Research Projects

|  Chronic Pain  |  Alcoholism  |  Proteomic Markers of Alcohol Abuse  |  Depression   |

Chronic Pain

Worldwide, 75-80 million people suffer from chronic pain. It is estimated that 100 million workdays are lost each year in the United States and 500 million in Europe due to chronic pain. In 2005, $18 billion was spent on pain medications and future sales are expected to reach $34.5 billion by 2009. Chronic pain can arise from a variety of different causes including cancer, arthritis, dental and back issues, and HIV/AIDS. Today, 40-50% of all patients are under-treated for pain. It is an ongoing issue that faces many people and, currently, there is not an ideal medication for pain treatment.

Existing medications have limited success in producing ideal results. There is a tremendous selection of drugs on the market, and those pain medications can be broken down into three main categories:

  1. Classic Analgesics
  2. Opioids
  3. NSAIDs

Side effects from classic analgesics include GI effects and other reactions. Opioids can be addictive and can lead to constipation; patients using opioids can also build a tolerance to the treatment. Side effects from NSAIDs include cardiovascular problems, GI issues, and kidney damage.

Even without an ideal medication, the pain market is still at $18 billion. Currently, there is a very large demand for a safer and more effective pain medication. With an aging population and the simultaneous rise in the conditions that lead to chronic pain, along with the need for better efficacy and safety profiles, a new treatment needs to be developed and brought to market.

Again, similar to the situation encountered with alcohol and tobacco dependence, numerous people suffer from chronic pain, and although an ideal drug has not been found, current yearly aggregated sales of pain products are estimated at several billion dollars. New therapeutics to assist chronic pain sufferers are a significant opportunity and an unmet market need with potential sales exceeding $35 billion worldwide.

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Alcohol-use disorder includes both alcohol abuse and alcohol dependence. Both contribute to one of society’s most expensive, destructive, and tragic problems. Alcohol-use disorder afflicts 17.6 million individuals in the U.S. and costs $185 billion in direct and indirect expenses yearly (Cf: NIAAA). Alcohol abuse kills at least 75,000 Americans each year and decreases longevity by an average of thirty years. Alcohol-abuse-related mortality includes cancer, liver failure, and accidents resulting from impairment. In the U.S., about 1.5 million persons enter alcoholism treatment centers annually.

It is generally agreed that there is a genetic component toalcoholism, although it is consideredmultifunctional and includes environmental influences. Several alcohol vulnerability genes (DRD2, ADH2, HR1B) have been proposed by others. Recent work by COGA has focused attention on the genes coding for GABA receptors, but no current marker or set of markers has provided a guide to diagnosing predisposition to alcohol dependence, nor provided for differential diagnosis of proper assignment of patients to appropriate therapies.

The goal of alcoholism treatment is to reduce or eliminate consumption. "Talking therapy" such as Alcoholics Anonymous and drug therapy are often employed. Drugs such as benzodiazepines, beta-blockers, clonidine, and carbamazepine are used during the acute withdrawal phase to lessen symptoms, especially in severely afflicted persons. Such acute withdrawal symptoms may include tremors, hallucinations, tachycardia, and delusions.

A longer term goal for a therapeutic agent is the reduction or elimination of the craving for alcohol that patients experience; this discovery represents a much larger market opportunity. Currently, a variety of serotonergic drugs are frequently prescribed. Some are more effective (and also more expensive), but have achieved limited market share. Others are less expensive (and not as effective), but have about twice the market share. These currently available drugs apparently are used by a relatively small percentage of alcohol-dependent persons, perhaps as few as 10% in aggregate, for reasons that may include: lack of awareness by patients or care providers, cost, lack of efficacy, and compliance problems. Other biotech companies are developing sustained release formulations in the belief that sustained release will address the compliance issue. Interestingly, there is not a single drug currently on the market for treatment of alcoholism that has been developed through a rational design process, taking into account the neuroadaptive changes that occur during the progress of addiction.

If one is to pursue the development of better therapeutics for alcohol abuse or dependence, one needs an objective biologic test for monitoring whether individuals in therapy are still consuming large amounts of alcohol. A reliable test for alcohol intake would be invaluable for use in clinical trials and, later, as an adjunct to alcoholism therapy to monitor treatment success.

There is also a significant diagnostic market for monitoring alcohol consumption/abuse for workers in “sensitive” positions, such as those operating certain machinery, common transport carriers, and those serving in defense activities. The mandatory testing market is potentially attractive, given a superior product at a reasonable cost.

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Proteomic Markers of Alcohol Abuse

Despite the prevalence of alcohol-related problems among medical patients, less than half are identified and even fewer are treated. There is a need for better diagnostics to identify patients who are abusing alcohol, in addition to the need for better therapeutics. Such markers of alcohol consumption will be useful in screening for problematic and hazardous drinking, determining whether a health problem has an alcohol-abuse or dependency component, and monitoring alcoholics for relapse during and after therapeutic intervention.

Lohocla has access to over 1,000 samples (plasma, serum, and platelets) from individuals well-characterized regarding alcohol consumption, other drug use, medical/psychiatric disorders, and family history. Lohocla is using a novel shot-gun proteomics technology to access platelet and plasma proteins. The goal is to identify and validate better diagnostic markers appropriate for monitoring level and/or recency of alcohol use, as well as markers for predisposition to alcohol dependence.

The initial trait marker discovered with this process is the MAO-B protein concentration in platelet membranes. Lower levels have been demonstrated to be diagnostic for hazardous and harmful alcohol intake during a prior week. The marker provides as good or better accuracy than any currently available markers. Additional state and trait markers may be identified as part of this effort.

Lohocla plans to evaluate a larger population of subjects to establish accurate estimates of the sensitivity and specificity of the candidate marker proteins to identify level of alcohol intake and/or individuals classified as being high-risk alcohol drinkers or alcohol dependent.

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Information from the National Institute of Mental Health website indicates that each year in the U.S. at least 12 million women and 6 million men suffer from depression; however, men may not seek assistance to the same degree as women and may not manifest depression in the same fashion as women. Nevertheless, regardless of whether, as conventional wisdom suggests, women are twice as likely as men to suffer from depression, the potential for improving treatment by determining a discernable trait marker is vast. Of the ten leading causes of disability in the U.S., four are attributed to mental disorders, including major depression and bipolar depression. It is, therefore, not surprising that the cost of depression, both direct and indirect, reaches tens of billions of dollars in the U.S. each year. A description of the causes and various types of depression may be found at the NIMH website or at NIMH website or at Depression and Bipolar Support Alliance.

Depression often co-exists with other physical (or mental) illnesses, such as substance abuse or dependence. Alcoholics are twice as likely to suffer from depression as non-alcoholics. In addition, half of all patients suffering from bipolar disorder (Type 1 with severe mania) also are abusing alcohol or other drugs. Whether substance abuse or dependence is the cause or effect of depression is frequently unclear. What is clear is that there is a significant unmet need in distinguishing between depression and substance abuse, thereby, being able to provide appropriate therapy for each malady. In fact, the differential diagnosis of various mental health diseases currently depends upon a health professional’s subjective assessment of clinical history and symptoms. It is not surprising that therapeutive intervention is many times modified as the character of the illness becomes clearer to the therapist over time, often a very inefficient process.

There is a critical need for both better diagnostics and better therapeutics for the various typesof depression and other mental health disorders. Current unmet needs include:

Despite these limitations, current sales of major antidepressants (monoamine oxidase inhibitors, tricyclics, and neurotransmitter reuptake inhibitors and neurotransmitter agonists) in the U.S. are substantial, especially in the latter two categories. According to IMS, antidepressant sales were about $13 billion in 2003, up from $424 million in 1987.

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