two-year study showed that working with an asthma coach significantly reduced hospitalizations in low-income, African-American children with asthma. Researchers from Washington University School of Medicine and the University of North Carolina at Chapel Hill worked with almost 200 parents of asthmatic children ages 2 to 8 on Medicaid who had been hospitalized for asthma at St. Louis Children’s Hospital. The youngsters were randomized into groups, with half receiving normal care and the others working with an asthma coach who provided support for parents dealing with the ongoing demands of their children’s illness.

    During the two years of coaching, 35 of the 96 patients in the coaching group were hospitalized at least once, compared to 55 of the 93 patients in the usual-care group. The asthma coaches were not medical professionals. “These coaches were African-American lay women who lived in the same neighborhoods as the participants and had had experience living with asthma,” explains Dr. Robert Strunk, a Washington University asthma specialist at St. Louis Children’s Hospital. “They understood what these families were dealing with.”

    Strunk is encouraged by the results of that study. He explains that each coach underwent a training program on the asthma disease process, ways to manage asthma and reduce triggers, communication techniques, social support and behavioral change. Paid by the grant, coaches visited parents at home and helped them understand the medications, the importance of regular clinic visits, and how to reduce exposure to secondhand smoke and cockroach allergen. Coaches also discussed issues important to the family, such as changes in housing and employment or other illnesses.

    A follow-up study will target 30 pediatric practices in the St. Louis area and their asthma patients. Children will be randomized into control and coaching groups for a year. “Our goal is for the children to be normal,” says Strunk. “That means sleeping through the night, having no limitations on their activities, missing only the normal amount of school, and not being in the hospital. ‘Normal’ does not mean off medication; meds are an important part of control.”

     Much of compliance with an asthma plan has to do with working around the barriers families have in their lives, he adds. “Like not being able to get off work for clinic visits, inability to afford the co-pay, or being homeless. Because trials have been so successful, St. Louis Children’s Hospital now offers a coach to children with severe asthma at risk for multiple hospitalizations. Coaching is cost-effective and has been used successfully in other chronic illnesses.”

Prostate Drug and Cancer

    We’ve seen them advertised on TV: drugs to treat enlarged prostate, a condition commonly called benign prostatic hyperplasia, or BPH. But as a recent study shows, these drugs are not all created equal: they work in different ways.

    While BPH by definition is benign, men with the condition may be at greater risk for prostate cancer. A four-year clinical trial with 8,200 men called REDUCE is the largest one yet to evaluate a medication for prevention of cancer in high risk men. Study participants had to have a PSA level over 2.5 and have had a negative prostate biopsy within the previous six months. The men, ages 50 to 75, were randomly assigned to receive either a placebo or a daily 0.5 mg dose of dutasteride (Avodart), manufactured by GlaxoSmithKline. As part of the study, the participating men had a second prostate biopsy at two years, and again at the four-year mark.

    Dr. Gerald Andriole, chief of urologic surgery at Washington University School of Medicine and Siteman Cancer Center, was the study’s lead investigator. “We found that at both the two-year and four-year marks, the incidence of prostate cancer was significantly lower in the dutasteride group. The most likely explanation is that dutasteride worked by shrinking tumors and/or slowing their growth, making them less likely to be detected on biopsy.”

    Andriole explains that prostate cancer occurs because of the male hormone dihydrotestosterone (DHT). Avodart blocks conversion of testosterone to DHT, while shrinking the prostate and preventing BPH. In earlier studies done to demonstrate Avodart’s effectiveness for BPH, researchers noted that men on this drug also had a 50 percent lower rate of cancer. An earlier study of the weaker drug finasteride (Proscar) showed that it also reduced cancer risk, but cancers that occurred tended to be more aggressive. “Finasteride blocks only Type II of the enzyme; dutasteride blocks both Type I and Type II,” Andriole explains. “Type I is more often present in high-grade, aggressive tumors. Other drugs for BPH, such as Flowmax, work by relaxing the muscles of the prostate to reduce symptoms, but have no inhibitory effect on cancer.”

    Andriole outlines the good news gained from the REDUCE study: “The men on dutasteride had no more high grade cancers than the placebo group; and when cancers occurred, they were smaller. As important, the incidence of cancer was also lower in the treatment group, and Dutasteride made their PSA tests more accurate. The study changes the way men with elevated PSAs are handled.”