Johns Hopkins study suggests the commonly prescribed anti-retroviral drug efavirenz attacks brain cells

Popular HIV drug may cause memory declines

Johns Hopkins study suggests the commonly prescribed anti-retroviral drug efavirenz attacks brain cells

The way the body metabolizes a commonly prescribed anti-retroviral drug that is used long term by patients infected with HIV may contribute to cognitive impairment by damaging nerve cells, a new Johns Hopkins research suggests.

Nearly 50 percent of people infected with HIV will eventually develop some form of brain damage that, while mild, can affect the ability to drive, work or participate in many daily activities. It has long been assumed that the disease was causing the damage, but Hopkins researchers say the drug efavirenz may play a key role.

People infected with HIV typically take a cocktail of medications to suppress the virus, and many will take the drugs for decades. Efavirenz is known to be very good at controlling the virus and is one of the few that crosses the blood-brain barrier and can target potential reservoirs of virus in the brain. Doctors have long believed that it might be possible to alleviate cognitive impairment associated with HIV by getting more drugs into the brain, but researchers say more caution is needed because there may be long-term effects of these drugs on the brain.

"People with HIV infections can't stop taking anti-retroviral drugs. We know what happens then and it's not good," says Norman J. Haughey, Ph.D., an associate professor of neurology at the Johns Hopkins University School of Medicine. "But we need to be very careful about the types of anti-retrovirals we prescribe, and take a closer look at their long-term effects. Drug toxicities could be a major contributing factor to cognitive impairment in patients with HIV."

For the study led by Haughey and described online in the Journal of Pharmacology and Experimental Therapeutics, researchers obtained samples of blood and cerebrospinal fluid from HIV-infected subjects enrolled in the NorthEastern AIDS Dementia study who were taking efavirenz. Researchers looked for levels of the drug and its various metabolites, which are substances created when efavirenz is broken down by the liver. Performing experiments on neurons cultured in the lab, the investigators examined the effects of 8-hydroxyefavirenz and other metabolites and found major structural changes when using low levels of 8-hydroxyefavirenz, including the loss of the important spines of the cells.

Haughey and his colleagues found that 8-hydroxyefavirenz is 10 times more toxic to brain cells than the drug itself and, even in low concentrations, causes damage to the dendritic spines of neurons. The dendritic spine is the information processing point of a neuron, where synapses — the structures that allow communication among brain cells — are located.

In the case of efavirenz, a minor modification in the drug's structure may be able block its toxic effects but not alter its ability to suppress the virus. Namandje N. Bumpus, Ph.D., one of the study's other authors, has found a way to mod

ify the drug to prevent it from metabolizing into 8-hydroxyefavirenz while maintaining its effectiveness as a tool to suppress the HIV virus.

"Finding and stating a problem is one thing, but it's another to be able to say we have found this problem and here is an easy fix," Haughey says.

Haughey says studies like his serve as a reminder that while people infected with HIV are living longer than they were 20 years ago, there are significant problems associated with the drugs used to treat the infection.

"Some people do seem to have this attitude that HIV is no longer a death sentence," he says. "But even with anti-retroviral treatments, people infected with HIV have shortened lifespans and the chance of cognitive decline is high. It's nothing you should treat lightly."

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The study was supported by grants from the National Institute on Alcohol Abuse and Alcoholism (AA0017408), the National Institute of Mental Health (MH077543, MH075673 and MH71150), the National Institute on Aging (AG034849) and the National Institute of Neurological Disorders and Stroke (NS049465).

Other Hopkins researchers involved in the study include Luis B. Tovar y Romo, Ph.D.; Lindsay B. Avery, Ph.D.; Ned Sacktor, M.D.; and Justin McArthur, M.B.B.S., M.P.H.

For more information: http://www.hopkinsmedicine.org/neurology_neurosurgery/research/jhu_nimh/researchers/nhaughey.html

FULL PAPER:
http://jpet.aspetjournals.org/content/early/2012/09/19/jpet.112.195701.full.pdf+html

Could Smart Drugs Help People With Cognitive Loss?

By Lily McCann

Smart drugs, also known as neuro enhancers, memory enhancers, intelligence enhancers, cognitive enhancers and nootropics, are drugs and supplements that improve functions of the brain, including attention, memory, concentration and intelligence. These mental function enhancers are believed to work by improving the brain’s oxygen supply, stimulating the growth of nerves in the brain and increasing the brain’s supply of enzymes, hormones and neurotransmitters.

Increasingly people are turning to smart drugs as a means of overcoming mental fatigue. Even people with ‘healthy brains’ are relying on smart drugs to improve mental performance. For example, in schools across India children are regularly taking little yellow and green pills as an attempt to do better in exams and get better grades at school. Whilst executives throughout the U.S are insisting their hair is becoming thicker and healthier as a result of their improved memory.

These so-called smart drugs include a plethora of over-the-counter herbal formulas as well as man-made prescription mixtures. For example, there are now many herbal smart drugs available over-the-counter which comprise in some cases of compounds derived from the brahmi plant found in rural India.

Despite the current trend for healthy individuals to pop smart drugs in order to become more mentally alert and subsequently perform better at school, university or work, do smart drugs however really help people with cognitive loss?

Smart drugs and Alzheimer’s and Parkinson’s Disease

Alzheimer’s and Parkinson’s diseases are neurogenerative disorders whereby the functions of the brain rapidly decline. With Alzheimer’s patients the neuron-toxic beta amyloid protein replaces amyloid precursor protein and in doing so effectively destroys neurons with the result being severe and often irreversible memory loss.

Aricept

Aricept is a smart drug that is currently licensed in Britain to treat Alzheimer’s patients suffering with cognitive loss. In blocking the action of a body chemical in the brain, Aricept works by breaking down a neurotransmitter that, according to the BBC, helps ‘pass messages between brain cells in the parts of the brain key to memory and conscious thought’.

Although Aricept is believed to delay the progression of Alzheimer’s, there are concerns about the side effects of this smart drug. As Dr Richard Harvey, from the Alzheimer’s Society told the BBC:

“In the short term, it causes diarrhoea and vomiting, so it might not be ideal.”

Tacrine

Tacrine is another smart drug that has been associated with treating Alzheimer’s patients suffering from cognitive loss. By blocking an enzyme involved in the breakdown of acetylcholine, Tacrine artificially enhances the number of failing neurotransmitters in the brain and temporarily assuages memory loss in the early stages of Alzheimer’s.

HIV and memory loss

Many HIV patients report cognitive problems such as memory loss, which are often resonant of the early stages of Alzheimer’s. Although whilst the majority of Alzheimer’s sufferers are elderly people in their 70s, 80s and 90s, people living with HIV who are suffering from cognitive loss are often as young as 40 and 50. The similarities between the neurological decline of HIV patients and people suffering from Alzheimer’s disease have been confirmed by a key commonality of an abnormal distribution in the brain of the amyloid beta protein. Whilst the cognitive problems related to Alzheimer’s are often rapid, severe and aggressive, the cognitive problems related to people with HIV are typically much milder. These minor cognitive motor disorders (MCMD) usually consist of the inability to think clearly, perform hand-eye coordinated movements and not remembering things as well as they once did. The more serious HIV-associated dementia (HAD) is much less common, particularly since effective HIV drugs became available.

Smart drugs and HIV

In order to improve the cognitive functions of the brain, namely memory, many HIV sufferers are turning to smart drugs. In 2002 a smart drug called Memantine was licensed in the UK, a cognitive enhancer that was used to improve the cognitive loss in patients suffering with some form of dementia, including Alzheimer’s, Huntington’s disease, HIV/AIDS related dementia and alcohol-related dementias. As will all cognitive enhancers or smart drugs, Memantine could not cure these diseases but were believed to have improved the symptoms of the diseases.

My Journey With AIDS

Kenn Chaplin was diagnosed with HIV in 1989. We would like to congratulate Kenn on his brave battle and winning against a range of AIDS-related illnesses, including bipolar II. You can read Kenn Chaplin’s remarkable and inspirational journey that gives hope and solace to others in Kenn’s situation at http://www.kwikmed.org/16-star-rated-aids-information-sites-blogs/. Kenn’s personal site includes a glossary of HIV/AIDS and information about this inspiring individual and his inspirational battle with HIV.