Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0039730 (thalassemia)
 10,305 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Desferrioxamine (DFX) alone (40-50 mg/kg/d s.c. over 8-12 h, five times weekly) was compared with combined DFX twice weekly and deferiprone (75 mg/kg/d) over 12 months in previously poorly chelated thalassaemia patients. Serum ferritin fell from 5506 +/- 635 microg/l (mean +/- SEM) to 3998 +/- 604 microg/l (P < 0.001; n = 14) in the DFX group and from 4153 +/- 517 microg/l to 2805 +/- 327 microg/l in the combined group (P < 0.01; n = 11). Deferiprone plus DFX produced a greater mean urine iron excretion (1.01 mg/kg/24 h) than iron intake from blood transfusion in each patient. Main side-effects were skin reactions (DFX alone), nausea and arthralgia (combined therapy). As chelation therapy, the combined protocol was as effective as DFX five times weekly.
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PMID:Comparison between desferrioxamine and combined therapy with desferrioxamine and deferiprone in iron overloaded thalassaemia patients. 1267 Mar 52

Iron is essential for all human cells as well as neoplastic cells and invading microbes. Natural and synthetic iron chelators could affect biological processes involving iron and other metal ions in health and disease states. Iron overload is the most common metal toxicity condition worldwide. There are currently two iron chelating drugs, which are mostly used for the treatment of thalassaemia and other conditions of transfusional iron overload. Deferoxamine was until recently the only approved iron chelating drug, which is effective but very expensive and administered parenterally resulting in low compliance. Deferiprone (L1 or 1,2-dimethyl-3-hydroxypyrid-4-one) is the world's first and only orally active iron chelating drug, which is effective and inexpensive to synthesise thus increasing the prospects of making it available to most thalassaemia patients in third world countries who are not currently receiving any form of chelation therapy. Deferiprone has equivalent iron removal efficacy and comparable toxicity to deferoxamine. There are at least four other known iron chelators, which are currently being developed. Even if successful, these are not expected to become available for clinical use in the next five years and to be as inexpensive as deferiprone. The variation in the chemical, biological, pharmacological, toxicological and other properties of the chelating drugs and experimental chelators provide evidence of the difference in the mode of action of chelators and the need to identify and select molecular structures and substituents based on structure/activity correlations for specific pharmacological activity. Such information may increase the prospects of designing new chelating drugs, which could be targeted and act on different tissues, organs, proteins and iron pools that play important role not only in the treatment of iron overload but also in other diseases of iron and other metal imbalace and toxicity including free radical damage. Chelating drugs could also be designed, which could modify the enzymatic activity of iron and other metal containing enzymes, some of which play a key role in many diseases such as cancer, inflammation and atherosclerosis. Other applications of iron chelating drugs could involve the detoxification of toxic metals with similar metabolic pathways to iron such as Al, Cu, Ga, In, U and Pu.
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PMID:The design and development of deferiprone (L1) and other iron chelators for clinical use: targeting methods and application prospects. 1527 56

Iron chelation is needed to prevent damage to the heart, liver and endocrine glands from iron overload in patients with refractory anaemias who receive regular blood transfusions. Desferrioxamine is still the first-line drug, but because of its expense in many countries, and lack of compliance because of difficulty with administration, there is a major need for an orally active (and cheaper) chelating drug. Seventeen years after the first clinical trials deferiprone, which is orally active, has emerged as suitable for patients for whom desferrioxamine is, for one reason or another, inadequate. Many patients are successfully chelated at a dose of deferiprone 75 mg/kg/day. Some patients may need higher doses (up to 100 mg/kg), or combination therapy of deferiprone every day and desferrioxamine on several days each week. Recent data suggest that deferiprone may be superior to desferrioxamine at protecting the heart from iron overload. The side-effects of deferiprone--agranulocytosis, neutropenia, gastrointestinal symptoms, arthropathy, transient changes in liver enzymes, and zinc deficiency--are now well recognized; they result in discontinuation of the drug in only 5-10% of patients. Deferiprone is now licensed in 43 countries for thalassaemia major patients for whom desferrioxamine is inadequate. If results of current trials confirm its superiority at reducing cardiac damage, it may well become the first-line drug for many patients.
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PMID:Deferiprone therapy for transfusional iron overload. 1573 92

With the introduction of "hypertransfusion" regimens the extent of disease- and therapy-related hemosiderosis has become the survival limiting factor for patients with beta-thalassemia major as iron transferred with transfusions cannot be excreted by physiological means. Subsequent introduction of deferoxamine therapy for iron elimination and prophylaxis of hemosiderosis has improved prognosis and life quality of these patients considerably. We report our experience with seven adolescent patients with beta-thalassemia and ineffective subcutaneous therapy and severe hemosiderosis-related organ complications. For that reason they received i. v. intensified chelate therapy. The patients were given 70 to 120 mg/kg DFO 7 days a week continuously via a Port-a-cath or Hickman central venous line. Under high-dose i. v. DFO therapy, serum ferritin levels significantly decreased in all patients. Target serum ferritin levels of 3 000 ng/ml were reached after 12 to 20 months of treatment. In 3 of the 5 patients that were treated for longer than 43 months serum ferritin levels even dropped below 2 000 ng/ml. Serum ferritin levels also correlated well with SQUID examinations. Therefore, monitoring of serum ferritin may be useful to monitor patient's compliance and control intensified DFO therapy. Continuous administration of the intensified DFO therapy induced normalization of liver function and left ventricular cardiac function in all patients who are still alive. Two patients died due to cardiac decompensation. In five patients 19 episodes of central catheter-related infections were observed (1.5 infections per 1 000 catheter days). No DFO-associated allergic reactions nor irreversible organ dysfunction were observed. Our results indicate that intensified i. v. DFO therapy is an effective and safe method for treatment of severe organ dysfunction in patients with thalassemia major. The most severe problems are catheter-related infections and inconsistent long-term compliance.
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PMID:Intensification of chelating-therapy in patients with thalassemia major. 1585 2

The conventional treatment with regular red-blood-cell transfusions and simultaneous chelation of excess iron with DFO (desferrioxamine) improves quality of life of thalassaemic patients while increasing their rate of survival considerably. Although DFO is the main iron- chelating drug currently utilized, it has various drawbacks, including high cost, poor oral effectiveness, toxicity and short plasma half-life. It has to be administered by slow, subcutaneous infusion during blood transfusion for 8-12 h at night, 5-7 nights a week, and this leads to a very poor patient compliance. In order to avoid frequent and uncomfortable infusions of DFO, application of controlled-release systems might be alternative routes in the supportive treatment of thalassaemia. In the present study, GMs (gelatin microspheres) and GFs (gelatin films) were prepared by coacervation and casting methods respectively to develop controlled DFO-release systems. Cross-linking by glutaraldehyde and carbodi-imide were performed to increase the stability of gelatin matrices. Microspheres and films prepared without the addition of cross-linker degraded completely in 4 h. On the other hand, addition of cross-linker extended this time from hours to weeks depending on the added amount. Therefore the amount of DFO released from microspheres in 7 days was found to be in the range 12-82%, whereas the amount permeated through the films in 5.0 h was found to be in the range 34-67%. GFs were elastic and demonstrated good mechanical properties. Films achieved 0.14-0.69 MPa tensile strength, with 0.12-1.29 MPa elastic modulus and 26.49-109.38% strain values at break point. These studies showed that gelatin-based controlled-release systems could be improved and could be good candidates for the production of long-term DFO-carrying systems.
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PMID:Desferrioxamine release from gelatin-based systems. 1598 29

Deferoxamine is a chelating agent that has extended the life expectancy of patients with thalassemia. In the 1980s, many investigators reported otologic and visual toxicity caused by deferoxamine. In July 1999 and 2 years later, the authors performed audiologic and ophthalmologic assessments in 30 transfusion-dependent patients receiving deferoxamine therapy (40-50 mg/kg per dose, subcutaneously for 8-10 hours, 4-7 days per week). In 1999, six patients (20%) had deferoxamine-related hearing impairment (>25 dB), all at high frequencies. Because the authors believed the benefits of chelation therapy outweighed the risk of ototoxicity, the dose of deferoxamine was not reduced. Two years later, the hearing impairment had not progressed in any of the patients. There was no association between ototoxicity and ferritin level. No patients had abnormalities of visual acuity or funduscopy in either 1999 or 2001. Based on this experience, deferoxamine at doses lower than 50 mg/kg/d was safe for the eyes and slightly toxic to the ears. The ototoxicity probably relates to individual susceptibility. Regular monitoring of auditory function and close follow-up of abnormal findings are recommended. According to this limited experience, reducing the dose or withdrawing deferoxamine might not be necessary if the hearing loss is stable in the face of ferritin levels above 2,000 ng/mL. Because of the relatively small patient numbers, more data are needed to confirm these conclusions.
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PMID:Auditory and visual toxicity during deferoxamine therapy in transfusion-dependent patients. 1634 69

Deferoxamine (DFO) therapy has been associated with improved survival of thalassemia patients. However, cardiac disease remains the main cause of death in those patients. In 1995, the oral chelator deferiprone became available for clinical use. We compared the occurrence of cardiac disease in patients treated only with DFO and in those whose therapy was switched to deferiprone during the period of observation, from January 31, 1995, to December 31, 2003. All patients with thalassemia major treated in 7 Italian centers who were born between 1970 and 1993 and who had not experienced a cardiac event prior to January 1995 were included. DFO only was given to 359 patients, and 157 patients received deferiprone for part of the time. A total of 3,610 patient-years were observed on DFO and 750 on deferiprone. At baseline, the 2 groups were comparable for age and sex, while ferritin levels were significantly higher in patients switched to deferiprone. Fifty-two cardiac events, including 10 cardiac deaths, occurred during therapy with DFO. No cardiac events occurred during deferiprone therapy or within at least 18 months after the end of it. In the setting of a natural history study, deferiprone therapy was associated with significantly greater cardiac protection than deferoxamine in patients with thalassemia major.
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PMID:Cardiac morbidity and mortality in deferoxamine- or deferiprone-treated patients with thalassemia major. 1637 63

Over the years, several reports have demonstrated involvement of the nervous system in beta-thalassemia patients. Neurological complications have been attributed to various factors such as chronic hypoxia, bone marrow expansion, iron overload, and desferrioxamine neurotoxicity. In most cases, neurological involvement does not initially present with relevant signs or symptoms (i.e., is subclinical) and can only be detected during neurophysiological or neuroimaging evaluation. Abnormal findings in the visual, auditory, and somatosensory evoked potential recordings are mainly attributed to DFO neurotoxicity. On the other hand, nerve conduction velocity abnormalities are associated either to chronic hypoxia and older age or to hemosiderosis, whether by means of pancreas involvement or not. Neuropsychological studies available reveal a considerably high prevalence of abnormal IQ, not correlating, however, to factors such as hypoxia or iron overload. It is proposed that factors associated to severe chronic illness, rather than the disease per se, could be responsible for these findings. Such factors include regular school absence due to transfusions and frequent hospitalizations, physical and social restrictions resulting from the disease and its treatment, abnormal mental state due to the awareness of being chronically ill, and, last, the overly protective family attitude that leads to restricted initiative and psychosocial development. As life expectancy for beta-thalassemia patients extends, the use of neurophysiologic and neuropsychologic monitoring becomes imperative, enabling early detection of neural pathway impairment and allowing for appropriate management, in order to achieve a better life quality for this patient group.
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PMID:Neurological complications in beta-thalassemia. 1657 62

This study was conducted to assess the effect of age, ferritin level, hemoglobin level and chelating agents on the physical growth in thalassemic children and to determine the prevalence of dental caries in thalassemic children. Weight, standing height, sitting height and subischial leg length were measured in 65 children attending the Thalassemia day care center at a tertiary hospital in Delhi. Their mean pre transfusion hemoglobin and ferritin levels over the previous two years were calculated. Dental caries indices, DMFT and DMFS were measured and compared with age matched controls. Weight, standing height, sitting height and subischial leg length expressed as percentage for age in children >or=10 y were significantly lower than those of children < 6 y, and those 6 to 10 y. Mean hemoglobin and ferritin did not affect growth significantly. Sitting height for age in children receiving Desferrioxamine alone or Desferrioxamine with Deferiprone was significantly lower than that of children receiving Deferiprone alone or no chelating agent. Dental caries were significantly higher in thalassemics.
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PMID:Physical growth patterns and dental caries in thalassemia. 1720 3

Post transfusionnal iron overload is related to both a degree of RBC units transfused and excess intestinal absorption of Fe related to dyserythopoiesis. This condition is associated with high rates of morbidity and mortality, mainly of cardiac origin. Iron chelation therapy in patients with thalassemia who were effectively chelated has prevented or partially reversed some of these consequences. However the reference treatment by deferoxamine is strenuous and compliance is poor. Two oral iron chelators, deferiprone and deferasirox, provide potentially useful treatment for iron overload, both agents are relatively well tolerated (mainly deferasirox). They were at least as effective as DFO for decreasing iron burdens in comparative trials, and were associated with improved cardiac outcomes (for deferiprone). A new enthusiastic area for iron chelation with less burdensome treatments is open; however a long term follow up is required before giving up pumps and needles.
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PMID:[Post transfusionnal iron overload]. 1741 52


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