Prevention of further absorption of poison

• intoxication by inhalation
• remove from the source of exposure
• intoxication by dermal exposure
• removal of contaminated clothing
• skin, mucosae and/or eye washing
• intoxication by oral ingestion :
• emesis. Contraindicated if the patient has ingested strong acid or alkali, CNS stimulants (further stimulation associated with vomiting may precipitate convulsions), if he is comatose or in a state of stupor or delirium or has inspirated a petroleum distillate (risk of aspiration of gastric contents => ab ingestis chemical pneumonia).
• stroking the posterior pharynx
• PO syrup of ipecac (Psychotria ipecacuanha) followed by a drink of water (15-30') : it acts on both the CTZ and as a local irritant on the GI tract (hence effective even when antiemetic drugs have been assumed. Risk : cardiotoxicity due to emetine.
• SC apomorphine (3-5')
• (oro)gastric lavage / stomach wash within 60' by inserting a 24-Fr (in children) or a 36-Fr (in adults) tube into the stomach of a left-side-placed patient and washing it with 120-300 mL normal saline at one time (so that the poison is not pushed into the intestine) for 10-12 washings and a total of 1.5 to 4 liters of lavage fluid. Contraindications as for emesis (aspiration preventable by endotracheal tube with inflatable cuff and elevated table foot) + mechanical damage
• chemical adsorption to prevent absorption and enterohepatic recirculation
• activated charcoal PO or via a gastric tube (Ultracarbon^®; it doesn't adsorb alcohols, hydrocarbons, metals, and corrosives) in a charcoal:drug ratio > 10:1
• universal antidote (in practice uneffective !) = 2 parts burned toast + 1 one part tannic acid (strong tea) + 1 part MgO₂
• polythiol resin against methylmercury intoxication
• chemical inactivation
• NH₄⁺ + formaldehyde => hexamethylenetetramine
• sodium formaldehyde sulfoxylate + mercuric ion => metallic mercury
• pH neutralization for intoxication with ...
• ... acids : bicarbonates (=> CO₂ may cause gastric distention and even perforation), antacids
• ... alkali : vinegar, orange juive, lemon juice
This may product excessive heat.
• diluition with water or milk
• purgation after > 1 hr by using
• osmotic cathartics
• whole-bowel irrigation using high-molecular-weight polyethylene glycol and isosmolar electrolyte solution (PEG-EESS) (Golytely^®, Colyte^®)

• antagonism at receptor level
• opioid receptors antagonists for opioids
• autoject nerve agent antidote L4A1 (Combopen^®; L5A1 is a training device). Each 2 mL dose contains :
• pralidoxime methane sulphonate (P2S : 31.5 mg) reactivates AChE by exerting a nucleophilic attack on the dialkylphosphate or dialkylphosphonate groups attached to a serine moiety of the esteratic site of the enzyme. Following poisoning with nerve agents the stability of the inhibiting group is enhanced by partial dealkylation (ageing), leaving a monoalkyl phosphate or phosphonate group. The rate at which this occurs is variable and depends on the nature of the alkyl groups. Pralidoxime will not reactivate aged enzymes. It might have caused the Gulf War syndrome (GWS).
• atropine sulphate (USP : 2 mg) antagonises the effects of ACh at muscarinic sites but has little effect at nicotinic sites.
• avizafone (10 mg) is rapidly hydrolysed in the blood and tissues to diazepam
Shelf-life : 7 ½ years. To be stored at 0-5°C and protected from light. The contents are not to be used if the pack is removed from cold for > 6 months. Personnel will normally have received NAPS : if symptoms persist, dose should be repeated at 15 minute intervals, with a maximum total dose of 3 injections
• immunotherapy
• antisera
• mAbs
• heavy metals chelation therapy
• lead (Pb²⁺) :
• succimer / 2,3-dimercaptosuccinic acid (DMSA) (Chemet^®) is an oral drug that binds to lead and mercury and is given every 8 hours for 5 days and then every 12 hours for 2 more weeks. It is usually used for blood lead levels between 45 and 69 mg/dl. The lead level should be rechecked 7 - 21 days after treatment is begun to determine if treatment has been adequate.
• edetate calcium disodium (CaNa₂EDTA) (Calcium Disodium Edetate^®, Versene^®) (please note dicalcium sodium EDTA is used as anticoagulant !) is used for blood lead levels > 69 mg/dl and is given as a continuous infusion or as intramuscular injections for 3-5 days. Nephrotoxic.
• 1-2 g/day i.v.
• 0.3 g/day i.m.
• dimercaprol / 2,3-dimercaptopropan-1-ol / British anti-lewisite (BAL)
• D-penicillamine + pyridoxine (25 mg/die; 1 g/day p.o. in 3 administrations per day)
• 2,3-dimercapto-1-propanesulfonic acid sodium (Dimaval^®) for 4 weeks
• mercury (Hg²⁺)
• dimercaprol / 2,3-dimercaptopropan-1-ol / British anti-lewisite (BAL)
• D-penicillamine + pyridoxine (25 mg/die)
• arsenic (As)
• dimercaprol / 2,3-dimercaptopropan-1-ol / British anti-lewisite (BAL) : 3-5 mg/kg deep IM q4h for 2 d, then q12h until recovery or until PO therapy can be started. May cause nausea, vomiting, chest pain, seizure, tachycardia, or abscess formation at the injection site; alkalinize urine to facilitate excretion; may be nephrotoxic and may cause hypertension; caution when administering to patients with oliguria or G-6-PD deficiency; may induce hemolysis in patients with G-6-PD deficiency
• D-penicillamine + pyridoxine : 15-40 mg/kg/d PO divided qid for 5 d; not to exceed 2 g/d (1 g/d in children). Has a high incidence of adverse effects that include hypersensitivity reactions, optic neuritis, nephrotoxicity, and thrombocytopenia; agranulocytosis and aplastic anemia may occur. Increases effects of immunosuppressants, phenylbutazone, and antimalarials; decreases digoxin effects; effects may decrease with coadministration of zinc salts, antacids, and iron; may cross react with penicillin in allergic patients
• succimer / 2,3-dimercaptosuccinic acid (DMSA) (Chemet^®) : 10 mg/kg PO q8h for 5 d, followed by 10 mg/kg PO q12h for 14 d; repeat dosing may be necessary. Do not administer concomitantly edetate calcium disodium or penicillamine
• Dimerval (DMPS) : international standard drug for heavy metal poisoning but not approved in USA. Adult Dose 200 mg IV q4h until PO therapy can be started, then 100 mg PO tid
• cadmium (Cd)
• edetate calcium disodium (CaNa₂EDTA) (Calcium Disodium Edetate^®, Versene^®)
• dimercaprol / 2,3-dimercaptopropan-1-ol / British anti-lewisite (BAL)
• dithiocarbamates
• iron (Fe) has 6 electrochemical coordination sites that should be tightly bound to block the ability of the iron ions to catalyze redox reactions and to allow efficient transport and excretion without iron redistribution.

Indications :
• thalassemia major or thalassemia/hemoglobin E disease : approximately 72,000 patients receive regular blood transfusions worldwide. Because DFO is expensive and cumbersome to administer, about 42,000 receive no chelation therapy; about 25,000 are prescribed DFO and 5000 (mainly in India) receive deferiprone (C.B. Modell). Some 2000–4000 thalassemia patients die each year from iron overload. The lack of an inexpensive orally active iron chelator has been a major reason why iron chelation therapy is not considered for these patients in poor countries. In many of these countries, regular blood transfusions, which in the absence of iron chelation will inevitably lead to death from iron overload, are not even contemplated. Indeed, only about 3500 of the 27,000 transfusion-dependent children born each year are transfused at all
• patients with non-transfusion-dependent but nevertheless severe genetic diseases of hemoglobin synthesis (thalassemia intermedia) who become iron overloaded because of increased iron absorption but are too anemic to undergo phlebotomy to reduce iron overload
• regularly transfused patients with, for instance, sickle cell anemia, myelodysplasia, myelofibrosis, red cell aplasia, aplastic anemia, congenital dyserythropoietic anemia, and congenital sideroblastic anemia
Iron chelators should reduce tissue iron levels, prevent excessive organ iron accumulation and neutralize toxic labile iron pools. Based on the number of the coordination sites, iron ligands are termed hexadentate, tridentate and bidentate. Denticity is directly related to the molecular weight: hexadentate chelators have a higher molecular weight as compared to tri- and bidentate molecules. However, the diffusion through biological membranes and hence the absorption from the gastrointestinal tract and the cellular penetration are governed not only by molecular size, but also by lipophilicity and net molecular charge^ref. For example, DFO, like many hexadentate chelators, is not absorbed in the gastrointestinal tract, but derivatives of hydroxybenzyl-ethylenediamine-diacetic acid (HBED), another hexadentate iron chelator, possess good oral availability. In recent years extensive research has been directed toward bidentate and tridentate ligands that are more likely than hexadentate chelators to be orally active and to penetrate cells. Selectivity and affinity for the ferric (Fe³⁺) oxidation state are important characteristics of an iron chelator. Important properties for an ideal iron chelator.
• high and specific affinity for Fe³⁺
• high chelating efficiency
• slow rate of metabolism
• tissue and cell penetration
• no iron redistribution
• relatively non-toxic
• achievement of negative iron balanceIn TM, about 100–200 mL of pure red cells/kg/y are transfused, equivalent to 0.32–0.64 mg/kg/d of iron^ref.1 In thalassemia intermedia, iron absorption is about 5–10 times the normal amount, around 0.1 mg/kg/d. Excretion levels of these rates must be achieved to maintain a "safe" level of body iron.
• low cost
• oral availability
These properties reduce the chelation of other biologically important bivalent metals, such as copper and zinc, while the effect on non-essential trivalent cations, such as aluminum and gallium, remains negligible. Under biological conditions the affinity of chelators for iron and the stability of ligand-metal complexes is expressed as pF³⁺ value, that is, the negative logarithm of the concentration of the free Fe³⁺, measured in a solution of 10 µM ligand and 1 µM Fe³⁺ at pH 7.4^ref. The larger the pF³⁺, the higher is the stability of the ligand-metal complex. Rapid conversion to glucuronidate metabolites limits the efficacy of many iron chelators. Most of the administered DFO and DFP is rapidly metabolized to the inactive glucuronide, resulting in a net chelating efficiency < 10%. Therefore, one strategy to increase chelating efficiency is to design compounds with a reduced rate of glucuronidation.
• toxic effects of iron chelators : designing an ideal iron chelator is a difficult challenge because of the iron paradox: iron is an essential element for many important metabolic functions (oxygen transportation and utilization, DNA synthesis, electron transport and many other biological processes), but it becomes toxic when accumulated. A chelator should remove only excess iron. Thus, in addition to possible direct toxic effects, iron chelators may alter iron homeostasis (absorption, distribution and utilization), interfere with iron-dependent enzymes (ribonucleotide reductase, lipooxygenase) or remove other metals such as zinc or calcium from essential metabolic pools. Characteristics of the compound such as molecular weight, lipophilicity/hydrophilicity balance, affinity and selectivity for Fe³⁺, pharmacokinetics, distribution and metabolism play a role in determining the boundary between safety and toxicity
• development of iron chelators : development of an iron chelator requires several distinct and rigorous procedures, the first being the definition of the chemical properties of the ligand and of the ligand-iron complex. The second step consists of cellular studies using red blood cells, reticulocytes, cell lines and primary cell cultures (hepatocytes, myocardial and reticuloendothelial cells). Subsequently, animal models, both non-iron overloaded and iron-overloaded, are critical to evaluate the safety and efficacy of iron chelators. Unfortunately, the predictive power of the animal models is low because of the frequent differences between iron-overloaded animals and humans, and because of differences between species in iron metabolism. Efficacy in animals may not translate into comparable efficacy at tolerable doses in man. Both acute and long-term toxicity studies in different species of animals are essential for planning clinical trials. To obtain the registration of a new compound, Phase I, II and III clinical trials, performed according to stringent requirements established by regulatory agencies, are necessary to define the safety and pharmacokinetic and pharmacodynamic characteristics of the chelator in humans, to find the therapeutic dose range and to evaluate the tolerability and the efficacy in comparison with the reference drug. Although the process of product development is very rigorous, the intrinsic limitations of clinical trials (e.g., efficacy-oriented, highly selected population, short duration, limited sample size, risk factors and exclusion criteria) make it difficult to detect all safety concerns during this phase. Post-marketing pharmacovigilance is defined as the ongoing process of evaluating and improving the safety of drugs. Once a product is marketed, there is generally a large increase in the number of patients exposed, including those with comorbid conditions and those being treated with concomitant medical products. Therefore, pharmacovigilance is critical to establish and regularly review the risk/benefit ratio of iron chelators.
Agents :

• deferoxamine (DFO) mesylate (Desferal Mesylate^®) : the management of iron overload using subcutaneous DFO has been extensively reviewed^ref. DFO is hexadentate, 1 molecule binding 1 atom of iron. Standard therapy is with 40 mg/kg infused subcutaneously over a period of 8–12 hours on 5–7 nights each week using a battery-operated infusion pump. Therapy is usually begun in children after 10–20 transfusions have been given or when serum ferritin levels reach 1000 µg/L. Vitamin C, 200 mg, given orally when the infusion is started, enhances urine iron excretion. Alternative routes of administration that have been tried include twice-daily bolus subcutaneous injections^ref, continuous infusions over 24 or 48 hours using disposable prefilled balloons^ref, and continuous intravenous infusion using an indwelling central line or Portacath^ref

First introduced in 1976 as subcutaneous treatment for TM, DFO has substantially improved the life expectancy in the disease^{ref1, ref2, ref3}. Deaths continue to occur from cardiac failure due to iron overload, but these are mainly caused by lack of compliance^{ref1, ref2}. Defining compliance as > 250 infusions a year, Gabutti and Piga^ref found that 95% of compliant patients are alive at 30 years of age, compared with only 12% of noncompliant patients. Modell et al^ref reported that only 50% of TM patients in the UK reach 35 years, the poor result again being attributable to cardiac failure due to poor compliance. DFO can reverse iron-induced cardiomyopathy in some but not all patients^{ref1, ref2}. Continuous intravenous DFO results in comparatively rapid improvement in ventricular function compared with the slow clearance of cardiac iron, which can remain high even after 1 year. Recent studies show that liver iron clears more rapidly and, despite severe iron overload initially, may be normal at 6 months (Anderson L, Bunce N, Davis B, et al. Reversal of siderotic cardiomyopathy: a prospective study with cardiac magnetic resonance (CMR) [abstract]. Heart. 2001;85(suppl 1):33).Although cost and lack of compliance are the main obstacles to DFO therapy, complications may also exclude some patients. High-frequency hearing loss, deafness, and retinal damage with impaired vision (e.g., night blindness) can occur when large doses of the drug are given to less severely iron-loaded patients, especially children, in whom growth retardation and skeletal damage have also been reported. Generalized hypersensitivity is rare, but painful local reactions at the injection site are common and often lead to lack of compliance. Infection with Yersinia is increased, and on rare occasions other infections (e.g. Klebsiella) are precipitated.
• 1,2-dimethyl-3-hydroxypyrid-4-one (L1) / deferiprone (DFP) / CP20 (Ferriprox^®, Kelfer^®) is an orally active iron chelator available for clinical use, designed in R.C. Hider’s laboratories^ref. First tested clinically in 1987, this drug is now licensed in 25 countries for patients with TM unable to be effectively treated with DFO. Reviews of its chemistry, pharmacology, and clinical results have recently been or are being published^{ref1, ref2, ref3}.. It was licensed first in India in 1995 and subsequently in Europe in 1999. At present, DFP is licensed in Europe for patients for whom treatment with DFO is inadequate. Overall DFP is currently available in approximately 50 countries. Studies have demonstrated a stable or declining mean serum ferritin and liver iron concentration during long-term therapy in most transfusiondependent patients, although iron accumulation continues in others^ref. Agranulocytosis is the most serious side effect, with a reported incidence of 0.6 per 100 patient-years^ref. More common but less serious side effects are gastrointestinal symptoms (e.g., nausea, vomiting, gastric discomfort), arthralgia, zinc deficiency, and fluctuating ALT levels, particularly in anti-HCV⁺ patients. Retrospective studies in patients treated with DFP have shown significant improvement in cardiac MRI, consistent with a reduction in cardiac iron overload and improved cardiac function, in comparison with patients treated with DFO^{ref1, ref2}. These observations support a potential cardioprotective role of DFP that needs to be confirmed in prospective randomized trials.

Pharmacokinetics : deferiprone is rapidly absorbed, appearing in plasma within 15 minutes of ingestion, with a peak plasma level within 45–60 minutes. It forms a 3:1 chelator:iron complex that is excreted with the free drug in urine. Only 4% of a single oral dose of the drug is excreted bound to iron, even in heavily iron-loaded patients. Its iron chelation site is inactivated by glucuronidation, the speed of which varies from patient to patient. This explains much of the individual variation in response, the area under the curve of the concentration of free drug in plasma being related to the amount of iron excreted^ref. Deferiprone mobilizes iron from parenchymal and reticuloendothelial pools and from transferrin, ferritin, and hemosiderin. Unlike DFO, it is also capable of chelating iron from intact red cells in vitro and in vivo, shown in patients with sickle cell anemia^ref and thalassemia intermedia^ref. The enhanced ability of DFP to cross cell membranes may underlie what is emerging as its superior ability, compared with DFO, to protect the heart from iron and also the "shuttle effect" for iron when the 2 drugs are given simultaneously. The concept of combination therapy.

Abbreviations: DFO, deferoxamine; DFP, deferiprone; NTBI, non-transferrin-bound iron.
Clinical studies : short-term studies showed that iron excretion occurs in the urine with negligible amounts in feces, although some subsequent studies have suggested excretion up to 33%. Iron excretion increases with the dose of the drug and the transfusional iron load of the patients. Although initial studies showed that 100 mg/kg/d was more effective^{ref1, ref2}, the dose used in most trials has been 75 mg/kg/day fractionated into 3 doses. This dose was reported in early studies to be as effective as standard-dose DFO at increasing urine iron excretion^{ref1, ref2}. In most patients urine iron excretion around 0.5 mg/kg/day was achieved with no indication of a diminishing response with time. There were early concerns that doses > 75 mg/kg might produce more side effects, e.g., arthropathy^ref. Balance studies suggest that total iron excretion with 75 mg/kg deferiprone is somewhat < that with 40 mg/kg DFO given over 8 hours subcutaneously, but only small numbers of patients have been studied and there is wide patient-to-patient variability (Grady RW, Berdoukas V, Rachmilewitz EA, et al. Combinations of desferrioxamine and deferiprone markedly enhance iron excretion [abstract]. Blood. 2002;100:241a). Final mean serum ferritin concentrations in 9 published trials in patients (mainly DFO ‘failures’ with TM) treated from 1 to 56 months with deferiprone have ranged from 1779 to 3273 µg/L^ref. In 7 of the trials, there was a significant fall in serum ferritin, and in 2 there was no significant change. Serum ferritin levels fell mainly in the patients starting with the highest levels. In 6 studies in which serial liver iron determinations were made, hepatic iron fell significantly in 1, rose significantly in 1, and did not change significantly in the other 4.22 When SQUID technique was used in 54 thalassemia patients (aged 7–22 years), median liver iron concentration rose from 1456 mg/g liver to 2029 mg at 2 years and 2449 mg at 3.2 years^ref. These patients were well chelated before starting deferiprone, but their iron intake from transfusions rose substantially during the study. Recent MRI data retrospectively comparing 15 patients treated long term with deferiprone with 30 matched patients treated with DFO, in which liver MRI T2* was converted to estimated dry-weight liver iron, showed significantly higher liver iron: 5.1 versus 3.5 mg/g in the deferiprone compared with the DFO group^ref. In a short-term study, raising the dose of deferiprone to around 100 mg/kg led to reduction of serum ferritin levels in patients inadequately chelated at 75 mg/kg^ref. Prospective trials are needed to assess whether doses of deferiprone (around 100 mg/kg daily) can safely be given long term and will result in more effective iron chelation in patients inadequately chelated on 75 mg/kg daily. There is also a need for further (> 3 years) long-term studies to determine liver iron levels in large numbers of patients receiving deferiprone to determine more accurately the proportion of patients in whom liver iron is adequately controlled. The most important aspect of iron chelation therapy is protection of the heart. Two recent studies, albeit retrospective, show significant benefit for the patients receiving deferiprone compared with DFO. In a London study, 15 TM patients who had received deferiprone 75 mg/kg/d for 3 years showed a lower incidence of cardiac disease (assessed by echocardiography and need for cardiac drug therapy) and lower cardiac iron estimated indirectly by MRI T2* than 30 age- and sex-matched patients who had received DFO 40 mg/kg/d subcutaneously on 5–7 days each week (median myocardial T2* 34.0 vs 11.4 ms, P = .02)^ref. Excess myocardial iron (T2* < 20 ms) was significantly less common in the deferiprone group (27%) than in the DFO group (67%), P = .025. In a Turin study, 54 patients who had received deferiprone were compared retrospectively with 75 patients who had received DFO; the drugs were given at standard doses over an average of 6 years^ref. No patient in the deferiprone group compared with 3 in the DFO group died of cardiac failure. Deterioration of preexisting cardiac dysfunction or new cardiac disease occurred in 2 (4%) of the deferiprone-treated patients compared with 15 (20%) of the DFO group (P = .007)^ref. Formal prospective studies are needed to confirm the apparent greater cardioprotective effect against iron toxicity of deferiprone compared with subcutaneous DFO suggested by these two retrospective studies. In a short-term (12 months) prospective randomized study, Maggio et al^ref found no difference in any of the parameters used to detect cardiac abnormalities between patients receiving DFO and patients receiving deferiprone.
Complications : the incidence of the now well-established complications of deferiprone therapy—agranulocytosis, neutropenia, arthralgia, gastrointestinal symptoms, transient changes in liver enzymes, and zinc deficiency—has been established in recent prospective trials^{ref1, ref2, ref3} and reviewed^ref. Hepatic fibrosis has also been suggested in one small retrospective study to be a consequence of deferiprone therapy^ref. However, recent evidence based on 56 repeat biopsies in patients treated for a mean of 3.1 years shows no evidence for this^ref. No other study has reported significant increase in hepatic fibrosis ascribed to deferiprone. Transient changes in ALT levels, especially in the first few months of therapy and in hepatitis C antibody–positive patients, have been observed. The mean ALT levels did not increase among 151 patients treated for 3 years^ref. Occasional patients have, however, been withdrawn from therapy in some trials because of concerns about raised ALT levels^ref. Agranulocytosis, the most serious complication of deferiprone, occurs in about 1% of patients and appears to be idiosyncratic; it is probably more frequent in females. Patients with agranulocytosis should be permanently withdrawn from therapy, although a proportion of patients with less severe degrees of neutropenia have successfully been re-exposed to the drug. Most patients with the other side effects can usually continue with the drug, often after a period of withdrawal and retreatment initially at a lower dose.
Combination therapy with DFO and deferiprone commenced in 1998, when it was reported that DFO and deferiprone could be safely given simultaneously and that the urine iron excretion achieved is at least equivalent to the iron excretion resulting when the 2 drugs are given on separate days^ref. 6 clinical studies of combination therapy have now been reported. All show decreasing serum ferritin levels and, where measured, decreasing liver iron. Mourad et al^ref, for instance, report that deferiprone 75 mg/kg 7 days a week and DFO 40 mg/kg subcutaneously over 8–12 hours 2 days a week gives approximately equivalent iron chelation, based on serum ferritin levels, to 5 days a week of DFO. Compliance is likely to be improved longer term for a patient needing 2 rather than 5 days of subcutaneous infusions. Combined therapy with deferiprone and deferoxamine (from Liu^ref) :

							urine iron excretion (UIE) (mg/24h or mg/kg/d
	no.	duration (months)	DFP dose (mg/kg/d)	DFO dose (/d)	DFO d/wk	DFP	DFO	DFP + DFO	initial	final	significance
Wonke et alref	5	6	75–110	2 g	2–6	23	36	70	6397	2439	not significant
Balveer K, Pryor K, Wonke B. Combined oral and parenteral iron chelation in beta thalassaemia major. Med J Malaysia. 2001;55:493–497	7 (one additional patient withdrew after 1 month because of gastrointestinal symptoms)	12	75–85	1 g	2	14	—	27	6619	3996	P < .01
Mourad et alref	11	12	75	2 g	2	—	—	49	4153	2805	P < .01
Farmaki K, Anagnostopoulos G, Platis O, Gotsis E, Toulas P. Combined chelation therapy in patients with thalassemia major: a fast and effective method of reducing ferritin levels and cardiological complications [abstract]. Hematol J. 2002;3(suppl 1):79	40 (significant improvement in ventricular dimensions and function and increase in myocardial T2 relaxation time)	6–12	75–100	40–60	2–6	—	—	—	1907	385	not given
Alymara V, Bourantas DK, Chaidos A, et al. Combined iron chelation therapy with desferrioxamine and deferiprone in ß-thalassemic patients [abstract]. Hematol J. 2002;3(suppl 1):81	21	6	60	50 mg/kg	6	—	0.34	0.76	3146	1799	not given
Galanello R, Doneddu I, Dessi E, et al. Iron chelation in thalassemia major: combined treatment with deferiprone and deferoxamine [abstract]. In: 11th International Conference on Oral Chelation in the Treatment of Thalassemia and Other Diseases. Catania; 2001:73	34 (agranulocytosis in 2 patients reversed after 4–5 days; 1 withdrawal with nausea. Transient moderate ALT rise in 6 HCV-negative and 12 HCV-positive patients. One stopped therapy)	3–10	75	20–50	2–5	0.37	0.48	0.77	5097	3963	not given
Kattamis et alref	18 (agranulocytosis in 2 patients—reversed with drug discontinuation)	12	50	2.53–3.0 g	3	0.50	0.46	0.69	4543	3297	P < .007

The basis for this additive or synergistic effect is given by the studies of Grady et al (Grady RW, Berdoukas V, Rachmilewitz EA, et al. Combinations of desferrioxamine and deferiprone markedly enhance iron excretion [abstract]. Blood. 2002;100:241a) and Breuer et al^ref. These suggest that deferiprone enters cells and chelates iron, which it brings into plasma. The iron is then transferred to DFO for excretion in urine and feces. If combination therapy in longer-term studies does not show any unexpected toxicity, it is an exciting therapeutic advance for improving compliance and avoiding large, potentially toxic doses of either drug. Alternating (sequential) therapy with DFO and deferiprone has also been studied in 7 children noncompliant to DFO^ref. Compliance was improved when deferiprone was given for 4 days and then DFO for 2 days each week. Over 6 months, liver iron fell significantly and there was a nonsignificant fall in mean serum ferritin from 5536 to 3778 µg/L. More prolonged studies are needed to determine the place of this approach.
Thalassemia intermedia : oral iron chelation therapy is a potentially attractive option for patients with iron overload who are too anemic for phlebotomy. Olivieri et al^ref first reported a patient with thalassemia intermedia in whom deferiprone was effective in reducing both liver iron and serum ferritin to normal within 12 months of therapy. In 8 thalassemia intermedia patients in Thailand (mainly suffering from thalassemia/HbE) deferiprone at the low dose of 50 mg/kg/d not only significantly reduced serum ferritin and red cell membrane liver iron over 12 months but also resulted in an increase in hemoglobin and serum erythropoietin levels and improvement in weight and appetite. No side effects requiring drug withdrawal were encountered^ref.
Other transfusion-dependent anemias : similar results to those in TM have been obtained with deferiprone in patients with myelodysplasia, myelofibrosis, and other acquired marrow diseases. Although there has been theoretical concern that agranulocytosis may be more frequent in these acquired bone marrow disorders than in TM, there are no data to suggest this.
• desferrithiocin (DFT) is a siderophore originally isolated from Streptomyces antibioticus in 1980 and then produced by chemical synthesis. DFT is an orally available, tridentate, potent iron chelator with a high affinity for Fe³⁺. Soon after its discovery, DFT was actively tested in iron overloaded rats, where effective reduction of liver ferritin iron was demonstrated. Initial single dose safety data showed no relevant acute toxic effects, but longer exposure in rats showed moderate to severe degenerative changes in the proximal tubules of the kidney. The damage was believed to be due to toxic effects of the Fe³⁺ complex, ferrithiocin^ref. Several DFT analogs have subsequently been synthesized and tested in animals. One of these analogs, 4-OH-desaza-desmethyldesferrithiocin, appears to be less toxic while remaining biologically active as an orally administered iron chelator in Cebus apella primates^ref. This analog may enter Phase I human trials shortly.
• hydroxybenzyl-ethylenediamine-diacetic acid (HBED) is a synthetic hexadentate phenolic aminocarboxylate chelator, first synthesized more than 30 years ago, which forms a 1:1 complex with Fe³⁺ with high affinity and selectivity. Initial studies in rodents showed that it was able to clear radiolabeled iron when administered parenterally and that it remained active after oral administration. However, further evaluation in both iron-loaded primates and humans revealed that the oral activity was too small to be of value in the treatment of iron overload^ref. Recently Bergeron et al13 continued the preclinical evaluation of the efficacy and safety of HBED monosodium salt for the treatment of both transfusional iron overload and of acute iron poisoning in animals. Na-HBED was compared with DFO at equimolar doses in iron-loaded Cebus apella monkeys, either as a subcutaneous (SC) bolus or a 20-minute intravenous infusion (IV). In both conditions Na-HBED was consistently about twice as efficient as DFO in promoting iron excretion. Safety evaluation showed no systemic toxicity after either IV administration once daily or SC administration every other day for 14 days in dogs without iron overload. No local irritation at injection sites was found when the Na-HBED concentration was reduced to < 15% in a volume that would be clinically tolerable. Interestingly, the rapid IV infusion of Na-HBED, as may be required for treatment of acute iron poisoning, had little detrimental effect on blood pressure and heart rate. If these results are confirmed in human studies, Na-HBED may prove to be an alternative to DFO for the treatment of acute iron poisoning or chronic iron overload, although it would still require parenteral administration^ref. This alternative may be particularly important for patients allergic to DFO since HBED is a member of a different family of chelators
• pyridoxal isonicotinoyl hydrazone (PIH) is one of a family of aromatic hydrazones produced by chemical synthesis and identified as an effective iron chelator in 1979. PIH is a tridentate chelator with a selectivity for iron comparable to that of DFO. Initially it was found to be effective when given parenterally to mice and orally to rats. Interestingly, PIH and some of its analogs were shown to be potent inhibitors of the production of toxic oxygen-free radicals^ref. Over the years, various PIH analogs have been synthesized and some of them, such as pyridoxal-benzoyl hydrazones, were as much as 280% more effective than PIH. Studies in iron-overloaded patients treated with 30 mg/kg/day of PIH have shown a modest net iron excretion of 0.12 ± 0.07 mg/kg/day, which is much less than the 0.5 mg/kg/day that is required, on average, to achieve negative iron balance in regularly transfused patients^ref. Despite these unsatisfactory results several arguments have been raised in favor of PIH^ref. First, the dose used was lower than the effective dose of 125–500 mg/kg used in experimental animals. Second, the preparation was given to patients after calcium carbonate to prevent acid hydrolysis of PIH, but this approach might have limited the chelator’s absorption because of the low solubility of PIH at a neutral pH. Progress in the development of PIH and its derivatives has been very slow, not only because of the discouraging results in humans, but also because its patent rights are limited. However, recently investigators have examined the chelating potential of 2 additional PIH analogs, alone or in combination with DFO, in cultured iron-loaded heart cells and in hypertransfused rats^ref. The latter studies have shown that the orally administered analogs are about 2–6 times more effective than intraperitoneally administered DFO in mobilizing liver iron in rats
• GT56-252 is a novel orally available iron chelator derived from DFT that forms a 2:1 complex with Fe^3+ref (Marquis JK, Aoude-Dagher R, Guillumat PO. Pharmacology and toxicology of GT56-252, a novel orally available iron chelator [abstract]. 12th International Conference on Oral Chelation in the Treatment of Thalassaemia & Other Disease (ICOC Santorini). 2002:112). Pharmacokinetics studies conducted in rats, dogs and Cebus apella monkeys showed that the compound was orally bioavailable in all 3 species, and the elimination half-life ranged from 3 hours in the rats to 7–8 hours in the dogs. Pharmacokinetic (PK) profiles were similar in iron-loaded and non-iron-loaded animals, plasma levels increased in a dose-related manner and maximum plasma levels were reached about 1 hour after dosing. In Cebus apella monkeys, the iron-clearing efficiency was 13–18%, about three times that of DFO in the same model. Approximately 80% of iron was excreted in the feces. Pharmacodynamics of repeat doses of GT56-252, from 5 to 45 mg/kg once a day over a 3-day period, in 8 iron-loaded Cebus monkeys showed a dose-related clearing efficiency in a range from 0.06 mg/kg/dose to 0.53 mg/kg/dose^ref. These studies provided sufficient background data to undertake Phase I clinical trials. Eighteen adult patients with ß-thalassemia received 3–8 mg/kg in 2 doses with food or fasting. The compound was well tolerated, with no related serious adverse clinical events, laboratory abnormalities or changes in the electrocardigram (ECG). GT56-252 was very well absorbed and area under the curve (AUC) values with or without food were similar (Donovan JM, Palmer PA, Plone MA, Wonke B. The safety and pharmacokinetics of GT56-252, a novel orally available iron chelator [abstract]. 38th Annual Meeting of the European Society for Clinical Investigation. Eur J Clin Invest. 2004;139:39). Further studies are in progress to define the effect of GT56-252 on iron balance
• 40SD02 / CHF1540 is a new entity synthesized by chemically attaching DFO to a modified starch polymer (Harmatz P, Madden J, Vichinsky E, et al. A phase Ib study of safety, pharmacokinetics, acute tolerability, and efficacy of ascending single doses of 40SD02 (CHF1540) in iron-loaded patients [abstract]. The International BioIron Society World Congress on Iron Metabolism. 2003;54). The resulting high molecular weight chelator has a prolonged half-life and preserves the affinity and specificity of DFO for Fe³⁺, but does not produce the acute toxic effects of DFO such as hypotension. A Phase I study in 10 patients with thalassemia and chronic iron overload showed that single doses of up to 600 mg/kg of the compound were safe and well tolerated, and stimulated a clinically significant amount of iron excretion. Average total iron excretion over 7 days was 0.46 mg/kg and 0.72 mg/kg in the 150 and 300 mg/kg dose groups, respectively. In a more recent Phase I clinical trial 12 patients were treated, each subject receiving a single dose, with 4 patients at 150 mg/Kg, 4 at 300mg/Kg, and 4 at 600 mg/Kg (Harmatz P, Grady WB, Vichinsky E, et al. A phase 1b study of safety, pharmacokinetics, acute tolerability, and efficacy of ascending single doses of 40SD02 (CHF1540, GS 460) in iron-loaded patients [abstract]. Blood. 2004;(suppl 1):121a). No drug-related adverse effects on vital signs, ECG, or laboratory tests have been described. A skin reaction, judged to be related to the drug, was reported in 3 different patients. At the highest dose level of 900 mg/kg, a single infusion induced cumulative urinary iron excretion of 0.84–1.93 mg/kg for 7 days following drug administration
• deferasirox / ICL670 / 4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-y1] benzoic acid (Exjade^®, Asunra^®) was developed by Novartis Pharma AG after 700 potential orally active iron chelators were screened. Preclinical studies show that it forms a 2:1 chelator:iron complex and produces an increase predominantly in fecal iron excretion after a single oral dose, only 6% of iron excretion accruing in the urine. It is highly selective for iron, is rapidly absorbed, and circulates for several hours. In the non-iron-loaded marmoset and rat, its main toxic effect was on the renal tubular epithelial cells, but this effect was abrogated in iron-loaded marmosets and substantially reduced in iron-loaded rats (Nick HP, Acklin P, Fallen B, et al. ICL 670A: a new, potent, orally active iron chelator. In: Bergeron R, Badman D, Brittenham G, eds. Iron Chelators: New Development Strategies. Ponte Vedra, FL: Saratoga Publishers; 2000:311–331). Short-term clinical trials have recently been reported^ref. Single daily doses of 10, 20, and 40 mg/kg body weight were studied. Peak plasma concentration after a single oral dose occurred at about 2 hours, and the drug was still detectable in plasma in almost all patients at 24 hours; the mean elimination half-life was between 11–16 hours after multiple dose administration. Net iron excretion after 6 days of exposure was linearly related to the dose of the drug. Iron excretion at 12 days was related to the area under the curve of the concentration of free drug in plasma. 5 of 6 patients receiving 20 mg/kg were calculated to excrete iron equivalent to the amount received in blood transfusions. Longer-term studies of the drug at the dose of 20 mg/kg have been carried out (Piga A, Galanello R, Cappellini MD, et al. Phase II study of oral chelator ICL 670 in thalassemia patients with transfusional iron overload: safety, pharmacokinetics (PK) and pharmacodynamics (PD) after 6 months of therapy [abstract]. Blood. 2002;100:5). These showed that total body iron excretion ranged from 7.7–28.5 mg iron/d. These did not show any additional toxic effects and showed that liver iron decreased in 12 (57.1%), was unchanged in 8 (38.1%), and rose in 1 (4.8%) of 21 patients studied using the SQUID technique. ICL670 represents a new class of tridentate iron chelators with a high specificity for iron that was developed on the basis of computer modeling^ref. Efficient and selective mobilization of tissue iron has been demonstrated in several animal models, with efficiency being greater than DFO and considerably greater than DFP at comparable levels of iron binding potential. The Phase I clinical evaluation of ICL670 showed this novel agent to be well tolerated, with no major safety concerns at doses up to 80 mg/kg/day^ref. Iron excretion is dose-dependent and is almost entirely in the feces. Excretion averaged 0.127, 0.344 and 0.564 mg/kg/day at the 10, 20 and 40 mg/kg doses, respectively^ref. The plasma half-life (11–19 hours) supports the once daily oral dosing regimen used in subsequent clinical studies. A 12-month Phase II study assessed the tolerability and efficacy of ICL670 in comparison with DFO in 71 patients with transfusional hemosiderosis. Patients were randomized to receive ICL670 (10 or 20 mg/kg/day) or DFO (40 mg/kg SC 5 days per week). The overall incidence of adverse events was similar in all groups.

Side effects : the main side effect was skin rashes that required withdrawal of 4 patients given the highest dose of 40 mg/kg over 8–10 days. Sporadic transaminase rises occurred in 1 of these patients and in 4 other patients. Mild nausea, diarrhea, and abdominal pain—none requiring discontinuation of the drug—occurred in other patients. Transient mild to moderate nausea and vomiting were more common in patients receiving ICL670 at 20 mg/kg/day but did not require discontinuation of the drug. One patient receiving ICL670 at a dose of 10 mg/kg/day developed a mild skin rash with a suspected relationship to the study drug; the rash subsided spontaneously despite continued therapy. Elevations in urinary ß₂ microglobulin, sometimes accompanied by a mild increase in urinary 24-hour total protein excretion, have been observed in all dose groups but predominantly in patients treated with ICL670 at 20 mg/kg/day. The clinical significance of these renal findings remains uncertain, even if in 2007 the FDA issued a warning after some fatal cases of acute renal failure. There were no significant changes in serum creatinine levels. Decreases in liver iron concentration (LIC), determined by biomagnetic susceptometry, were similar in the groups treated with ICL670 at 20 mg/kg/day and DFO. At baseline, LIC values in the 2 groups were 8.5 and 7.9 mg/g dry weight respectively, falling to 6.6 and 5.9 mg/g dry weight at 12 months. A Phase III international study including about 500 patients was completed by the end of 2004
• combined chelation therapy : simultaneously or sequentially. Chelators with distinct chemical properties may have different ironcarrying capacities. Potential advantages :
• access to different iron pools
• prevention of nontransferrin bound iron (NTBI) accumulation
• increased efficacy
• decreased toxicity
• better compliance
• improved quality of life
Formal balance studies have shown that 2 chelators may have additive or synergistic effects, resulting in an increased efficacy^{ref1, ref2} (Grady RW, Berdoukas V, Rachmilewitz EA, et al. Iron chelation therapy: metabolic aspects of combining deferiprone and deferoxamine [abstract]. 11th International Conference on Oral Chelation in the Treatment of Thalassaemia Major and Other Disease (Catania). 2001;74–78; Galanello R, Doneddu I, Dessi’ E, et al. Iron chelation in thalassemia major: combined treatment with deferiprone and deferoxamine [abstract]. 11th International Conference on Oral Chelation in the Treatment of Thalassaemia and Other Disease (Catania). 2001;Abs:73). To explain these effects, it has been proposed that a bidentate or tridentate ligand, with access to a variety of tissues, acts as a "shuttle" to mobilize iron from tissue compartments to the bloodstream, where the chelator may exchange iron with a larger hexandentate "sink" (Grady RW, Berdoukas V, Rachmilewitz EA, et al. Iron chelation therapy: metabolic aspects of combining deferiprone and deferoxamine [abstract]. 11th International Conference on Oral Chelation in the Treatment of Thalassaemia Major and Other Disease (Catania). 2001;74–78).
• DFO + DFP : "shuttle effect"^ref. While monotherapy with DFP resulted in temporary accumulation of chelated iron in the plasma, the addition of DFO produced a transfer of DFP-chelated iron to DFO and an increase in total chelated iron. Giving DFP every day and DFO 2 days a week produced iron excretion comparable to that achieved with DFO administered 5 days a week^ref. This regimen of chelation is more tolerable and may be attractive for patients who are unable to comply with regular daily use of DFO. Since some of the toxic effects of the chelators are dose-dependent, combination therapy might make it possible to lower the dose of one or both drugs, reducing toxicity but maintaining effective chelation. Giving 2 drugs sequentially, e.g., DFP during the day and DFO at night, might also reduce the level of NTBI. To date, no unexpected side effects have been consistently observed in patients receiving combination therapy with DFO and DFP. However, prospective, randomized studies are needed to establish firmly the risks and benefits of this approach. Using the iron-loaded gerbil model, combined DFP and DFO treatment was particularly efficient in reducing liver iron concentration and normalizing the mitochondrial respiratory enzyme activity^ref.
• DFP and HBED to patients with thalassemia greatly enhanced the effectiveness of HBED (Grady RW, Giardina PJ. Oral iron chelation: a potential role for HBED in combination therapy [abstract]. Blood. 1999;94(Suppl1): #3293). Total iron excretion was 148% and 227% of that with each drug alone.
• PIH analogs + DFO have shown an additive effect on hepatocellular iron excretion^ref
• DFO + ICL670 : studies in heart cell cultures have shown a favorable interaction, manifested as improved chelating efficiency of ICL670^ref
Monitoring of iron chelation therapy :
• estimation of tissue iron content of different organs :
• serum ferritin : this is a useful technique for assessing changes in body iron, although the absolute level is an imprecise measure of body iron. This is partly because inflammation—for example, hepatitis C—raises the level, while vitamin C deficiency lowers it, both frequent complications of TM. Most studies have found a wide range in liver iron at any given serum ferritin level. The Thalassemia International Federation guidelines (Capellini N, Cohen A, Eleftheriou A, Piga A, Porter J, eds. Guidelines for Clinical Management of Thalassemia. Nicosia, Cyprus: Thalassemia International Federation; 2000) recommend maintaining serum ferritin levels around 1000 µg/L; nevertheless, levels below this may in some individuals be associated with cardiac complications. One study in TM patients receiving DFO found that those with at least two-thirds of serial serum ferritin estimations < 2500 µg/L had significantly less cardiac disease than those with higher levels^ref. More recently, a level consistently below 1500 µg/L was found to be associated with few complications in 32 patients with TM followed for approximately 15 years^ref. When effective chelation therapy is initiated, the serum ferritin falls more rapidly than body iron. This may happen partly because of improvement in liver function and partly because serum ferritin may reflect predominantly reticular endothelial iron rather than parenchymal iron in the liver and other organs^ref.
• liver iron has been described as the "gold standard" for determining body iron and has been recently shown to correlate with total body iron stores^ref. It can be measured chemically after liver biopsy (which can be inaccurate because of fibrosis, cirrhosis, or uneven distribution of iron) or noninvasively by the superconducting quantum interface device (SQUID) (available in only a few centers) or by magnetic resonance imaging (MRI). Brittenham et al^ref studied 59 TM patients who were > 7 years old. All patients who died had liver iron concentrations > 15 mg/g dry weight, and this level has been subsequently regarded as an index of high risk of death from cardiac disease. More recently, Angelucci et al^ref have shown that this level is also associated with liver fibrosis and cirrhosis. The level of 7 mg/g is the upper limit found in carriers of genetic hemochromatosis. For levels between 7 and 15 mg/g, Angelucci et al found no evidence of liver damage except in patients who had hepatitis C and were messenger RNA positive; the combination of iron overload and hepatitis C infection is particularly damaging to the liver. The value of liver iron, whether > 15 mg/g or in the range of 7 to 15 mg/g, as a predictor of cardiac iron has recently been questioned. MRI data using the T2* technique (Figure 5)^ref and spin-echo^ref have shown no correlation between cardiac and liver iron, although other MRI techniques, possibly less sensitive and accurate, have shown such a correlation. Possible explanations for these discrepant observations have been discussed^{ref1, ref2}
• cardiac iron : direct measurement of cardiac iron by endomyocardial biopsy of the right atrium is inappropriate since iron locates mainly to the myocardium of the ventricles. The recent development of a reproducible, sensitive, and accurate indirect measure of cardiac iron using the MRI T2* technique^ref has provided substantial important new data. A T2* value < 20 ms has been found to correlate with the presence of cardiac dysfunction, detected by echocardiography, 24-hour monitoring, or the need for cardiac therapy. It is also valuable for monitoring changes in cardiac iron during intensive chelation therapy (Anderson L, Bunce N, Davis B, et al. Reversal of siderotic cardiomyopathy: a prospective study with cardiac magnetic resonance (CMR) [abstract]. Heart. 2001;85(suppl 1):33)
• non-transferrin-bound iron : in severely iron-loaded patients, non-transferrin-bound iron (NTBI) is present in plasma. It occurs in 80% of patients with TM and represents a highly toxic species causing tissue iron loading. NTBI is also found in patients receiving chemotherapy or undergoing heart bypass operations and those having other conditions in which large amounts of iron from hemoglobin breakdown are released into the circulation^ref. NTBI is removed by administration of DFO or DFP but reappears rapidly (i.e., usually within 1 hour of discontinuing intravenous DFO therapy) unless body iron burden is substantially reduced.
• urine iron excretion : iron excreted in response to a single dose of DFO or deferiprone has been taken as an index of body iron burden. It will vary, however, with the dose of chelator used and, for DFO, whether vitamin C is also given and with the hemoglobin level. There is also considerable day-to-day variation, even with apparently the same conditions^ref. Nevertheless, in one recent study it has been found to correlate closely with cardiac iron measured by MRI^ref
• estimation of iron-induced tissue damage : in addition to measuring iron status, it is important to assess the function of the heart, liver, and endocrine glands, the organs particularly damaged by iron overload. Early detection of cardiac dysfunction is especially important so that increased chelation therapy can be instituted before cardiac damage is irreversible. Once the patient has started chelation therapy, it will also be necessary to monitor for potential side effects of the iron chelator being used

	deferoxamine	deferiprone	ICL 670
	hexadentate	bidentate	tridentate
molecular weight	560	139	373
iron:chelator complex	1:1	1:3	1:2
plasma clearance, T1/2	20 minutes	53–166 minutes	1–16 hours
oral absorption	negligible	peak 45 minutes	peak 1–2.9 hours
iron excretion	urine + fecal	urine	fecal
therapeutic daily dose	40 mg/kg	75 mg/kg	20 mg/kg
route	parenteral	oral	oral
clinical experience	30 years	16 years	1–2 years
side effects	ototoxicity, retinal toxicity, growth, cartilage	agranulocytosis, arthropathy, gastrointestinal disturbance, transient transaminitis, zinc deficiency	Skin rashes, gastrointestinal disturbance, transient transaminitis

• assessment of the function of the heart, liver, and endocrine glands, the organs particularly damaged by iron overload. These aspects have recently been extensively reviewed and are only briefly discussed here^{ref1, ref2}.
• cuprum (Cu)
• D-penicillamine (1 g/die) + pyridoxine (25 mg/die)
• trientine / triethylenetetramine dehydrochloride (Cuprid^®)
• dimercaprol / 2,3-dimercaptopropan-1-ol / British anti-lewisite (BAL)
• zinc (Zn)
• clioquinol / iodochlorhydroxyquin (a 8-hydroxyquinoline no longer used as antiprotozoal)
• tallium (Tl)
• ferric ferrocyanide / Prussian blue binds Tl in the intestine and enhances its fecal excretion
• internal contamination with radioactive heavy metals
• diethylenetriaminepentaacetic acid (DTPA) / pentetic acid
• pentetate calcium trisodium (Ca-DTPA)
• pentetate zinc trisodium (Zn-DTPA)
• nonmetallic environmental toxicants chemical antagonists
• cyanide (CN^-)
• amyl nitrite and 4-dimethylaminophenol oxidize hemoglobin to methemoglobin, which competes with cytochrome oxidase for the CN^- ion, creating cyanmethemogobin : the reactions favor methemoglobin because of mass action.
• Co₂EDTA
• hydroxocobalamin (Cyanokit^® (containing hydroxocobalamin, intravenous tubing and a sterile spike for reconstituting the drug product with saline; source : EMD Pharmaceuticals, Inc = Dey, L.P.) => cyanocobalamin. The initial dose of Cyanokit for adults is 5 g, administered by intravenous infusion. Depending upon the severity of the poisoning and the clinical response, a second dose of 5 g may be administered up to a total dose of 10 g.
• O₂

• biotransformation
• induction of CYPs requires days to be valuable
• ethanol to inhibit alcohol dehydrogenase (ADH) preventing methanol conversion to formic acid
• N-acetylcysteine (NAC) to maintain the concentration of glutathione, which detoxifies active catabolytes of phase I / II reactions
• sodium thiosulfate IV + CN^- / cyanide ==mt rhodanese / thiosulfate sulfurtransferase=> SCN^- (a thiocyanate readily excreted in urine) + Na₂SO₃
• bacterial phosphotriesterase genetically engineered via directed evolution destroys the nerve gas soman 1,000-folds faster : a more efficient version could form part of a mask to protect against nerve agents. In bacteria, phosphotriesterase severs chemical bonds between phosphorus and oxygen atoms. It has been investigated before for cleaning up pollution from toxic organophosphorus pesticides and herbicides
• biliary excretion can be enhanced by CYPs inducers but the effect is slow in onset
• urinary excretion :
• diuretics decrease passive reabsorption by decreasing the concentration gradient of the drug from the lumen to the tubular cell and by increasing flow through the tubule
• nonionized compounds are reabsorbed far more rapidly than ionized, polar molecules; for acids with 3 < pK_a < 7.5 and bases with 7.5 < pK_a < 10.5, a shift from the nonionized to the ionized species of the toxicant by alteration of the pH of the tubular fluid (IV sodium bicarbonate to alkalinize and ammonium chloride or ascorbic acid to acidify) may hasten elimination.
• tricyclic antidepressants are weak bases => acidify urine
• hemodyalisis >> peritoneal dyalisis, for toxicants with low volume of distribution and low plasma protein binding
• hemofiltration / hemoperfusion

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