Haem iron versus ferrous iron salts to treat iron deficiency anaemia in Gambian children: protocol for randomised controlled trial {1}.

BACKGROUND: The World Health Organization recommends universal iron supplementation for children aged 6-23 months in countries where anaemia is seen in over 40% of the population. Conventional ferrous salts have low efficacy due to low oral absorption in children with inflammation. Haem iron is more bioavailable, and its absorption may not be decreased by inflammation. This study aims to compare daily supplementation with haem iron versus ferrous sulphate on haemoglobin concentration and serum ferritin concentration after 12 weeks of supplementation. METHODS: This will be a two-arm, randomised controlled trial. Gambian children aged 6-12 months with anaemia will be recruited within a predefined geographical area and recruited by trained field workers. Eligible participants will be individually randomised using a 1:1 ratio within permuted blocks to daily supplementation for 12 weeks with either 10.0 mg of elemental iron as haem or ferrous sulphate. Safety outcomes such as diarrhoea and infection-related adverse events will be assessed daily by the clinical team (see Bah et al. Additional file 4_Adverse event eCRF). Linear regression will be used to analyse continuous outcomes, with log transformation to normalise residuals as needed. Binary outcomes will be analysed by binomial regression or logistic regression, Primary analysis will be by modified intention-to-treat (i.e., those randomised and who ingested at least one supplement dose of iron), with multiple imputations to replace missing data. Effect estimates will be adjusted for baseline covariates (C-reactive protein, alpha-1-acid glycoprotein, haemoglobin, ferritin, soluble transferrin receptor). DISCUSSION: This study will determine if therapeutic supplementation with haem iron is more efficacious than with conventional ferrous sulphate in enhancing haemoglobin and ferritin concentrations in anaemic children aged 6-12 months. TRIAL REGISTRATION: Pan African Clinical Trial Registry PACTR202210523178727.

Effects of Supplemental Drugs on Hexaminolevulinate (HAL)-Induced PpIX Fluorescence in Bladder Cancer Cell Suspensions.

Seven different inhibitors of the heme metabolic pathway were applied in combination with HAL to study the formation of PpIX in bladder cancer HT1197 and normal fibroblast HFFF2 cells ex vivo, specifically with the aim to increase the fluorescence contrast between cancer and non-cancer cells. The mRNA expression of enzymes involved in the heme biosynthesis pathway were measured via PCR following incubation with the drugs in order to link the fluorescence levels and metabolic activity. The exogenous administration of HAL does lead to cancer-specific PpIX accumulation. However, the contrast between cancer and normal cells in suspension was not enhanced by the enzyme inhibitors and iron-chelating agents tested, nor did the mRNA expression necessarily correlate with the fluorescence intensity. The results indicate that a difference in the metabolic activity of cells in suspension may limit the applicability of exogenous enzyme inhibitor administration as a mean to improve the fluorescence-based detection of cancer cells shed in body fluids.

The role and current status of heme iron preparations in people with iron depletion.

Iron deficiency is a common but underestimated condition in the population. Its correlate is far from only sideropenic anemia, but is due to the variety of involvement of this element in a number of bio-chemical reactions; several other possible clinical manifestations can be expected. Appropriately selected oral supplementation is often necessary. Here, we should carefully consider the possible ratio of expected benefits and potential risks of side effects, or interaction with dietary components or concomitant medications. The available preparations are not equivalent; they differ not only in atomically different amounts of iron but also, above all, in the form that determines the way in which the iron will be absorbed. This ultimately defines the rate of adjustment for depletion and the tolerability of a particular product.

Heme supplementation ameliorates lupus nephritis through rectifying the disorder of splenocytes and alleviating renal inflammation and oxidative damage.

Heme is an important iron-containing porphyrin molecule expressed ubiquitously in organisms. Recently, this endogenous molecule has been widely reported to be involved in the pathogenesis of numerous diseases such as sepsis, atherosclerosis and inflammatory bowel disease. However, the role of heme during systemic lupus erythematosus (SLE) pathogenesis has not been previously evaluated. Herein, we have measured the levels of heme in lupus-prone mice and explored the influence of heme on the pathogenesis of lupus. We revealed that heme levels in serum, kidney and spleen lymphocytes are all negatively associated with the levels of proteinuria in lupus-prone mice. Heme supplementation at 15 mg/kg could significantly ameliorate the syndromes of lupus in MRL/lpr mice, extending lifespan, reducing the level of proteinuria and alleviating splenomegaly and lymphadenopathy. Further study demonstrated that heme replenishment corrected the abnormal compartment of T cell subsets, plasma cells and macrophages in the spleen and alleviates inflammation and oxidative damage in kidney of MRL/lpr mice. Our study well defined heme as a relevant endogenous molecule in the etiology of SLE, as well as a potential therapeutic target for treating this autoimmune disease. Meanwhile, heme replenishment might be a new choice to therapeutically modulate immune homeostasis and prevent SLE.

Preservation of myocardial contractility during acute hypoxia with OMX-CV, a novel oxygen delivery biotherapeutic.

The heart exhibits the highest basal oxygen (O2) consumption per tissue mass of any organ in the body and is uniquely dependent on aerobic metabolism to sustain contractile function. During acute hypoxic states, the body responds with a compensatory increase in cardiac output that further increases myocardial O2 demand, predisposing the heart to ischemic stress and myocardial dysfunction. Here, we test the utility of a novel engineered protein derived from the heme-based nitric oxide (NO)/oxygen (H-NOX) family of bacterial proteins as an O2 delivery biotherapeutic (Omniox-cardiovascular [OMX-CV]) for the hypoxic myocardium. Because of their unique binding characteristics, H-NOX-based variants effectively deliver O2 to hypoxic tissues, but not those at physiologic O2 tension. Additionally, H-NOX-based variants exhibit tunable binding that is specific for O2 with subphysiologic reactivity towards NO, circumventing a significant toxicity exhibited by hemoglobin (Hb)-based O2 carriers (HBOCs). Juvenile lambs were sedated, mechanically ventilated, and instrumented to measure cardiovascular parameters. Biventricular admittance catheters were inserted to perform pressure-volume (PV) analyses. Systemic hypoxia was induced by ventilation with 10% O2. Following 15 minutes of hypoxia, the lambs were treated with OMX-CV (200 mg/kg IV) or vehicle. Acute hypoxia induced significant increases in heart rate (HR), pulmonary blood flow (PBF), and pulmonary vascular resistance (PVR) (p < 0.05). At 1 hour, vehicle-treated lambs exhibited severe hypoxia and a significant decrease in biventricular contractile function. However, in OMX-CV-treated animals, myocardial oxygenation was improved without negatively impacting systemic or PVR, and both right ventricle (RV) and left ventricle (LV) contractile function were maintained at pre-hypoxic baseline levels. These data suggest that OMX-CV is a promising and safe O2 delivery biotherapeutic for the preservation of myocardial contractility in the setting of acute hypoxia.

Dietary hemoglobin rescues young piglets from severe iron deficiency anemia: Duodenal expression profile of genes involved in heme iron absorption.

Heme is an efficient source of iron in the diet, and heme preparations are used to prevent and cure iron deficiency anemia in humans and animals. However, the molecular mechanisms responsible for heme absorption remain only partially characterized. Here, we employed young iron-deficient piglets as a convenient animal model to determine the efficacy of oral heme iron supplementation and investigate the pathways of heme iron absorption. The use of bovine hemoglobin as a dietary source of heme iron was found to efficiently counteract the development of iron deficiency anemia in piglets, although it did not fully rebalance their iron status. Our results revealed a concerted increase in the expression of genes responsible for apical and basolateral heme transport in the duodenum of piglets fed a heme-enriched diet. In these animals the catalytic activity of heme oxygenase 1 contributed to the release of elemental iron from the protoporphyrin ring of heme within enterocytes, which may then be transported by the strongly expressed ferroportin across the basolateral membrane to the circulation. We hypothesize that the well-recognized high bioavailability of heme iron may depend on a split pathway mediating the transport of heme-derived elemental iron and intact heme from the interior of duodenal enterocytes to the bloodstream.

[Dietary supplement of iron for iron deficiency]. / Kosttilskudd med jern ved jernmangel.

BACKGROUND: A low supply of iron in the diet may result in iron deficiency and mild iron-deficiency anaemia in healthy individuals. Women are more susceptible than men because of menstrual iron loss. We compared the effect of a low dose of iron, administered as a dietary supplement, with a high pharmacological dose of iron to otherwise healthy individuals with iron deficiency and mild iron deficiency anaemia. MATERIAL AND METHOD: In a randomised, double-blind trial conducted in 2000-2001, 73 women and three men with iron deficiency received either 27.6 mg of iron consisting of ferrous fumarate enriched with 13% haem iron, or 100 mg ferrosulphate daily for 12 weeks. Blood samples were analysed four times in the course of the treatment. RESULTS: The median ferritin value rose by 13 and 7 µg/l in the high-dose and low-dose group, respectively. The increase in ferritin was significantly higher in the high-dose than in the low dose group ( < 0.001). There was no statistically significant difference between the groups in the change in Hb, serum-iron or serum-iron binding capacity. The median haemoglobin value increased by 0.4 g/100 ml in both groups. Gastrointestinal side effects were experienced by 58% in the high-dose group and 35% in the low-dose group. Four subjects in the high-dose group and one in the low-dose group broke off the treatment because of side effects. INTERPRETATION: A supplement of low-dose iron is enough to increase iron stores in cases of nutritional iron deficiency in healthy individuals and to optimise haemoglobin. High-dose iron caused the largest increase in iron stores. Low-dose iron resulted in the least side effects.

Treatment with Actovegin® improves sensory nerve function and pathology in streptozotocin-diabetic rats via mechanisms involving inhibition of PARP activation.

BACKGROUND: Diabetic neuropathy is one of the most severe complications of diabetes, affecting approximately one-third of diabetic patients. We investigated the potential neuroprotective effect of Actovegin®, a deproteinized hemoderivative of calf blood, in an animal model of diabetic neuropathy. METHODS: A single intravenous injection of streptozotocin (STZ, 55 mg/kg) was used to induce experimental diabetes in male Sprague-Dawley rats. Actovegin® (200 or 600 mg/kg) was administered intraperitoneally from day 11 to day 40 post-STZ exposure. N-acetylcysteine (NAC) was used as a positive control and was added to drinking water (0.2 g/l) from day 2 until day 40. Measurements to assess efficacy included sensory nerve conduction velocity (SNCV), intraepidermal nerve fiber density (IENFD), and poly(ADP-ribose) content. RESULTS: A decrease (35%) in sensory nerve conduction velocity (SNCV) was seen in STZ-induced diabetic rats from day 10 post-STZ administration and persisted at days 25 and 39. At study completion (day 41), a decrease (32%) in intraepidermal nerve fiber density (IENFD) was found in hind-paw skin biopsies from STZ-rats. Reduced SNCV and IENFD were significantly ameliorated by both doses of Actovegin®. More-over, 600 mg/kg Actovegin® markedly decreased poly(ADP-ribose) polymerase (PARP) activity in sciatic nerves from STZ-diabetic rats as assessed by poly(ADP-ribose) content. CONCLUSION: Actovegin® improved several para-meters of experimental diabetic neuropathy via mechanisms involving suppression of PARP activation, providing a rationale for treatment of this disease in humans.

[Pharmacological neuroprotection against brain damage in ischemiai/reperfusion experiment].

Experiment carried out on laboratory animals (rats) were aimed at comparative evaluation of the effect of several neuroprotective drugs under the conditions of model brain ischemia-reperfusion. The experimental methods included staining of brain tissue sections by hematoxiline-eosine, Nissl staining, and expression of NOS1, NOS3, TRAIL by imunnohistological means. The intensity of damage in various parts of brain and the nature of apoptosis without neuroprotection and with popular neuroprotectors (cytoflavin, actovegin, mexidol) and a test drug at the stage ofpreclinical trial (AKF-90-7) were evaluated. Characteristic cytotoxic (coagulative pycnomorphic and colliquative necrosis of neurons) and vascular (hemostasia, erythropedesis) changes were revealed. The neuroprotective effectof drugs decreases in the following order: AKF-90-7 > cytoflavin > actovegin > mexidol.

Bioavailability of a heme-iron concentrate product added to chocolate biscuit filling in adolescent girls living in a rural area of Mexico.

A heme-iron concentrate product derived from swine hemoglobin was used to enrich the chocolate-flavored filling of biscuits and the bioavailability of this source of heme-iron was assessed in adolescent girls. The placebo control (PC) group consisted of 35 teenagers with the highest baseline hemoglobin concentrations. The supplemented groups were randomized to receive biscuits fortified with iron sulfate (IS, n = 37) or heme-iron concentrate (HIC, n = 40). Both groups were supplemented with 10.3 mg Fe/d for 7 wk. Blood chemistry and hematology analyses were performed at baseline and at the end of the study. The baseline prevalence of anemia (hemoglobin <12 g/dl) in the entire group was 3.9% and by the end of the study it had fallen to 2.3%. The hemoglobin levels in both supplemented groups increased (P < 0.05) during the study period from 13.6 and 13.5 g/dl for HIC and IS, respectively, at baseline to 14 g/dl at the end of the study. Serum ferritin concentrations decreased by the end of the study in both the PC and IS groups (P < 0.05), but not in the heme group. In conclusion, iron bioavailability from HIC-fortified biscuits was calculated to be 23.7% higher than that observed for IS, as shown by the differences observed in serum ferritin levels during the study. The iron contained in the heme-iron concentrate was well absorbed and tolerated by the adolescents included in the study.

[Neurological complications of acute intermittent porphyria precipitated by porphyrinogenic drugs and efficiency of heme-arginate treatment]. / Complications neurologiques de la porphyrie aiguë intermittente précipitées par les médicaments porphyrinogéniques et efficacité du traitement par l'hème-arginate.

BACKGROUND: Acute intermittent porphyria (AIP) is a rare metabolic disorder of heme biosynthesis characterized by enzymatic defect of porphobiligen desaminase with accumulation and increased excretion of porphyrins and their precursors. Clinical picture is characterized by attacks with a triad of abdominal pain, psychiatric disorder and neurological involvement (central and peripheral). Peripheral nervous system manifestations, often precipitated by porphyrinogenic medications are of poor outcome. AIM: We report a new cases A 13-year-old girl who presented several attacks of AIP and developed acute severe axonal motor neuropathy, three weeks after porphyrinogenic medications (Famotidin, Phenobarbital and Nifedipine). CONCLUSION: We stress on the importance of early diagnosis of AIP to prevent serious neurological complications often precipitated by medications and the efficiency of heme arginate treatment when administrated early during the attacks.

Refractory status epilepticus due to acute hepatic porphyria in a pregnant woman: induced abortion as the sole therapeutic option?

A 22-years old, 55 kg female patient in the twelfth week of pregnancy developed neuropsychiatric syndromes and in the following status epilepticus. Raised porphyrines and porphyrine precursors were found in the patient's urine. Despite intravenous glucose infusions and appropriate medication no reduction in seizure-frequency and neuropsychiatric syndromes was observed. An abortion was induced. After the interruption and starting of haem arginate therapy, seizure activity stopped and porphyrine precursors returned to normal levels, and after 6 weeks the patient was discharged in excellent clinical condition. This report describes a status epilepticus caused by acute hepatic porphyria, triggered by pregnancy, in a 22-years old woman. To our knowledge this is the first report of induced abortion as successful treatment in acute hepatic porphyria induced status epilepticus.

[Intraocular correction of aphakia in patients after kidney transplantation]. / Intraokuliarnaia korrektsiia afakii u bol'nykh, perenesshikh transplantatsiiu pochki.

It was for the first time in the ophthalmologic practice that a possibility was demonstrated to ensure relatively high and stable functional results, in a significant number of patients with transplanted kidney (TK), related with different-type cataract extraction and with implantation of a variety of PMMA IOLs, i.e. model of B.A. Alexeev, "Storz" company models made from domestic and foreign-made PMMA and domestic-silicone models (P = 70). It was established that IOL implantation in patients with TK is possible in all cases provided the kidney transplant is compensated for and there are no foci of acute or chronic inflammation in the body. A minimal trauma caused by surgery and the suggested scheme of postoperative management (intramuscular injections of antibiotics and supplementary administration of solutions of poludan, naclof, catachrom and actovegin-gel made alongside with routine instillations) cuts the risk of infectious-and-inflammatory as well as of degenerative-and-dystrophic complications in patients with TK receiving the suppressor therapy. Clinical examinations denoted that the intraocular aphakia correction in patients with TK is a method of choice accelerating the medical and social rehabilitation in the discussed patients' category provided the therapeutic-and-diagnostic as well as preventive measures, as required by their status, are being taken.

[Therapeutic efficiency of a combined use of low-intensity laser radiation and actovegin in gastroduodenal ulcers with inhibited cicatrix formation]. / Otsenka terapevticheskoi éffektivnosti sochetannogo primeneniia nizkointensivnogo lazernogo izlucheniia i aktovegina pri trudno rubtsuiushchikhsia iazvakh zheludka i dvenadtsatiperstnoi kishki.

AIM: To validate use of intravenous laser blood irradiation (ILBI) combined with actovegin administration in indolent gastroduodenal ulcers. MATERIAL AND METHODS: Modern endoscopic, morphological, device, biochemical techniques and radioimmunoassay were used in examination of 92 patients with indolent gastroduodenal ulcers aged 24 to 69 years. ILBI plus actovegin was given in failure of standard medicinal therapy. RESULTS: ILBI plus actovegin combination produced marked analgetic, anti-inflammatory and detoxication effects. Favourable trends were observed in the composition of gastric mucus, detoxication, reparative and metabolic processes in the gastroduodenal mucosa, neurohumoral regulation. CONCLUSION: Combination of ILBI with actovegin proved highly effective in indolent gastroduodenal ulcers.

Management of acute and cutaneous porphyrias.

The porphyrias comprise a group of disorders of the haem biosynthesis pathway that can present with acute neurovisceral symptoms, skin lesions or both. Acute porphyrias present with severe abdominal pain, confusion and seizures which may be life-threatening. Specific treatment with haem preparations should be instituted as soon as possible following confirmation of increased excretion of porphobilinogen in the urine. Supportive treatment includes opiate analgesia, monitoring for and treating complications such as hypertension and hyponatraemia. Follow-up should include counselling on lifestyle modification involving avoidance of alcohol, smoking and known porphyrogenic drugs and diet. Identification and counselling of at risk relatives is essential. The cutaneous porphyrias result from porphyrin-induced photosensitivity and can present with either acute photosensitivity or skin fragility and blisters. All cutaneous porphyrias can be alleviated by avoidance of sunlight. Treatment of erythropoietic protoporphyria involves administering large doses of beta-carotene, which may improve tolerance to sunlight. Porphyria cutanea tarda can be effectively treated by phlebotomy or low dose chloroquine. Congenital erythropoietic porphyria is a rare, early onset, severe, photomutilating condition for which bone marrow transplantation has been shown to be successful.

[Actovegin treatment of duodenal ulcer associated with ischemic heart disease and diabetes mellitus]. / Lechenie aktoveginom bol'nykh iazvennoi bolezn'iu dvenadtsatiperstnoi kishki, sochetannoi s ishemicheskoi bolezn'iu serdtsa i sakharnym diabetom.

Actovegin, a deproteinized hemoderivative, was used to correct bioenergetic defects of duodenal mucosa, to reduce inflammatory-cell infiltration, to stimulate blood supply of patients with duodenal ulcer associated with ischemic heart disease or diabetes mellitus. As shown by the results obtained in 194 patients (119 males and 75 females), adjuvant actovegin in patients with duodenal ulcer associated with ischemic heart disease and diabetes mellitus stimulates the ulcer healing, prolongs the recurrence-free interval. It can be used both in outpatient departments and specialized hospitals.

Improvement of glucose metabolism in patients with type II diabetes after treatment with a hemodialysate.

Insulin resistance of skeletal muscle glucose uptake is a prominent feature of Type II diabetes (NIDDM); therefore, pharmacological intervention should aim to improve insulin sensitivity. Previous studies have shown that Actovegin, a hemodialysate of calf blood, which has been used for treatment of circulatory disorders for many years, improves glucose tolerance in NIDDM without affecting insulin levels; in vitro studies found an improvement of insulin-stimulated glucose uptake in adipocytes. This pilot study was initiated to see whether this compound augments insulin sensitivity after repeated treatment. Ten patients with NIDDM received the hemodialysate (Actovegin 2.000 pro infusions, 500 ml as daily infusions) over a period of 10 days. A hyperinsulinaemic, isoglycaemic glucose-clamp was done on day 0 and day 11; oral glucose tolerance test (oGTT) was done on day -4 and day 12. Parenteral administration of the hemodialysate markedly augmented insulin stimulated glucose disposal (glucose infusion rate and metabolic clearance rate) by more than 80% (p < 0.003 day 11 vs. day 0). Although tested 44 h after the last infusion, oGTT also improved significantly, as documented by the diminished area under the curve (AUC) for glucose, whereas the AUC for insulin remained unchanged. This is the first clinical study to show that parenteral administration of the tested hemodialysate results in a significant increase of insulin-stimulated glucose disposal in NIDDM. The exact mode of action of the hemodialysate in improving insulin sensitivity is currently not known. The hemodialysate possibly acts via a supplementation of inositol-phosphate-oligosaccharides (IPO), as in experimental studies IPOs isolated from the hemodialysate improved glucose uptake in adipocytes in an insulin-independent manner. Further studies are needed to elucidate the underlying mechanisms.