A 5-year follow-up in deferasirox treatment: improvement of cardiac and hepatic iron overload and amelioration in cardiac function in thalassemia major patients.

Deferasirox (DFX) is an oral iron chelator with established efficacy and safety. We evaluated by T2* cardiovascular magnetic resonance (CMR) the efficacy of DFX in preventing and removing cardiac and liver iron load and cardiac volume changes, along 5 years in adult thalassemia major (TM) patients. Twenty-three TM patients (9 males/14 women, mean age 36 ± 4 years) were included in this study. Repeated CMR was performed to assess myocardial and liver iron load (baseline t0, after 2.5 years t1, after 5 years t2). Myocardial T2* values changed progressively and increased significantly between t0 and t2 (t0: 27.15 ± 9.58 vs t2: 36.64 ± 6.68, p = 0.0001). At baseline evaluation, a cardiac T2* value <20 ms was detected in six patients (26 %): they showed an improvement of cardiac T2* values between t0 and t1, with normal T2* levels reached in all patients at t2. In the overall population, a significant reduction of both end-diastolic and end-systolic left ventricular volumes (EDV, ESV) were detected between t0 and t2 (EDV, t0: 132 ± 31 ml vs t2: 124 ± 22 ml, p = 0.033; ESV, t0: 48 ± 14 ml vs t2: 41 ± 10 ml, p = 0.0007). A significant reduction in liver iron concentration (LIC) was detected at t1 (5.36 ± 3.58 mg/g dw at baseline vs 3.35 ± 2.68 mg/g dw at t1, p = 0.004). In patients with cardiac iron overload at baseline (n.6), mean cardiac T2* values doubled at t2, and mean LIC value is reduced of 29 %. After 5 years of treatment, DFX continually and significantly reduced myocardial and liver iron overload, and it prevented further iron deposition.

Combination of deferasirox and deferoxamine in clinical practice: an alternative scheme of chelation in thalassemia major patients.

The availability of three iron chelators improved the scenario of chelation therapy for transfusion-dependent thalassemia (TDT) patients, allowing tailoring of drugs according to the goals expected for each patient. The use of Deferiprone/Deferoxamine (DFP/DFO) combined in different schemes has been reported since many years. Only recently data from combination of Deferasirox/Deferoxamine (DFX/DFO) have been reported showing that it can be safe and efficacious to remove iron overload, particularly in patients who do not respond adequately to a single chelating agent. We investigated the efficacy, tolerability and safety of combined DFX/DFO in thalassemia major patients. Ten TDT patients have started DFX/DFO for different reasons: 1) lack of efficacy in removing liver/cardiac iron with monotherapy; 2) agranulocytosis on DFP; and 3) adverse events with elevated doses of monotherapies. The study design included: cardiac and hepatic T2* magnetic resonance (CMR), transient elastography evaluation (Fibroscan), biochemical evaluation, and audiometric and ocular examinations. The drugs' starting doses were: DFO 32 ± 4 mg/kg/day for 3-4 days a week and DFX 20 ± 2 mg/kg/day. Seven patients completed the one-year follow-up period. At baseline the mean pre-transfusional Hb level was 9.4 ± 0.4 g/dl, the mean iron intake was 0.40 ± 0.10mg/kg/day, the median ferritin level was 2254 ng/ml (range 644-17,681 ng/ml). Data available at 1 year showed no alteration of renal/hepatic function and no adverse events. A marked reduction in LIC (6.54 vs 11.44 mg/g dw at baseline) and in median ferritin (1346 vs 2254 ng/ml at baseline) was achieved. A concomitant reduction of non-transferrin-bound iron (NTBI) at six months was observed (2.1 ± 1.0 vs 1.7 ± 1.2 µM). An improvement in cardiac T2* values was detected (26.34 ± 15.85 vs 19.85 ± 12.06 at baseline). At 1 year an increased dose of DFX was administered (27 ± 6 mg/kg/day vs 20 ± 2 mg/kg/day at baseline, p=0.01) with a stable dose of DFO (32 ± 4 mg/kg/day). Combined or alternated DFX/DFO can be considered when monotherapy is not able to remove the iron overload or in the presence of adverse events.

Thalassemic osteopathy: a new marker of bone deposition.

Osteopathy represents a prominent cause of morbidity in patients with beta-thalassemia major (TM) and manifests as osteopenia/osteoporosis. Biochemical turnover markers (BTMs) are considered a useful, non-invasive tool for the clinical follow-up of osteoporotic patients; they can provide a dynamic view of the remodeling process and give information on the metabolic activity of bone tissue as well as on the pathogenesis of bone loss. The amino-terminal pro-peptide of type I procollagen (P1NP) is a recently introduced marker that is considered the most sensitive index of bone formation. Although demonstrated in several categories of patients with bone disease, there is little information on the clinical usefulness of this bone formation index in thalassemic patients. We evaluated the P1NP levels of 53 adult patients with b-thalassemia major (21 males and 32 females, mean age 34.5 ± 5.7, range 22-46 years) and associated osteopathy. We investigated the correlation between P1NP and bone condition as examined by dual X-ray photon absorptiometry and with BTMs expressing bone resorption and bone mineralization (carboxyterminal collagen cross-linked (CTX) terminal regions of type I collagen and osteocalcin, respectively). P1NP serum levels were correlated with CTX levels (r=0.545, p<0.001); the results were unchanged when males and females, as well as osteoporotic and osteopenic subgroups, were considered separately. No correlation was demonstrated neither between OC and CTX (r=0.17, p=ns), nor between P1NP and OC levels (r=0.11, p=ns). No correlation was demonstrated among the P1NP/CTX ratio and age, OC or densitometric values and no difference was found in the same ratio between osteopenic (0.19 ± 0.16) and osteoporotic (0.15 ± 0.14) patients. Similar results were obtained for the OC/CTX ratio, as it was not correlated with age, P1NP or densitometric values. This is the first report of circulating P1NP in patients with TM-associated osteoporosis. P1NP and CTX assays show good precision and low analytical CV, and, compared to other markers, they can acceptably reflect bone metabolic processes and promptly respond to antiosteoporotic treatments. We trust that this sensitive marker can be useful in the assessment of treatment efficacy and can overcome the pitfalls due to wide variability in the normal values of most BTMs that create difficulty in pinpointing the individual patient's response.

[Serum lipoproteins and coronary disease in diabetes. Changes in the lipoprotein pattern in relation to the type of antidiabetic therapy]. / Lipoproteine sieriche e malattia coronarica nel diabete. Modificazione del quadro lipoproteico in relazione al tipo della terapia antidiabetica.

One hundred and fifty seven maturity-onset diabetics (77 males and 80 females) with coronary heart disease (CHD) were compared with 130 non-CHD diabetic patients (62 males and 68 females) of the same age-range. Integrated mean blood pressure, duration of diabetes, serum triglycerides, beta and prebeta-lipoproteins were significantly higher and alpha lipoproteins significantly lower in CHD than in non-CHD patients. Alpha lipoproteins, duration of diabetes and beta lipoproteins were the variables of highest weight in discriminating CHD from non-CHD patients. Alpha lipoprotein had a greater discriminating power than beta lipoprotein in man, while in women the opposite occurred. In patients on insulin and on sulfonylurea therapy, both with and without CHD, the concentration of alpha lipoproteins, but not of other lipoproteins, was higher than in the corresponding subgroups of the diet-treated patients. However, within each treatment group, patients with CHD had lower alpha lipoproteins.

Effects of acetylsalicylic acid on plasma lipids and on post-heparin lipase activities.

Acetylsalicylic acid (ASA) was administered orally at the dose of 3 g a day for 2 days to healthy subjects. Plasma free fatty acids, serum triglycerides and prebetalipoproteins were significantly decreased, while cholesterol, beta and alpha 1 lipoproteins did not change. The two fractions (protamine-resistant and protamine-inactivated) of plasma post-heparin lipoprotein lipase activity (PHLA) significantly fell after ASA. PHLA diminution was reproduced by direct addition of ASA or sodium salicylate or of plasma from individuals under treatment with ASA to post-heparin plasma of untreated subjects and is, therefore, explained by a direct inactivation. The inhibition of PHLA was not followed by a significant impairment of the removal of circulating triglycerides.

Influence of two non-steroidal anti-inflammatory drugs on lipolysis and on plasma post-heparin lipoprotein lipase activity in normal man.

Indomethacin 50 mg i.v. or p.o. and diclofenac sodium 50 mg p.o. produced a prompt and significant increase in plasma free fatty acid concentration. In 10 subjects who took indomethacin 150 mg/d p.o. for 3 days, plasma post-heparin lipoprotein lipase activity was also significantly increased. The same effect occurred in 9 subjects treated for 3 days with diclofenac sodium 50 mg t.d.s. Since both indomethacin and diclofenac sodium are potent inhibitors of prostaglandin synthetase, these findings are consistent with the hypothesis tht prostaglandins are involved in the feed-back regulation of lipolysis, and mediate the inhibitory effect of lipolysis on lipoprotein lipase activity.

Evidence of an effect of inhaled disodium cromoglycate on lipid metabolism in man: enhanced lipolysis and decreased plasma post-heparin lipase activities.

Inhalation of therapeutic doses of disodium cromoglycate (DSCG) was followed by a prompt increase of plasma free fatty acids (FFA). After treatment with DSCG for 3 days both hepatic and non-hepatic (lipoprotein lipase sensu strictiori) plasma post-heparin lipoprotein lipase activities were significantly depressed. No significant change was induced on serum lipids and lipoproteins, nor on the fat tolerance curve, though a trend to an elevation of this last parameter was noted. Our results show that the inhalation of DSCG produces systemic metabolic effects, being in accord with the view that this drug raises intracellular cyclic adenosine monophosphate. Furthermore, they support the contention that lipoprotein lipase activity is controlled by intracellular concentration of FFA and/or cyclic adenosine monophosphate.

Increase in lipolysis and decrease in plasma-heparin lipoprotein lipase activity and alpha 1 lipoprotein level after aminophylline in man.

Intravenous aminophylline 0.48 g produced a sharp increase in plasma free fatty acids. After three days of treatment with aminophylline 0.96 g/day i.v., plasma post-heparin lipoprotein lipase was significantly reduced, and post-heparin hepatic triglyceridase remained unchanged. alpha 1 lipoprotein was reduced by treatment, in parallel with lipoprotein lipase, while other lipoprotein fractions, serum cholesterol and triglycerides were unaffected.

Serum lipoproteins in diabetes: relation of alpha-lipoprotein level to therapy.

Three hundred and sixty diabetic patients (125 on insulin, 109 on sulfonylureas and 126 on diet alone) were selected to investigate the effect of the type of treatment and of the degree of metabolic control on serum lipoproteins. Prebeta-lipoprotein concentration was higher than normal in all treatment groups. Beta-lipoproteins were significantly higher in diabetic women than in controls. No difference in beta- and prebeta-lipoprotein concentration existed between the 3 treatment groups. Alpha-lipoproteins were significantly higher in insulin-treated than in diet-treated patients irrespective of the degree of metabolic control. The daily dose of insulin and, in patients on diet or sulfonylureas, serum IRI were positively correlated to alpha-lipoprotein concentration while this lipoprotein fraction was not significantly correlated to fasting blood sugar. Alpha-lipoprotein concentration, then, appears to be markedly influenced by exogenous and endogenous insulin, independently of the degree of metabolic control.