Nilotinib and Parkinson's Disease

Parkinson’s disease: a diagnosis that marks the beginning of end of a patient’s motor functions. It is the most common of the neurodegenerative diseases, and in terms of treatment, also happens to be the most elusive. The disease is characterized by the unexplained death of dopaminergic neurons in the substantia nigra (SN) portion of the brain. Dopamine is vital for control of motor function, thus the death of these neurons begins the start of the disease. Thus far, we have only learned how to treat the symptoms of the disease. Patients are treated with Levodopa, a precursor to dopamine, coupled with carbidopa to ensure its safe delivery to the brain and even distribution to the central nervous system.

Patients diagnosed with Parkinson’s disease will experience resting tremors (especially in the hands), bradykinsesia (slowness of movements), limb rigidity, and gait and balance issues. In addition to motor function loss, there are non-motor symptoms as well. These include, but are not limited to: depression, loss of sense of smell, and cognitive impairment.

Molecular causes of the disease are largely unknown. Only 10-15% of cases can be attributed to genetics, while the remaining are sporadic with no known cause. There are currently one million people in the United States living with PD. Because of the late onset of symptoms, the majority of cases are only caught when the symptoms have begun and the patient’s motor function is already degenerating, they are already late stage patients. This gives doctors and PD researchers no time to focus on prevention or see what exactly is causing it.      

Nilotinib, advertised as Tasigna, is currently approved for treating newly diagnosed adult patients with Philadelphia chromosome–positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP). Studies have shown that Nilotinib decreases levels of alpha-synuclein in the brain as well as the blood. The primary component of the Lewy Bodies found in the substantia nigra, the site of this neuron death, is alpha-synuclein. Alpha-synuclein activates Abl, a tyrosine kinase that has many functions, including apoptosis. In trials with mice, the drug was found to not only increase dopaminergic levels and improve motor function, but also to clear cytosolic debris in SN neurons.

Is Nilotinib scraping the surface of new treatment options for Parkinson’s? Are we finally understanding the molecular events that lead up to this devastating neurodegenerative disease?

Resources

Dauer, W., & Przedborski, S. (2003). Parkinson’s Disease: Mechanisms and Models. Neuron,

39, 889-909. Retrieved November 16, 2017.

Hebron, M. L., Lonskaya, I., & Moussa, C. E. (2013). Nilotinib reverses loss of dopamine

neurons and improves motor behavior via autophagic degradation of  -synuclein in           

Parkinsons disease models. Human Molecular Genetics, 22(16), 3315-3328.

doi:10.1093/hmg/ddt192

Karuppagounder, S. S., Brahmachari, S., Lee, Y., Dawson, V. L., Dawson, T. M., & Ko, H. S.

(2014). The c-Abl inhibitor, Nilotinib, protects dopaminergic neurons in a preclinical

animal model of Parkinsons disease. Scientific Reports, 4(1). doi:10.1038/srep04874

Pagan, F., Hebron, M., Valadez, E. H., Torres-Yaghi, Y., Huang, X., Mills, R. R., . . . Moussa, C.

(2016). Nilotinib Effects in Parkinson’s Disease and Dementia with Lewy Bodies.

Journal of Parkinson's Disease,6, 503-517. Retrieved November 15, 2017.

Parkinson Disease Treatment & Management. (2017, November 15). Retrieved November 16,

2017, from https://emedicine.medscape.com/article/1831191-treatment?pa=hQpeeo

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Tasigna. (n.d.). Retrieved November 16, 2017, from https://www.hcp.novartis.com/products/ta

signa?site=43700014833112206&source=0100

What Is Parkinson's? (2017, October 18). Retrieved November 16, 2017, from http://www.parkinson.org/understanding-parkinsons/what-is-parkinsons
By Savannah Tucker, Bachelor of Public Health Student, University of Kentucky

Crohn's Disease

     The feeling one just cannot shake. That sudden urge to go to the restroom. It is monstrous and undeniable. But, what if that urge is more often than the norm? And, it is followed with abdominal pain, diarrhea and a fever? It may be something to look in to. A disease known as Crohn’s disease.  Crohn’s disease is increasing among all ethnicities; but, it is not something that cannot be treated. With extensive research and years of testing, adalimumab (Humira) has provided a treatment for those who suffer from this irritable disease. Because Crohn’s disease is growing in incidence and prevalence, adalimumab has been created to assist those who are battling with this disease.

      Crohn’s disease is a relapsing systematic inflammatory disease effecting the gastrointestinal tract that is associated with immune disorders. The exact cause of Crohn’s disease is unclear (1). However, it can be linked to environmental factors, aberrant immune function and bacterial factors (1). Those who suffer from the disease experience an array of symptoms such as consistent abdominal pain, high fever, unintended weight loss and frequent diarrhea with passage of blood or mucus (1). Crohn’s disease and Ulcerative colitis are the two main components of inflammatory bowel disease.

     There are five known types of Crohn’s disease that affect different location of the gastrointestinal tract (2). The severity of each depends on the progression of the disease and the genetic and environmental build-up of a person. The five types of Crohn’s disease are gastroduodenal which affects the stomach and duodenum. Those who suffer from this form of Crohn’s disease experience symptoms such as loss of appetite, weight loss, nausea and vomiting. Crohn’s colitis is also a form of Crohn’s disease but only affects the colon. Those who suffer from Crohn's colitis experience diarrhea, rectal bleeding and complications around the anus. Another type is ileocolitis. It is the most common form of Crohn’s disease and affects the ileum and colon. Those who suffer from ileocolitis experience symptoms such as diarrhea, cramping or pain in the right lower part or middle of the abdomen, and weight loss. Jejunoileitis is also a form of Crohn’s disease. Jejunoileitis creates patchy areas of inflammation in the jejunum and ileum. Those who suffer from jejunoileitis experience abdominal pain, cramps following meals and diarrhea. The fifth form of Crohn's disease is ileitis. It affects only the ileum and its symptoms are similar to those of ileocolitis (2).

     Large concordance studies in twins in northern Europe were early indicators of a genetic component in Crohn’s disease. The study showed that thirty five percent of monozygotic pairs and only three percent of dizygotic pairs were concordant for the disorder. In seventy percent of discordant monozygotic pairs, the first-born had inflammatory bowel disease. Substantial   phenotypic (such as the location, behavior, and age at diagnosis) concordance exists, both at diagnosis and longitudinally, in monozygotic twins. As stated above there has been a prevalence in all ethnicities. For example, prevalence in Ashkenazi Jews is higher than any other ethnic group. Genome wide association studies and computerized (in silico) meta-analyses have identified and confirmed seventy-one susceptibility loci for Crohn’s disease on seventeen chromosomes (3).

Environmental factors also affect the rate of Crohn’s disease. Rates of the disease in the northern and southern are equal. Because of industrialization, most people focus on their career and higher education. This led to a change in life events like breast feeding and there are smaller families with larger less crowded living conditions. The improved domestic hygiene and sanitation, consumption of diet and less active lifestyle are all factors that contribute to the gain (3) of Crohn’s disease. One of the most prominent risk factors is the use of tobacco products. Also, use of tobacco significantly increases the risk of developing the disease. An estimated three million U.S. adults have been diagnosed with either Crohn’s disease or ulcerative colitis. This is a one million person increase since the year 1999.

     But, let’s get down to the nitty gritty. How is it treated… with adalimumab of course? Adalimumab was approved by the FDA December 2002. It was initially launched for the treatment of rheumatoid arthritis but was later found to assist in the treatment of irritable bowel diseases such as Crohn’s disease. In two clinical studies, adalimumab showed fifty-eight and fifty-two percentage approval compared to the thirty-four percent who consumed the placebo. Thirty-six and twenty-one percent also achieved remission in comparison to the twelve and seven percent who consumed the placebo (4). This is how it works. Adalimumab binds to TNF-alpha and blocks its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface TNF expressing cells in vitro in the presence of complement. This mechanism blocks cytokine effects, thereby reducing TNF-induced inflammation and halting tissue destruction (5).

     With extensive research and years of testing, Humira has provided a treatment for those who suffer from this irritable disease. Because Crohn’s disease is growing in incidence and prevalence, adalimumab has been created to assist those who are battling with this disease. A total of sixty genes have been studied and evaluated to determine whether genetic variants are associated with irritable bowel syndrome. Also, there are five main pathways effected by Crohn’s: serotonin, adrenergic, inflammation, intestinal barrier, and psychiatric that have been found. As technology improves hopefully there will be further research for a cure for irritable bowel syndrome/disease.

Work Cited

1. Baumgart, Daniel C, and William J Sandborn. “Crohn's Disease .” Lancet, vol. 2012, no. 380, ser. 1590-1605, 20 Aug. 2012, pp. 1–16. 1590-1605, doi:http://dx.doi.org/10.1016/ S0140-6736(12)60026-9.

2. “HUMIRA (Adalimumab) Clinical Data | Ulcerative Colitis.” HUMIRA (Adalimumab) | Official Healthcare Professional Site, www.humirapro.com/gastroenterology/ulcerative-colitis-clinical-data.

3. Saito, Yuri A. “The Role of Genetics in IBS.” Gastroenterology clinics of North America 40.1 (2011): 45–67. PMC. Web. 28 Nov. 2017

4. HUMIRA (Adalimumab), Abbott Laboratories - Package Insert, www.accessdata.fda.gov/drugsatfda_docs/label/2002/adalabb123102lb.htm

5. “Adalimumab.” DrugBank, www.drugbank.ca/drugs/DB00051.

By Lexus Cabiness, Post Baccalaureate Student, University of Kentucky

Preventing Noncompliance in Psychotic Patients

Image from:  Youthvillage.co.za

Non-adherence to medication and medical recommendations in patients is very common across all branches of the healthcare field. In fact, it is one of the challenges healthcare providers face on a daily basis with their patients. We all know or have heard of the patient with diabetes type 2 consuming carbohydrates in excessive amount regularly or the elderly man who recently suffered from a heart attack eating food high in cholesterol regularly or even the patient with a microbial infection rejecting the full course of the antibiotic treatment prescribed by the physician. I have to admit that I have been guilty of the latter. So, when patients become noncompliant to their medications, it makes it very difficult to provide effective medical care. Unfortunately, for psychotic patients, these noncompliant behaviors can pose greater risks, as studies show a higher frequency of noncompliance in psychotic patients.

Many psychotic patients rely on their medications alone to control and regulate their mental disorders. Neuroleptic drugs are essential in treating psychotic disorders such as bipolar disorder, schizophrenia, clinical depression and many more. Some patients require several months or years of medication or even lifelong medication is necessary.  However, up to 80% of psychotic patients fail to comply with their treatment (1). This is a major problem! I think the first question we need to ask ourselves is why so many patients with mental disorders are either rejecting treatment, self-medicating with illegal drugs, or discontinuing a prescribed medication? Is it due to the patient’s negligence? Carelessness? In the case of an acquaintance with schizophrenia that is not the case. He informed me that his medication was making him gain an excessive amount of weight, something he despises. He proceeded to tell me he felt like a “zombie”. I asked him if he was still taking his medication but he informed me that he was self-medicating with marijuana. A few months later, I found out he relapsed and got hospitalized. Sadly, this has been an ongoing battle with many patients. For many the side effects are just too much to bear.  You see, one of the major reasons these patients are noncompliant to their treatment is due to the side effects of these drugs. Although these medications can cause great relief to a mental condition that has been affecting the lives of these individuals, they are not of small risks.

Almost all psychotropic medications cause some serious side effects which can be life-threatening and irreversible. In many cases, these psychotropic medications fail to help patients. So, it really makes me wonder if these patients are being treated in the most effective way. Healthcare providers can only hope that their patients are actually following the course of treatment. Unfortunately, it is difficult to ensure compliance. According to the National Institute of Neurological Disorders and Strokes of the National institutes of Health, antipsychotic drugs can cause neuroleptic malignant syndrome (NMS)(3). NMS is characterized by fever, muscular rigidity, altered mental status and autonomic dysfunctions. One of the most common side effects of antipsychotic drugs is a condition known as akathisia. Between 20 to 75 percent of patients develop this condition.(4) Akathisia is a movement disorder characterized by uncontrollable physical restlessness, agitation, shaking of arms and legs, anxiety and panic. The condition can develop as soon as the patient start taking the drug. Many of these side effects are associated with older neuroleptic drugs. There have been major advancement of modern psychopharmacology with the development of newer drugs. But even with these new drugs, weight gain and sexual dysfunction can be two of the most common side effects associated. Some other common side effect associated with these drugs are nausea, dizziness, sleepiness, Diarrhea, suicidal behaviors etc.

There are many factors associated with noncompliance in psychotic patients. The lack of insight and lack of awareness of the illness itself pose a challenge especially in schizophrenia.(2) However, we cannot deny that adverse effects of these psychiatric drugs contribute greatly to this critical issue. So, what is the solution? How do we reduce the lack of compliance due to psychotic drugs’ adverse effects? Firstly, it is the responsibility of clinicians to educate their patients on the illness and the different side effects of the drugs prescribed. In addition, patients need to be part of the decision-making process. Pharmacological strategies such as dose adjustment and the use of long-acting injections would be a great way to ensure patients comply with treatment. Dose adjustment is especially important because prescribing medication is not a “one size fits all” process. Reducing medication dose can reduce the side effects in patients. Of course, I understand that some patients require higher dose and in that case, clinicians could add another class of medication, such as anticholinergic for extrapyramidal side effects.(2) Another interesting approach would be the use of psychotherapy in addition to drug therapy. Psychotherapy provides a holistic approach to treating a psychotic patient, something that drugs cannot do on their own. There are different types of psychotherapy and research has shown that Cognitive Behavioral Therapy can change thinking and behavior patterns that are harmful or ineffective and replace them with functional behaviors.(4)

There is not just one strategy to use to improve compliance. Every patient is different and has different requirements.  Some clinicians use a combination of strategies and approaches to improve compliance in their patients. The ultimate goal is to ensure that psychotic patients are being treated efficiently and thoroughly to avoid relapse and psychiatric hospitalization. In the end, we need to put more emphasis on new drugs development, the use of psychotherapies and drugs adjustments to reduce noncompliance in patients with psychotic disorders and improve the quality of life of these patients.

References:

1.Gray, R. “Compliance Therapy in Psychotic Patients. Many Ethical Questions Arise from Study.” BMJ (Clinical Research Ed.)., U.S. National Library of Medicine, 18 May 1996,

2.Kane, John M, Taishiro Kishimoto, and Christoph U Correll. “Non-Adherence to Medication in Patients with Psychotic Disorders: Epidemiology, Contributing Factors and Management Strategies.” World Psychiatry 12.3 (2013): 216–226. PMC. Web. 30 Nov. 2017.

3.Medical Whistleblower Advocacy Network.” Psychiatric Drugs Side Effects | Medical Whistleblower, medicalwhistlebloweradvocacynetwork.com/psychiatric-drugs-side-effects-.

4.Pareck, Ranna. “What Is Psychotherapy.” Psychiatry.org, July 2016, www.psychiatry.org/patients-families/psychotherapy.

5.Balon, Richard. “Managing Compliance.” Managing Compliance | Psychiatric Times, 1 May 2002, www.psychiatrictimes.com/articles/managing-compliance/page/0/1.

By Tressie Charles, Master of Science in Medical Sciences, University of Kentucky

Autism Spectrum Disorder

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A blue puzzle piece. This has become the renowned symbol for autism awareness. We all know someone who has been diagnosed with autism or is close to someone who was. Autism has actually been absorbed into a group of conditions called Autism Spectrum Disorder or ASD. Autism, Childhood Disintegrative Disorder, Rett disorder, Asperger’s syndrome, and a broad category, Pervasive Development Disorders Not Otherwise Specified (PDDNOS), are all diagnosed as a form of Autism Spectrum Disorder.  Autism Spectrum Disorder is a neurodevelopmental disorder. Its origins are unknown but it is thought to stem from a multifaceted genetic complication.  No, vaccinations do not cause autism! However, researchers have not ruled out environmental factors that may contribute to the onset of Autism. ASD covers a broad range of individuals that are affected by a variety of symptoms. The most commonly recognized symptoms are severely impaired social skills, challenges with speech and non-verbal communication, and exhibit repetitive behaviors. Commonly individuals will avoid eye contact, resist making social relationships, and will fail to show interest in the feelings of others. Autism Spectrum Disorder also has become known to be a full body disorder It is often accompanied by other serious conditions like epilepsy, gastro Intestinal disorders, sleep disruption, feeding issues, and mental health problem such as anxiety, depression, schizophrenia, ADHD, and bipolar disorder.

ASD is an unusual disorder because those affected may also have unique strengths when it comes to learning, thinking, and problem solving. Each person with ASD is likely to experience different levels of strengths and challenges. Some are high-functioning and are able to become accustomed to living day to day with autism. Others struggle to recognize emotions and social cues that make it difficult for them to interact with family and their peers on a daily basis. The signs if autism are likely to emerge and be recognized by the age of 3.  The CDC reports about 1 in every 68 children in the United States are afflicted with some sort of disorder on the Autism spectrum, a majority of which are male. The prevalence of this disorder and our lack of knowledge about it makes autism a relevant area for pharmacologic research. Behavioral therapy is usually the first treatment for ASD. Medications are currently just administered to assist patients with functioning in daily activities.

Currently the FDA has approved only two drugs, risperidone and aripiprazole, for ASD patients. These drugs are used only to manage irritability and aggression. Risperidone is an antipsychotic drug used in Autistic patients aged 5 and older. Studies of the use of this drug in children between the ages of 5 and 17 produced results that indicated risperidone was effective in reducing the number of tantrums and aggressive episodes in autistic children. While this drug has its benefits, there are also some concerning side effects like dizziness, drooling fatigue, hepatotoxicity, and weight gain.

Aripiprazole is also an antipsychotic drug used in autistic children aged 6 and older. It’s mechanism of action is not completely understood but it is suspected to involve agonist activity at dopamine type 2 and serotonin 1A receptors and antagonist activity at serotonin 2A receptors. This therapy was shown to increase the quality of life inventory scores in autistic children as well as significantly reduce irritability, hyperactivity, and repetitive actions. Aripiprazole also has some discouraging side effects that include dizziness, vomiting, fatigue, sedation, and weight gain. Many parents are most concerned with the weight gain that is associated with these drugs because of the chronic illnesses that accompany obesity such as heart disease and diabetes.

While there are only two FDA approved drugs for use in ASD cases, there are a variety of other pharmacotherapeutic options being studied for use in individuals with ASD to manage other symptoms. Anti-psychotics Clozapine and Haloperidol which are dopamine receptor antagonists also have been looked at to treat irritability is ASD patients but have harsher adverse effects like seizures and dyskinesia. Methylphenidate, which is a CNS stimulant used to treat ADD/ADHD has been studied to reduce inattention and hyperactivity in ASD patients. It is effective for those purposes at medium and high doses but alternatively increases irritability. Anxiety, repetitive behavior, and some social withdrawal symptoms seem to respond well to selective serotonin reuptake inhibitors which are intended for use as antidepressants. Melatonin, the sleep hormone has been used to reduce insomnia. A few other treatments such as Naltrexone and Oxytocin have been discussed as treatments for ASD but until the mechanism of the disorder is better understood, it will be very difficult to prove these treatments are effective against ASD not just the symptoms.

References:

“Autism Spectrum Disorder (ASD).” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 26 Feb. 2015, www.cdc.gov/ncbddd/autism/signs.html.

“How Is Autism Treated?” Autism Speaks, 24 July 2012, www.autismspeaks.org/what-autism/treatment.

King, Bryan H, and Jeff Q Bostic. “An Update on Pharmacologic Treatments for Autism Spectrum Disorders.” Child & Adolescent Psychiatric Clinics of North America, vol. 15, no. 1, pp. 161–175.

LeClerc, Sheena, and Deidra Easley. “Pharmacological Therapies for Autism Spectrum Disorder: A Review.” Pharmacy and Therapeutics 40.6 (2015): 389–397. Print.

Lee, Seung Yup et al. “Is Oxytocin Application for Autism Spectrum Disorder Evidence-Based?” Experimental Neurobiology 24.4 (2015): 312–324. PMC. Web. 11 Nov. 2017.

By Jordan Wells, Master of Medical Science Student, University of Kentucky

Energy Drinks

Caffeine, taurine, glucoronolactone, thiamine, pantothenic acid, pyridoxine hydrochloride, biotin, cyanocobalamin, guarana, ginseng, Ginkgo biloba, I-Carnitine, and sugars: a long and intimidating list of common ingredients. Common ingredients for what? Energy drinks.

Image from:  Caffeineformer.com

 Energy drinks first came on the market in 1997 in the United States. Since their introduction, they have gained mass popularity throughout the country, resulting in an average of 290 million gallons of energy drinks consumed in 2007. Energy drinks can be spotted everywhere, in the hand’s of students, soldiers, healthcare professionals, or anyone who ever really finds themselves in need of a boost. While the average US citizen may resort to a cup of coffee, an energy drink contains a close amount of caffeine, hovering around 90mg. Energy drinks contain many more chemicals and sugar than coffee though, including the list of aforementioned names. So what do all of the ingredients in energy drinks do to the body, and could they be potentially harmful over time?

               Caffeine, the most commonly known ingredient in energy drinks, is a psychoactive drug that is available to anyone across the world that seeks it. The drug is an adenosine and benzodiazepine receptor antagonist and a nervous system stimulant. Ingesting caffeine, something most children and adults do on a regular basis, can cause a wide range of physiological effects. Caffeine can cause the stimulation of smooth muscle, cardiac stimulation and antagonism, cerebral vasoconstriction, reduces insulin sensitivity, and causes increased urine flow. While caffeine is known to increase focus, cognitive ability, and exercise endurance, the amount of caffeine consumed can greatly influence the side effects on the body. Adults and children who consume too much caffeine can experience more extreme symptoms such as irritability, anxiety, insomnia, vomiting, abdominal pain, hallucinations, cerebral edema, arrhythmias, stroke, and in severe cases of caffeine intoxication, death. Guarana, a second form of caffeine found in energy drinks, adds to the overall “energizing” effects on the body found in caffeine drinks. A study in Australia found that the added caffeine contained in guarana may not be added into the official label, meaning a drink could potentially contain more caffeine than advertised. Throughout the years, caffeine intoxication has been widely reported as a result of energy drink consumption and has lead to death in several cases.

Another common ingredient found in energy drinks is taurine. Taurine is an amino acid that naturally occurs in the body that is a normal ingredient of the human body. The amino acid helps aid in skeletal muscle contraction and plays different roles in both the cardiac and nervous system. The amount of taurine in a single energy drink is low, and no official studies in humans have shown adverse reactions. In Norway, France, and Denmark, Red Bull was banned after a study performed on rats showed that the rats were prone to anxiety and self-mutilation after exposure to taurine.

               Energy drinks also contain a wide array of Vitamin B subclasses that can help convert the sugar available in energy drinks to energy. On average, an energy drink contains around 54 mg of sugar. Ingesting 54 mg of sugar is equivalent to eating ¼ cup of sugar, for each energy drink consumed. High levels of sugar in the diet can lead to extreme health problems such as heart disease that can cause fatal side effects or even death.

               Another factor to consider when examining the potential effects of energy drinks is to review the potentially hazardous effects when energy drinks are mixed with other substances such as alcohol. Many common drinks and shots now contain alcohol mixed with energy drinks that can have negative side effects. Energy drinks can decrease the overall feeling of intoxication, leading a person to believe there are less drunk than they are.

               Many people use energy drinks commonly, and the side effects and long-term problems should be seriously examined since they play such a large role in the American beverage industry. Children and adolescents should be made aware of the potentially negative effects of the ingredients listed on the back of an energy drink that the average consumer may not understand.  

Sources:

Higgins, John P., et al. “Energy Beverages: Content and Safety.” NCBI, Mayo Clinic Proceedings, 11 Nov. 2010, www.ncbi.nlm.nih.gov/pmc/articles/PMC2966367/.

Seifert, Sara, et al. “Health Effects of Energy Drinks on Children, Adolescents and Young Adults.” Pediatrics, pediatrics.aappublications.org/content/pediatrics/early/2011/02/14/peds.2009-3592.full.pdf.

Strain, Eric C, and Roland R. Griffiths. “Caffeinated Energy Drinks-A Growing Problem.”Drug and Alcohol Dependence, Elsevier, 21 Sept. 2008, www.sciencedirect.com/science/article/pii/S0376871608002858.

Article by: Olivia Murphy, Master of Science in Medical Sciences, University of Kentucky