NITROSYL FERREDOXINES MIMETICS AS PHOSPHODIESTERASE INHIBITORS: SYNTHESIS, STRUCTURE AND ACTIVITY IN VITRO

The paper presents and discusses experimental data on the synthesis, study of the structure and properties in the solid phase and in solutions of new low-molecular-weight iron dinitrosyl complexes with N,S-ligands of the 1,2,4 -1-H-triazole N,S-ligands of the“g = 2.03” family, nitric oxide (NO) donors, and effective inhibitors of cGMP phosphodiesterases.

Efficacy and Safety of Low Molecular Weight Iron Dextran (LMWID) Vs. Ferumoxytol in Treating Iron Deficiency Anemia

Introduction: Iron deficiency anemia is the most common form of anemia and hematologic problem worldwide. Treatment options include oral or intravenous (IV) iron replacement. Although oral iron is commonly employed as first-line therapy, many studies suggest that IV iron more effective and associated with better quality of life when compared to oral iron. Yet, adverse infusion reactions are possible. Several forms of IV iron are used in clinical practice, including low molecular weight iron dextran (LMWID), ferumoxytol, ferric gluconate, iron sucrose, and ferric carboxymaltose. We sought to compare the efficacy and safety of LMWID and ferumoxytol, the two most frequently used products at our center. Methods: A retrospective cohort analysis was conducted using internal pharmacy records. Adults with an ICD-10 diagnosis of iron deficiency anemia treated with LMWID or ferumoxytol from 2018 to 2019 were identified. Records were reviewed for demographics, comorbidities, allergies, type and frequency of iron administered. Outcomes of interest were comparisons of baseline and post-treatment hemoglobin [Hgb] and ferritin levels and adverse events (AEs) following infusion. Results: In total 55 patients received one of the two included iron preparations. Of the 40 cases of iron deficiency treated with LMWID, only 4 patients (10%) received a second dose. Of the first LMWID infusions (dose of 1000 mg), all patients demonstrated an increase in Hgb from a mean of 12.21 to 13.15 within an average of 2.75 months. Mean ferritin levels went from 28.34 pre-treatment to 231.14 post-treatment, within an average of 3.26 months. 2 patients (5%) received premedication, one with diphenhydramine or promethazine, based on prior history of an AE. AEs were documented in 3 patients (7.5%) and included arm swelling, dysphagia with globus sensation, and nausea. No patients received premedication prior to ferumoxytol infusion. Those receiving ferumoxytol demonstrated an increase in hemoglobin from a mean of 10.25 to 12.17 within an average of 4.2 months. Ferritin increased from baseline 75.93 to 150.33 within 3 months. AE of diarrhea and nausea were reported in only one patient (6.67%) upon second infusion of ferumoxytol. No patient in either group experienced AEs requiring hospitalization, nor did any patient develop severe hypersensitivity reactions, hypotension, or hypophosphatemia. Discussion: In our retrospective cohort, LMWID or ferumoxytol for treatment of iron deficiency were well tolerated with minimal AEs, limited to arm swelling, dysphagia and nausea in 3 patients. Those treated with ferumoxytol experienced similarly few AEs, with only one patient developing transient diarrhea and nausea. Hesitancy to utilize IV iron has persisted due to concerns for potential side effects including anaphylaxis. Our encouraging results provide additional evidence for the efficacy and safety of LMWID and furomoxytol, and should help to assuage fears that IV iron might be poorly tolerated or ineffective. Disclosures Shatzel: Aronora, Inc.: Consultancy.

Desideromastica: Tactile Chew Cravings in Iron Deficiency Anemia

Introduction: The compulsive craving and consumption of non-food substances, known as pica, is a well-documented symptom associated with iron deficiency anemia (IDA). Olfactory cravings associated with IDA are a recently described phenomenon known as desiderosmia. In our practice we observed a subset of patients with IDA who report specific tactile cravings associated with mastication. Methods: This study included patients from the Mayo Clinic (Rochester, MN) and Ankara Training and Research Hospital (Ankara, Turkey) Hematology practices who self-reported tactile mastication cravings during initial evaluation for IDA between 1/1/18 and 6/30/19. Information including sociodemographics, substance craved, values of hemoglobin (Hgb), mean corpuscular volume (MCV), and ferritin before and after iron replacement therapy, and symptom resolution after treatment were recorded. Results: We observed 12 patients with IDA who self-reported chew cravings during initial evaluation. All patients were female and the median age was 41.5 years (33-59). Of these 12 patients, median baseline Hgb, MCV, and ferritin were 9.4 g/dL (6.6-12.9), 73.7 fL (59.1-95.1), and 6 µg/L (2-21), respectively. Tactile cravings included chewing gum (3), mastic gum (2), ginseng (1), dry oats (1), crackers (1), pickles (1), chips (1), sawdust (1), and knitting rope (1). Many patients reported the frequency and satisfaction of these cravings resulted in jaw pain as well as the persistence of cravings despite this discomfort. Only 16.7% (2/12) reported concurrent ice pica. In total, 9 patients proceeded with observed treatment of their IDA with clinical follow-up and laboratory confirmation of iron repletion. Oral (ferrous glyconate or ferrous fumarate) and intravenous (ferric carboxymaltose, iron sucrose, or low molecular weight iron dextran) iron replacement were used in 33.3% (3/9) and 66.7% (6/9) patients, respectively. Post-treatment median laboratory values include: Hgb 12.7 g/dL (10.8-14.7), MCV 80.1 fL (76.1-91.7), and ferritin 98 µg/L (24-398). Overall, 88.9% (8/9) reported resolution of chew cravings after iron repletion. The lone patient with persistent symptoms had a baseline ferritin of 10 µg/L, improved to 398 µg/L after replacement, and settled back at 42 µg/L three months later. Discussion: Our patient experience provides suggestive evidence that oral tactile craving symptoms, distinct from ice pica, exists in a subset of patients suffering from IDA. For this, we propose the term "desideromastica" derived from the Latin words "desiderare" for desire and "mastica" for chew. "Desidero" can also be indicative of a reduction in iron, which relates to iron deficiency. Our hope in naming this relatively unexplored symptom associated with IDA will encourage additional clinicians to share their experience and guide future investigation. Disclosures No relevant conflicts of interest to declare.

Safety and Efficacy of Rapid (one hour) Single Intravenous Dose Low Molecular Weight Iron Dextran for Treatment of Oral Iron Intolerant Maternal Iron Deficient Anemia

OBJECTIVE: Determine safety and efficacy of rapid (one hour) intravenous infusion of 1,000 mg low molecular weight iron dextran to pregnant women with moderate to severe iron deficient anemia. INTRODUCTION: Up to 70% of pregnant women to whom oral iron is prescribed report significant gastrointestinal side effects. Intravenous iron is an efficient, but often overlooked, therapeutic alternative. METHODS: We conducted an observational treatment study of 1000 mg low molecular weight iron dextran for moderate to severe iron deficient anemia of pregnancy in 189 consecutive, unselected second and third trimester gravidas intolerant of, or unresponsive to, oral iron. All received an intravenous test dose of approximately 25 mg low molecular weight iron dextran. They were then monitored closely for adverse reactions during the balance of a 60 minute infusion. No premedication was administered unless two or more drug allergies or asthma was present in which case prophylactic intravenous methylprednisolone was administered. All subjects were followed through pregnancy and delivery. Monitored parameters included hemoglobin (Hgb), mean corpuscular volume (MCV), serum ferritin, and percent transferrin saturation. RESULTS: One hundred eighty-nine subjects received a single intravenous dose of 1000 mg low molecular weight iron dextran. No first trimester gravidas were treated. No serious adverse events occurred. Minor, self-limited infusion reactions (myalgias or flushing), occurred in 2% of subjects. The mean number of days from treatment to delivery was 58.6 (range 5-190) days. The change in Hgb was positively correlated with the time from treatment to delivery (r2 =0.17, p=0.0039). The initial Hgb was 10.1 g/dl (SD 1.03, SE 0.07) and at delivery 11.5 g/dl (SD=1.04, SE 0.10), with the mean change from diagnosis to delivery of 1.39 g/dl (p<0.0001). An improvement in Hgb was observed in 174 (92% (Figure 1)). In 110 (58%) the observed increment was 1.00-1.99 g/dl (hemoglobin response) and in 45 (24%) ≥ 2.00 g/dl (hematopoietic response). Second trimester treatment was not associated with a greater improvement in Hgb than third trimester treatment. MCV increased by 3.27 femtoliters (fl) for those treated in the second (p<0.0001), and 1.34 in the third(p<0.0001). The mean increment in MCV for those treated in the second trimester was 1.93 fl higher than those treated in the third (p=0.02). Post-partum data were available on 64 (34%). For this subgroup the mean change in Hgb from diagnosis to delivery was 1.48 g/dl, not significantly different than the observed increment for the entire group of 189. From delivery to post-partum follow-up, an additional Hgb increment of 0.66 g/dl was observed (p<0.0001) consistent with sustained iron repletion and post-partum contraction of plasma volume. The increment in Hgb from diagnosis to delivery and diagnosis to post-partum was similar irrespective of trimester of treatment. Anemia resolved in 95%. CONCLUSION: Administration of a rapid (one hour) single large dose (1000 mg) of intravenous low molecular weight iron dextran is a convenient, effective, well tolerated and safe treatment for maternal iron deficient anemia in women who are intolerant of, or unresponsive to, oral iron. These data are relevant in light of recent publications reporting iron deficient neonates have both delayed growth and development and a statistically significant increment in both cognitive and behavioral abnormalities persisting up to ten years after iron repletion. Figure 1. Change in mean hemoglobin concentration (g/dL) +/- SE from diagnosis to delivery to postpartum follow up. Figure 1. Change in mean hemoglobin concentration (g/dL) +/- SE from diagnosis to delivery to postpartum follow up. Disclosures Off Label Use: Total dose infusion of low molecular weight iron dextran is off label.