IRONUR-IPS TM Abstracts and References

Iron Protein Succinylate (IPS)

Arzneimittel-Forschung Drug Research 34 (III), 9, 952-958 (1984)
Pharmacological and Toxicological Studies on an Iron Succinyl-Protein
Complex (ITF282) for Oral Treatment of Iron Deficiency Anemia.
Pagella P.G., Bellavite O., Agozzino S., Dona G.C.

Abstract:

ITF282, a soluble iron succinyl-protein complex orally administered to the rat elevates the concentration of iron in the serum to a greater extent than ferritin. The serum iron increase induced by ITF282 is delayed when compared with ferrous sulphate. The ITF282 absorption process, like that of ferritin, proceeds along the physiological pathways without bypassing the transfer system of the intestinal mucosal cells since no further increase of serum metal is
observed when giving high doses of ITF282 to the rat pretreated with a saturating dose of ferrous sulphate. Hypochromic and microcytic anemia induced in growing rats by bleeding and feeding a low iron diet is sensitive to both prophylactic and therapeutic oral treatment with ITF282. Iron deficiency
anemia and cardiomegaly induced in suckling rats by feeding the pregnant and lactating dams with the low iron diet are reversed by oral treatment of the dams with ITF282. Comparative investigations of the therapeutic efficacy of ITF282 and ferritin made on uncomplicated iron deficiency anemia show that the drugs, p.o. administered during 4 weeks are equally effective. Preliminary toxicological data in the rat, after single and chronic administrations, show that ITF282 is well tolerated. These findings prove that ITF282 gives an adequate supply of iron from which to make hemoglobin.


Italfarmaco Research Center, Cinisello Balsamo, Italy

Iron protein succinylate: preclinical safety assessment Forster, R.

Abstract:

In this brief review the preclinical safety studies on iron protein succinylate (synonym: ITF282) are presented. Iron protein succinylate is an iron-protein complex, in which iron is present in ferric form. It has been developed for oral iron-supplementation therapy and is characterized by a very favorable tolerability profile. The acute toxicity of iron protein succinylate to rodents is very low, indicating a substantial margin of safety with respect to accidental child poisonings. In chronic toxicity studies of 52-week duration in rats and dogs, there were no findings of toxicological significance. In particular, there were no alterations in hematological parameters and no histopatholgical findings consistent with iron overload damage. Some deposition of iron was noted in the spleen and liver of the treated dogs. A series of reproductive toxicology studies
were performed to assess the effects on fertility (in the rat), peri- and postnatal reproductive function (in the rat) and fetal toxicity (in the rant and the rabbit). Treatment with iron protein succinylate did not result in any adverse effect on reproductive performance nor did it affect the incidences of malformations, visceral and skeletal anomalies or skeletal variants. There was no evidence of mutagenic activity in a comprehensive series of in vitro and in vivo mutagenicity
studies. No secondary pharmacological effects of the product were noted in a wide range of single and repeated administration studies. Overall, the available toxicology and safety profile of this product offers ample assurances of the safety of iron protein succinylate in clinical use.

Arzneimittel-Forschung/Drug Research 45 (II), 11, 1211-1216 (1995)


Meta-analysis of Efficacy and Tolerability Data on Iron
Proteinsuccinylate in Patients with Iron Deficiency Anemia of Different
Severity.
Kopcke W., and Sauerland M.C.

Abstract:

Iron proteinsuccinylate (ITF 282, CAS 93615-44-2) is an iron derivative for the oral treatment of iron deficiency anemia. Its efficacy and tolerability have been proved in about 1800 patients, enrolled in 3 multicenter clinical trials.
The first aim of this meta-analysis is to verify the increase of hemoglobin (Hb) in these patients (891 treated with IFT282, 644 treated with iron sulphate and 236 treated with iron-polysterene sulphonate).
The 3 studies show homogeneous Hb increases. ITF282 appeared to provide, from time 0 to the 30 th day of the treatment, a similar or lesser increase in Hb in comparison to the reference drugs, while from the 30 th day to the 60 th day its efficacy was always greater than that of the reference medications.
The time course of Hb increases and the tolerability data suggest a different mechanism by which ITF282 and the reference drugs are effective. Since the main difference between ITF282 and the reference drugs is the form in which the iron is presented to the gastrointestinal mucosa, it may be supposed that the reface drugs, providing free divalent iron ions for absorption, could induce
some kind of irritative condition of the gastrointestinal mucosa, which results in a reduced long-term absorption capacity, as well as in a higher indicence of gastro enteric adverse events. ITF282, providing protein=bound iron, would not permit the process supposed with divalent iron, thus resulting in prolonged absorption capacity (that is higher hemoglobin recovery) and higher gastrointestinal tolerability.


Italfarmaco Research Center, Cinisello Balsamo/Milan, Italy
Chemical and biological characterization of iron-protein succinylate
(ITF282)
Cremonesi P. and Caramazza I.

Abstract:

ITF282 is an iron succinylate casein complex containing 5% iron. The main property of the derivative is to keep iron bonded at acidic pH values. This accounts for a better tolerability of the compound compared with iron salts, during the treatment of iron deficiency. Pharmacological studies in normal and anemic rats demonstrated that this iron complex is almost as active as
ferrous sulphate against iron deficiency anemia, but it is significantly less potent in increasing serum iron, better gastrointestinal tolerability of ITF 282 was demonstrated in rats and dogs. Chemical and pharmacological properties of iron-protein succinylate are described.


SOME MORE REFERENCES:

CARAMAZZA I, ANDRIUOLI G, SCAGNOL I, DEL SOLDATO P.
Comparison of anti-aneaemic effects of iron protein succinylate (ITF282) and Ferrous Sulphate in the rat. Drugs Exptl Clin Res XVI: 333-342. 1990.


CREMONESI P, STRADA D, GALIMBERRI G, SPORTOLETTI G.
Iron Derivatives of Modified Milk Protein. Arzneim Forsch Drug Research 34 (II), 9: 948-952. 1984.


DIETZFELBINGER H.
Bioavailability of Bi- and Trivalent Oral Iron Preparations. Arzneim Forsch ,Drug Research 37 (I): 1a. 1987.

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Iron protein succinylate:
preclinical safety assessment.

Forster R. Int J Clin Pharmacol Ther Toxicol. 1993 Feb;31(2):53-60.
Italfarmaco Research Centre, Cinisello Balsamo, Italy.

In this brief review the preclinical safety studies on iron protein succinylate (synonym: ITF 282) are presented. Iron protein succinylate is an iron-protein complex, in which iron is present in ferric form. It has been developed for oral iron-supplementation therapy and is characterized by a very favorable tolerability profile. The acute toxicity of iron protein succinylate to rodents is very low, indicating a substantial margin of safety with respect to accidental child poisonings. In chronic toxicity studies of 52-week duration in rats and dogs, there were no findings of toxicological significance. In particular, there were no alterations in hematological parameters and no histopathological findings consistent with iron overload damage. Some deposition of iron was noted in the spleen and liver of the treated dogs. A series of reproductive toxicology studies were performed to assess the effects on fertility (in the rat), peri- and postnatal reproductive function (in the rat) and fetal toxicity (in the rat and the rabbit). Treatment with iron protein succinylate did not result in any adverse effect on reproductive performance nor did it affect the incidences of malformations, visceral and skeletal anomalies or skeletal variants. There was no evidence of mutagenic activity in a comprehensive series of in vitro and in vivo mutagenicity studies. No secondary pharmacological effects of the product were noted in a wide range of single and repeated administration studies. Overall, the available toxicology and safety profile of this product offers ample assurances of the safety of iron protein succinylate in clinical use.

IronAid™ Iron Protein Succinylate (IPS): An advancement in the treatment of iron deficiency and anemia
S. L. HAGERMAN, Chemi Nutraceuticals, Inc., 4463 White Bear Pkwy., Ste. 105, White Bear Lake, MN 55110

The potential marketability for efficacious, new, and innovative iron supplements is tremendous, since it is estimated that as many as 30% of women and 10% of mixed elderly people are iron deficient. Subgroups of the major population include pregnant women and adolescent female athletes, who have a serious need for iron that can only be met through nutritional supplement intervention. Iron Protein Succinylate (IPS) is a proprietary form of ferric iron (Fe+++) bound with a chemically modified protein (casein) in a process called succinylation, which dramatically stabilizes the complex. This process is responsible for the specific way in which IPS is totally dependent on pH for absorption. Because IPS is insoluble in the stomach, it completely bypasses the stomach without exposing the gastric mucosa to iron. This is the optimal method to transport iron where absorption takes place – the duodenum. Here, IPS becomes completely soluble in the duodenum, where the pH level allows for rapid hydrolysis of the protein component, and liberation of the elemental ferric iron for immediate absorption. Essentially all other iron compounds severely irritate the stomach, causing stomach pain and heartburn, and also affect the lower GI tract, causing constipation. This often causes people using iron supplements to withdraw from use, which impacts negatively on the required treatment for iron deficiency and anemia. IPS is the only iron compound that provides this proven, highest degree of tolerability. Since IPS provides a steady, controlled release of iron in a low concentration form, the iron overload is nearly impossible. IPS is a new, innovative, effective, highly tolerable iron compound that provides benefits that no other iron compound provides. IPS can provide the opportunity for a new and exciting family of novel, profitable, safe, and efficacious iron-based nutraceuticals.


Controlled, double-blind, multicenter clinical trial of iron protein succinylate in the treatment of iron deficiency in children.

Careddu P, Scotti A. Int J Clin Pharmacol Ther Toxicol. 1993 Apr;31(4):157-69

Ist Pediatric Clinic, University of Milan, Italy.

A total of 502 children up to the age of 14 years were treated for iron deficiency or overt anemia. ITF 282 was prescribed to 256 children, and a commercially available ferrous polystyrene sulphonate preparation to 246, in a randomized double-blind, double-dummy, ten-center trial. One oral vial of ITF 282 (60 mg iron) was administered once a day to children weighing up to 40 kg; and twice a day to children with body weight equal or superior to 40 kg. In the reference group, oral vials of polystyrene sulphonate (52.5 mg iron) were administered once a day to children weighing up to 40 kg, and twice a day to children weighing 40 kg or more. Treatments lasted 60 days. The treatments' efficacy and tolerability were evaluated taking into consideration: special hematology, symptomatology, safety hematology and hematochemistry, urinalysis. At the end of treatment, the trend was detected to the normalization of the main hematologic parameters in both groups (hemoglobin, hematocrit, ferritin, blood iron, transferrin saturation, MCHC). Although in the first month the reference treatment appears to provide somewhat faster results, significantly greater values of blood iron are observed at the end of the observation in the ITF 282 group, indicating a more progressive and steady therapeutic effect. The overall clinical rating was, although not significant, in favor of ITF 282, with a failure rate of 18.0 vs 24.0%. The general tolerance, although favorable with both treatments, was significantly more favorable with ITF 282. With this medication, 13 patients complained of 13 events (1 heartburn, 6 constipation, 6 abdominal pain) vs 48 events reported by 43 patients with the reference medication (1 heartburn, 2 epigastric pain, 14 constipation, 14 abdominal pain, 3 skin rash, 14 vomiting). These observations confirm that, although the most modern preparations of ferrous ions exhibit a relatively low frequency of adverse events of limited clinical concern, it is nevertheless possible to decrease (with the use of more "physiologic" preparations in which the iron is reversibly bound to a protein carrier) the prevalence and, tendentially, duration and intensity of such events without prejudice for the clinical efficacy. Therefore, the good clinical tolerability of ITF 282 effectively removed one of the main obstacles to the correct compliance with iron treatments (necessarily to be taken long-term), as reduced the risks of undesired events in a particularly susceptible population subgroup, such as children.

Comparative study of tolerability and efficacy of iron protein succinylate versus iron hydroxide polymaltose complex in the treatment of iron deficiency in children.

Haliotis FA, Papanastasiou DA. Int J Clin Pharmacol Ther. 1998 Jun;36(6):320-5.

Department of Pediatrics, School of Medicine, University of Patras, Greece.

One-hundred children, 48 males and 52 females, mean age +/- SD 39.9 +/- 28.2 months (range 12 to 113) with sideropenia or sideropenic anemia were randomly divided into 2 groups of 50 patients each (groups A and B) and were treated with iron protein succinylate (group A) or iron hydroxide polymaltose complex (group B). Patients of both groups received 4 mg/kg elemental iron, maximally 80 mg daily, for 2 months. Side-effects of therapy and laboratory values (RBC, hematocrit, hemoglobin, MCV, serum iron, total iron binding capacity, and ferritin) were registered before treatment, 30 days after the beginning of therapy as well as after 60 days in order to evaluate tolerability and efficacy of the drugs. Both drugs were well tolerated and showed only few adverse reactions, which were comparable in severity and frequency. Iron protein succinylate led not only to a faster increase of hemoglobin, hematocrit, MCV, serum iron, and ferritin than iron hydroxide polymaltose complex, but the laboratory values remained higher in group A than in B even after 2 months of treatment.

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