A phase 2 study of the safety, tolerability, and pharmacodynamics of FBS0701, a novel oral iron chelator, in transfusional iron overload

This was a 24-week, multicenter phase-2 study designed to assess safety, tolerability, and pharmacodynamics of FBS0701, a novel oral chelator, in adults with transfusional iron overload. Fifty-one patients, stratified by transfusional iron intake, were randomized to FBS0701 at either 14.5 or 29 mg/kg/d (16 and 32 mg/kg/d salt form). FBS0701 was generally well tolerated at both doses. Forty-nine patients (96%) completed the study. There were no drug-related serious adverse events. No adverse events (AEs) showed dose-dependency in frequency or severity. Treatment-related nausea, vomiting, abdominal pain, and diarrhea were each noted in < 5% of patients. Mean serum creatinine did not change significantly from Baseline or between dose groups. Transaminases wer increased in 8 (16%), three of whom acquired HCV on-study from a single blood bank while five had an abnormal baseline ALT. The 24 week mean change in liver iron concentration (ΔLIC) at 14.5 mg/kg/d was +3.1 mg/g (dw); 29% achieved a decrease in LIC. Mean ΔLIC at 29 mg/kg/d was -0.3 mg/g (dw); 44% achieved a decrease in LIC (P < .03 for ΔLIC between doses). The safety and tolerability profile at therapeutic doses compare favorably to other oral chelators.     

Sonographic assessment of carpal tunnel syndrome in rheumatoid arthritis: prevalence and correlation with disease activity

Carpal tunnel syndrome (CTS) is one of the most frequent extra-articular manifestations of rheumatoid arthritis (RA). High frequency ultrasonography (US) is a sensitive and specific method in diagnosis of CTS. This study is aimed to: firstly assess diameter frequency of CTS in RA with US and compare with a control group; secondly, investigate relationship of CTS with disease activity. One hundred consecutive RA patients (women/men: 78/22) fulfilling ACR 1987 RA criteria and 45 healthy controls (women/control: 34/11) were enrolled into study. Disease activity parameters, RA and CTS patient global assessment and health assessment questionnaire (HAQ-DI) were recorded. Both patient and control group were questioned about secondary causes of CTS, and Katz hand diagram, Boston CTS questionnaire and Phalen ve Tinel tests were applied once for each hand. Wrist joint and carpal tunnel were assessed with US grey scale and power Doppler US, then cross-sectional area of median nerve (CSA) was calculated. Patients with median nerve CSA between 10.0 and 13.0 mm(2) were evaluated with electromyography (EMG). CTS was diagnosed if CSA of median nerve >13.0 mm(2) or CTS was shown with NCS. Although there was no difference between RA patients and controls in age, sex, history of DM (+) and goitre, CTS was more frequent in RA group (respectively, 17.0% vs. 4.4%, P = 0.038). In RA group with CTS, age, history of DM, disease duration, HAQ-DI score, CTS patient global score, Boston symptom severity and functional status scores were elevated compared to without CTS [respectively, 57 (36-73) vs. 50 (24-76), P = 0.041; 35.3% vs. 6.0%, P < 0.001; 108 (12-396) months vs. 72 (6-360) months, P = 0.036; 1.93 (0.75-2.87) vs. 1.125 (0-2.75), P = 0.013; 52 (1-97) vs. 25 (0-91), P = 0.001; 2.81 (1.18-4.17) vs. 2.0 (1.0-4.01), P = 0.01; 3.37 (1.37-5.0) vs. 2.25 (1.0-5.0), P = 0.008]. No difference was found between CTS (+) and (-) RA patients in acute phase reactants, disease activity and US findings (P > 0.05). Sensitivity of Katz hand diagram was higher than Tinel and Phalen tests (respectively, 100, 60.0, 66.7%). Boston symptom and functional scores of RA patients with CTS diagnosed by EMG were increased than patients CTS (-) by EMG [respectively, 3.05 (1.90-4.27) vs. 1.55 (1.0-2.90), P = 0.002; 3.25 (1.73-3.82) vs. 1.12 (1.0-2.10), P = 0.008]. CTS frequency in RA was found higher than normal population, especially in patients with additional risk factors of CTS. There was no relationship between CTS and disease activity. CTS group had long disease duration and worse functional status. CTS could be a result of the chronic course in RA. In patient with CSA between 10 and 13 mm(2), Boston CTS questionnaire might give additional idea about CTS.     

Timed non-transferrin bound iron determinations probe the origin of chelatable iron pools during deferiprone regimens and predict chelation response

Background

Plasma non-transferrin bound iron refers to heterogeneous plasma iron species, not bound to transferrin, which appear in conditions of iron overload and ineffective erythropoiesis. The clinical utility of non-transferrin bound iron in predicting complications from iron overload, or response to chelation therapy remains unproven. We undertook carefully timed measurements of non-transferrin bound iron to explore the origin of chelatable iron and to predict clinical response to deferiprone.

Design and Methods

Non-transferrin bound iron levels were determined at baseline and after 1 week of chelation in 32 patients with thalassemia major receiving deferiprone alone, desferrioxamine alone, or a combination of the two chelators. Samples were taken at baseline, following a 2-week washout without chelation, and after 1 week of chelation, this last sample being taken 10 hours after the previous evening dose of deferiprone and, in those receiving desferrioxamine, 24 hours after cessation of the overnight subcutaneous infusion. Absolute or relative non-transferrin bound iron levels were related to transfusional iron loading rates, liver iron concentration, 24-hour urine iron and response to chelation therapy over the subsequent year.

Results

Changes in non-transferrin bound iron at week 1 were correlated positively with baseline liver iron, and inversely with transfusional iron loading rates, with deferiprone-containing regimens but not with desferrioxamine monotherapy. Changes in week 1 non-transferrin bound iron were also directly proportional to the plasma concentration of deferiprone-iron complexes and correlated significantly with urine iron excretion and with changes in liver iron concentration over the next 12 months.

Conclusions

The widely used assay chosen for this study detects both endogenous non-transferrin bound iron and the iron complexes of deferiprone. The week 1 increments reflect chelatable iron derived both from liver stores and from red cell catabolism. These increments correlate with urinary iron excretion and the change in liver iron concentration over the subsequent year thus predicting response to deferiprone-containing chelation regimes. This clinical study was registered at clinical.trials.gov with the number {"type":"clinical-trial","attrs":{"text":"NCT00350662","term_id":"NCT00350662"}}NCT00350662.     

Deferasirox for up to 3 years leads to continued improvement of myocardial T2* in patients with β-thalassemia major

Background

Prospective data on cardiac iron removal are limited beyond one year and longer-term studies are, therefore, important.

Design and Methods

Seventy-one patients in the EPIC cardiac substudy elected to continue into the 3^rd year, allowing cardiac iron removal to be analyzed over three years.

Results

Mean deferasirox dose during year 3 was 33.6±9.8 mg/kg per day. Myocardial T2*, assessed by cardiovascular magnetic resonance, significantly increased from 12.0 ms ±39.1% at baseline to 17.1 ms ±62.0% at end of study (P<0.001), corresponding to a decrease in cardiac iron concentration (based on ad hoc analysis of T2*) from 2.43±1.2 mg Fe/g dry weight (dw) at baseline to 1.80 ±1.4 mg Fe/g dw at end of study (P<0.001). After three years, 68.1% of patients with baseline T2* 10 to <20 ms normalized (≥20 ms) and 50.0% of patients with baseline T2* >5 to <10 ms improved to 10 to <20 ms. There was no significant variation in left ventricular ejection fraction over the three years. No deaths occurred and the most common investigator-assessed drug-related adverse event in year 3 was increased serum creatinine (n=9, 12.7%).

Conclusions

Three years of deferasirox treatment along with a clinically manageable safety profile significantly reduced cardiac iron overload versus baseline and normalized T2* in 68.1% (32 of 47) of patients with T2* 10 to <20 ms.     

Low plasma renin activity and high aldosterone/renin ratio are associated with untreated isolated systolic hypertension

Abstract Objective. Isolated systolic hypertension (ISH) is generally encountered in elderly patients and there are scarce data regarding the renin-angiotensin-aldosterone system (RAAS) activity in patients with ISH. We aimed to determine the plasma renin activity (PRA), plasma aldosterone levels (PAL) and aldosterone/PRA ratio (PAL/PRA) in patients (age >50 years) with ISH and to compare these values with patients with essential hypertension (EH) as well as subjects with normal blood pressure values (control) who have similar age and cardiovascular risk profile. Methods. Consecutively, 42 untreated ISH patients, 30 patients with EH and 29 normal subjects were included in the study. Parameters were presented as median (interquartile range). Results. There were no significant differences regarding age, gender and other cardiovascular risk factors among groups. As expected, systolic, diastolic blood pressure and pulse pressure values were significantly different among groups. Besides, PRA values were found to be significantly lower in patients with ISH (0.4 [0.2-1.1] ng/ml/h) compared with the EH (0.95 [0.5-2.6] ng/ml/h, p =0.024) and control (1.3 [0.7-2.1] ng/ml/h, p =0.001) groups. Although, PAL were similar among groups, PAL/PRA ratio was significantly higher in ISH group (134.1 [73-224]) compared with those with EH (42.2 [35-84], p <0.001) and the control group (53.3 [30-106], p =0.001). No significant difference was present with respect to PAL/PRA ratio between EH and control groups. Conclusions. Our findings suggested that in patients with ISH, despite lower PRA levels, PAL/PRA ratio is significantly higher compared with the patients with EH and subjects with normal blood pressure. Since higher PAL/PRA levels is an indicator of relative aldosterone excess, medications blocking RAAS activity including aldosterone antagonists may have useful cardiovascular consequences in addition to their antihypertensive effects in ISH.     

Thalassemia

Thalassemia is the most common form of inherited anemia worldwide. The World Health Organization reports suggest that about 60,000 infants are born with a major thalassemia every year. Although individuals originating from the tropical belt are most at risk, it is a growing global health problem due to extensive population migrations. Despite important advances on curative approaches such as stem cell transplantation and promising results of gene therapy, blood transfusions and iron chelation still remain as cornerstones of disease management. The purpose of this article is to focus on mainly the clinical aspects and management of beta-thalassemia major.     

The detection of sensitivity of proprioception by a new clinical test: The dual joint position test

Objectives

To date, very few studies have paid attention to the joint sense (proprioception) of toes other than the big toe. We evaluated the sensitivity of joint position sense at the joint of the great toe in comparison to other digits, and with that determined by the dual digit stimulation test, in a sample of healthy normal controls and patients with clinical diagnosis of the lemniscal system dysfunction.

Material and methods

Seventy-two patients with lemniscal system dysfunction (55 clinically definitive multiple sclerosis, 17 vasculitis) and 110 healthy volunteers participated in the study. All subjects underwent the joint position sense test of all digits of upper and lower extremities. The position sense resulting from the combined operation of the joints of the second and the fourth digits (simultaneous two digits position sense) was also measured and subsequently compared with the results of the great toe position sense.

Results

Upper extremities: no difference was found in recognition of the position sense in the single digits of the upper extremities between patients and healthy volunteers. There was a significant difference in the dual joint position test of the right upper extremity between patients and the case group (p < 0.05) but not in the left upper extremity. Lower extremities: there was no significant difference in proprioception of the great toe neither in the right and nor in the left side between patients and normal subjects. However, the joint position sense of other single digits was deteriorated in the patients, a difference that was significant compared to normal controls (p < 0.05). Additionally, patients and normal controls displayed a difference in dual digit position sense of the right and left lower extremities (p < 0.05).

Conclusions

We show in this paper that the proprioception of simultaneous dual digits is diminished in patients when compared to a single digit position sense. Moreover, the great toe proprioception is less sensitive than other digits. Taken together, these observations lend evidence for a new clinical method which we named as dual joint position test. We suggest this novel method offers clinical utility to demonstrate lemniscal system dysfunction.     

Three-dimensional ultrasonographic placental volume in gestational diabetes mellitus

Objectives: We aimed to evaluate the placental volume and placental mean gray value in gestational diabetes mellitus (GDM) and healthy placentas using three-dimensional (3D) ultrasound and Virtual Organ Computer-aided AnaLysis (VOCAL).

Methods: This case-control prospective study consisted of 39 singleton pregnancies complicated by GDM and 42 healthy singleton pregnancies matched for gestational age, maternal age and parity. Placental volume and placental volumetric mean gray values were evaluated. The placental volume (cm³) was analyzed using the VOCAL imaging analysis program and 3D histogram was used to calculate the volumetric mean gray value (%).

Results: Placental volume was significantly larger in GDM (411.59?±?170.82 versus 343.86?±?128.94?cm³; p?=?0.046). There was no significant difference in mean gray value between GDM and healthy placentas (36.65?±?7.02 versus 38.71?±?7.91, respectively; p?=?0.277). Placental volume was significantly correlated with gestational week (r?=?0.219, p?=?0.035) and parity (r?=?0.228, p?=?0.048). There was negative significant relation between placental volume and umbilical artery systolic/diastolic ratio, pulsatility index and resistance index (r?=??0.278, p?=?0.007; r?=??0.315, p?=?0.002; r?=??0.322, p?=?0.001, respectively).

Conclusions: Placental volume increases significantly in GDM, whereas mean gray values do not alter significantly. These data may reflect the placental changes in GDM placentas that may help to understand the pathophysiology better.     

Influence of serous retinal detachment on the outcome of ranibizumab treatment in diabetic macular oedema

Purpose: The purpose of this study was to evaluate the influence of serous retinal detachment (SRD) on the outcome of intravitreal ranibizumab (IVR) therapy in diabetic macular oedema (DME).

Materials and methods: Fifty-one eyes with cystoid macular oedema (CME) and SRD (study group) and 57 eyes with only CME (control group) that received pro re nata (PRN) IVR injections during a 6-month period were retrospectively evaluated. The outcome measures included changes in the central macular thickness (CMT) and best corrected visual acuity (BCVA) and injection numbers.

Results: The mean initial CMT in the study and control groups was 467?±?101 and 440?±?89?µm, respectively. The mean BCVA in the study and control groups was 0.75?±?0.38 and 0.59?±?0.36 logarithm of minimal angle of resolution (LogMAR), respectively (p?=?0.010). The study group received a mean of 2.2?±?0.92 injections, whereas the control group received a mean of 2.54?±?0.9 injections. The decrease in CMT was greater, but not significantly greater, in the study group than in the control group.

Conclusion: The presence of SRD resulted in a less favourable visual acuity (VA) outcome with IVR. Disruption of the ellipsoid zone and abnormality of the foveal avascular zone at the baseline examination were correlated with a lower VA. Both of the pathologies occurred more frequently in the SRD group.