Effect Of Splenectomy And Iron Status On Pharmacokinetics Biology Essay

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Limenta et al 2010 studied the effect of splenectomy & iron status on pharmacokinetics of deferiprone in β-Thalassemia patients. These patients are on iron chelation therapy and results in increase in transfusional iron over load because without chelation it starts accumulate in the body. Therefore, deferiprone have the ability to reduce iron overload but there was wide variation between patients in deferiprone-induced urinary iron excretion (UIE). A hypothesis was made & aimed to evaluate, that the pharmacokinetic parameters of deferiprone may influence splenectomy & iron status in patients with β-Thalassemia. A total of 31 overnight fasted patients were enrolled. Each receives a single dose of 25mg/kg/day. Blood Samples were collected at 12 points for 480 min and urine sample at interval of 2hrly, 4hrly & 12hrly. Deferiprone & its metabolite concentrations in serum and urine were analyzed via HPLC. Colourimetric method was used for analyzing UIE and serum deferiprone-chelated iron. Pharmacokinetic parameters of non-conjugated deferiprone have found to be no significant difference but Cmax & AUC0-∞ show lower value of deferiprone glucuronide in splenectomized as compared to non-splenectomized patients. In the same way Cmax & AUC0-t serum deferiprone-chelated iron & UIE was higher in splenectomized as compared to non-splenectomized patients. There was no difference in urinary excretion of both conjugated & non-conjugated deferiprone. Multiple linear regressions indicated that iron profiles were significant predictors of the pharmacokinetic parameters of non-conjugated deferiprone, deferiprone-chelated iron and UIE. In addition, AUC(LAST) of deferiprone-chelated iron & UIE was identified as the strongest predictor of splenectomy. Therefore, it is concluded that both iron & splenectomy have significant effects on the pharmacokinetic and iron chelation efficacy of deferiprone as greater degree of iron overload in splenectomized patient's results in alterations in pharmacokinetics parameters of deferiprone glucuronide & deferiprone-chelated iron, as well as increase UIE.

Morales et al 2009 studied the bioequivalence of film coated tablet of deferiprone in Thai volunteers. Their objective was to evaluate bioequivalence of tablet manufacture locally (Test drug) with a reference formulation. Study design include 24 healthy volunteers with randomized, two-treatment, two-period, two-sequence cross over. Single dose of 3 tablets 500mg of deferiprone of both formulations was given with two week washout period. Blood samples collected at 12 points for 480 min. Serum were analyzed using validated HPLC method. Pharmacokinetic parameters were analyzed non-compartmentally and statistical comparison of Cmax, AUC(0-t), AUC(0-∞) were evaluated. Result concluded that 90% CI of mean ration of both AUC fell within acceptable range (0.80-1.25) for bioequivalent eligibility. Efficacy was also in acceptable range of WHO criteria (0.75-1.33). Therefore, both formulations were proven bioequivalent in healthy Thai volunteers.

Cappellini 2008, describe the present status of iron chelation in patients suffering from hemoglobinopathies that they require regular blood transfusions and this chronic transfusion excess the iron overload that cannot actively remove from human body. Therefore, accumulation of iron leads to significant morbidity and mortality if untreated. Deferoxamine, an iron chelator was a drug of choice with established safety and efficacy. Side effects of deferoxamine (DFO) are acceptable and treatable but its long term s/c dosage regimen of 5-7 days/week is very demanding and leads to poor health outcome for patients. Deferiprone, is a bidentate molecule used orally in the treatment of iron overload t.d.s to whom DFO therapy was contraindicated. Preliminary evidence suggested that use of deferiprone is more effective than DFO I chelating cardiac iron. Side effects include GIT symptoms, liver dysfunction, joint pain, neutropenia & agranulocytosis, so WBC weekly assessment is recommended to overcome risk of agranulocytosis. Deferasirox was also discussed in the article as new and convenient iron chelator with good efficacy & safety profile having long life of 16-18hrs.

Lie Michael et al 2008, studied the genotype-related pharmacokinetics of deferiprone (L1) in healthy volunteers. The aim of the study was to examine the effects of UGT1A6, a gene that encodes a UDP-glucuronosyltransferase, an enzyme of deferiprone glucuronidation (Tukey RH, Strassburg CP 2000) in healthy volunteers. A total of 24 overnight fasted volunteers were enrolled and grouped according to genotype. A single oral dose of 25mg/kg was received. Blood samples were collected at 11 points for 360 min & urine output collected at 2hrly, 4hrly & 8hrly intervals. Validated HPLC method was used for analyzing serum & urine concentration of deferiprone & deferiprone-glucuronide. UGT1A6 genotype was evaluated by PCR resistant fragment length polymorphism analysis. Result found no significant difference in any pharmacokinetic parameter & 24hr urinary excretion of both among genotype groups. Men & women show significant difference in AUC, Vd, CL of deferiprone. Therefore, it was concluded that UGT1A6 do not exert statistically significant pharmacokinetics effects while gender influences serum pharmacokinetics but urinary excretion not.

Kontoghiorghes 2008, reviewed the assessment concerning ethical issues & risk/benefits, safety & efficacy, & cost of iron chelation therapy with deferiprone/deferasirox. Deferasirox (DFRA) even after its approval from FDA was found ineffective and unsafe for patients undergoing transfusional iron overload & clearing excess cardiac iron. Cases of irreversible liver and renal failure & other toxicities have been reported with it. DFRA found expensive 60 euro/g especially for patients of under developing countries, on the other hand DFO 8.3 euro/g & Deferiprone being more inexpensive i.e. 5.5 euro/g was effective and safe but not yet approved by FDA and deprived the thalassemia patients by lifesaving treatment. Therefore, combination of both L1 & DFO provide universal solution for transfusional iron loaded patients, excess cardiac iron and hence provide safety & efficacy.

Maggio 2007, review the main chelator groups and provide their evidence of clinical effectiveness. Three commercially available iron chelator DFO, Deferiprone (L1), Deferisirox on three hematological disorders i.e. Thalassemia, sickle cell disorder and myelodysplasia for their therapeutic efficacy. For each treatment guidelines were provided by American College of Cardiology & American Heart Association, according to which DFO is the drug of choice for chelation treatment but if it was not tolerable or alteration in therapy was required than Deferiprone was used. However, if there was high concentration of ferritin in liver than deferasirox was prescribed, if ferritin level was >2500mcg/l & liver iron concentration >7mg/g/day require continuous s/c or i/v DFO or combination of DFO with Deferiprone. Recent data suggests that combination of both DFO+L1 was best choice in case of risk of heart failure and deferasirox support sickle-cell or myelodysplastic syndromes.

Neufeld 2006, provides new data of deferiprone & DFO in transfusional iron overload in thalassemia major, which describes that these patients depend on nightly DFO infusion for iron chelation for nearly 30 years. Inspite of gaining life expectancy with DFO in transfusion-dependent anemias, cardiac disease from myocardial iron deposits was the leading cause of death in young adult with thalassemia major & related disorder. Strategies are developed with improved chelation regimen to reduce cardiac disease. Deferiprone, an oral novel iron chelator was developed to improve compliance, improved assessment of cardiac iron status. Randomized trial based on cardiac T2* MRI suggests that deferiprone can unload myocardial iron faster than DFO. Retrospective data of Italian subjects exposed to deferiprone compared with DFO suggest dramatic reduction in cardiac events and mortality.

Kontoghiorghes 2006, review the strategies for combination therapy & chelation monotherapy in Thalassemia & other conditions. Deferiprone in combination with DFO can be used effectively in thalassemia. But other iron chelators like deferasirox, deferitin & starch DFO polymers are still under clinical evaluation. Among these only deferasirox is found to be effective in removing excess iron from the liver but at the same time found to be ineffective in removing cardiac iron. However, high efficacy and low toxicity can be attained by using L1 & DFO as combination therapy rather monotherapy. These newly developed chelating agents may not be available to thalassemia patients of underdeveloped countries due to their high cost.

Greenberg 2006 reviewed the results of iron overload & its chelation therapy in myelodysplastic syndromes. In these patients chronic RBC's transfusion is necessary but may cause hemosiderosis and ultimately leads to generation of toxic oxygen free radicals. Both myelodysplastic & thalassemia patients are at risk of developing cardiac problems due to iron overload. Iron chelation therapy in these patients can reduce the cardiac risk. Side effects of DFO have shown considerable improvement in patients of myelodysplastic. Since infusions of DFO in elderly patients have logical difficulties so two oral iron chelators deferiprone & deferasirox are found potentially effective in reducing iron overload and are relatively well tolerated. Both are as effective as DFO but Deferiprone is more prone towards cardiac outcomes reducing risks in myelodysplastic patients.

Victor 2005 described transfusional iron overload therapy with deferiprone and its need, which states that iron chelation was necessary for the prevention of damaging effects to heart, liver & endocrine gland in patients with refractory anemias taking regular blood transfusions. Although DFO is still the 1st line drug but due to its high cost, non-compliance due to administration there was a major need of having orally active iron chelator that have to be cheap. In the first trail of deferiprone, it was found that Deferiprone was suitable for patients whom DFO was contraindicated or inadequate. Patients are chelated successfully with oral Deferiprone at a dose of 75mg/kg/day, while some need a higher doses up to 100mg/kg/day or combination therapy of deferiprone every day and DFO on several days each week. Recent studies also suggested the superiority of deferiprone upon DFO in protecting the heart from iron overload, only 5-10% results in discontinuation of deferiprone. It was licensed in 43 countries for treating thalassemia major for which DFO is contraindicated or inadequate.

Kwiatkowski et 2004 reviewed the therapy of sickle-cell disease & transfusion-dependent anemias with iron chelation. Sickle-cell anemias was a hematological disorder that need regular blood transfusion in order to save life but its repeated infusion can cause iron overload with organ failure and death. Standard therapy in this case would be combination of Deferoxamine (DFO) with other chelating agents. DFO was non-compatible to patients for its parenteral administration. However, orally effective Deferiprone have been introduced for patients who cannot tolerate DFO. Combined therapies including transfusional methods to reduce iron load with parenteral & oral chelators have greatly enhance patient compliance and efficacy of the therapy in patients undergoing long-term transfusion.

Kontoghiorghes et al 2003 reviewed the risks & benefits of deferiprone in thalassemia patients & other conditions along with comparative aspects with deferoxamine. Deferiprone, an orphan drug designed to be administered orally & was iron chelator used clinically in transfusional iron overload. It has broader clinical application including metal imbalance conditions. It has high affinity for iron and therefore a dose of 50-120mg/kg/day diminishes iron overload. Increase in rate of urinary excretion depends on the dose & iron overload in patient. More the 80mg/kg/day reduce serum ferritin levels, liver & cardiac iron load in chronic transfusions. It was metabolized by glucuronide conjugate with clearance of 3:1 (deferiprone: iron complex) of metabolized & non-metabolized form. Cmax reached within 1hr & Clearance from blood within 6hrs. Adverse effects of deferiprone are reversible, controllable and manageable including 0.6% agranulocytosis, 6% neutropenia, 15% musculosketal & joint pain, GIT complaint 6% & Zinc deficiency 1%. Drug was to be discontinued if patient developed agranulaocytosis. Both deferiprone and deferoxamine has same therapeutic index but deferiprone is more effective in removing iron from heart as it was a target organ of iron toxicity. Combination therapy was given to patient who cannot comply with s/c DFO or having toxic effect, or unable to excrete sufficient iron if used alone. Although new iron chelator was developed bout deferiprone was not expensive. It was used more than 50% in India & 25% in Europe.

Stobie et al 1993 studied the comparative pharmacokinetics of deferiprone in healthy volunteers with & without ferrous sulphate to thalassemia patients. In every case of acute iron intoxication, the iron chelation must be ideal. A study conducted determines pharmacokinetic parameters like elimination half-life, excretion AUC in healthy volunteers & thalassemia patients. When deferiprone was given with ferrous sulphate to the 5 healthy volunteers on three separate days in 3 weeks and blood samples were collected at regular interval. A 20% decrease in AUC of plasma iron and deferiprone was observed with no necessary excretion of iron, whereas increase in iron excretion was observed when deferiprone was given to thalassemia patients as they were beyond saturation of their Fe binding capacity, comparative to healthy volunteers in which transferrin did not allowed deferiprone to remove absorbed iron. Similarly, elimination half-life of deferiprone in thalassemia patients was found longer (137.65 ± 48.65 min) than in normal volunteers (77.56 ± 13 min). None of the other pharmacokinetic parameters were found different when compared between both groups.

Kontoghiorghes et al 1990 studied long term trial of deferiprone for iron chelation & metabolic process. A total of 13 transfusion-dependent iron load patients were enrolled for 1-15 months in clinical trial. Patients with thalassemia have greater urinary excretion which was related to previous transfusions but not to serum ferritin level. Double daily dose of deferiprone resulted in substantial increases in urinary iron excretion on the other hand 25 mg of iron which was accumulated through transfusion resulted in more than 25 mg of its excretion when daily 6g (2Ã-3g) deferiprone was given orally in 11 out of 12 patients. Overall Serum ferritin level remained unchanged despite of fluctuation. There was rapid absorption of deferiprone from the stomach followed by glucuronidation with variation in half-life of 77+/- 35 min. As compared to single dose repeated administration of deferiprone in short term studies resulted in further increase in urinary iron excretion, like in one case 325mg iron was excreted in urine following administration of 16g (5Ã-2g + 2Ã-3g) within 24 hr. Therefore, high level of urinary excretion & compliance with deferiprone increased the prospect for oral chelation in transfusional iron-loaded patients.

Konoghioghes et al 1990 studied the pharmacokinetics of deferiprone (L1) in normal human & seven transfusional iron loaded volunteers using HPLC for serum analysis. A dose of 3g was administered followed by its rapid absorption from stomach & was reached to blood with absorption half-life of 0.7 to 32 min. Cmax reached after 12 to 120 min of administration with elimination of 85% to 90% within the 1st 5-6 hrs. having half-life of 47-134 min. Deferiprone & its metabolite was identified in serum & urine but not in feces. 24-hr urine hydrolysis resulted in complete recovery from dose administered. Therefore, urinary iron excretion depends on iron over load rather than on serum and urine concentration of deferiprone. So, it was found that repeated administration of L1 2-3g every 6 hr. resulted in therapeutic efficacy.

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