© F e r r a t a S t o r t i F o u n d a t i o nN o c o m m e r c i a l u s e metabolite (NO x ) levels. 16 The lowest arginine levels were found in children requiring admission for VOE, 16 with arginine levels returning to baseline during convalescence in the hospital. Of interest, low plasma arginine alone was a sensitive predictor for admission, 16 while NO x levels were not, suggesting a function for arginine bioavailability in VOE severity that goes beyond NO. Although supplemental arginine increases plasma NO x in normal controls, when given to SCD patients at steady-state, a paradoxical decrease in NO x occurs that is not overcome by higher doses, 20 indicating that arginine is metabolized differently in patients with SCD than in healthy volunteers. However, when a single dose of arginine is given to patients with SCD during VOE, there is a robust dosedependent increase in plasma NO x . 20 Based on these promising data, we designed a randomized, placebo-controlled trial to determine the safety and efficacy of arginine therapy in children with SCD requiring hospitalization for severe pain necessitating parenteral narcotics. Methods Study designThis study was a single-center, prospective, randomized, double-blind, placebo-controlled, phase 2 trial designed to explore the effectiveness of the arginine intervention in participants with SCD requiring hospitalization for VOE. Data outcome measures included length of stay (LOS) in hospital (days), total narcotic use over the course of the emergency department visit and hospitalization (mg/kg), and pain scores (10-cm linear visual analog scale and Faces Pain Scale). Further details are provided in the Online Supplementary Methods.Standard intravenous (IV) opioid analgesic equivalents were used: 10 mg morphine sulfate = 100 mg meperidine = 2 mg hydromorphone hydrochloride. A hospital admission for a pain episode was considered a distinct event if it occurred more than 2 weeks after a previous pain episode requiring parenteral opioid therapy.The study protocol was approved by the Institutional Review Board at the Children's Hospital & Research Center at Oakland (CHRCO): informed consent was obtained for all patients enrolled, and assent was obtained from all children age 7 years and older. Children with an established diagnosis of SCD age 3-19 years with VOE requiring parenteral opioids and admission to hospital were recruited from emergency departments, hematology clinics, day hospitals and wards. Patients were recruited as a convenience sample during times when the principal investigator or study nurse was on-site and available to consent, a legal guardian was present, and the research pharmacist was available to perform the randomization.Patients were consented within 24 hours of admission to the hospital and randomized to receive IV or oral (PO) study drug, Larginine hydrochloride (100 mg/kg/dose three times/day with a maximum dose of 10 g for 15 doses or until discharge, whichever occurred first) or placebo. Placebo capsules appeared identical to the s...
To determine the effects of l‐arginine (l‐Arg) supplementation on nitric oxide metabolite (NOx) production, oral l‐Arg was given to normal controls, sickle cell disease (SCD) patients at steady state and SCD patients hospitalized with a vaso‐occlusive crisis (VOC). l‐Arg (0·1 g/kg) increased NOx formation by 18·8 ± 68% in normal controls, whereas steady‐state SCD patients demonstrated a paradoxical decrease in NOx of −16·7 ± 4% (P = 0·004). In contrast, patients with VOC demonstrated a dramatic increase in NOx production by +77·7 ± 103%, a response that was dose dependent. l‐Arg appears to be the rate‐limiting step in NOx production during VOC. Oral arginine may therefore benefit SCD patients by inducing an increase in NO production during VOC.
Iron overload is the primary cause of mortality and morbidity in thalassemia major despite advances in chelation therapy. We performed a pilot clinical trial to evaluate the safety and efficacy of combined therapy with deferasirox (DFX, 20-30 mg/kg daily) and deferoxamine (DFO, 35-50 mg/kg on 3-7 days/week) in 22 patients with persistent iron overload or organ damage. In the 18 subjects completing 12 months of therapy, median liver iron concentration decreased by 31% from 17.4 mg/g (range 3.9-38.2 mg/g) to 12.0 mg/g (range 0.96-26.7 mg/g, P<0.001). Median ferritin decreased by 24% from 2,465 ng/mL (range 1,110-10,700 ng/mL) to 1,875 ng/mL (range 421-5,800 ng/mL, p=0.002). All 6 subjects with elevated myocardial iron showed improvement in MRI T2* (p=0.031). The mean ± S.E. plasma non-transferrin-bound iron (NTBI) declined from 3.10 ± 0.25 μM to 2.15 ± 0.29 μM (p=0.028). The administration of DFX during infusion of DFO further lowered NTBI (-0.28 ±0.08 μM, p=0.004) and labile plasma iron (LPI, -0.03 ± 0.01 μM, p=0.006). The simultaneous administration of DFO and DFX rapidly reduced systemic and myocardial iron, and provided an excellent control of the toxic labile plasma iron species without an increase in toxicity.
SummaryThis study aimed to demonstrate the validity, reliability and responsiveness of a new disease-specific quality of life (QoL) questionnaire for children and adults with thalassaemia major, the Transfusion-dependent QoL questionnaire (TranQol). 106 participants (51 adults and 55 children) were recruited from six North American thalassaemia treatment centres with a mean age of 20Á7 years (standard deviation [SD] 9, range 7-51 years). The mean total TranQol score was 71 (SD 17, 32-97) on a scale of 0-100. Patients with co-morbidities had significantly lower scores (63 vs. 75, P = 0Á001). TranQol scores showed substantial agreement (P < 0Á001) with the Health Utilities Index Mark 3 (all patients, r = 0Á65), the Pediatric QoL (children, r = 0Á77) and the Short Form (36) physical (adults, r = 0Á69) and mental summary scores (r = 0Á76). In the subgroup who rated their QoL as better, there was a 4Á0 point (SD 9Á0) improvement in TranQol scores, from baseline of 67Á1-71Á1 one week later (P = 0Á008). Test-retest reliability was excellent (intra-class correlation coefficient, 0Á93). The TranQol was valid, with acceptable correlation for all administered measures and was reliable and responsive to change. The TranQol can be incorporated into future studies of thalassaemia major.
IntroductionPulmonary hypertension (PH) is emerging as a significant cause of mortality and morbidity in patients with hemolytic anemias. 1,2 Mortality rates associated with PH are universally high in conditions in which the natural history has been established, including sickle cell disease (SCD), 3,4 scleroderma and other connective tissue diseases, chronic obstructive lung disease, thromboembolic disorders, and idiopathic pulmonary artery hypertension. 5 Although the frequent occurrence of PH has been recognized in both thalassemia intermedia (TI) and major (TM) for some time, 1,6-14 the natural history and mortality risk of this comorbidity in the thalassemia syndromes has yet to be established, and prospective longitudinal studies are limited. Prevalence rates vary by study design with an elevated tricuspid regurgitant jet velocity (TRV) noninvasively measured by Doppler echocardiography (echo), suggesting risk for PH detected in up to 75% in some cohorts. 15,16 Although the high prevalence of PH in nontransfused TI patients has now been well documented, 14,16,17 PH risk was established in Ͼ 50% of patients with -thalassemia major despite transfusion. 6,17,18 In another study of TM, pulmonary systolic pressure Ͼ 30 mm/Hg was found in all patients Ͼ 22 years of age. 6 However, recent studies in more uniformly treated patients have shown a lower frequency of PH risk in TM patients who undergo transfusion regularly. 7,12 The etiology of PH in thalassemia is multifactorial, involving a complex interaction of platelets, the coagulation system, erythrocytes, and endothelial cells along with inflammatory and vascular mediators. 13,19 Contributing mechanisms include oxidative stress, 20 hemolysis, 21,22 thrombosis, 23-25 splenectomy, 17,22,26 abnormal arginine-nitric oxide bioavailability, 13,21 red cell membrane pathology, 27 and iron overload. 28 Although overlap in pathways contributing to vasculopathy and PH is expected in all forms of thalassemia, 13 the pathophysiology of PH is fundamentally different in patients with TI compared with TM. Hemolysis is likely a driving force toward PH in nontransfused TI patients, whereas the consequences of iron overload and oxidative stress may play a more significant role in TM patients receiving transfusion therapy. 19 Autopsy studies in patients with thalassemia revealed histopathologic findings that are common to all forms of PH, including plexiform and concentric medial hyperplastic pulmonary vascular lesions, and in situ pulmonary artery thrombosis. 29 However, despite multiple similarities with pulmonary artery hypertension of various etiologies, PH in hemolytic disease is a unique disorder that differs from other forms Submitted November 29, 2010; accepted July 1, 2011. Prepublished online as Blood First Edition paper, July 19, 2011; DOI 10.1182 DOI 10. /blood-2010 An Inside Blood analysis of this article appears at the front of this issue.The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by pa...
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