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=Abilify v. 43 States=

Abilify (Aripiprazole)
Abilify is a psychiatric drug of the atypical antipsychotic subclass used to treat schizophrenia, manic episodes as a result of bipolar disorder and autistic children with aggressive behaviour. It is also used in conjunction with anti-depressants in the case of clinical depression. The active ingredient in Abilify is aripiprazole.

Mental Illness
Mental illness is something that affects many people in different ways, with differing levels of severity. Schizophrenia is a form of mental illness which is difficult to fully describe and occurs in approximately 1% of the population. Its cause is not entirely understood but it is likely related to changes in dopamine and serotonin levels. Symptoms include, but are not limited to, anxiety, moodiness, difficulty thinking logically and in more severe cases, delusions and hallucinations, including seeing or hearing things that are not there. (Schultz, North, Shields, 2007) Schizophrenia and bipolar disorder were the first psychiatric disorders to be treated with Abilify.

Bipolar disorder is characterized by extreme highs, known as manic episodes, and extreme lows, known as depression. This condition affects approximately 1% of the population, with the most extreme cases resulting in psychotic events. (Belmaker, R.H., 2004)

Clinical depression is much more common than schizophrenia or bipolar disorder, though exactly how common is not clear since definitions for depression vary greatly between sources. Clinical depression is due to changes in dopamine and serotonin levels and can result in changes in appetite, libido and sleep, as well as adversely affecting work and relationships. (Belmaker, R.H., Agam, G., 2008)

Autism is a disease that has come to the forefront in recent years, its cause is uncertain though there are many theories. It is characterized by difficult interacting and communicating with others, difficulty developing language skills, difficulty focusing, and attachment to inanimate objects. In many people it also manifests as hyperactivity and aggressive behaviour or tantrums. (Kaneshiro, N.K., Zieve, D., 2010)

Antipsychotics
Antipsychotics are used to treat the various forms of mental illness mentioned above. Typical antipsychotics were developed decades ago and include various subtypes including phenothiazines (chlorpromazine), thioxanthenes (thiothixene) and butyrophenones (haloperidol) in figure 1. These were the first generation of antipsychotics which had very broad modes of action which are believed to have caused a wide variety of side effects. (Jafari, S., Fernandez-Enright, F., Huang, X., 2012)

Figure 1. Examples of typical antipsychotics with functional groups outlined in red.

The second and third generations of antipsychotics are referred to as atypical antipsychotics. These include benzisoxazoles (risperidone), dibenzothiazepines (quetiapine, sold as Seroquel) and phenylpiperazines (aripiprazole, sold as Abilify) shown in figure 2. These were produced for their greater selectivity for receptors and the hope of fewer side effects. (Jafari, S., Fernandez-Enright, F., Huang, X., 2012)

Figure 2. Examples of atypical antipsychotics with functional groups outlined in red.

Synthesis
Aripiprazole was synthesized as part of a study by Oshiro et al. in which numerous antipsychotic agents that were intended to act as dopamine autoreceptor agonists were synthesized. The following synthesis is reproduced from Oshiro et al. (1998) ([|U.S. 5,006,528]).



Figure 3. Synthesis of aripiprazole.

Patents
U.S. Patent no. 5,006,528 regarding synthetic route and structure
 * Filed October 20, 1989
 * Approved October 20, 1994
 * Expires October 20, 2014 (6 month extension granted to April 20, 2015)

Another patent has recently been granted regarding an injectable formulation by Bristol-Myers Squibb. The formulation includes a cyclodextrin inclusion compound which acts as a cage to solubilize the aripiprazole. This is registered under [|U.S. patent no. 7,115,587]. [] Retrieved March 6, 2012 [|www.uspto.gov] Retrieved March 6, 2012
 * Filed August 14, 2003
 * Approved January 21, 2005
 * Expires January 21, 2025

Dosage
Abilify is available as a tablet and as an injection. Tablets are taken daily and range between 2 and 30 mg depending on the needs of the patient, particularly the severity of their symptoms. Injections are 9.7mg in 1.3mL and are used primarily to treat acute agitation since they are faster acting. [] Retrieved March 5, 2012

//Absorption//
When tablets are ingested, the peak plasma concentration is attained 3-5 hours after ingestion with bioavailability of 87%. Taken as an oral solution bioavailability is higher than with similar tablet doses.

//Distribution//
Aripiprazole`s volume of distribution is 404L or 4.9L/kg with more than 99% bound to serum proteins, specifically albumin.

//Metabolism//
Aripiprazole is metabolised by the liver, primarily undergoing dehydrogenation by CYP3A4, hydroxylation by CYP2D6 and N-dealkylation by CYP3A4. The dehydrogenation reaction produces an active metabolite, dehydro-aripiprazole in figure 4.



Figure 4. Aripiprazole and its active metabolite dehydro-aripiprazole.

//Elimination//
The half life of aripiprazole ranges from 75 to 146 hours depending on the individual. Radioactive carbon-14 aripiprazole was given orally with 25% of the radiation recovered in the urine and 55% recovered in the faeces. 18% of the unchanged drug is eliminated in the faeces while only 1% is eliminated in the urine. [] Retrieved March 13, 2012 [] Retrieved March 13, 2012

Mode of Action
Abilify is a partial dopamine receptor antagonist, acting on the D2 receptor as well as a serotonin1A and serotonin2A antagonist. It has also been shown that aripiprazole has some affinity for histamine and alpha adrenergic receptors which may account for the side effects experienced. The D2 receptor is a G-protein coupled receptor which, in the presence of Abilify increases adenylate cyclase, specifically in the limbic system. This is believed to relieve symptoms such as hallucinations and delusions (positive symptoms) in schizophrenics. Antagonism at the 5HT2A receptor occurs in the frontal cortex, decreasing negative symptoms like the lack of emotion and antisocial behaviour. ([]).

Pharmacophore
In a 2D-QSAR study by Avram et al. (2008) it was shown that altering the groups circled in red in figure 5 affected the affinity for the D1-D4 receptors. Of particular interest was the addition of large hydrophobic groups at R3 which resulted in better affinity for the D2 receptor due to the additional Van der Waals forces. Changing the groups at R1, R2, R4, and R5 showed no change or negative effects on binding. The hope with this study is that the greater the affinity for D2, the lower the dose of drug required and perhaps decreased side effects as a result.



Figure 5. Pharmacophore's studied by Avram et al (2008).

Side Effects
A great cause for concern currently is the wide range of side effects that have been caused by Abilify and include the following which vary in intensity on a patient by patient basis. > (www.drugs.com; Otsuka Pharmaceutical Co, Ltd) >
 * Stiff muscles
 * Rapid heart rate
 * Severe headaches
 * Vision problems
 * Thinking impairment
 * Uncontrollable permanent muscle movements
 * Thoughts of suicide or suicide attempts
 * Trouble sleeping
 * Aggression or violence
 * Restlessness and agitation
 * Panic attacks
 * Diabetes
 * Seizures
 * Heart Failure
 * Sudden Death

Possible Drug Interactions and Pre-existing Conditions
The efficacy of Abilify is not dependent on food but alcohol should not be taken if on Abilify. This can cause an increase in the number and intensity of the side effects listed above. Intense exercise should also be avoided as this will increase the likelihood of dehydration.

There are a number of drugs that could interact with Abilify including fluoxetine (Prozac), various medications for high blood pressure and various heart conditions, muscle relaxants and narcotics, cold and allergy medicines, carbamazepine, phenobarbial, phenytoin, quindine, ketoconazole, itraconazole, rifabutin, rifampin and others.

Your doctor should be made aware of any of the following pre-existing conditions since Abilify could worsen them and increase the number of, or severity of side effects and even result in death. ([])
 * Liver disease
 * Kidney disease
 * Heart disease
 * Seizures/epilepsy
 * Family history of diabetes
 * History of heart attack or stroke
 * Difficulty swallowing
 * History of breast cancer

Quetiapine
Quetiapine, which is the main ingredient in Seroquel, is Abilify`s largest competitor with $3.2 billion in sales for AstroZeneca compared to $3.5 billion in sales of Abilify for Bristol-Myers Squibb in 2010. It is also an atypical antipsychotic and can be seen in figure 2. Receptor binding for aripiprazole and quetiapine are very similar as outlined in table 1, which may explain their similar side effects. (Woo, V., Harris, S.B., Houlden, R.L., 2005)



Table 1. Summary of receptor interactions for aripiprazole and quetiapine.

[] Retrieved March 6, 2012 [] Retrieved March 6, 2012

Abilify and Lawsuits
Initially Abilify was only approved for use by people with schizophrenia and bipolar disorder which only makes up a small portion, about 2%, of the population. Later, the drug was approved for use by people with depression, resulting in a much larger target market. The most recent approval has been as a treatment for aggression and irritability in people with autism. Abilify was also originally used only in adults and not the elderly or young children, however, aggressive marketing to these groups and their doctors resulted in a larger market share yet again. This was done by successfully marketing Abilify as safer than first generation antipsychotics, a claim which many experts consider to be a gross exaggeration. The allegations of unethical marketing seem to be only the beginning of the controversy. Bristol-Myers Squibb and its subsidiary, Apothecon have been accused of many other illegal and unethical practices including falsified information in studies, ghost writing articles in medical journals and kickbacks to doctors and highly respected members of the scientific community to push for wider use. They have also been accused of reporting higher prices than what was actually charged, resulting in Medicaid paying millions of dollars in extra payments. Lawsuits have been carried out at both the federal and state level in the U.S. and have involved the U.S. Department of Justice beginning in the early 2000's. In 2007 Bristol-Myers Squibb and its subsidiaries settled out of court for a total of $499 million paid out to 43 states, never admitting any guilt. (Wilson, 2010)

Unfortunately, this is not merely an issue with Abilify and Bristol-Myers Squibb. Similar lawsuits are quite common in the pharmaceutical industry and have affected Seroquel, Abilify's biggest competitor among others. Abilify and Seroquel have also been the target of numerous lawsuits regarding side effects including weight gain and diabetes and the falsified information these companies released showing no effects with regard to these side effects. All of these cases fall under the False Claims Act in the U.S., of which there were over 1000 cases under way in 2010, many of which relating to antipsychotics. (Wilson, 2010)