Biochemical Analysis And Therapeutic Potentials Of Deferiprone Are Explored In An Essay.

Metabolic Manipulators Biochemical Analysis of cells, tissue, blood and urine is important in the detection of disease, organ failure, doping/drug cheating in forensic investigations, and sports (human or animal). This assignment will enable you to relate your laboratory experience to real world biochemical analysis. You should include a brief outline of the analysis method(s) used to detect or confirm the condition, from the topic list provided.

You will be assessed on the following: The Assignment must use the Headings (in bold) below and address the following:

1. Overview Identify the name(s), class and structure of the ‘Metabolic Disorder’ ‘Metabolic Manipulator’ (Assignment Part B) molecule and contextualize the intracellular metabolic biochemical pathways they affect (i.e. Protein, Carbohydrate and/or Lipid). Briefly outline the effect(s) Manipulator (Part B) has on the organism locally (i.e. specific cells or tissue) and/or as a whole (i.e. the whole organism). Identify the Substrates/Precursors and the biochemical steps to produce the Manipulator (Part B) (i.e. parent molecule, key enzymes & cofactors involved in synthesis) and describe the transport, half-life, receptor activation and fate following action - Manipulator (Part B) degradation within the cell/organism. Describe the biochemical pathway(s) (i.e. Protein, Carbohydrate and/or Lipid), Manipulator (Part B) alters, including key enzymes/cofactors and intermediates directly affected.

2. Research Describe the most recent research (published scientific article(s)) effort pertaining Manipulator. This may include, but not limited to, characterization of metabolic status, biochemical pathways, receptors and signal transduction within cells or tissue and the identification of potential therapeutic(s).

3. Diagnosis Identify the disease state(s)/or consequence(s) Manipulator (Part B) that arise if there is a chemical perturbation (Part B) in the metabolic /biosynthetic pathway of target cells/tissues.

4. Treatment Describe the current treatment(s)/strategy(ies), approved for use, to overcome the disease state as a consequence Manipulator . Comment on, with the aid of statistical information, the change in prognosis as a consequence of treatment.

5. Policy Outline the current policies/legislation (federal, state or international) Manipulator (e.g. adverse health outcomes or legislation for therapeutic use).

Identification, structure, and class of manipulator

The name of the metabolic manipulator is deferiprone which belongs to the class of 4- pyridines. It is substituted by methyl group at position 1 and 2 and by hydroxyl group at position 3.

Deferiprone has the following effects on organisms; nausea, vomiting, stomach, back pain. It also causes a decrease in the number of white blood cells a condition known as neutropenia and an increase in the level of enzymes found in the liver such as alanine transaminase and alkaline phosphatase, an indicative of liver damage or tissue damage. Deferiprone is a chelating agent that has a high affinity for ferric ion and thus binds to ferric ions in the body to form a stable complex substance. Its mechanism of action is referred to as iron chelating activity and by binding to iron, it is able to remove excess iron in the body. Deferiprone binds to plasma protein and the enzyme involved in activity chelating activity is UGT1A. The enzyme metabolizes deferiprone to 3-O-glucuronide. The half-life of deferiprone is 1.9 hours. The process can cause agranulocytosis and neutropenia which can lead to hepatoxicity and fatal infections.

Several studies have been carried out to identify therapeutic potentials of deferiprone, its biochemical pathways and characterization of its metabolic status. One of the most recent studies on deferiprone was carried out in the United States to find out whether deferiprone is effective in the treatment of neurodegeneration with brain iron accumulation disorder (NBIA) (4,3). The disorder is characterized by an accumulation of iron in the brain and the progressive degeneration of the nervous system, a condition known as basal ganglia. As per the study, the disorder is very common to children. According to the research, iron chelator therapy which has the ability to effectively cross blood-brain barrier has been proposed as one of the possible therapies for NBIA.

Deferiprone is effective oral iron chelator which is utilized internationally in the curing of iron overload. In regards to clinical studies, deferiprone effectively crosses the blood-brain barrier and has a radiographic and clinical efficacy in symptomatic patients with excess iron in brain cells. According to the results of this research, deferiprone was found to be effective in the management of this disorder.

The other research regarding deferiprone is a comparative study of deferiprone and silymarin versus deferiprone and placebo. The objectives of the study were to compare the iron chelating efficacy of combination therapy of oral deferiprone. The research was carried out on forty children who had beta thalassemia, in Tanta university hospital. The study took place from October 2012 to October 2013. Patients who were suffering from thalassemic were grouped into two by simple random allocation. The first group received a combination of daily oral deferiprone and oral silymarin in form of legal tablets and the second group received a combination of oral deferiprone and placebo.  

After the combination of these dosages, the finding of the research was that there was a significantly lower serum iron and serum ferritin in both groups. The researchers also found out that their serum iron and serum ferritin were significantly lower and TIBC was significantly higher in the first group than the second group.  From the results of the study, the authors concluded that the dosage of Deferiprone in combination with silymarin is more effective iron chelators in iron-loaded thalassemic patients than the dosage combination of deferiprone and placebo.

Research on therapeutic potentials of Deferiprone

There are dangerous conditions that may arise if there is a chemical perturbation of deferiprone. Deferiprone interacts with other drugs resulting in agranulocytosis or neutropenia. Management of agranulocytosis should be done before starting any dosage of deferiprone. Also, other medications should be avoided since they react can react with deferiprone thus resulting in agranulocytosis or neutropenia. Agranulocytosis is a condition whereby bone marrow fails to produce enough white blood cells. The type of white blood cells that are most affected is neutrophils thus resulting in a condition known as neutropenia. Neutrophils are an essential part of the immune system in the body since they destroy and kill harmful bacteria that invade the body. Agranulocytosis can come up with symptoms such as a sore throat, bleeding gums, chills and a sudden fever.

Another condition that may come up as a result of an interaction of deferiprone with other drugs is hepatic impairment. The liver is organ found in the body which plays important role in the body. It filters out harmful substances in the body thereby fighting off infection. Liver failure is a very serious condition and thus should be avoided while taking deferiprone. As per the studies, research was carried out to find out the impact of impaired hepatic function on the pharmacokinetics of deferiprone. As per the result of these studies, caution is required when using the chelating iron agent in patients with serious liver damage as this has a serious impact on the pharmacokinetics of deferiprone (3). Also, deferiprone interacts with some minerals or vitamins contained in some food to produce a dangerous substance that can harm the body. Deferiprone also interacts with alcohol and thus it should not be used together with alcohol.

There are different strategies and treatments that have been approved to use in the management of effects caused by the use of deferiprone. One of the strategies is the use of combined dosage of deferiprone and silymarin or the use of deferiprone combined with placebo. (Tricta et al., 2017) one of the recent studies showed that using a combination of deferiprone dosage together with silymarin or placebo increased its efficacy in the treatment of thalassemia. Also, a combination of silymarin together with deferiprone reduces the side effects that are caused by deferiprone.

Also, to avoid agranulocytosis or neutropenia, patients are adviced not to mix deferiprone with other medication. This is because deferiprone, when taken with other drugs, can lead into agranulocytosis and thus other drugs should be avoided at all means. The patient is advised to tell doctors the drugs they are already taking in order for the doctor to advise the way forward. Also, to avoid hepatic impairments, patients should not take drink alcohol or eat some food that is associated with minerals and vitamins. This is because deferiprone interacts with these vitamins, minerals and alcohol which leads to the production of a harmful substance that can result harm the body or result into death. Before administering deferiprone to patients, the physician is supposed to advise patients on what food they are supposed to take and what they should not take.

Consequences associated with chemical perturbation of Deferiprone

Deferiprone belongs to the class of iron chelating agents which is utilized to reduce the amount of iron in the blood for individuals who are linked to thalassemia. Several clinical studies have (4, 5) suggested that the drug should be used when other types of therapy cannot work out.

One of the policies of deferiprone was developed in 2016 (7). The policy was developed to provide options for members who are required to use deferiprone for therapeutic use. According to the policy, the initial approval criteria for individuals diagnosed with iron overload as a result of transfusion must meet several requirements. First, the patient must have been diagnosed with transfusional iron overload as a result of thalassemia symptoms. Secondly, the patient must be 18 years and above and should have a transfusion history of above 100ml/kg of red blood cells and should also have a serum ferritin level consistent of above 1000 mcg/L. according to the policy, the patients should have an inadequate response to deferiprone.

For those in the group of continued approval for iron overload as a result of transfusion should be currently receiving medication through health plan benefit. Also, the entire members should have met all the initial criteria and should have serum ferritin level of above 500 mcg/L. In conclusion, the policy provides criteria for members who are supposed to use deferiprone. It includes age, efficacy criteria and transfusion history (2).

Also according to (6, 1), if someone is allergic to deferiprone or any ingredients of deferiprone is not supposed to be subscribed to it. Also, if someone is pregnant, breastfeeding or has a very low level of white blood cells are not supposed to take medication. The other clinical policy regarding the use of deferiprone is that it is not supposed to be used by individuals who are under other medications. This is because the use of deferiprone may interact with other medications thereby causing agranulocytosis, neutropenia and different kinds of liver disorders. Also, Deferiprone should not be used by members who abuse drugs like alcohol and tobacco. This is because deferiprone interacts with alcohol and tobacco substances to produce dangerous reactions that can cause harm or death.

References

El?Beshlawy AM, El?Alfy MS, Sari TT, Chan LL, Tricta F. Continuation of deferiprone therapy in patients with mild neutropenia may not lead to a more severe drop in neutrophil count. European journal of haematology. 2014 Apr;92(4):337-40.

Elalfy M, Wali YA, Qari M, Al Damanhouri G, Al?Tonbary Y, Yazman D, Al Hawsawi Z, Karakas Z, Kilinc Y, Yesilipek MA, Badr M. Deviating from safety guidelines during deferiprone therapy in clinical practice may not be associated with higher risk of agranulocytosis. Pediatric blood & cancer. 2014 May;61(5):879-84.

Elalfy MS, Adly A, Awad H, Tarif Salam M, Berdoukas V, Tricta F. Safety and efficacy of early start of iron chelation therapy with deferiprone in young children newly diagnosed with transfusion?dependent thalassemia: A randomized controlled trial. American journal of hematology. 2018 Feb;93(2):262-8.

Hagag AA, Elfrargy MS, Elfatah MA, El-Lateef AM. Comparative Study of Deferiprone and Silymarin versus Deferiprone and Placebo as Iron Chelators in Children with Beta Thalassemia with Iron Overload. J Leuk. 2014 Jan 16;2(130):

Huang V, Luini C, El-Ali A, Kessabi S. Iron chelation therapy: a review of the literature on the issues and importance of adherence to treatment in iron overload.

Martin-Bastida A, Ward RJ, Newbould R, Piccini P, Sharp D, Kabba C, Patel MC, Spino M, Connelly J, Tricta F, Crichton RR. Brain iron chelation by deferiprone in a phase 2 randomised double-blinded placebo controlled clinical trial in Parkinson’s disease. Scientific reports. 2017 May 3;7(1):1398.

Tricta F, Uetrecht J, Galanello R, Connelly J, Rozova A, Spino M, Palmblad J. Deferiprone?induced agranulocytosis: 20 years of clinical observations. American journal of hematology. 2016 Oct;91(10):1026-31.