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Briefly review the cause and effect of Î²-thalassemia, outlining the symptoms of the disease.
Beta-thalassemia is a blood disorder where a reduction in beta haemoglobin production is seen. It is caused by mutations in the HBB gene on chromosome 11.
Haemoglobin is made up of two alpha and two beta globin molecules but due to the lack of beta haemoglobin in thalassemia, alpha globin accumulates in the red blood cells and is unable to bind with anything leading to low production of haemoglobin. The excess alpha chain precipitate within the cells and this leads to an impairment of various cellular functions and the phagocytosis and degradation of a proportion of the precipitate containing erythroblasts by bone marrow macrophages. This leads to fewer red blood cells circulating around the body with a lack of oxygen which then results in anaemia which causes fatigue; weakness and to compensate for this the bone marrow increases cell production but most of the cells still die. Due to this the size of the bone marrow increases giving bone problems and a slowed growth in children/delayed puberty. An enlarged spleen can also be an effect of the increased cell production. Other severe symptoms include pale appearance, poor appetite, dark urine, jaundice and enlargement of liver and heart.
What is the standard treatment for Î²-thalassemia?
The treatment depends on the type of thalassemia. For beta thalassemia major, blood transfusions are vital, giving healthy red blood cells with normal haemoglobin. The IV transfusion takes usually 1-4 hours, every 2-4 weeks as RBC's only live up to 120 days. Alongside, iron chelating therapy is essential to remove iron in regularly transfused patients. Other treatments may include folic acid supplements. Sufferers with Î²-thalassemia minor (only one normal Î² chain) normally don't need frequent blood transfusions and rarely require iron chelation therapy, depending on the patients needs.
What effect does this type of treatment have on the iron status of the patient and why?
Blood transfusion results in iron overload because haemoglobin in RBC's is an iron rich protein. A test to measure the amount of iron present in the blood is the serum ferritin test which is a better estimate of total body iron than the serum iron test. The normal values for men are 12-300 ng/ml and for females it is 12-150 ng/ml. Due to frequent blood transfusions, iron levels can get very high in patients. Most patients already have an adequate iron store which leads to the accumulation of excess iron, as the body is unable to get rid of iron of such amount. Red blood cells become unable to divide anymore and are degraded by reticuloendothelial macrophages. Plasma iron binds to small molecular weight compounds in the form of non-transferrin bound iron (NTBI). Most of the iron gets deposited in the heart, liver and endocrine glands but some is also absorbed gastro-intestinally due to being highly vascular.
The iron-overloaded heart and liver leads to fatal tissue damage and fibrosis due to oxidative reactions initiated by the redox activity of iron. Overall, the human body does not excrete a great amount of iron to be able to deal with the additional iron being added into the blood.
What would be the long-term effect of this altered iron status if left untreated?
In the long term, the iron deposition can cause tissue damage which eventually leads to organ dysfunction. In the heart it can lead to Cardiomyopathy (less blood flow from the heart) which can lead to heart failure.
It can lead to cirrhosis (scarring) of the liver and a high risk for liver cancer. The endocrine system may be affected leading to temporary or permanent loss of menstruation and infertility. It affects children with delayed puberty and slow growth.
There is also an increased risk for diabetes. Other long term effects include osteoarthritis, joint pain, stiffness, redness, or warmth. Change in skin colour to a slate-gray or bronze. Jaundice, or yellow colour, of the skin or whites of the eyes.
Increased risk for getting sick due to weaker immune system. Increased risk for cuts and scrapes becoming infected.
Describe the requirements of a drug to be used in the treatment of these iron-related side effects.
The main requirement is for the drug to lower the iron level in the blood to avoid the side effects and eventually avoid iron toxicity which could be fatal. It needs to have good chelating properties and mobilise intracellular iron stores as well as the extracellular. It needs to be specific by only chelating iron and not other metals to avoid deficiencies. Excretion of the chelate produced should be easy and should not redistribute the iron. It should be non-toxic with minimal side effects should be as low as possible. Ideally, the drug should have a large therapeutic index to further minimise toxic effects. It should have good GI absorption if it is to be taken orally or good tissue penetration if taken as an injection. Oral bioavailiabily should also be good i.e. the extent of the drug becoming available to the target tissue after administration. Patient compliance is essential so the drug should have low number of doses/day with the most suitable dosage form being orally.
Desferrioxamine is the standard treatment for the iron imbalance resulting from the management of Î²-thalassemia:
Give the structure of desferrioxamine.
With reference to the structure of this drug, discuss the extent to which desferrioxamine fulfils the requirements outlined in question 5.
Desferrioxamine fills some of the requirements. Pharmacodynamically, the drug is a success as it has good iron chelating properties. It is freely soluble in water, indicating that it is easily mobilised and excreted in the urine which is due to the -OH and =O groups. However, it is difficult to administrate. It requires long subcutaneous infusions (4-7days per week) leading to poor compliance and high cost. Poor absorption from the GI tract makes it inappropriate for oral administration, giving low bioavailability. It is orally inactive due to its high molecular weight and charge. It has numerous side effects such as blood disorders, visual disturbances, decreased kidney function, fever (pyrexia), hearing disturbances, nausea and vomiting. It can also cause an extreme allergic reaction (anaphylaxis) or pain, swelling, redness and hardening of the skin at the injection site.
Discuss the metal-binding properties of desferrioxamine. How do they relate to the suitability of desferrioxamine in the treatment of Î²-thalassemia. Discuss any likely metal-dependent side effects associated with this drug.
Desferrioxamine has multiple carbonyl and hydroxyl groups that provide electrons to coordinate with those in Fe3+. Desferrioxamine chelates iron tightly in a one-to-one ratio and is therefore a hexadentate (6 binding sites). Desferrioxamine can bind to all six sites and completely inactivate the "free" iron, forming a stable complex in a 1:1 ratio. It has a high affinity towards iron as well as high selectivity which is an important factor in the treatment of Î²-thalassemia and makes this drug suitable. It also has a low affinity for other metal ions, avoiding deficiencies of other metals. It is metabolised by plasma enzymes, forming a chelate that is readily soluble in water. It is able to pass through the kidney which discolours the urine, causing a reddish colour.
Describe the protocol for desferrioxamine treatment, giving reasons for such a regime. What problems arise as a result of such a protocol?
A daily dose of 1000-2000 mg (20-40 mg/kg/day) should be administered subcutaneously (due to lack of permeability and short biological half-life) over 8-24 hours overnight to maintain therapeutic levels, utilizing a small portable pump which is capable of providing continuous mini-infusion. Durations of the infusions have to be set according to the patient's individual needs. Such subcutaneous infusions have been shown to limit iron accumulation and prolong life. Problems are low compliance due to the long infusion durations, making it uncomfortable overnight and causing disruptions to day to day life for patients. Other problems include injection site reactions (hardness and swelling), high cost; limiting its use in developing countries which are more in need of treatment. Hypotension can be caused if the intravenous injection is given too quickly; this indicates that a medical professional would have to administer the treatment or use a portable electronic pump, causing more inconvenience.
Problems include infections caused by a Yersinia enterocolitica siderophilic (iron-loving) bacterium, which causes diarrhoea. Patients with iron overload usually become vitamin C deficient, probably because iron oxidizes the vitamin. Vitamin C increases availability of iron for chelation and is given in addition to iron chelation therapy.
In view of the shortcomings associated with desferrioxamine, there has been considerable research into developing drugs which more closely relate to the ideal requirements. This has resulted in an alternative agent, Deferiprone (1,2-dimethyl-3-hydroxypyrin-4-one), being licensed for clinical use in several countries:
Give the structure of deferiprone.
Compare desferrioxamine and deferiprone in terms of structure and function and their respective metal binding characteristics
Iron has 6 binding sites (co-ordination sites) and one molecule of Deferiprone has 2 co-ordination sites meaning that 3 molecules of Deferiprone are needed to bind to one atom of iron. The iron and Deferiprone complex is removed from the body via urine/faeces. Deferiprone is therefore a bidentate chelator and does not mobilize iron as efficiently as desferrioxamine. Intermediate chelation products could continue to produce cell and organ injury in patients treated with this drug. Desferrioxamine is a hexadentate (6 co-ordination sites) chelating agent; one molecule of Desferrioxamine binds one iron atom. Desferrioxamine has a larger molecular size and deferiprone has a smaller size which explains why Deferiprone is more efficient in removing excess iron compared to Desferrioxamine. Other factors include, lack of charge, and partition characteristics, which favour penetration of cellular and sub cellular membranes with Deferiprone. The iron chelate of deferiprone doesn't carry any net charge which enables it to penetrate membranes easily, removing potentially toxic iron from tissues. There was a controversy over the safety of deferiprone that arose in the late 1990s because of an observation of hepatic fibrosis during a clinical trial. However, in subsequent studies this problem has not been a significant toxicity issue for deferiprone. On the other hand, Deferiprone is more patient compliant due to being an oral dosage form with less frequent doses. Due to being absorbed gastro intestinally, it has a low bioavailability which is due to the 1st pass effect and this is not a factor that affects Desferrioxamine.
To what extent is deferiprone a better drug than desferrioxamine?
Deferiprone has better compliance due to being an oral administrated drug with less frequent dosing. It doesn't have as good chelating properties as Desferrioxamine, as explained above. It has side effects such as agranulocytosis which is the reduction in the number of granulocytes in the blood and makes the patient susceptible to infections (sore throats/ fevers). It doesn't mobilize iron as efficiently as Desferrioxamine which is a hexadentate and is more iron specific. Desferrioxamine has a long term safety profile, whereas deferiprone does not. Efficacy and safety of deferiprone are yet to be verified. Deferiprone removes excess cardiac iron more efficiently than Desferrioxamine which is due to the molecular size and lack of charge that favour the penetration of cellular membranes. However, deferiprone has a high affinity for other metals such as zinc, copper and aluminium which is the cause of zinc deficiency in patients treated with deferiprone. Overall, Deferiprone is much more cost effective due to not requiring medical professionals to administer the drug or the use of special equipment (pump). This proves Deferiprone more available for poorer countries which are in high need of treatment.
Is deferiprone sucessful in treating the side effects associated with the control of Î²-thalassemia?
Yes, because deferiprone does treat iron overload by chelating iron and lowering iron level in blood, avoiding death by iron toxicity. However, it is not as efficient as Desferrioxamine due to the reasons discussed above. It has higher patient compliance with less frequent dosing as compared to Desferrioxamine. However, Deferiprone and Desferrioxamine can both be used in combination, which many patients do, as it is safe and effective.
What, if any, are the side effects associated with deferiprone?
Neutropenia/ Agranulocytosis, where the number of neutrophils decrease making infections more likely. Increased liver enzymes, nausea, vomiting or gastrointestinal distress, Arthropathies (joint pains) and Zinc deficiency.
Is deferiprone likely to replace desferrioxamine as the agent of choice for the treatment of iron-imbalance in thalassemic patients?
It is unlikely that deferiprone will replace Desferrioxamine because both drugs have serious disadvantages. Desferrioxamine has higher molar iron chelating efficiency due to being a charged hexadentate compared to Deferiprone which has low iron chelating efficincy as it is an uncharged bidentate. Deferiprone is usually used when desferrioxamine is contraindicated (inadvisable/intolerable) in patients. Factors that make deferiprone more favourable include high patient compliance and low cost which is significant for poorer countries that have a high prevalence of the disease. It is quite likely that both drugs will be continued to be used as a combination therapy. It can increase patient compliance by reducing the number of daily administrations per week via subcutaneous infusions. Due the possibility of using lower doses of the drugs in combination, it decreases the toxicity that is experienced by either drug.
A third drug, ICL670 (4-[3,5-bis(2-hydroxyphenyl)1,2,4-triazol-1-yl]-benzoic acid), has recently been used in clinical trails
Give the structure of this drug
Compare the iron-binding characteristics of this drug to those of desferrioxamine and deferiprone.
Deferasirox (Exjade®, ICL670) is an N-substituted bishydroxyphenyltriazole
and represents a new class of tridentate iron chelators with high specificity for iron. It is a tridentate chelator (2 molecules of ICL670 are required to bind to one iron atom) and has moderate iron chelating efficiency. It is similar in stability to deferiprone which is also a tridentate. Only one molecule of desferrioxamine is required to bind one atom of iron indicating that desferrioxamine is the most efficient iron chelator. ICL670 can also form an alternative structure which is bidentate and tends to form unwanted polymeric complexes with other metals and has low iron chelation efficiency. It does not have high absorption efficiency, due to its net charge and high molecular weight like desferrioxamine, but it is very hydrophobic and this allows it to have good oral bioavailability. ICL670 has high selectivity for iron unlike deferiprone and does not induce the excretion of zinc or copper.
Do you consider ICL670 to be a promising new drug?
Yes, because it has been proven to be safe and effective in clinical programmes and has been studied in clinical trials. It doesn't require the use of pumps or infusion such as in Desferrioxamine, which makes it more promising. Its low molecular weight and high lipophilicity allows the drug to be taken orally unlike desferoxamine which has to be administered by IV route (intravenous infusion) or subcutaneously for long durations. ICL670 is mixed with orange juice, apple juice, or water and taken only once a day, which gives high patient compliance compared to the other drugs. Together with deferiprone, deferasirox seems to be capable of removing iron from cells (cardiac myocytes and hepatocytes) as well as removing iron from the blood.
However, it has severe side effects such as serious kidney problems, liver problems, and bleeding in the stomach or intestines which have been fatal in some cases. Such problems are more common in elderly patients. Therefore, the drug may not be very promising for elderly patients.
There is currently insufficient clinical data available for ICL670's ability to chelate iron in intracellular cardiac tissue or other tissue. However, it does look promising in new laboratory studies which may prove ICL670 to be more safe and effective.
Finally, imagine you have just been awarded a grant to research into the treatment of Î²-thalassemia. What area would you consider the most fruitful to pursue. (N.B. there is no correct answer to this question but you must justify your choice).
I would research into deferiprone to consider further developments in enhancing the structure and making changes that would improve efficiency and lower side effects. It is an effective oral administrated drug that may be more promising for the future in the treatment of iron overload along with Desferrioxamine. It is more cost effective and has more patient compliance compared to Desferrioxamine and therefore it is worth researching into deferiprone to make it as effective as Desferrioxamine. Being a bidentate, it doesn't chelate iron as efficiently as Desferrioxamine and intermediate chelation products could continue to produce cell and organ injury in patients treated with this drug. This is why I would research into ways of changing the structure to make it more efficient in iron chelating. Compared to the other two drugs deferiprone has less common side effects which is significant in terms of researching into ways of eliminating the other disadvantages of this drug and make it more effective in treating iron overload.
However, I would also consider researching into ICL670's long term effects. Clinical trials that have already been conducted have shown that patients were more satisfied with desferasirox than desferrioxamine due to its convenience and having less impact on daily life, giving more patient compliance. Furthermore, I would also consider researching into combination therapy of desferrioxamine and deferiprone which has been quite positive. If desferrioxamine could be replaced by ICL670, it might eliminate the need of pumps or bolus injections. There are some studies for desferrioxamine and ICL670 which are at the early stages and have only been tested on animals. It is of great significant that the combined therapy was fairly good tolerated by the test subjects. . Future research could include considering deferiprone because it is an effective oral drug that is cost-effective, giving rise to a promising future for developing countries which have high prevelance rates of beta thalassemia.