The drug itself should firstly correct the condition, i.e. it should bring about a negative balance of iron in the blood stream to avoid the effects discussed above, as either extreme is not acceptable. Too little iron in the blood will cause the patient to become anaemic and thereby lead to fatigue and weakness. Too much iron in the blood will have adverse effects regarding tissue damage and other complications. It should be able to mobilise intracellular iron stores as well as the extracellular. The chelate produced should also be easily excreted and should not redistribute the iron. It should also have minimal side effects other than just the iron related side effects, such as nausea and vomiting. The drug should only chelate iron and not other metals, as this could cause deficiencies. To be patient compliant the drug should also have a minimal number of doses a day, i.e. have a long half-life and must be in a convenient dosage form. However we know that is an injectable, so it should have good tissue penetration to facilitate intestinal absorption.
Desferrioxamine is a hydroxamate-type sideropre, which means it is a naturally occurring iron chelator. Its role is to solubilise and transport iron, as it has a high affinity and specificity towards hard metals. [16]
The chelator binds tightly to the iron (Fe+3) via the charged hydroxamate donor atoms and blocks its ability to catalyze redox reactions. [17] Iron itself has six co-ordination sites, therefore the desferrioxamine can bind to all six sites and completely inactivate the the "free" iron. This forms a stable complex in a 1:1 ratio. As it has six co-ordination sites, desferrioxamine can also be termed as hexidentate, which provides stability. [18]
It is metabolised mainly by plasma enzymes and the chelate is readily soluble in water, which can pass through the kidney, but this discolours the urine, giving it a reddish colour. [19]
d) Describe the protocol for desferrioxamine treatment, giving reasons for such a regime. What problems arise as a result of such a protocol?
The treatment is taken intravenously or through slow subcutaneous infusions (due to lack of permeability and short biological half-life) over 8-12hours (to maintain therapeutic levels), 5-7 times a week. [20] It has a short plasma life and poor oral bioavailability. [21] This makes it very impractical as not many people like having injections and can cause injection site reactions (hardness and swelling); it is also quite costly (thereby limiting its use in developing countries [22] ) and time consuming causing disruptions to day to day life for patients. Also if the intravenous injection is given too quickly hypotension can be experienced by the patient, this indicates that a medical professional would have to administer the treatment or use a portable electronic pump, causing more inconvenience. Side effects such as infections caused by a Yersinia enterocolitica siderophilic (iron-loving) bacterium, which induces diarrhoea can also be a problem. [23] Desferrioxamine can be administered with vitamin C to enhance iron excretion. [24]
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:
a) Give the structure of deferiprone.
25
Ferriprox® - 3-hydroxy-1, 2-dimethylpyridin-4(1H)-one
(Drawn in ISIS draw)
b) Compare desferrioxamine and deferiprone in terms of structure and function and their respective metal binding characteristics.
Whereas desferrioxamine is a hexidentate as it has six co-ordination sites, deferiprone is a bidentate and referred to as a 'hard' ligand. This means that a single molecule interacts with only two of the available co-ordination sites on the iron, due to this property it does not mobilise iron as efficiently as desferrioxamine, i.e. three molecules of deferiprone bind to one iron molecule. [26] Also intermediate chelation products can continue to produce cell and tissue damage, for example, there have been cases were liver damage has continued in patients taking deferiprone. [27] However, deferiprone does have better patient compliance as it is available in an oral dosage form, although it has a low bioavailability, due to the first pass effect; this produces a non-chelating metabolite. [28] It also has to be taken less frequently (three times a day, 25mg/kg/day) and is not an expensive treatment that has to be carried out by a medically trained person or via an infusion pump. [29] But it does have a very narrow therapeutic margin and a risk of serious side effects, such as agranulocytosis, which is the reduction in the number of granulocytes in the blood. This makes the patient susceptible to infections like sore throats and fevers. [30]
Deferiprone, as can be seen above is in a cyclic formation, pyridine structure, whereas desferrioxamine is an open molecule, is five times bigger and is more lipid soluble.
It also has a high affinity for metals such as zinc, copper and aluminium and it has been noted that patients have suffered from zinc deficiency due to treatment with deferiprone. [31]
c) To what extent is deferiprone a better drug than desferrioxamine?
Deferiprone is better in that it comes in an oral dosage from, which is extremely patient compliant, it also doesn't have to be taken as regularly as desferrioxamine. It is very stable at room temperature and in solutions of physiological or acid pH. [32] However, desferrioxamine is better at mobilising iron due it being a hexidentate and is also more iron specific. It also has a long term safety profile, whereas deferiprone does not. [33]
Deferiprone removes excess cardiac iron more efficiently than desferrioxamine; this is most likely due to the compounds molecular size and lack of charge that favour the penetration of cellular membranes. [34] This is an important property as death is usually related to cardiac dysfunction. [35]
It also does not have any injection site reactions, which is one of the main reasons why desferrioxamine has low patient compliance, which can reduce the effectiveness and result in increased mortality.
d) Is deferiprone successful in treating the side effects associated with the control of β-thalassemia?
Deferiprone is good at treating the side effects (iron overload); however it is not as efficient as desferrioxamine, for reasons discussed above. But as with all drugs of this nature some compromises have to be made and I believe deferiprone can provide the best of both worlds. In saying this, many patients do use a combination of both drugs; this has proved to be very effective, safe and satisfactory.
e) What, if any, are the side effects associated with deferiprone?
The side effects of deferiprone are gastrointestinal disturbances, urine discoloration (reddish-brown in colour), neutropenia (reduced number of neutrophils in the blood stream), agranulocytosis (in extreme cases), nausea, joint pain and stiffness. [36]
f) Is deferiprone likely to replace desferrioxamine as the agent of choice for the treatment of iron-imbalance in thalassemic patients?
Personally I do not think it is likely that desferrioxamine will be replaced by deferiprone, because both come with disadvantages and also deferiprone is usually used when desferrioxamine is contraindicated (meaning inadvisable/intolerable) in patients. [37] It is more likely that they will continue to be used as a combination therapy. This is because it can increase patient compliance by reducing the number of daily administrations per week via subcutaneous infusions. It can also decrease the toxicity that is experienced by using either deferiprone or desferrioxamine, due the possibility of using lower doses of the drugs in combination.
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
a) Give the structure of this drug
Deferasirox - Exjade® [38]
(Drawn in ISIS draw)
b) Compare the iron-binding characteristics of this drug to those of desferrioxamine and deferiprone.
ICL670 is a tridentate chelator, also referred to as bishydroxyphenyltriazole and is a 'soft' ligand. The tridentate molecule includes least 2 nitrogen atoms within the chelating site. [39] The actual chelation site consists of two phenolate oxygen's and one triazolyl nitrogen. This results in a 3:1 ratio iron complex, which is similar in stability to deferiprone. It is also not at risk of going through redox cycling. [40] ICL670 can also form an alternative structure which is bis-bidentate; however this tends to form unwanted polymeric complexes with other metals. 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. [41]
ICL670 is very selective for iron unlike deferiprone and does not induce the excretion of zinc or copper. [42]
One oral dose of ICL670 is up to five times more potent than one dose of desferrioxamine and ten times more potent that one dose of deferiprone. [43]
Do you consider ICL670 to be a promising new drug?
I believe it is a promising new drug. It has been proved to be safe and effective in clinical programmes. It has many advantages and few side effects (nausea, diarrhoea and skin rashes at high doses), which meets the specification of a good drug. [44] However the long term effects are yet unknown and it has been noted that in some patients there have been elevations in liver transaminases, which is an indicator of liver damage. Also, it is hasn't been determined whether or not intracellular iron can be removed. [45] I think due to its once-daily oral dosage and affordability many people's lives will be improved not only in wealthy countries but also in developing countries, where using drugs such as desferrioxamine is not an option, as it is just far too expensive for them to use, but ICL670 has only been on the market for a short time and many people still prefer to use deferiprone or desferrioxamine or a combination of the two. [46]
Finally, imagine you have just been awarded a grant to research into the treatment of β-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 think I would conduct longer studies on ICL670 to assess the long term effects of this drug as at Phase III trials it has proven to be highly effective at doses of 20 and 30 mg/kg/day. [47] Clinical trials that have already been conducted have shown that patients were more satisfied with desferasirox therapy than desferrioxamine as it was more convenient and had less impact on their daily activities as less time was lost each month. [48] Also I would look into a combination therapy. The desferrioxamine and deferiprone combination therapy has been quite a success so if desferrioxamine could be substituted for ICL670 then it could potentially eliminate the need of a battery/power operated pump or bolus injections. Studies have already been conducted in this area using desferrioxamine and ICL670, however are at the early stages and have only been tested on animals. The combined therapy was well tolerated by the test subjects. [49] So maybe the next step would be try it with deferiprone as it has proved to be very successful as it too comes in an oral dosage form and is affordable.
Another path the research could go down would be to conduct further research on deferiprone itself, to find a way to eliminate or reduce the side effects associated with it, as this is the limiting factor of the drug and the reason why it is second in line to desferrioxamine. [50]
