Iron chelators infection

Deravirdine (Rescnptor) [Antiretroviral/NNRTI] Uses HIV Infxn Action Nonnucleoside RT inhibitor Dose 400 mg PO tid Caution [C, ] CDC recommends HIV-infected mothers not to breast-feed (transmission risk) w/ renal/hepatic impair Contra Use w/ drugs dependent on CYP3A for clearance (Table VI-8) Disp Tabs SE Fat redistribution, immune reconstitution synd, HA, fatigue, rash, T transaminases, N/V/D Interactions T Effects W/ fluoxetine T effects OF benzodiazepines, cisapride, clarithromycin, dapsone, ergotamine, indinavir, lovastatin, midazolam, nifedipine, quinidine, ritonavir, simvastatin, terfena-dine, triazolam, warfarin effects W/ antacids, barbiturates, carbamazepine, cimetidine, famotidine, lansoprazole, nizatidine, phenobarbital, phenytoin, ranitidine, rifabutin, rifampin effects OF didanosine EMS Use of benzodiazepines and CCBs should be avoided may cause a widespread rash located on upper body and arms OD May cause an extension of nl SEs symptomatic and supportive Deferasirox (Exjade) [Iron Chelator] Uses Chronic iron overload d/t transfusion in pts >2 y Action Oral iron chelator Dose Initial 20 mg/kg... 

Iron(n) is known to decompose hydrogen and dialkyl peroxides to free radicals by reductive cleavage of the 0—0 bond and early investigations established the parasite s sensitivity to these species. When treated with radiolabelled C-artemisinin, the hemin-hemozoin fraction of the lysed malaria-infected erythrocytes was shown to contain a radiolabel, though the mechanism of incorporation is not clear. Meshnick and coworkers demonstrated that uninfected cells did not contain radiolabelled proteins whereas six radiolabelled proteins were isolated from cells infected with the Plasmodium falciparum (P. falciparum) strain of the parasite. It was suspected that one of the alkylated proteins was the Histidine Rich Protein (HRP) that was known to bind multiple heme monomers and therefore thought to be instrumental to the parasite s detoxification process. Moreover, iron chelators were found to inhibit the lethal effects of peroxides on the parasite. ... 

The question of iron chelation as an antibacterial detense is receiving increasing attention. It appears to be far more general than had previously been supposed. t0 An interesting sidelight is that the fever that often accompanies infection enhances the bacteriostatic action of the body s transferrins. 

Malaria is a worsening problem worldwide. More than 110 million people suffer from infection every year and up to 2 million of these die. A growing number of countries are now affected by drug-resistant strains of the parasites. The introduction of an iron chelator to control such infection is a novel approach, and as chelation is particularly critical at the late trophozoite stage, it may prove possible to limit treatment to relatively short time periods. 

The important role played by iron availability during infections in vertebrate hosts has only been recognized relatively recently. The ability of the host to withhold growth-essential iron from microbial and, indeed, neoplastic invaders whilst retaining its own access to this metal has led to suggestions that microbial iron chelators or their semisynthetic derivatives may be of use in antimicrobial and anticancer chemotherapy. Preliminary work has shown some encouraging results. 

Infection risk Iron is an essential nutrient in many species, and iron overload increases the risk of infections. Deferoxamine is a natural siderophore, and its use is a susceptibility factor for infections with a variety of microbes, notably Yersinia enterocolitica and Mucorales infections, and increases their infectivity. On the other hand, iron chelators, by extracting iron, may also have cm anti-infectious action, which may be therapeutically beneficial, in particular in the treatment of malaria (deferiprone) [4 ] or mucormycosis (deferasirox) [5 ]. While the use of iron-chelating drugs is currently being further investigated, for the... 

Excessive iron in specific tissue sites is associated with development of infection, neoplasia, cardiomyopathy, arthropathy, and a variety of endocrine and neurological diseases. Chelators, which remove excess iron, while not depriving cells of the essential iron needed for normal metabolism and prevent iron from participating in the generation of harmful free radicals, are potential drugs. We mention a few examples only. 

Deferoxamine (see also Chapters 58 and 59) Chelates excess iron Reduces the toxicity associated with acute or chronic iron overload Treatment of acute iron poisoning and for inherited or acquired hemochromatosis that is not adequately treated by phlebotomy Preferred route of administration is IM or SC Toxicity Rapid IV administration may cause hypotension acute respiratory distress has been observed with long infusions neurotoxicity and increased susceptibility to certain infections has occurred with longterm use... 

Aerobic and facultative aerobic bacteria produce extremely powerful chelating agents to specifically facilitate the uptake of iron, particularly under conditions of iron deficiency. The availability of Fe to microbes plays an important role in infections. These complexing agents are referred to as siderophores (formerly siderochromes). Much of the work in this area has been carried out by Raymond, Neiland and their collaborators.82,83... 

The molluscidal action of 5,2 -dichloro-4 -nitrosalicylanilide has been attributed to the chelation of iron(III)62. The importance of chelation of iron as an antiprotozal therapy is emphasized by the suppression of experimentally induced Plasmodium vinckei infections in mice63. ... 

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