For adults and children with ADHD
(attention deficit hyperactivity disorder), sometimes finding the right
medication is more difficult than getting diagnosed in the first place.
Individual genetics also play a large role in how children and adults
with ADHD will react to certain medications and doses, with side effects
ranging from stomach ache to adverse cardiovascular reactions.
The National Institutes of Health (NIH) has granted the Medical
University of South Carolina (MUSC) $1.3 million to examine how
medications used to treat ADHD (methylphenidate, amphetamine,
atomoxetine and modafinil) work in the brain. Discoveries from this body
of work could help in decreasing the amount of time patients spend
finding the right medication, as well as significantly reducing the
possibility of side effects and adverse drug events.
John S. Markowitz, PharmD., associate professor of pharmaceutical
sciences and principal investigator of the study, said that a
multidisciplinary approach to the work, as well as the potential
benefits to patients, were likely deciding factors that enabled MUSC to
obtain the highly competitive funding.
"Physicians have tried to monitor how much ADHD medication a patient is
actually getting by looking at the amount in a person's blood level,
similar to how they monitor the amount of immunosuppressant drugs in
transplant patients, or lithium in patients with bipolar disorder," he
said. "The problem is there is no guaranteed way to know how much of the
medicine is actually making it into the brain to exert its intended
effects without leading to untoward adverse effects. Presently, patients
treated with one or more of these medications may be experiencing a lot
of side effects, possibly even toxicity, yet that person's blood level
of the medication may appear normal and within expected ranges for the
particular medication."
For years the assumption has been that blood concentrations of
medications reflect those typically attained within the brain.
Additionally, there have been few practical means to determine
concentrations of medications in the brain. It is becoming more apparent
that blood concentrations can differ substantially from brain
concentrations through use of a variety of research techniques.
From day to day, physicians try to help patients who respond
differently to one medication versus another. Patients A and B might be
of the same sex, weight and height, but while one medication will offer
patient A relief from ADHD symptoms, patient B could experience serious
side effects or, in rare cases, life-threatening reactions.
The key is learning more about how the body allows substances in and out
of its most important and complex organ: the brain. The blood brain
barrier (BBB) functions as a gatekeeper to keep potential toxins from
entering the central nervous system, while allowing "cleared" substances
in. Specific drug transporters (proteins found in the body and BBB)
allow passage of various molecules required for normal function while
also serving a protective role. In the case of the BBB, some drug
transporters can determine the degree to which therapeutic medications
gain access to the brain, and their function once inside. Some
transporters allow the movement of medications in and out, while other
transporters only work to bounce out substances that threaten the
brain's delicate balance of what it needs and what can become toxic.
Depending on an individual's genetics, different levels of various
transporters are found in the body. Preliminary studies at MUSC examined
the potential role of transporters known as organic cation transporters
(OCTs) which are abundant in many tissues, including the heart, brain
and placenta. Results of these investigations provided strong evidence
that OCTs may have some involvement in transporting ADHD medications to
the brain, which could have consequences for the ultimate effectiveness,
tolerability, and safety of these agents.
The current NIH study will examine the role of OCTs in the disposition
and action of drugs used to treat ADHD by using a number of experimental
methods. One interesting method includes a unique genetically engineered
mouse that lacks OCT transporters to examine how ADHD medications make
it into the brain, and how the pharmacological effects may differ from
normal animals.
About MUSC
Founded in 1824 in Charleston, The Medical University of South Carolina
is the oldest medical school in the South. Today, MUSC continues the
tradition of excellence in education, research, and patient care. MUSC
educates and trains more than 3,000 students and residents, and has
nearly 10,000 employees, including 1,300 faculty members. As the largest
non-federal employer in Charleston, the university and its affiliates
have collective annual budgets in excess of $1.3 billion. MUSC operates
a 600-bed medical center, which includes a nationally recognized
Children's Hospital and a leading Institute of Psychiatry. For more
information on academic information or clinical services, visit
musc or muschealth.
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