Safety and Tolerability of Deferoxamine Mesylate in Patients With Acute Intracerebral Hemorrhage
Background and Purpose—Treatment with the iron chelator, deferoxamine mesylate (DFO), improves neurological recovery in animal models of intracerebral hemorrhage (ICH). We aimed to evaluate the feasibility, safety, and tolerability of varying dose-tiers of DFO in patients with spontaneous ICH, and to determine the maximum tolerated dose to be adopted in future efficacy studies.
Methods—This was a multicenter, phase-I, dose-finding study using the Continual Reassessment Method. DFO was administered by intravenous infusion for 3 consecutive days, starting within 18 hours of ICH onset. Subjects underwent repeated clinical assessments through 90 days, and computed tomography neuroimaging pre- and post-drug-administration.
Results—Twenty subjects were enrolled onto 5 dose tiers, starting with 7 mg/kg per day and ending with 62 mg/kg per day as the maximum tolerated dose. Median age was 68 years (range, 50–90); 60% were men; and median Glasgow Coma Scale and National Institutes of Health Stroke Scale scores on admission were 15 (5–15) and 9 (0–39), respectively. ICH location was lobar in 40%, deep in 50%, and brain stem in 10%; intraventricular hemorrhage was present in 15%. DFO was discontinued because of adverse events in 2 subjects (10%). Six subjects (30%) experienced 12 serious adverse events, none of which were drug-related. DFO infusions were associated with mild blood-pressure-lowering effects. Fifty percent of patients had modified Rankin scale scores ≤2, and 39% had modified Rankin scale scores of 4 to 6 on day 90; 15% died.
Conclusions—Consecutive daily infusions of DFO after ICH are feasible, well-tolerated, and not associated with excessive serious adverse events or mortality. Our findings lay the groundwork for future studies to evaluate the efficacy of DFO in ICH.
At present, there is no treatment for intracerebral hemorrhage (ICH) beyond supportive and aggressive medical care. The iron chelator, deferoxamine mesylate (DFO), is a potentially promising therapeutic intervention to target secondary effects of ICH to limit brain injury, facilitate neuronal repair, and improve outcome.
Hemoglobin and its degradation products, particularly iron, released from hemolyzed red blood cells after ICH are implicated in neuronal injury via several mechanisms; these include exacerbation of excitotoxicity, autophagy, hydroxyl radical formation, and oxidative stress.1–8 DFO has diverse neuroprotective effects independent of its iron-chelating properties9; these include antiapoptosis, antioxidative stress, antiphagocytosis, and anti-inflammatory effects10–12; it also blocks hemoglobin-mediated accentuation of glutamate excitotoxicity.5 Animal studies have shown that DFO reduces hemoglobin-induced neurotoxicity in vitro and in animal models of hemorrhage, and it improves neurological function after experimental ICH in several species.13–15
To translate these preclinical data, we undertook the current study to assess the tolerability and safety of DFO in patients with ICH, and to determine the maximum tolerated dose (MTD) to be investigated in future studies to determine whether treatment with DFO would improve overall outcome after ICH.
Subjects and Overall Study Design
This was a multicenter, Phase I, dose-finding study using the Continual Reassessment Method (CRM).16 Subjects with spontaneous ICH, presenting to the emergency department within 18 hours of symptom onset, were enrolled from July 2008 to January 2010 at 4 sites: Beth Israel Deaconess Medical Center (n=6), Massachusetts General Hospital (n=5), Medical College of Wisconsin (n=5), and Hartford Hospital (n=4). The Data Coordination Unit, housed in the Division of Biostatistics and Epidemiology at the Medical University of South Carolina, served as the statistical and data management center for the study. The study was approved by the local Institutional Review Boards, and all subjects (or their legal representatives) were required to sign written informed consent before enrollment. Supplemental Table S1, http://stroke.ahajournals.org, lists inclusion and exclusion criteria.
The study was supported by the National Institute of Neurological Disorders and Stroke (NINDS), and registered with clinicaltrials.gov as NCT00598572. An Investigational New Drug (IND) was granted from the US Food and Drug Administration to conduct the study (IND #77306).
All patients with ICH were screened on presentation. A pretreatment baseline plain computed tomography scan establishing the presence of ICH was required to confirm the diagnosis. Neurological examination included assessments of National Institute of Health Stroke Scale (NIHSS) and Glasgow Coma Scale (GCS) scores, as well as study-specific visual and auditory tests (whenever possible in awake patients), which included assessments for cataracts, hearing loss, color blindness, and tinnitus. Consecutive eligible patients were approached for consent and underwent baseline examination (repeated NIHSS, GCS, and physical examination including vital signs) 3 to 6 hours later to assure neurological stability. Stable subjects received the first dose of the study drug within 45 minutes of baseline assessments and 18 hours of ICH-symptom onset. All subjects were admitted to neurological intensive care or stroke units; the general care of subjects conformed to guidelines from the Stroke Council of the American Heart Association.17 Supplemental Table S2 summarizes the timing and type of various assessments throughout the study. Subjects were monitored for safety and vital signs recorded every 30 minutes during each infusion and hourly afterward. The subjects were contacted by phone on day 90 (±7 days) to assess modified Rankin scale (mRS), Barthel Index (BI), and Extended Glasgow Outcome Scale (GOS-E) scores and mortality. All AEs were assessed until day 7 or discharge (whichever was earlier), and serious adverse events (SAE) until the completion of the study on day 90. Administration of DFO can result in a vin rosé discoloration of urine in patients with systemic iron overload, which raised concerns regarding the potential for unblinding in future controlled trials of DFO. Therefore, we performed urine analyses at multiple points during treatment with DFO.
Weight-adjusted intravenous infusions of DFO were administered at a rate of 7.5 mg/kg per hour and repeated daily for 3 consecutive days. The first cohort received a dose of 7 mg/kg per day, with subsequent cohorts treated at dose-tiers determined according to the Piantadosi modified CRM.16 Regardless of subject weight or assigned dose, the maximum daily dose was restricted to 6000 mg/d, in accordance with the manufacturer’s brochure and U.S. Food and Drug Administration recommendations, to minimize risk of toxicity. A minimum cohort size of 3 subjects was prespecified for each dose. The safety information guiding the transition from 1 dose to the next was based on number of subjects in a cohort who experienced prespecified dose-limiting toxicities (DLT). To guard against rapid dose escalation, we prespecified incremental increases of ≤25 mg/kg per day until DLT was observed, at which time the CRM was implemented to determine the dose for each of the subsequent cohorts.
To assure safety, we conservatively defined DLTs as any of the following AEs occurring within 7 days of initiation of treatment with DFO or until discharge (whichever was earlier): anaphylaxis at any time point during DFO infusion; hypotension, defined as a decrease in systolic blood pressure >20 mm Hg or diastolic blood pressure >10 mm Hg, or systolic blood pressure <85 mm Hg, confirmed by 3 consecutive readings, and requiring medical treatment at any time point during DFO infusion, that cannot be explained by other causes; worsening neurological status, defined as an increase ≥4 points on NIHSS or a decrease of ≥2 points on GCS, that cannot be explained by other causes, occurring at any time point during DFO infusion; mortality, regardless of relationship to DFO; and any AE prolonging hospital stay, resulting in emergent medical therapy, or resulting in death, regardless of relationship to DFO.
An independent Medical Safety Monitor reviewed all SAEs and DLTs on an ongoing basis. The Medical Safety Monitor communicated his decisions directly to the Chair of the NINDS-appointed Data and Safety Monitoring Board. As a safety precaution, we planned to suspend enrollment if 2 of 3 subjects in a cohort experienced DLTs to allow the Data and Safety Monitoring Board to review the accumulated data and make a recommendation for early termination versus resumption of the study.
The primary outcome measure was safety, defined as the occurrence of DLTs as defined above. There was no lost-to-follow up with regard to safety outcomes, because the CRM was based on safety assessments conducted during hospitalization through day 7 or discharge (whichever was earlier).
Because this study was envisioned as a prelude to future efficacy studies, we assessed various neurological and functional outcome scales (mRS, BI, and GOS-E) on day 90. We also explored effects of treatment on the progression of hematoma and relative perihematoma edema (PHE) volumes on serial computed tomography scans, primarily for safety purposes, to ensure that DFO does not aggravate hematoma or PHE growth. We used relative PHE, as opposed to absolute PHE volume, to adjust for underlying ICH volume.18 Computerized radiological volumetric measurements were performed by a single investigator, blinded to the assigned dose and clinical data, as previously described.19 The blinded investigator examined ICH and PHE volumes in 10 randomly selected, deidentified scans twice at an interval of several months apart. The test-retest intraclass correlation coefficients for intraobserver agreements were 1.0 for both ICH and PHE volume measurements. The concordance correlation coefficient was 0.996 (95% CI, 0.990–0.999) for ICH and 0.998 (95% CI, 0.993–0.999) for PHE volumes.
The CRM was used to identify the maximum tolerated DFO dose, defined a priori as the dose associated with a 0.40 DLT probability. The maximum acceptable DLT probability of 0.40 was prespecified based on the weighted average of all SAEs reported in placebo-treated patients who participated in recent ICH trials (FAST, CHANT, GAIN).20–22 Under the CRM, when the third subject in each cohort completed the 7-day or discharge period, the dose-toxicity curve was updated based on DLTs observed in all previously enrolled subjects, and the estimated MTD obtained from the updated curve. Subjects enrolled onto the following cohort were then treated at the re-estimated MTD. This reassessment process was repeated until the stopping convergence criterion was reached. The CRM algorithm was considered to have converged when the re-estimated MTD following completion of the current cohort was within 5% of the current dose. Analysis of CRM data was performed on an ongoing basis throughout the study. The DLT data were available to the study statistician (S.Y.), who implemented the CRM algorithm and updated the dose for subsequent cohorts.
AEs were assigned to a system-organ class and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA). Exploratory descriptive statistics (median, range, percentages) of additional safety parameters and clinical and radiological data were computed by dose group. The effect of DFO on laboratory parameters and vital signs is summarized by the median change in the corresponding parameter and 95% CI.
Subjects Baseline and Clinical Characteristics
A total of 20 subjects were enrolled onto 6 cohorts during the course of the study. Two subjects (10%) withdrew consent following the treatment period; neither withdrawal was because of an AE. No other subjects were lost to follow-up.
The first cohort (n=4) was treated at 7 mg/kg per day, the prespecified starting dose, with subsequent cohorts treated at doses identified by the CRM algorithm as follows: 32 mg/kg (n=3), 47 mg/kg (n=3), 57 mg/kg (n=4), and 62 mg/kg (n=3). On completion of the fifth cohort, the updated dose-toxicity curve indicated that the next cohort should maintain the 62 mg/kg per day dose. As this met our prespecified convergence criterion, the final estimated MTD is 62 mg/kg per day. Thereafter, following consultation with the Data and Safety Monitoring Board, we enrolled 3 additional subjects at the MTD to collect additional safety data at this dose. Table 1 summarizes the demographic, baseline, and clinical characteristics of trial subjects by assigned dose.
The infusions of DFO were, overall, well-tolerated. Seventeen subjects (85%) completed the 3-day study drug infusions. In 2 subjects (10%), infusions were prematurely discontinued because of AEs. These were shoulder pain, initially thought to be infusion-related, which was later determined to be unrelated, and visual hallucinations, thought to be possibly study-drug-related. One subject only received the first infusion, without experiencing AEs, but subsequent infusions were not continued because his family declined additional treatment.
A total of 94 AEs (12 serious [13%], 82 nonserious), were reported during the study. The 12 SAEs occurred in 6 subjects (30%). Six of these 12 SAEs occurred in 3 subjects during the first 7 days of hospitalization. One subject (in the 62 mg/kg dose-tier) experienced 5 SAEs. Three subjects (15%) experienced 4 DLTs; of these, 2 subjects, both treated at the 62 mg/kg dose, developed aspiration pneumonia and required intubation. These were considered DLTs, because intubation prolonged their hospital stay. Because the rate of DLTs in this cohort (0.33) was less than was our prespecified acceptable probability of 0.40, the 62 mg/kg per day dose still met our predefined criteria for the MTD. Table 2 summarizes the occurrence of DLTs and SAEs by dose tier.
Three subjects (15%) died during the 90-day follow-up period; 1 subject (5%) died in hospital within 7 days of ICH onset, and 2 subjects died between 7 and 30 days after ICH onset. None of the SAEs, DLTs, or mortalities were adjudicated to be related to the study drug.
Sixteen nonserious AEs (20%) were possibly or probably related to the study drug. They were mild, self-limited, and did not require specific treatment. These included: injection site irritation (15%) and intravenous infiltration (20%), itching or rash (10%), visual hallucinations (5%), blurred vision (5%), decrease in blood pressure (20%), and arm pain (10%). Supplemental Table S3 summarizes all AEs by Medical Dictionary for Regulatory Activities body system and by dose-tier.
Vital Signs and Laboratory Studies
Administration of DFO did not result in important alterations in heart rate, respiratory rate, oxygen saturation, or temperature. Overall, median mean blood pressure (MAP) at baseline was 95.8 mm Hg (95% CI, 84–100.3) versus 93.2 mm Hg (95% CI, 87.6–98.1) during the infusions. A total of 8 patients (40%) experienced a maximal drop in MAP >20% (median, 29%; 95% CI, 27–39) at some point during the infusions compared with baseline values. One subject, in the 62 mg/kg dose-tier, required vasopressors; his hypotension was thought to be related to intubation and anesthesia. None of the remaining 7 subjects required any medical treatment. In the 62 mg/kg dose-tier cohorts, 4 of 6 subjects (67%) experienced a maximal drop in MAP >20% during the infusions (median, 29%; 95% CI, 25–39; mean absolute change, 22.4 mm Hg; standard error, 0.49); median MAP at baseline was 87.7 mm Hg (95% CI, 80.7–96.7) versus 87.4 mm Hg (95% CI, 79.5–96.0) during the infusions. However, the blood pressure drop was not clinically significant, did not meet our definition for a DLT, and did not require treatment, except in the subject mentioned above.
Analyses of laboratory data indicated no safety concerns. There were no differences in routine laboratory values and in the incidence of abnormalities and change from baseline in electrocardiogram parameters. Serum hemoglobin and hematologic parameters, renal and hepatic functions, and electrolytes were stable over time. We observed no changes in urine output or color over the 3-day course of DFO infusions in any subject. Treatment with DFO did not result in iron deficiency or anemia. We found no relationship between DFO dose-tier and changes in serum iron studies. Supplemental Table S4 summarizes laboratory values at baseline, 72 hours, and day 30.
Analysis of volumetric measurements of ICH and relative PHE volumes over time indicated no safety concerns at any of the tested dose-tiers. These data are summarized in Table 3. Overall, treatment with DFO was not associated with increase in hematoma or PHE growth. Median change in ICH volume from baseline to after the third DFO infusion was −0.05 cm3 (95% CI, −0.87–0.64). Overall median change in relative PHE volume from screening to post-third DFO infusion was 0.48 (95% CI, 0.10–0.76) and from screening to day 7 or discharge (whichever occurred first) was 0.87 (95% CI, 0.51–1.28).
Functional Outcome Data
We collected data on mRS, BI, and GOS-E at day 90. These data are summarized in Table 3. Two subjects (10%) withdrew consent, 1 after the 7-day visit (mRS=5), and 1 after the 30-day visit (mRS=1). Among the remaining 18 subjects, 9 subjects (50%) had mRS scores of 0 to 2; 2 subjects (11%) had a score of 3; and 7 subjects (39%) had scores of 4 to 6. Three subjects died before completing the 90-day assessments. Among the 15 survivors, 9 subjects (60%) had a BI score ≥95; 2 subjects (13%) had scores of 60 to 80 and 4 subjects (27%) had scores of 0 to 50; 6 subjects achieved upper good recovery on GOS-E at day 90, 1 subject achieved lower good recovery, and 8 subjects achieved moderate-to-severe disability.
Animal studies have shown that human-equivalent doses of DFO ≥16 mg/kg are associated with improved outcome after experimental ICH.15 Therefore, we explored trends in functional outcome data among 14 subjects who completed the study in the 32 mg/kg to 62 mg/kg dose-tier cohorts. Seven subjects (50%) had mRS of 0 to 2 and 6 subjects (43%) had mRS of 4 to 6 at day 90. The baseline characteristics for this subgroup were as follows: median age, 71 years; admission ICH volume, 16.5 mL; baseline NIHSS, 7; baseline GCS, 14.
The primary objectives of this phase-I study were to investigate the feasibility, tolerability, and safety of repeated infusions of DFO in patients with acute spontaneous ICH, and to determine its MTD to be used in future Phase II and Phase III studies. We found that repeated daily infusions of DFO for 3 consecutive days after ICH onset are feasible and well-tolerated; are not associated with an increase in SAEs or mortality, when compared with placebo-treated patients in recent ICH trials20–22; and do not result in substantial biochemical, hematologic, or radiological AEs. DFO has been used in clinical practice for over 40 years, mostly for the treatment of acute iron intoxication and chronic iron overload in patients requiring repeated blood transfusions. The safety profile of DFO in this study is in line with previous clinical experience of DFO use in nonstroke patients.23 In rat models of ICH, DFO doses of 100 mg/kg per day and 200 mg/kg per day were both effective in improving neurological and functional recovery15; based on mass constant conversion factors, the calculated human equivalent doses are approximately 16 mg/kg per day and 32 mg/kg per day. We identified 62 mg/kg per day (up to a maximum daily dose of 6000 mg/d, irrespective of body weight) as the MTD for DFO infusions.
There is growing experimental and clinical evidence linking iron-mediated toxicity to secondary neuronal injury after ICH.1–7 Animal studies demonstrate an increase in iron-positive cells, heme oxygenase protein, and markers of DNA damage in the perihematoma area within the first day after ICH, which peak by day 3.3,10 In ICH patients, serum ferritin on admission correlates with relative PHE on day 3 (which coincides with the timing for hemoglobin hemolysis24)19 and with functional outcome at 3 months25; iron content within the hematoma, estimated by magnetic resonance imaging, correlates with the relative PHE volume.26 There is also extensive preclinical evidence that the iron chelator, DFO, confers substantial neuroprotection and reduces hemoglobin-induced neurotoxicity after ICH in different species and by different investigators.6,10,13–15 These studies have shown that the benefit of DFO in ameliorating secondary neuronal injury after ICH is mediated via several diverse mechanisms and may be at least partly independent of its iron-chelating effects.5,10–12 Our findings that the MAP decreases by approximately 2 mm Hg during DFO infusions indicates that DFO also exerts a mild blood-pressure-lowering effect, which may be of some potential benefit in ICH.27 Therefore, DFO is a rational choice for additional investigation as a potential therapeutic intervention to improve the outcome of patients with ICH.
This study represents the first translational attempt in this regard. Most attention in ICH research has been focused on targeting hematoma and its expansion, utilizing various approaches such as surgical evacuation, endoscopic aspiration with or without lysis, ultrahemostatic therapy, or intensive blood-pressure-lowering. In contrast, treatment with DFO aims to target the pathophysiological mechanisms that contribute to secondary neuronal injury, which continues for days after ICH onset, and if successful can provide a complementary therapy to ongoing efforts targeting hematoma and its expansion.
Treatment with DFO at all tested dose-tiers did not result in significant alterations in hematologic or serum iron studies. Serum ferritin, however, showed a trend toward increase following treatment (Supplemental Table S4). This may be related to a paradoxical increase in serum ferritin following ICH as part of an acute stress response.28 Our study did not include a placebo arm to address adequately this possibility and to assess whether treatment with DFO in our study might have blunted an otherwise greater rise in serum ferritin. The lack of significant reduction in serum iron studies after 3-day treatment with DFO may be similarly explained, and does not necessarily imply lack of its potential efficacy in ICH. Again, the benefit of DFO may be, at least partly, independent of its iron-chelating effects.5,10–12 Previous animal studies have shown that DFO decreases ferritin-positive cells in the brain following ICH.14 However, they did not examine the effects of DFO on serum ferritin levels. Future studies should examine levels of serum ferritin and iron following experimental ICH and the effects of DFO on these measures; they should also carefully probe temporal changes in these serum measures during the days following ICH in DFO- and non-DFO treated patients, ideally in a randomized, placebo-controlled, trial setting.
Animal studies show that: PHE volume increases rapidly between day 1 and 3 after ICH onset, at which point it reaches its peak,28–29 delayed brain edema formation is largely related to hemoglobin- and iron-mediated toxicity,2,30 and treatment with DFO attenuates the development of brain edema after ICH.10,14–15 Human studies, however, suggest that the peak in PHE is delayed beyond 3 days.31–32 Our radiological data regarding relative PHE volume, where it increased by 0.48 from admission to day 3 and 0.87 to day 7 or discharge, are consistent with these reports. They also compare favorably with previous studies evaluating the natural progression of PHE, which showed that relative PHE volume almost doubles within the first 24 to 72 hours.18–19 Although debatable, relative PHE might influence recovery after ICH.33 Animal studies have shown that DFO decreases PHE in a dose-dependent manner.13 We did not observe a clear dose-dependent effect on PHE progression in our study. This may be because of the small number of subjects treated at each dose cohort. Future studies will need to include larger number of subjects and non-DFO-treated subjects to clarify conclusively the effect of DFO on PHE. It is important, however, to point out that our study was focused on safety and dose finding. It was not designed to assess efficacy, mechanisms of action of DFO, or surrogate measures of its biological activity. It was also not powered or blinded to address properly clinical outcomes. Therefore, the above findings are purely exploratory at this stage.
We started DFO infusions within 18 hours of ICH onset. Recent animal studies indicate that the beneficial effects of DFO are maintained when it is administered up to 48 hours after ICH induction, and that the optimal therapeutic time window is up to 24 hours.15
Our study utilized the modified CRM statistical design, which represents a novel approach to conducting phase-I safety and dose-finding studies in stroke. The CRM provides greater responsiveness to the occurrence of AEs, minimizes exposing additional subjects unnecessarily to doses below the MTD, and allows for determination of the MTD with a small sample size.
In conclusion, the current study provides data demonstrating the feasibility, tolerability, and safety of DFO in doses up to 62 mg/kg per day, up to a maximal daily dose of 6000 mg/d, in patients with ICH. These results support continued development of DFO as a potential therapy for ICH. Development of a multicenter, Phase II trial of DFO in ICH is currently underway.
Sources of Funding
The study was sponsored by the NIH/NINDS (1R01-NS 057127). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
All investigators received modest support from the NINDS (1R01-NS 057127). Dr. Selim received significant support as the Principal Investigator. L.B.M. and G.X. received additional significant support from the NINDS (U01 NS052510).
We thank the NINDS-appointed Data and Safety Monitoring Board; Adnan Qureshi, MD, who served as the Independent Data Safety Monitor for the study; and all the DFO in ICH study investigators.
The DFO in ICH Study Group:
Project Management and Data Coordination Unit: The Dept. of Biostatistics, Bioinformatics, and Epidemiology at the Medical University of South Carolina, Charleston, SC: Sharon Yeatts, PhD; Yuko Palesch, PhD; Catherine Dillon; Bonnie Waldman; Lynn Patterson; Andre Thornhill.
Clinical Sites: Beth Israel Deaconess Medical Center, Boston, MA: PI: Magdy Selim; Richard Goddeau, Jr.; Coordinators: Shunaiber Tauhid and Kathrin Lieb. Medical College of Wisconsin, Milwaukee, WI: PI: Michel Torbey; Coordinator: Erin McGuire. Massachusetts General Hospital, Boston, MA: PI: Joshua Goldstein/Jonathan Rosand; Coordinator: Alex Oleinik; University of Connecticut/Hartford Hospital, Hartford, CT: PI: Joao Gomes; Coordinator: Martha Ahlquist. Central Imaging Laboratory–BIDMC, Boston, MA: Gottfried Schlaug; Lin L. Zhu. Consultants: Guohua Xi, Lewis Morgenstern, and Steven Greenberg.
Natan M. Bornstein, MD, was the Guest Editor for this paper.
The online-only Data Supplement is available at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.111.617589/-/DC1.
- Received February 15, 2011.
- Accepted June 1, 2011.
- © 2011 American Heart Association, Inc.
- Wu J,
- Hua Y,
- Keep RF,
- Nakamura T,
- Hoff JT,
- Xi G
- Winterbourn CC
- Selim M
- Ratan RR,
- Siddiq A,
- Aminova L,
- Langley B,
- McConoughey S,
- Karpisheva K,
- et al
- Okauchi M,
- Hua Y,
- Keep RF,
- Morgenstern LB,
- Xi G.
- Gu Y,
- Hua Y,
- Keep RF,
- Morgenstern LB,
- Xi G
- Okauchi M,
- Hua Y,
- Keep RF,
- Morgenstern LB,
- Schallert T,
- Xi G
- Broderick J,
- Connolly S,
- Feldmann E,
- Hanley D,
- Kase C,
- Krieger D,
- et al
- Gebel JM Jr.,
- Jauch EC,
- Brott TG,
- Khoury J,
- Sauerbeck L,
- Salisbury S,
- et al
- Mehdiratta M,
- Kumar S,
- Hackney D,
- Schlaug G,
- Selim M
- Lyden PD,
- Shuaib A,
- Lees KR,
- Davalos A,
- Davis SM,
- Diener HC,
- et al
- Haley EC Jr.,
- Thompson JL,
- Levin B,
- Davis S,
- Lees KR,
- Pittman JG,
- et al
PDR Health. Physicians’ Desk Reference. http://www.pdr.net/search/searchResult.aspx?searchCriteria=deferoxamine+mesylate. Accessed May 3, 2011.
- Pérez de la Ossa N,
- Sobrino T,
- Silva Y,
- Blanco M,
- Millán M,
- Gomis M,
- Agulla J,
- et al
- Venkatasubramanian C,
- Mlynash M,
- Finley-Caulfield A,
- Eyngorn I,
- Kalimuthu R,
- Snider RW,
- et al
- Zazulia AR,
- Diringer MN,
- Derdeyn CP,
- Powers WJ
- McCarron MO,
- Hoffmann KL,
- DeLong DM,
- Gray L,
- Saunders AM,
- Alberts MJ