- Email: [email protected]
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IRON CHELATORS At the 16th International Conference on Chelation in 2006, it was emphasized that around the world the current regulations and practices for the development, approval, post-introduction safety evalua tion and pricing of new medicines are inap propriate and may disadvantage patients (1R). Drastic reforms are deemed neces sary, in particular with regard to diseases that are common in less affluent countries, such as thalassemia major. In the past few decades, thanks to the introduction of effective, tolerable, and last ing iron chelation regimens, the life expec tancy, in both duration and quality, of patients with thalassemia major has improved tremendously. In a medical records study in the Mazandaran Province of Iran, where thalassemia major is the most common genetic disease, morbidity and mortality among 1010 patients with tha lassemia have been reviewed (2CR). The complexity and seriousness of the secondary pathology in these patients demonstrates the devastating nature of the disease, in particu lar when supplies of iron chelators are lim ited and non-adherence is common. In other countries, myelodysplastic syndromes, aplastic anemia, Diamond– Blackfan anemia and other transfusiondependent anemia are more frequent indications for transfusion and can cause iron overload. Novel tests for measuring iron accumulation in the heart and liver, Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32023-X 2010 Elsevier B.V. All rights reserved.
such as superconducting quantum inference devices (SQUIDs) and magnetic resonance imaging (MRI), and new oral chelators enable even more sophisticated, effective, and tolerable treatment of thalassemia. In order to ensure that these new technologies are used to their best advantage, the Italian Society of Hematology has developed struc tured consensus clinical treatment guide lines, covering critical matters such as the level of iron storage requiring chelation therapy, when to start chelation, how to monitor chelation and switching to an alter native treatment (3R). There have been reviews of current knowledge about iron overload in myelo dysplastic syndromes, describing the com plexity of intra- and extracellular iron homeostasis and metabolism and the impor tance of the peptide hormone hepcidine produced by the liver and emphasizing the crucial role of non-transferrin-bound iron in damaging organs and the rationale of chela tion treatment (4R–6R). Until recently the use of deferoxamine for transfusional iron overload in myelodysplastic syndromes has been sparse, but the literature on the use of iron chelators in these patients is expanding (7R, 8R). A retrospective study in Japan has also confirmed that in these patients iron storage is a major cause of morbidity and mortality, in particular cardiac and hepatic dysfunction, underlining the fact that iron chelators should be started in time in these patients when the iron burden increases (e.g. when the serum ferritin concentration exceeds 1000 µg/l) (9CR). While awaiting further trials, it seems appropriate to offer, of the five general subtypes of myelodys plastic syndromes, iron chelation to at least patients with refractory anemia and refrac tory anemia with ringed sideroblasts.
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In the treatment of iron storage disease, the use of chelators aims at detoxifying and excreting surplus iron. Reactive oxygen spe cies should be scavenged as far as possible. Chelators containing ‘hard’ oxygen donor atoms stabilize the ferric state, resulting in redox-inactive complexes, and are suitable for the treatment of iron storage disease. The careful choice of ‘soft’ donor atoms, such as nitrogen or sulfur, on the other hand, results in redox-active iron complexes with high redox affinity and may be effective in oncolytic chemotherapy. Several series of such compounds are in development (10R): 2-pyridylcarboxaldehyde isonicotinoyl hydra zone series di-2-pyridylketone isonicotinoyl hydrazone series di-2-pyridylketone thiosemicarbazone series 3-aminopyridine-2-carboxaldehyde thiosemicarbazone
Their toxicological properties differ consider ably from the classical iron chelators and they should receive more attention in future. Combination studies Deferoxamine + deferiprone The advantage of combining deferoxamine with deferiprone is that deferoxamine can be given less often and for a shorter duration, which may improve adherence. In a randomized, double-blind, controlled comparison of clinically equivalent doses of deferoxamine with deferiprone (n = 32) and deferoxamine with placebo (n = 33) in adults with thalassemia major, combination treat ment was superior in reducing myocardial iron and improving ventricular and endothelial functions (11cr). Mild gastrointestinal symp toms (nausea, vomiting, or abdominal pain) were the most common adverse events, in 38% of patients who received the combination and in 24% of those who received deferoxa mine monotherapy. Such events were more often recurrent in the combination group (19% versus only 3%). Pain and/or swelling of joints occurred in 9% of patients taking the combination and were more frequent in patients who only received deferoxamine, which is unexpected, since arthropathy typi cally occurs in connection with deferiprone.
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Because it is common in clinical practice to alternate treatment with deferiprone and deferoxamine, in a comparative study in Egypt alternating use of these drugs (n = 30) was compared with simultaneous use in combination (n = 30) (12cr). Alternat ing administration of deferiprone 75 mg/kg/ day orally for 4 days and deferoxamine 40 mg/kg/day by subcutaneous infusion for the next 2 days was safe and effective in patients with thalassemia major. Taste dis turbances (a metallic taste and inability to distinguish between bitter and sweet) occurred in two patients after the first month. Taste returned to normal sponta neously while treatment was continued. Oral deferiprone alone 75 mg/day (n = 12) has been compared with deferiprone þ defer oxamine 40–50 mg/kg twice weekly (n = 12) and with deferoxamine alone 40–50 mg/kg on 5 days/week (n = 12) (13cr). There was neutropenia in two patients taking deferi prone (one with deferiprone alone, one with the combination). In one patient two episodes of neutropenia (in weeks 4 and 10) were fol lowed by full-blown agranulocytosis (in week 11), which was treated with granulocyte sti mulating factor and recovered within 11 days. In no case was there progressive hepatic fibrosis, and only in the patients taking com bination therapy did the histology activity index and liver iron scores fall substantially. There was grade 2 arthralgia in one patient taking combination therapy. Aseptic meningi tis occurred in week 45 in one patient taking deferiprone alone, and in another taking deferiprone alone an acute and transient cer ebellar syndrome was observed, which was thought not to be drug-induced but to have followed an infection. A quality-of-life assess ment questionnaire showed improvement in 64% of those who took deferiprone and only in 20% of those who took deferoxamine.
Deferasirox (SEDA-29, 236; SEDA-30, 273; SEDA-31, 401) There is increasing knowledge of the pharma cology of deferasirox and interest in its ther apeutic use, in particular in non-hemolytic
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transfusion-dependent anemias (8CR, R R 14 –20 ). At the same time, post-marketing reports have raised concerns about the possi ble occurrence of serious adverse reactions, such as anaphylaxis, gastrointestinal ulceration and hemorrhage, neurosensory hearing loss, lenticular opacities, acute renal insufficiency, liver damage, agranulocytosis, and thrombo cytopenia (8R, 16r, 17r, 21R, 22S). However, detailed information is sparse, and there is an urgent need for clarification of the current uncertainty. It is possible that deferasirox can damage various organs, especially the kidneys, by increasing iron absorption and de-compartmentalizing chelated iron in these tissues (1R). Drug–drug interactions A large but incomplete list of drugs that are assumed to interact with deferasirox is available on the Internet (23S). Aluminium salts Deferasirox has affinity for aluminium and forms lipophilic complexes with it. It should not be combined with aluminium-containing antacids (22S). Theoretically, long-term use of deferasirox might increase the gastrointestinal absorption of aluminium and lead to accumulation in the brain and perhaps to dementia (1R). Cytochrome P450 (CYP) isoenzymes Deferasirox is involved in both enzyme inhi bition and enzyme induction and affects CYP3A4, CYP2C8, CYP1A2, CYP2A6, CYP2D6, and CYP2C19. In particular, its effects on CYP3A4 and CYP2C8 may be clinically important. Potentiation of ciclos porin, hormonal contraceptives, midazolam, paclitaxel, repaglinide, and simvastatin has been documented or is expected, and it may be necessary to adjust the dose of these drugs (22S). Midazolam In healthy volunteers co-administration of deferasirox with midazolam, a CYP3A4 substrate, resulted in a 23% reduction in the Cmax of midazolam and a 17% reduction in AUC (22S). This was presumably due to induction of CYP3A4 by deferasirox.
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Repaglinide In healthy volunteers con comitant administration of deferasirox 30 mg/kg/day for 4 days with the CYP2C8 probe substrate repaglinide in a single dose of 0.5 mg increased the AUC of repaglinide 2.3 times and the Cmax by 62% (22S). The manufacturers recommended reducing the dose of repaglinide and monitoring blood glucose concentrations if this combination is used.
UDP glucuronyltransferase inducers Deferasirox is metabolized by uridine 50 diphospho- (UDP) glucuronyltransferase (UGT), and concomitant use of inducers of UGT, such as rifampicin, phenytoin, or phenobarbital, can therefore lead to lower concentrations of deferasirox; monitoring of serum ferritin is indicated.
Drug–food interactions The effect of a high-fat or standard breakfast on the phar macokinetics of deferasirox has been investigated in healthy volunteers and patients with transfusional hemosiderosis (24c). The type of food, its caloric content and the fat content of the meal affected the systemic availability of deferasirox, but not when it was taken at least 30 minutes before a meal, which is the preferred timing.
Deferiprone (SED-15, 1054; SEDA-29, 237; SEDA-30, 273; SEDA-31, 402) Observational studies In an open trial in 13 patients with Friedreich’s ataxia aged 14–23 years, deferiprone 20–30 mg/kg/day for 6 months removed accumulated iron from a specific brain area (detected using MRI scanning) and produced significant neurological improvement compared with age-matched controls (25cr). Four patients withdrew because of adverse events, two because of musculoskeletal pain, one because of Guillain–Barré syndrome, and one because of reversible agranulocytosis.
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Guillain–Barré syndrome is not an estab lished adverse effect of deferiprone. During the study there was a clear reduction in body iron, as shown by reductions in serum iron, ferritin, and hemoglobin con centrations. It is not clear for how long deferiprone can be continued safely in Friedreich’s ataxia and whether iron supple ments are beneficial.
Hematologic An underlying susceptibility may have played a part in a case of fatal agranulocytosis that was probably caused by deferiprone (26AR). • A 10-year-old girl was given deferiprone 45 mg/kg/day for excess iron storage following erythrocyte transfusions for congenital Diamond–Blackfan anemia. A fall in white cell count during week 8 rapidly progressed to agranulocytosis in week 9 followed by Staphylococcus aureus sepsis and pneumonia. She was given antibiotics and filgrastim, followed by glucocorticoids and ciclosporin, because of persistent agranulocytosis. However, the neutrophil count remained low and she died.
While in Diamond–Blackfan anemia only red cell production is affected, bone marrow examination in this patient on day 23 showed variable cellularity, with lympho cytic infiltration and fibrosis. In areas of low cellularity, mainly macrophages and megakaryocytes were found. Granulopoi esis and erythropoiesis were scarce. The lymphoid infiltrates consisted mainly of a mixture of CD4þ and CD8þ9 cells (CD, cluster of differentiation). CD117 staining showed a diffuse increase in mast cells. Bone-marrow flow cytometry showed that 72% of the cells were in the lymphocyte region, of which 86% were T cells with signs of activation. This report also illus trates that, despite regular monitoring, agranulocytosis can occur unexpectedly and can progress rapidly. There is one more case on record of agranulocytosis (together with reversible thrombocytope nia) in a patient with Diamond–Blackfan anemia who received deferiprone (27A) and another of neutropenia that slowly
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progressed to aplastic anemia (28A). Patients with Diamond–Blackfan may be more susceptible to agranulocytosis from deferiprone than those with thalassemia. In vitro progenitor cell cultures, using venous blood samples from 16 patients with major thalassemia and normal blood counts, yielded unexpected findings (29CR). Nine patients (three with splenect omy) received subcutaneous deferoxamine 45 mg/kg/day on 5 days/week, 7 patients (four with splenectomy) took deferiprone 75 mg/kg/day and there were 10 healthy controls. Granulocyte–erythrocyte–monocyte– megakaryocyte colony-forming units were more common in those who received defer oxamine or deferiprone than in the controls. Granulocyte–macrophage colony-forming units were more common and macrophage colony-forming units less common with deferiprone than in the controls. Granulo cyte colony-forming units were more com mon with deferoxamine than in the controls. Addition of serum from patients taking deferiprone to cultures of cells from the controls resulted in maturation arrest of the granulocytic lineage. These findings sug gest that deferiprone can cause maturation arrest of granulocyte–macrophage colonyforming units, an effect that may play a role in the pathogenesis of deferiprone induced agranulocytosis. Immunologic Rare serious adverse drug reactions probably result often from a com bination of different susceptibility factors, both known and unknown. Henoch–Schönlein purpura, with renal and pulmonary involve ment and intestinal invagination, has been reported in temporal association with expo sure to deferiprone (30AR). • A 7-year-old splenectomized boy with b-thalassemia, who had been receiving erythrocyte transfusions and deferoxamine for most of his life for a Coombs-positive hemolytic anemia, was given low-dose prednisolone and cyclophosphamide. Because of non-adherence and a serum ferritin concentration of 11489 ng/ml, the deferoxamine was replaced by deferiprone 60 mg/kg/day. After 5 months he developed arthritis of the ankles and palpable purpuric
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lesions on the legs. There was no history of infection, and virus serology and bacterial cultures were negative. A renal biopsy showed diffuse Henoch–Scho¨ nlein nephritis with crescent formation and immunoglobulin A (IgA) deposition in the mesangium and glomerular basement membrane. Deferiprone was withdrawn. At follow-up 2 years later renal function was normal and there was no proteinuria. DNA analysis because of recurrent attacks of abdominal pain showed familial Mediterranean fever and a homozygous M694V mutation.
therapeutic index of less than 0.025 she remained asymptomatic, but whereas initi ally her fundi had been normal, she slowly developed a pigmentary retinopathy. At 33 years the dose of deferoxamine was increased to 49 mg/kg/day and the deficits in dark-adapted visual sensitivity and postreceptor retinal sensitivity relapsed. When the dose of deferoxamine was again reduced, the dark-adapted visual sensitivity recovered. Mild deficits in post-receptor sensitivity persisted, as did deficits in photo receptor sensitivity.
In this patient Henoch–Scho¨ nlein purpura was thought to have developed because of the co-occurrence of M694V homozyg osity (an established susceptibility factor), profound cellular and humoral immunolo gical disturbances secondary to thalasse mia, and perhaps treatment with deferiprone.
The recovery of post-receptor sensitivity suggests that ‘remodelling’ of the retina and its functional processes is the basis for recovery of visual sensitivity despite irreversible compromise of photoreceptor function, leaving the retina particularly vulnerable to new exposure to deferox amine. The relation between retinal injury resulting from iron storage and that secondary to chelation treatment with deferoxamine has been reviewed (32AR).
Deferoxamine (SED-15, 1058; SEDA-29, 237; SEDA-30, 274; SEDA-31, 402)
Special senses Eyes A detailed case study of a woman with major thalassemia, receiving long-term deferoxamine 50 mg/kg/ day, yielded valuable information on deferoxamine-related retinopathy (31AR). • A 28-year-old woman with previously nor mal visual and retinal responses found that her eyes did not adjust to the dark. Eight weeks before, heart failure and raised liver iron concentrations had prompted a dou bling of the dose of deferoxamine. Visual acuity was 20/200 in both eyes. There were dense central and paracentral scotomata, and dark-adapted visual sensitivity was 2 log units below normal. Scotopic electrore tinography showed deficits in rod photore ceptor and post-receptor sensitivity. Deferoxamine was withdrawn and her visual acuity and visual fields rapidly normalized, while her dark-adapted visual sensitivity gradually improved. Three weeks later deferoxamine was restarted in a dose of 12 mg/kg/day and gradually increased to 25 mg/kg/day. During follow-up dark-adapted visual sensitivity gradually became normal, as did post-receptor sensitivity, but deficits in rod photoreceptor sensitivity persisted (at less than half the baseline sensitivity). While receiving deferoxamine doses adjusted to a
Ears The physiological capacity for elimination of iron from intracranial spaces is limited. Chronic or recurrent subarachnoidal bleeding, a rare condition, can cause superficial hemosiderosis in the central nervous system (33CR). As the vestibulocochlear nerve runs through the pontine cistern and has a long glial segment, superficial hemosiderosis almost always has auditory effects and causes bilateral sensorineural hearing loss. MRI scanning is very sensitive to ironcontaining hemosiderin and typically shows a rim of hypointensity on T2-weighted images, predominantly affecting the surfaces of the brainstem and cerebellum, the cranial nerves and the spinal cord. Pure-tone audiometry is used in the early detection of deferoxamine ototoxi city but may be insufficiently sensitive. In 60 patients with thalassemia receiving sub cutaneous deferoxamine 40 mg/kg/day on 5 days/week, distortion-product otoacous tic emission was compared with pure-tone audiometry (34C). The former was more sensitive than the latter and as a screening
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tool has the advantage of being non invasive, objective, rapid, and easy to use. Urinary tract Deferoxamine is contraindi cated in patients with severe kidney disease, and in overdose acute renal failure can occur (SEDA-28, 256). However, deferoxamine is commonly used off-label to remove alumi nium and to prevent or treat aluminiumrelated bone disease in patients with chronic kidney disease stage 4 (GFR 15–30 ml/min ute). The clinical and pathological findings in deferoxamine-induced acute renal failure in a patient with a renal transplant have been described (35AR). • A 58-year-old man with a cadaveric kidney transplant for Goodpasture’s syndrome who was taking long-term oral ciclosporin (trough concentration 90 µg/l), prednisolone, candesar tan, carvedilol, furosemide, verapamil, panto prazole, benzbromarone, pravastatin, ezetimibe, and warfarin was given subcutaneous deferox amine 2 g/day for 3 weeks, and 1 day after the last infusion was found to have renal impair ment. The serum creatinine concentration had increased to 250 µmol/l, there was proteinuria 1.1 g/day and the creatinine clearance was 31 ml/minute. To exclude graft rejection, a renal biopsy was performed. There were no signs of acute humoural or cellular rejection. There was no isometric vacuolization or microcalcification, as signs of calcineurin inhibitor toxicity, although the arterioles had marked cuff-like hyalinosis, indicating chronic vascular ciclosporin toxicity. There was about 15% cor tical tubular atrophy, interstitial fibrosis in a non-striped pattern and a partially flattened epithelium with attenuated brush borders, indicating acute tubular damage in the remain ing cortical tubules. The acutely damaged cor tical tubular epithelial cells had degenerated mitochondria, with myelin-like figures and loss of cristae, but there was no swelling of mitochondria or endoplasmic reticulum.
The authors suggested that the underlying mechanism of renal tubular toxicity in this patient was removal of iron from the mito chondria and subsequent depletion of mito chondrial ATP. The mitochondrial changes in this patient were different from the pat tern commonly seen in acute tubular injury, and may be diagnostic of deferoxamine toxicity. It is advisable to monitor renal function in patients with renal disease who receive deferoxamine.
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Infection risk Deferoxamine and changes in iron metabolism may increase the infec tivity of a variety of fungi and bacteria (SED-15, 1064; SEDA-29, 237). In a case of endocarditis due to Salmonella enterica subsp. arizonae, chelation therapy with deferoxamine was thought to have been a possible susceptibility factor (36Ar).
PENICILLAMINE AND RELATED DRUGS (SED-15, 2729; SEDA-29, 238; SEDA-30, 274; SEDA 31, 403)
Penicillamine Uses In children, penicillamine-stimulated urinary copper excretion is a reliable non invasive test for Wilson’s disease. In a liver biopsy-controlled study in 43 patients it was also reliable and safe in adults; patients with penicillamine-stimulated urinary copper excretion below 1057 µg/day are unlikely to have Wilson’s disease and are unlikely to benefit from liver biopsy (37cr). In patients with an acute Wilsonian crisis, prompt copper chelation plus plasmapher esis can be life-saving. In an 18-year-old girl with Wilson’s disease, acute hemolysis and impending liver failure, chelation with peni cillamine (dose unspecified) and plasma pheresis led to recovery (38A). Observational studies In a trial in 15 preterm neonates, daily enteral penicillamine (in a locally produced formulation, dose not specified) for 2 weeks after birth elimi nated stage I and II retinopathy of prema turity but not of laser surgery (39cr). There were no adverse effects in these babies. The finding that penicillamine in high doses, as used in Wilson’s disease, reduces total skin collagen has prompted a trial in diffuse cutaneous systemic sclerosis. In a retrospec tive analysis of 84 patients with recent onset progressive disease, penicillamine, median dose 750 mg/day for at least 3 months, caused
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significant reduction in skin disease and improvement of renal, cardiac and pulmon ary involvement (40cr). At the last followup, 20% of the patients were still taking penicillamine, 30% had stopped because of disease improvement and 21% had stopped because of adverse effects, showing the familiar pattern of proteinuria (n = 7), rash (n = 4), neutropenia (n = 3), and pemphigus (n = 2). In addition, 23% had died, mainly from complications of the disease. Four patients were lost to follow-up. Systematic reviews Penicillamine 600– 1200 mg/day has been compared with pla cebo or no intervention in primary biliary cirrhosis, another disorder in which peni cillamine has been tried because of its effects on collagen, in a meta-analysis of seven randomized trials in 706 patients (41M). Although the treatment group had significantly reduced serum AlT activity, there were differences neither in other liver tests nor in pruritus, fatigue, liver complications, progression of liver histolo gical stage, liver transplantation, or mortality. Skin An eruption resembling elastoma perforans serpiginosa, with the typical lumpy-bumpy histological appearance and pruritic lesions of 5–7 cm, is a late complica tion of the use of high doses of penicilla mine, and was originally described by Gephart and Bardach (42AR).
OTHER CHELATORS Edetic acid (ethylenediaminetetraacetic acid, EDTA) (SED-15, 1300; SEDA-30, 276; SEDA-31 405)
Uses A newly identified inherited disorder in a 12-year-old girl, characterized by
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manganese storage, dystonia, polycythemia, and liver injury, was successfully treated with monthly infusions of calcium disodium eden tate 40 mg/kg/day for 5 consecutive days (43A). Penicillamine had previously been ineffective.
Urinary tract Lead compounds are nephrotoxic. In a placebo-controlled trial, the protective effect of lead chelation was studied in a follow-up study of 4 years duration in 58 Chinese patients with a high normal lead burden and non-diabetic chronic kidney disease (serum creatinine concentrations 133–345 µmol/l) (44cr). Compared with placebo there was a sub stantial reduction in the progression of renal insufficiency.
Interference with diagnostic tests The use of EDTA as an anticoagulant in blood samples can cause pseudothrombo cytopenia in automated cell counts (SED 15, 1202), usually because of clumping of neutrophil leukocytes and only rarely lym phocytes. In vitro EDTA caused artifactual agglutination of lymphocytes in a patient with a large B-cell non-Hodgkin’s lym phoma (45A).
Trientine
(SED-15, 3508; SEDA-29, 239)
Comparative studies In patients with Wilson’s disease initial worsening of neu rological symptoms is a notorious compli cation of chelation therapy. In an 8-week double-blind trial, initial treatment with trientine 1 g/day and zinc 100 mg/day (salt not specified) was compared with tetrathiomolybdate 60 mg/day and zinc 100 mg/day, with special reference to the worsening of neuropsychiatric symptoms (46A). The adverse events are shown in Table 1. Of the 23 patients who received trien tine, 6 fulfilled the criteria for neurological deterioration, while of the 25 patients
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Table 1. Adverse events in a comparison of trientine and tetrathiomolybdate Adverse event
Trientine (n = 23)
Tetrathiomolybdate (n = 25)
Rise in aminotransferases Anemia and/or leukopenia Neurological deterioration Death
0 1 6 4
4 3 1 2
who received tetrathiomolybdate, dete rioration occurred in only 1, suggesting that tetrathiomolybdate is superior to tri entine in the initial treatment of neurolo gical Wilson’s disease. Four patients in the trientine arm died and two in the tetra thiomolybdate arm. With one exception of a case of fatal leukemia, all the patients who died had severe neurological impair ment. As four of the seven patients with neurological deterioration died, this event may forecast poor survival. Drug dosage regimens Trientine and zinc have become major tools in the manage ment of Wilson’s disease. Zinc (usually zinc acetate dehydrate 75–150 mg/day in three divided doses) inhibits the enteric absorption of copper by stimulating intest inal and hepatic metallothioneins. As a cop per chelator, trientine when taken with meals also reduces enteric copper absorp tion and promotes urinary copper excretion; the usual daily dose is 500–1500 mg/day, in two to four divided doses. However, non-adherence is a common problem. In a retrospective review of the clinical records of 22 children with Wilson’s disease, new increases in serum aminotransferase activities during long-term treatment (mostly with trientine and/or zinc) were commonly found to be secondary to non adherence (47CR). In a retrospective study in five patients, trientine 500–1000 mg/day as a single dose was effective in controlling Wilson’s dis ease (48c). Larger prospective trials are needed to confirm the efficacy of oncedaily trientine and to determine the required dose.
POLYSTYRENE SULFONATES (SED-15, 2894; SEDA-29, 239; SEDA-30, 275)
Treatments for non-oliguric hyperkalemia in preterm neonates, including ion exchange resins, have been reviewed (49M). Comparative studies In a comparison of rectal sodium polystyrene sulfonate 1 g/kg every 4 hours (n = 15) and salbutamol infu sion 4 micrograms/kg every 4 hours (n = 30) for non-oliguric hyperkalemia in preterm infants, there were no important adverse events in those who received salbutamol, but two cases of severe ventricular tachycar dia and one of intestinal obstruction in those who received the polystyrene sulfonate (50c). Gastrointestinal Perforated necrotizing enterocolitis requiring resection has been reported in a 27-week, 850 g infant after rectal administration of sorbitol-free sodium polystyrene sulfonate for life-threatening hyperkalemia due to progressive anuria (51A). Although sorbitol has previously been blamed for gastrointestinal damage after the administration of Kayexalate (SED-15, 2896), this case suggests that sodium polystyrene sulfonate can also cause such damage. Rectal stenosis due to sodium polystyrene sulfonate crystals, requiring colonic resec tion, has been reported in a 46-year-old man who was given sorbitol-free Kayexa late by a nasogastric tube (52A). Histology showed fibrosis of the submucosa with numerous basophilic polygonal crystals sur rounded by macrophages.
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of transfusional chronic iron overload. Drugs 2007;67:2211–30. Kontoghiorghes GJ. Deferasirox: uncertain future following renal failure fatalities, agranulocytosis and other toxicities. Expert Opin Drug Saf 2007;6(3):235–9. Novartis. EXJADE® (Deferasirox) tablets for oral suspension. http://www.pharma.us. novartis.com/product/pi/pdf/exjade.pdf. Drug Information Online. Deferasirox drug interactions. http://www.drugs.com/drug interactions/deferasirox.html. Galanello R, Piga A, Cappellini MD, Forni GL, Zappu A, Origa R, Dutreix C, Belleli R, Ford JM, Rivière GJ, Balez S, Alberti D, Séchaud R. Effect of food, type of food, and time of food intake on deferasirox bio availability: recommendations for an optimal deferasirox administration regimen. J Clin Pharmacol 2008;48(4):428–35. Boddaert N, Hanh Le Quan Sang K, Ro¨ tig A, Leroy-Willig A, Gallet S, Brunelle F, Sidi D, Thalabard J-C, Munnich A, Cabantchik ZI. Selective iron chelation in Friedreich ataxia: biologic and clinical impli cations. Blood 2007;110(1):401–8. Henter J-I, Karlén J. Fatal agranulocytosis after deferiprone therapy in a child with Dia mond–Blackfan anemia. Blood 2007;109 (12):5157–9. Hofbrand AV, Bartlett AN, Veys PA, O’Connor NT, Kontoghiorghes GJ. Agranulocytosis and thrombocytopenia in a patient with Blackfan–Diamond anemia and hemo chromastosis. Lancet 1989;2:457. € Muller A, Soyano A, Soyano-M€ uller A, Torres MA, Lanes R, Ponte B. et al. Irrever sible aplastic anemia after treatment with deferiprone in a patient with Blackfan–Dia mond anemia and hemochromatosis. Blood 2000;96:Abstract 3707. Vlachaki E, Ioannidou-Papagiannaki E, Tziomalos K, Haralambidou-Vranitsa S, Perifanis V, Klonizakis I, AthanassiouMetaxa M. Peripheral blood haematopoietic progenitor cells in patients with beta thalas saemia major receiving desferrioxamine or deferiprone as chelation therapy. Eur J Haematol 2007;78(1):48–51. Unal S, G€ ucer S, Kale G, Besbas N, Ozen S, G€ umr€ uk F. Severe Henoch–Schonlein ¨ purpura in a thalassemic patient under
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deferiprone treatment. Am J Hematol 2007;83(2):165–6. Lu M, Hansen RM, Cunningham MJ, Eklund SE, Fulton AB. Effects of desferox amine on retinal and visual function. Arch Ophthalmol 2007;125(11):1581–2. Reddy S, Slakter J, Aaberg TM Jr, Singh RP, Kaiser PK. Diagnostic and therapeutic chal lenges. Retina 2007;27(5):642–7. Ayache D, Blaivie C, El Kohen A, Tosello L, Williams MT. Auditory manifestations of superficial hemosiderosis of the central ner vous system. Eur Arch Oto-Rhino-Laryngol 2007;264(6):701–4. Delehaye E, Capobianco S, Bertetto I, Mel oni F. Distortion-product otoacoustic emis sion: early detection in deferoxamine induced ototoxicity. Auris Nasus Larynx 2008;35(2):198–202. Clajus C, Becker JU, Stichtenoth DO, Wort mann J, Schwarz A, Kielstein JT. Acute kid ney injury due to deferoxamine in a renal transplant patient. Nephrol Dial Transplant 2008;23(3):1061–4. Starakis I, Siagris D, Karatza C, Solomou H, Bassaris H. Endocarditis due to Salmonella enterica subsp.arizonae in a patient with sickle cell disease: a case report and review of the literature. Cardiovasc Hematol Disord Drug Targets 2007;7(3):199–204. Foruny JR, Boixeda D, López-Sanroman A, Va´ zquez-Sequeiros E, Villafruela M, Va´ zquez-Romero M, Rodríguez-Gandía M, de Argila CM, Camarero C, Milicua JM. Usefulness of penicillamine-stimulated urin ary copper excretion in the diagnosis of adult Wilson’s disease. Scand J Gastroenterol 2008;43(5):597–603. Asfaha S, Almansori M, Qarni U, Gutfreund KS. Plasmapheresis for hemolytic crisis and impending acute liver failure in Wilson dis ease. J Clin Apher 2007;22(5):295–8. Christensen RD, Alder SC, Richards SC, Lambert DK, Schmutz N, Wiedmeier SE, Burnett J, Baer VL, Horn JT, Richards M, Barraza J. D-Penicillamine administration and the incidence of retinopathy of prema turity. J Perinatol 2007;27(2):103–11. Derk CT, Huaman G, Jimenez SA. A retro spective randomly selected cohort study of D-penicillamine treatment in rapidly progres sive diffuse cutaneous systemic sclerosis of
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recent onset. Br J Dermatol 2008;158 (5):1063–8. Gong Y, Klingenberg SL, Gluud C. Systema tic review and meta-analysis: D-penicillamine vs. placebo/no intervention in patients with primary biliary cirrhosis – Cochrane HepatoBiliary Group. Aliment Pharmacol Ther 2006;24(11–12):1535–44. Devillière M, Ingen-Housz-Oro S, Weber N, Cordoliani F, Vignon-Pennamen M-D, Man ciet J-R Sigal-Grinberg M. Élastome perfor ant serpigineux induit par D-pénicillamine. [D-penicillamine-induced elastosis perforans serpiginosa.] Ann Dermatol Venereol 2007;134(10 Pt 1):799–800. Tuschl K, Mills PB, Parsons H, Malone M, Fowler D, Bitner-Glindzicz M, Clayton PT. Hepatic cirrhosis, dystonia, polycythaemia and hypermanganesaemia – a new metabolic disorder. J Inherit Metab Dis 2008; 31(2): 151–63. Lin-Tan DT, Lin JL, Yen TH, Chen KH, Huang YL. Long-term outcome of repeated lead chelation therapy in progressive non diabetic chronic kidney diseases. Nephrol Dial Transplant 2007;22(10):2924–31. Lesesve JF, Fediuk T, Merseille JM, Braun F. EDTA-dependent lymphoaggluti nation in a patient with non-Hodgkin lym phoma. Int J Lab Hematol 2007;29(3):221–4. Brewer GJ, Askari F, Lorincz MT, Carlson M, Schilsky M, Kluin KJ, Hedera P, Moretti P, Fink JK, Tankanow R, Dick RB, Sitterly J.
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Tetrathiomolybdate versus trientine in the initial treatment of neurologic Wilson’s dis ease. Prog Neurother Neuropsychopharma col 2008;3(1):153–65. Arnon R, Flores Calderon J, Schilsky M, Shneider ES, Benjamin L. Wilson disease in children: serum aminotransferases and urin ary copper on triethylene tetramine dihy drochloride (trientine) treatment. J Pediatr Gastroenterol Nutr 2007;44(5):596–602. Fox AN, Schilsky M. Once daily trientine for maintenance therapy of Wilson disease. Am J Gastroenterol 2008;103:494–5. Vemgal P, Ohlsson A. Interventions for non oliguric hyperkalaemia in preterm neonates. Cochrane Database Syst Rev 2007;(1): CD005257. Yaseen H, Khalaf M, Dana A, Yaseen N, Darwich M. Salbutamol versus cationexchange resin (kayexalate) for the treat ment of nonoliguric hyperkalemia in preterm infants. Am J Perinatol 2008;25(3):193–7. Rugolotto S, Gruber M, Solano PD, Chini L, Gobbo S, Pecori S. Necrotizing enterocolitis in a 850 gram infant receiving sorbitol-free sodium polystyrene sulfonate (Kayexalate): clinical and histopathologic findings. J Peri natol 2007;27(4):247–9. Chatelain D, Brevet M, Manaouil D, Yzet T, Regimbeau JM, Sevestre H. Rectal stenosis caused by foreign body reaction to sodium polystyrene sulfonate crystals (Kayexalate). Ann Diagn Pathol 2007;11(3):217–9.
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IRON CHELATORS At the 16th International Conference on Chelation in 2006, it was emphasized that around the world the current regulations and practices for the development, approval, post-introduction safety evalua tion and pricing of new medicines are inap propriate and may disadvantage patients (1R). Drastic reforms are deemed neces sary, in particular with regard to diseases that are common in less affluent countries, such as thalassemia major. In the past few decades, thanks to the introduction of effective, tolerable, and last ing iron chelation regimens, the life expec tancy, in both duration and quality, of patients with thalassemia major has improved tremendously. In a medical records study in the Mazandaran Province of Iran, where thalassemia major is the most common genetic disease, morbidity and mortality among 1010 patients with tha lassemia have been reviewed (2CR). The complexity and seriousness of the secondary pathology in these patients demonstrates the devastating nature of the disease, in particu lar when supplies of iron chelators are lim ited and non-adherence is common. In other countries, myelodysplastic syndromes, aplastic anemia, Diamond– Blackfan anemia and other transfusiondependent anemia are more frequent indications for transfusion and can cause iron overload. Novel tests for measuring iron accumulation in the heart and liver, Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32023-X 2010 Elsevier B.V. All rights reserved.
such as superconducting quantum inference devices (SQUIDs) and magnetic resonance imaging (MRI), and new oral chelators enable even more sophisticated, effective, and tolerable treatment of thalassemia. In order to ensure that these new technologies are used to their best advantage, the Italian Society of Hematology has developed struc tured consensus clinical treatment guide lines, covering critical matters such as the level of iron storage requiring chelation therapy, when to start chelation, how to monitor chelation and switching to an alter native treatment (3R). There have been reviews of current knowledge about iron overload in myelo dysplastic syndromes, describing the com plexity of intra- and extracellular iron homeostasis and metabolism and the impor tance of the peptide hormone hepcidine produced by the liver and emphasizing the crucial role of non-transferrin-bound iron in damaging organs and the rationale of chela tion treatment (4R–6R). Until recently the use of deferoxamine for transfusional iron overload in myelodysplastic syndromes has been sparse, but the literature on the use of iron chelators in these patients is expanding (7R, 8R). A retrospective study in Japan has also confirmed that in these patients iron storage is a major cause of morbidity and mortality, in particular cardiac and hepatic dysfunction, underlining the fact that iron chelators should be started in time in these patients when the iron burden increases (e.g. when the serum ferritin concentration exceeds 1000 µg/l) (9CR). While awaiting further trials, it seems appropriate to offer, of the five general subtypes of myelodys plastic syndromes, iron chelation to at least patients with refractory anemia and refrac tory anemia with ringed sideroblasts.
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In the treatment of iron storage disease, the use of chelators aims at detoxifying and excreting surplus iron. Reactive oxygen spe cies should be scavenged as far as possible. Chelators containing ‘hard’ oxygen donor atoms stabilize the ferric state, resulting in redox-inactive complexes, and are suitable for the treatment of iron storage disease. The careful choice of ‘soft’ donor atoms, such as nitrogen or sulfur, on the other hand, results in redox-active iron complexes with high redox affinity and may be effective in oncolytic chemotherapy. Several series of such compounds are in development (10R): 2-pyridylcarboxaldehyde isonicotinoyl hydra zone series di-2-pyridylketone isonicotinoyl hydrazone series di-2-pyridylketone thiosemicarbazone series 3-aminopyridine-2-carboxaldehyde thiosemicarbazone
Their toxicological properties differ consider ably from the classical iron chelators and they should receive more attention in future. Combination studies Deferoxamine + deferiprone The advantage of combining deferoxamine with deferiprone is that deferoxamine can be given less often and for a shorter duration, which may improve adherence. In a randomized, double-blind, controlled comparison of clinically equivalent doses of deferoxamine with deferiprone (n = 32) and deferoxamine with placebo (n = 33) in adults with thalassemia major, combination treat ment was superior in reducing myocardial iron and improving ventricular and endothelial functions (11cr). Mild gastrointestinal symp toms (nausea, vomiting, or abdominal pain) were the most common adverse events, in 38% of patients who received the combination and in 24% of those who received deferoxa mine monotherapy. Such events were more often recurrent in the combination group (19% versus only 3%). Pain and/or swelling of joints occurred in 9% of patients taking the combination and were more frequent in patients who only received deferoxamine, which is unexpected, since arthropathy typi cally occurs in connection with deferiprone.
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Because it is common in clinical practice to alternate treatment with deferiprone and deferoxamine, in a comparative study in Egypt alternating use of these drugs (n = 30) was compared with simultaneous use in combination (n = 30) (12cr). Alternat ing administration of deferiprone 75 mg/kg/ day orally for 4 days and deferoxamine 40 mg/kg/day by subcutaneous infusion for the next 2 days was safe and effective in patients with thalassemia major. Taste dis turbances (a metallic taste and inability to distinguish between bitter and sweet) occurred in two patients after the first month. Taste returned to normal sponta neously while treatment was continued. Oral deferiprone alone 75 mg/day (n = 12) has been compared with deferiprone þ defer oxamine 40–50 mg/kg twice weekly (n = 12) and with deferoxamine alone 40–50 mg/kg on 5 days/week (n = 12) (13cr). There was neutropenia in two patients taking deferi prone (one with deferiprone alone, one with the combination). In one patient two episodes of neutropenia (in weeks 4 and 10) were fol lowed by full-blown agranulocytosis (in week 11), which was treated with granulocyte sti mulating factor and recovered within 11 days. In no case was there progressive hepatic fibrosis, and only in the patients taking com bination therapy did the histology activity index and liver iron scores fall substantially. There was grade 2 arthralgia in one patient taking combination therapy. Aseptic meningi tis occurred in week 45 in one patient taking deferiprone alone, and in another taking deferiprone alone an acute and transient cer ebellar syndrome was observed, which was thought not to be drug-induced but to have followed an infection. A quality-of-life assess ment questionnaire showed improvement in 64% of those who took deferiprone and only in 20% of those who took deferoxamine.
Deferasirox (SEDA-29, 236; SEDA-30, 273; SEDA-31, 401) There is increasing knowledge of the pharma cology of deferasirox and interest in its ther apeutic use, in particular in non-hemolytic
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transfusion-dependent anemias (8CR, R R 14 –20 ). At the same time, post-marketing reports have raised concerns about the possi ble occurrence of serious adverse reactions, such as anaphylaxis, gastrointestinal ulceration and hemorrhage, neurosensory hearing loss, lenticular opacities, acute renal insufficiency, liver damage, agranulocytosis, and thrombo cytopenia (8R, 16r, 17r, 21R, 22S). However, detailed information is sparse, and there is an urgent need for clarification of the current uncertainty. It is possible that deferasirox can damage various organs, especially the kidneys, by increasing iron absorption and de-compartmentalizing chelated iron in these tissues (1R). Drug–drug interactions A large but incomplete list of drugs that are assumed to interact with deferasirox is available on the Internet (23S). Aluminium salts Deferasirox has affinity for aluminium and forms lipophilic complexes with it. It should not be combined with aluminium-containing antacids (22S). Theoretically, long-term use of deferasirox might increase the gastrointestinal absorption of aluminium and lead to accumulation in the brain and perhaps to dementia (1R). Cytochrome P450 (CYP) isoenzymes Deferasirox is involved in both enzyme inhi bition and enzyme induction and affects CYP3A4, CYP2C8, CYP1A2, CYP2A6, CYP2D6, and CYP2C19. In particular, its effects on CYP3A4 and CYP2C8 may be clinically important. Potentiation of ciclos porin, hormonal contraceptives, midazolam, paclitaxel, repaglinide, and simvastatin has been documented or is expected, and it may be necessary to adjust the dose of these drugs (22S). Midazolam In healthy volunteers co-administration of deferasirox with midazolam, a CYP3A4 substrate, resulted in a 23% reduction in the Cmax of midazolam and a 17% reduction in AUC (22S). This was presumably due to induction of CYP3A4 by deferasirox.
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Repaglinide In healthy volunteers con comitant administration of deferasirox 30 mg/kg/day for 4 days with the CYP2C8 probe substrate repaglinide in a single dose of 0.5 mg increased the AUC of repaglinide 2.3 times and the Cmax by 62% (22S). The manufacturers recommended reducing the dose of repaglinide and monitoring blood glucose concentrations if this combination is used.
UDP glucuronyltransferase inducers Deferasirox is metabolized by uridine 50 diphospho- (UDP) glucuronyltransferase (UGT), and concomitant use of inducers of UGT, such as rifampicin, phenytoin, or phenobarbital, can therefore lead to lower concentrations of deferasirox; monitoring of serum ferritin is indicated.
Drug–food interactions The effect of a high-fat or standard breakfast on the phar macokinetics of deferasirox has been investigated in healthy volunteers and patients with transfusional hemosiderosis (24c). The type of food, its caloric content and the fat content of the meal affected the systemic availability of deferasirox, but not when it was taken at least 30 minutes before a meal, which is the preferred timing.
Deferiprone (SED-15, 1054; SEDA-29, 237; SEDA-30, 273; SEDA-31, 402) Observational studies In an open trial in 13 patients with Friedreich’s ataxia aged 14–23 years, deferiprone 20–30 mg/kg/day for 6 months removed accumulated iron from a specific brain area (detected using MRI scanning) and produced significant neurological improvement compared with age-matched controls (25cr). Four patients withdrew because of adverse events, two because of musculoskeletal pain, one because of Guillain–Barré syndrome, and one because of reversible agranulocytosis.
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Guillain–Barré syndrome is not an estab lished adverse effect of deferiprone. During the study there was a clear reduction in body iron, as shown by reductions in serum iron, ferritin, and hemoglobin con centrations. It is not clear for how long deferiprone can be continued safely in Friedreich’s ataxia and whether iron supple ments are beneficial.
Hematologic An underlying susceptibility may have played a part in a case of fatal agranulocytosis that was probably caused by deferiprone (26AR). • A 10-year-old girl was given deferiprone 45 mg/kg/day for excess iron storage following erythrocyte transfusions for congenital Diamond–Blackfan anemia. A fall in white cell count during week 8 rapidly progressed to agranulocytosis in week 9 followed by Staphylococcus aureus sepsis and pneumonia. She was given antibiotics and filgrastim, followed by glucocorticoids and ciclosporin, because of persistent agranulocytosis. However, the neutrophil count remained low and she died.
While in Diamond–Blackfan anemia only red cell production is affected, bone marrow examination in this patient on day 23 showed variable cellularity, with lympho cytic infiltration and fibrosis. In areas of low cellularity, mainly macrophages and megakaryocytes were found. Granulopoi esis and erythropoiesis were scarce. The lymphoid infiltrates consisted mainly of a mixture of CD4þ and CD8þ9 cells (CD, cluster of differentiation). CD117 staining showed a diffuse increase in mast cells. Bone-marrow flow cytometry showed that 72% of the cells were in the lymphocyte region, of which 86% were T cells with signs of activation. This report also illus trates that, despite regular monitoring, agranulocytosis can occur unexpectedly and can progress rapidly. There is one more case on record of agranulocytosis (together with reversible thrombocytope nia) in a patient with Diamond–Blackfan anemia who received deferiprone (27A) and another of neutropenia that slowly
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progressed to aplastic anemia (28A). Patients with Diamond–Blackfan may be more susceptible to agranulocytosis from deferiprone than those with thalassemia. In vitro progenitor cell cultures, using venous blood samples from 16 patients with major thalassemia and normal blood counts, yielded unexpected findings (29CR). Nine patients (three with splenect omy) received subcutaneous deferoxamine 45 mg/kg/day on 5 days/week, 7 patients (four with splenectomy) took deferiprone 75 mg/kg/day and there were 10 healthy controls. Granulocyte–erythrocyte–monocyte– megakaryocyte colony-forming units were more common in those who received defer oxamine or deferiprone than in the controls. Granulocyte–macrophage colony-forming units were more common and macrophage colony-forming units less common with deferiprone than in the controls. Granulo cyte colony-forming units were more com mon with deferoxamine than in the controls. Addition of serum from patients taking deferiprone to cultures of cells from the controls resulted in maturation arrest of the granulocytic lineage. These findings sug gest that deferiprone can cause maturation arrest of granulocyte–macrophage colonyforming units, an effect that may play a role in the pathogenesis of deferiprone induced agranulocytosis. Immunologic Rare serious adverse drug reactions probably result often from a com bination of different susceptibility factors, both known and unknown. Henoch–Schönlein purpura, with renal and pulmonary involve ment and intestinal invagination, has been reported in temporal association with expo sure to deferiprone (30AR). • A 7-year-old splenectomized boy with b-thalassemia, who had been receiving erythrocyte transfusions and deferoxamine for most of his life for a Coombs-positive hemolytic anemia, was given low-dose prednisolone and cyclophosphamide. Because of non-adherence and a serum ferritin concentration of 11489 ng/ml, the deferoxamine was replaced by deferiprone 60 mg/kg/day. After 5 months he developed arthritis of the ankles and palpable purpuric
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lesions on the legs. There was no history of infection, and virus serology and bacterial cultures were negative. A renal biopsy showed diffuse Henoch–Scho¨ nlein nephritis with crescent formation and immunoglobulin A (IgA) deposition in the mesangium and glomerular basement membrane. Deferiprone was withdrawn. At follow-up 2 years later renal function was normal and there was no proteinuria. DNA analysis because of recurrent attacks of abdominal pain showed familial Mediterranean fever and a homozygous M694V mutation.
therapeutic index of less than 0.025 she remained asymptomatic, but whereas initi ally her fundi had been normal, she slowly developed a pigmentary retinopathy. At 33 years the dose of deferoxamine was increased to 49 mg/kg/day and the deficits in dark-adapted visual sensitivity and postreceptor retinal sensitivity relapsed. When the dose of deferoxamine was again reduced, the dark-adapted visual sensitivity recovered. Mild deficits in post-receptor sensitivity persisted, as did deficits in photo receptor sensitivity.
In this patient Henoch–Scho¨ nlein purpura was thought to have developed because of the co-occurrence of M694V homozyg osity (an established susceptibility factor), profound cellular and humoral immunolo gical disturbances secondary to thalasse mia, and perhaps treatment with deferiprone.
The recovery of post-receptor sensitivity suggests that ‘remodelling’ of the retina and its functional processes is the basis for recovery of visual sensitivity despite irreversible compromise of photoreceptor function, leaving the retina particularly vulnerable to new exposure to deferox amine. The relation between retinal injury resulting from iron storage and that secondary to chelation treatment with deferoxamine has been reviewed (32AR).
Deferoxamine (SED-15, 1058; SEDA-29, 237; SEDA-30, 274; SEDA-31, 402)
Special senses Eyes A detailed case study of a woman with major thalassemia, receiving long-term deferoxamine 50 mg/kg/ day, yielded valuable information on deferoxamine-related retinopathy (31AR). • A 28-year-old woman with previously nor mal visual and retinal responses found that her eyes did not adjust to the dark. Eight weeks before, heart failure and raised liver iron concentrations had prompted a dou bling of the dose of deferoxamine. Visual acuity was 20/200 in both eyes. There were dense central and paracentral scotomata, and dark-adapted visual sensitivity was 2 log units below normal. Scotopic electrore tinography showed deficits in rod photore ceptor and post-receptor sensitivity. Deferoxamine was withdrawn and her visual acuity and visual fields rapidly normalized, while her dark-adapted visual sensitivity gradually improved. Three weeks later deferoxamine was restarted in a dose of 12 mg/kg/day and gradually increased to 25 mg/kg/day. During follow-up dark-adapted visual sensitivity gradually became normal, as did post-receptor sensitivity, but deficits in rod photoreceptor sensitivity persisted (at less than half the baseline sensitivity). While receiving deferoxamine doses adjusted to a
Ears The physiological capacity for elimination of iron from intracranial spaces is limited. Chronic or recurrent subarachnoidal bleeding, a rare condition, can cause superficial hemosiderosis in the central nervous system (33CR). As the vestibulocochlear nerve runs through the pontine cistern and has a long glial segment, superficial hemosiderosis almost always has auditory effects and causes bilateral sensorineural hearing loss. MRI scanning is very sensitive to ironcontaining hemosiderin and typically shows a rim of hypointensity on T2-weighted images, predominantly affecting the surfaces of the brainstem and cerebellum, the cranial nerves and the spinal cord. Pure-tone audiometry is used in the early detection of deferoxamine ototoxi city but may be insufficiently sensitive. In 60 patients with thalassemia receiving sub cutaneous deferoxamine 40 mg/kg/day on 5 days/week, distortion-product otoacous tic emission was compared with pure-tone audiometry (34C). The former was more sensitive than the latter and as a screening
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tool has the advantage of being non invasive, objective, rapid, and easy to use. Urinary tract Deferoxamine is contraindi cated in patients with severe kidney disease, and in overdose acute renal failure can occur (SEDA-28, 256). However, deferoxamine is commonly used off-label to remove alumi nium and to prevent or treat aluminiumrelated bone disease in patients with chronic kidney disease stage 4 (GFR 15–30 ml/min ute). The clinical and pathological findings in deferoxamine-induced acute renal failure in a patient with a renal transplant have been described (35AR). • A 58-year-old man with a cadaveric kidney transplant for Goodpasture’s syndrome who was taking long-term oral ciclosporin (trough concentration 90 µg/l), prednisolone, candesar tan, carvedilol, furosemide, verapamil, panto prazole, benzbromarone, pravastatin, ezetimibe, and warfarin was given subcutaneous deferox amine 2 g/day for 3 weeks, and 1 day after the last infusion was found to have renal impair ment. The serum creatinine concentration had increased to 250 µmol/l, there was proteinuria 1.1 g/day and the creatinine clearance was 31 ml/minute. To exclude graft rejection, a renal biopsy was performed. There were no signs of acute humoural or cellular rejection. There was no isometric vacuolization or microcalcification, as signs of calcineurin inhibitor toxicity, although the arterioles had marked cuff-like hyalinosis, indicating chronic vascular ciclosporin toxicity. There was about 15% cor tical tubular atrophy, interstitial fibrosis in a non-striped pattern and a partially flattened epithelium with attenuated brush borders, indicating acute tubular damage in the remain ing cortical tubules. The acutely damaged cor tical tubular epithelial cells had degenerated mitochondria, with myelin-like figures and loss of cristae, but there was no swelling of mitochondria or endoplasmic reticulum.
The authors suggested that the underlying mechanism of renal tubular toxicity in this patient was removal of iron from the mito chondria and subsequent depletion of mito chondrial ATP. The mitochondrial changes in this patient were different from the pat tern commonly seen in acute tubular injury, and may be diagnostic of deferoxamine toxicity. It is advisable to monitor renal function in patients with renal disease who receive deferoxamine.
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Infection risk Deferoxamine and changes in iron metabolism may increase the infec tivity of a variety of fungi and bacteria (SED-15, 1064; SEDA-29, 237). In a case of endocarditis due to Salmonella enterica subsp. arizonae, chelation therapy with deferoxamine was thought to have been a possible susceptibility factor (36Ar).
PENICILLAMINE AND RELATED DRUGS (SED-15, 2729; SEDA-29, 238; SEDA-30, 274; SEDA 31, 403)
Penicillamine Uses In children, penicillamine-stimulated urinary copper excretion is a reliable non invasive test for Wilson’s disease. In a liver biopsy-controlled study in 43 patients it was also reliable and safe in adults; patients with penicillamine-stimulated urinary copper excretion below 1057 µg/day are unlikely to have Wilson’s disease and are unlikely to benefit from liver biopsy (37cr). In patients with an acute Wilsonian crisis, prompt copper chelation plus plasmapher esis can be life-saving. In an 18-year-old girl with Wilson’s disease, acute hemolysis and impending liver failure, chelation with peni cillamine (dose unspecified) and plasma pheresis led to recovery (38A). Observational studies In a trial in 15 preterm neonates, daily enteral penicillamine (in a locally produced formulation, dose not specified) for 2 weeks after birth elimi nated stage I and II retinopathy of prema turity but not of laser surgery (39cr). There were no adverse effects in these babies. The finding that penicillamine in high doses, as used in Wilson’s disease, reduces total skin collagen has prompted a trial in diffuse cutaneous systemic sclerosis. In a retrospec tive analysis of 84 patients with recent onset progressive disease, penicillamine, median dose 750 mg/day for at least 3 months, caused
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significant reduction in skin disease and improvement of renal, cardiac and pulmon ary involvement (40cr). At the last followup, 20% of the patients were still taking penicillamine, 30% had stopped because of disease improvement and 21% had stopped because of adverse effects, showing the familiar pattern of proteinuria (n = 7), rash (n = 4), neutropenia (n = 3), and pemphigus (n = 2). In addition, 23% had died, mainly from complications of the disease. Four patients were lost to follow-up. Systematic reviews Penicillamine 600– 1200 mg/day has been compared with pla cebo or no intervention in primary biliary cirrhosis, another disorder in which peni cillamine has been tried because of its effects on collagen, in a meta-analysis of seven randomized trials in 706 patients (41M). Although the treatment group had significantly reduced serum AlT activity, there were differences neither in other liver tests nor in pruritus, fatigue, liver complications, progression of liver histolo gical stage, liver transplantation, or mortality. Skin An eruption resembling elastoma perforans serpiginosa, with the typical lumpy-bumpy histological appearance and pruritic lesions of 5–7 cm, is a late complica tion of the use of high doses of penicilla mine, and was originally described by Gephart and Bardach (42AR).
OTHER CHELATORS Edetic acid (ethylenediaminetetraacetic acid, EDTA) (SED-15, 1300; SEDA-30, 276; SEDA-31 405)
Uses A newly identified inherited disorder in a 12-year-old girl, characterized by
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manganese storage, dystonia, polycythemia, and liver injury, was successfully treated with monthly infusions of calcium disodium eden tate 40 mg/kg/day for 5 consecutive days (43A). Penicillamine had previously been ineffective.
Urinary tract Lead compounds are nephrotoxic. In a placebo-controlled trial, the protective effect of lead chelation was studied in a follow-up study of 4 years duration in 58 Chinese patients with a high normal lead burden and non-diabetic chronic kidney disease (serum creatinine concentrations 133–345 µmol/l) (44cr). Compared with placebo there was a sub stantial reduction in the progression of renal insufficiency.
Interference with diagnostic tests The use of EDTA as an anticoagulant in blood samples can cause pseudothrombo cytopenia in automated cell counts (SED 15, 1202), usually because of clumping of neutrophil leukocytes and only rarely lym phocytes. In vitro EDTA caused artifactual agglutination of lymphocytes in a patient with a large B-cell non-Hodgkin’s lym phoma (45A).
Trientine
(SED-15, 3508; SEDA-29, 239)
Comparative studies In patients with Wilson’s disease initial worsening of neu rological symptoms is a notorious compli cation of chelation therapy. In an 8-week double-blind trial, initial treatment with trientine 1 g/day and zinc 100 mg/day (salt not specified) was compared with tetrathiomolybdate 60 mg/day and zinc 100 mg/day, with special reference to the worsening of neuropsychiatric symptoms (46A). The adverse events are shown in Table 1. Of the 23 patients who received trien tine, 6 fulfilled the criteria for neurological deterioration, while of the 25 patients
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Table 1. Adverse events in a comparison of trientine and tetrathiomolybdate Adverse event
Trientine (n = 23)
Tetrathiomolybdate (n = 25)
Rise in aminotransferases Anemia and/or leukopenia Neurological deterioration Death
0 1 6 4
4 3 1 2
who received tetrathiomolybdate, dete rioration occurred in only 1, suggesting that tetrathiomolybdate is superior to tri entine in the initial treatment of neurolo gical Wilson’s disease. Four patients in the trientine arm died and two in the tetra thiomolybdate arm. With one exception of a case of fatal leukemia, all the patients who died had severe neurological impair ment. As four of the seven patients with neurological deterioration died, this event may forecast poor survival. Drug dosage regimens Trientine and zinc have become major tools in the manage ment of Wilson’s disease. Zinc (usually zinc acetate dehydrate 75–150 mg/day in three divided doses) inhibits the enteric absorption of copper by stimulating intest inal and hepatic metallothioneins. As a cop per chelator, trientine when taken with meals also reduces enteric copper absorp tion and promotes urinary copper excretion; the usual daily dose is 500–1500 mg/day, in two to four divided doses. However, non-adherence is a common problem. In a retrospective review of the clinical records of 22 children with Wilson’s disease, new increases in serum aminotransferase activities during long-term treatment (mostly with trientine and/or zinc) were commonly found to be secondary to non adherence (47CR). In a retrospective study in five patients, trientine 500–1000 mg/day as a single dose was effective in controlling Wilson’s dis ease (48c). Larger prospective trials are needed to confirm the efficacy of oncedaily trientine and to determine the required dose.
POLYSTYRENE SULFONATES (SED-15, 2894; SEDA-29, 239; SEDA-30, 275)
Treatments for non-oliguric hyperkalemia in preterm neonates, including ion exchange resins, have been reviewed (49M). Comparative studies In a comparison of rectal sodium polystyrene sulfonate 1 g/kg every 4 hours (n = 15) and salbutamol infu sion 4 micrograms/kg every 4 hours (n = 30) for non-oliguric hyperkalemia in preterm infants, there were no important adverse events in those who received salbutamol, but two cases of severe ventricular tachycar dia and one of intestinal obstruction in those who received the polystyrene sulfonate (50c). Gastrointestinal Perforated necrotizing enterocolitis requiring resection has been reported in a 27-week, 850 g infant after rectal administration of sorbitol-free sodium polystyrene sulfonate for life-threatening hyperkalemia due to progressive anuria (51A). Although sorbitol has previously been blamed for gastrointestinal damage after the administration of Kayexalate (SED-15, 2896), this case suggests that sodium polystyrene sulfonate can also cause such damage. Rectal stenosis due to sodium polystyrene sulfonate crystals, requiring colonic resec tion, has been reported in a 46-year-old man who was given sorbitol-free Kayexa late by a nasogastric tube (52A). Histology showed fibrosis of the submucosa with numerous basophilic polygonal crystals sur rounded by macrophages.
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