Chelator‐induced iron excretion in iron‐overloaded marmosets

Abstract

Summary. In order to test new orally active iron chelators in a predictive way, a primate model has been developed. This model makes use of the marmoset monkey (Callithrix jacchus) and its overall design is similar to a previously reported monkey model. However, this new model enables a higher compound throughput and requires lower amounts of test compound because the animals are much easier to handle and have much lower body weights. The marmosets were iron-overloaded by three intraperitoneal injections of iron (III) hydroxide polyisomaltose. For the iron-balance studies, the animals were kept in metabolic cages and were maintained on a low-iron diet in order to reduce faecal background. After compound administration, the excretion of iron in urine and faeces was followed for 2 d. A series of well-known chelators was tested for validation of the model. In particular, comparison of the iron-clearing properties of DFO, L1, CP94 and HBED in marmosets and humans demonstrated the predictive value of the model and justify our expectation that if iron chelators such as CGP65015, ICL670A and CGP75254A are active in marmosets, they will be active in humans as well.

Antioxidant Effects of Quinoline Alkaloids and 2,4-Di-tert-butylphenol Isolated from Scolopendra subspinipes

“…Compounds 1-3 (100 mM) were mixed with 50 mM of CuSO 4 in PBS buffer (pH 7.4) and the UV spectra were measured between 200 and 400 nm either in the presence or absence of compound. 22) RESULTS AND DISCUSSION As shown in the extraction and isolation procedures, the methanol and acetone extracts obtained exhibited significant antioxidant activity against LDL-oxidation. Subsequently, bioassay-guided fractionation using an LDL-antioxidant assay led to the isolation of the two known compounds 1 and 2 and a new compound 3 (Fig.…”

The Evolution of Iron Chelators for the Treatment of Iron Overload Disease and Cancer

“…The remarkable iron clearing activity of ICL670A has been illustrated through several in vivo trials, including those performed using rats (Hershko et al, 2001) and primates (Sergejew et al, 2000). When administered orally during a rodent study, ICL670A was able to induce iron clearance 4 to 5 times greater than that of DFO, reaching a plateau between a dose of 100 and 200 mg/kg (Hershko et al, 2001).…”

Recent Developments Centered on Orally Active Iron Chelators

“…The lead compound ( Figure 1J) was found to be orally active 74 and highly effective at removing iron from both the iron-loaded rat 74 and marmoset. 75 In similar fashion, Hider and coworkers have demonstrated that the introduction of either a 1-hydroxyalkyl group ( Figure 1K) 76 or an amido function ( Figure 1L) 77 at the 2-position of 3-hydroxypyridin-4-ones enhances the affinity for iron(III) over the pH range 5-8. Although such an effect reduces the overall iron(III) stability constant, it reduces the pKa value of the chelating function by a larger margin.…”

“…Although such an effect reduces the overall iron(III) stability constant, it reduces the pKa value of the chelating function by a larger margin. These combined changes result in an increase in the corresponding pFe 3+ values [75][76][77] due to the reduced competition with hydrogen ions; thus the 2amidopyridin-4-one ( Figure 1L) has a pFe value of 21.7 as compared with that of the analogous deferiprone ( Figure 1H), which possesses a pFe value of 20.5. In practical terms this means that at pH 7.4 ( Figure 1L) binds iron over ten times more tightly than deferiprone.…”