The Protective Effects of Pyridoxine on Linezolid-Induced Hematological Toxicity, Hepatotoxicity, and Oxidative Stress in Rats.

OBJECTIVE: Linezolid is often used to treat antibacterial-resistant infections. Linezolid can cause side effects. To date, the effectiveness of the simultaneous administration of pyridoxine and linezolid is unclear. Here we investigate the protective effect of pyridoxine on linezolid-induced hematological toxicity, hepatotoxicity, and oxidative stress in rats. MATERIAL AND METHODS: The 40 male pediatric Spraque-Dawley rats were separated into 4 groups: control, linezolid, pyridoxine, and linezolid-pyridoxine. A complete blood count, liver function test, and measurements of antioxidant enzyme activities for superoxide dismutase, glutathione peroxidase, catalase, and lipid peroxidation were performed in blood before treatment and 2 weeks after administration of the treatment. RESULTS: White blood cell and hemoglobin counts for the linezolid group decreased, and the alanine aminotransferase level in the linezolid group increased compared to their respective baseline values. Post-treatment white blood cell decreased in the linezolid and linezolid- pyridoxine groups compared to those in the control group (P < .001). Alanine aminotransferase levels increased in the linezolid and linezolid-pyridoxine groups compared to those in the control group (P < .001 and P < .05, respectively). The activity of superoxide dismutase, catalase, glutathione peroxidase, and malondialdehyde levels increased in the linezolid group compared to the control group (P < .001, P < .05, P < .001, and P < .001, respectively). Linezolid plus pyridoxine treatment caused a significant decrease in malondialdehyde levels and superoxide dismutase, catalase, and glutathione peroxidase enzyme activities compared to the linezolid group (P < .001, P < .01, P < .001, and P < .01, respectively). CONCLUSION: Pyridoxine may be an effective adjuvant agent for the prevention of linezolid toxicity in rat models.

Marital status and paternity in patients with Transfusion- Dependent Thalassemia (TDT) and Non Transfusion-Dependent Thalassemia (NTDT): an ICET - A survey in different countries.

BACKGROUND: More than five decades ago, thalassemia major (TDT) was fatal in the first decade of life. Survival and quality of life have improved progressively thanks to the implementation of a significant advance in diagnostic and therapeutic methods, consisting mainly of a frequent transfusion program combined with intensive chelation therapy. Improvement also includes imaging methods used to measure liver and cardiac iron overload. Improved survival has led to a growing number of adults requiring specialised care and counselling for specific life events, such as sexual maturity and acquisition of a family. AIMS OF THE STUDY: The main aim is to present the results of a survey on the marital and paternity status in a large population of adult males with TDT and NTDT living in countries with a high prevalence of thalassemia and a review of current literature using a systematic search for published studies. RESULTS: Ten out of 16 Thalassemia Centres (62.5%) of the ICET-A Network, treating a total of 966 male patients, aged above 18 years with ß- thalassemias (738 TDT and 228 NTDT), participated in the study. Of the 966 patients, 240 (24.8%) were married or lived with partners, and 726 (75.2%) unmarried. The mean age at marriage was 29.7 ± 0.3 years. Of 240 patients, 184 (76.6%) had children within the first two years of marriage (2.1 ± 0.1 years, median 2 years, range 1.8 - 2.3 years). The average number of children was 1.32 ± 0.06 (1.27 ± 0.07 in TDT patients and 1.47 ± 0.15 in NTDT patients; p: >0.05). Whatever the modality of conception, 184 patients (76.6%) had one or two children and 1 NTDT patient had 6 children. Nine (4.8%) births were twins. Of 184 patients, 150 (81.5%) had natural conception, 23 (12.5%) required induction of spermatogenesis with gonadotropins (hCG and hMG), 8 (4.3%) needed intracytoplasmic sperm injection (ICSI) and 3 adopted a child. 39 patients with TDT and NTDT asked for medical help as they were unable to father naturally: 7 TDT patients (17.9%) were azoospermic, 17 (37.7%) [13 with TDT and 4 with NTDT] had dysspermia and 15 (33.3%) [13 with TDT and 2 with NTDT] had other "general medical and non-medical conditions". CONCLUSIONS: Our study provides detailed information in a novel area where there are few contemporary data. Understanding the aspects of male reproductive health is important for physicians involved in the care of men with thalassemias to convey the message that prospects for fatherhood are potentially good due to progressive improvements in treatment regimens and supportive care.

An ICET- A survey on Hypoparathyroidism in Patients with Thalassaemia Major and Intermedia: A preliminary report.

Hypoparathyroidism (HPT) is a rare disease with leading symptoms of hypocalcemia, associated with high serum phosphorus levels and absent or inappropriately low levels of parathyroid hormone (PTH). In patients with thalassemias it is mainly attributed to transfusional iron overload, and suboptimal iron chelation therapy. The main objectives of this survey were to provide data on the prevalence, demographic and clinical features of HPT in thalassemia major (TM) and intermedia (TI) patients living in different countries, and to assess its impact in clinical medical practice. A questionnaire was sent to all Thalassemia Centres participating to the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescence Medicine (ICET-A) Network.Seventeen centers, treating a total of 3023 TM and 739 TI patients, participated to the study. HPT was reported in 206 (6.8%) TM patients and 33 (4.4%) TI patients. In general, ages ranged from 10.5 to 57 years for the TM group and from 20 to 54 years for the TI group. Of the 206 TM patients and 33 TI patients with HPT, 117 (48.9%) had a serum ferritin level >2.500 ng/ml (54.3% TM and 15.1% TI patients) at the last observation. Hypocalcemia varied in its clinical presentation from an asymptomatic biochemical abnormality to a life-threatening condition, requiring hospitalization. Calcium and vitamin D metabolites are currently the cornerstone of therapy in HPT. In TM patients, HPT was preceded or followed by other endocrine and non-endocrine complications. Growth retardation and hypogonadism were the most common complications (53.3% and 67.4%, respectively). Although endocrine complications were more common in patients with TM, non-transfused or infrequently transfused patients with TI suffered a similar spectrum of complications but at a lower rate than their regularly transfused counterparts.In conclusion, although a large international registry would help to better define the prevalence, comorbidities and best treatment of HPT, through the result of this survey we hope to give a clearer understanding of the burden of this disease and its unmet needs. HPT requires lifelong therapy with vitamin D or metabolites and is often associated with complications and comorbidities.Therefore, it is important for endocrinologists and other physicians, who care for these patients, to be aware of recent advances of this disorder.

Gonadal dysfunction in adult male patients with thalassemia major: an update for clinicians caring for thalassemia.

INTRODUCTION: Hypogonadism is the most frequently reported endocrine complication, affecting 40%-80% of thalassemia major (TM) patients. The prevalence and severity of hypogonadism in TM varies among studies, depending on patients' age, genotype, transfusion frequency and starting age and efficiency of iron chelation. Areas covered: The diagnosis requires careful clinical assessment and appropriate laboratory testing. Its management is more complex compared to other 'classical' causes of hypogonadism because of multiple associated disorders (cardiac, hepatic and endocrine) and other contributing factors basically iron overload and iron toxicity. Expert commentary: Early recognition and treatment of hypogonadism in TM patients is most important to prevent late complications and to enhance the chances of parenthood. The goal of management is to restore deficient glandular function. If fertility is the issue and the testis is under-stimulated because of gonadotropin deficiency, it is possible to induce or restore spermatogenesis with exogenous gonadotropins in some patients. Assisted reproductive techniques may supplementary help to overcome previously untreatable causes of male infertility. These positive achievements should encourage health care providers to pay closer attention to the reproductive health of TM patients. This would involve the collaboration of clinicians caring for thalassemia with endocrinologists and specialists in assisted reproductive technologies.

Review and Recommendations on Management of Adult Female Thalassemia Patients with Hypogonadism based on Literature Review and Experience of ICET-A Network Specialists.

BACKGROUND: Multi-transfused thalassemia major (TM) patients frequently develop severe endocrine complications, mainly due to iron overload, anemia, and chronic liver disease, which require prompt diagnosis, treatment and follow-up by specialists. The most common endocrine complication documented is hypogonadotropic hypogonadism which increases with age and associated comorbidities. It is thus important for physicians to have a clear understanding of the pathophysiology and management of this disorder. Also to be aware of the side effects, contraindications and monitoring of sex steroid therapy. In this paper, practical ICET-A recommendations for the management of hypogonadism in adult females with TM are addressed. METHODS: In March 2015, the Coordinator of the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A) conducted a two-step survey to assess the attitudes and practices of doctors in the ICET-A network taking care of adult female TM patients with hypogonadism. They were clinically characterized by the absence of pubertal development or discontinuation or regression of the maturation of secondary sex characteristics, and biochemically by persistent low FSH, LH and estradiol levels. Recently a supplementary survey on adult female hypogonadism in TM was undertaken within the ICET-A network. RESULTS: The completed questionnaires were returned by 16 of 27 specialists (59.2%) following 590 female TM patients over the age of 18 years; 315 patients (53.3%) had hypogonadism, and only 245 (74.6%) were on hormone replacement therapy (HRT). Contraceptive oral pills (COC) were the first treatment choice in 11 centers (68.7%). A wide range of COCs was used with different progestin contents. In general, the patients' compliance to treatment was reported as good in 81.2 % of centers. The frequency of required tests for follow-up HRT, in addition to the regular check-up for thalassemia, was variable in the participating centers. CONCLUSIONS: Doctors taking care of TM patients should have sound knowledge of the pathophysiology of hypogonadism in adult females with TM. They should know the potential effects of HRT including advantages and disadvantages of estrogen and progestins. Moreover, they should keep in consideration the emotional needs of these patients dreaming of attaining a full pubertal development.

The protective effect of Capparis ovata on 6-mercaptopurine-induced hepatotoxicity and oxidative stress in rats.

Capparis ovata is a member of Capparidacaeae family has been used in phytomedicine with a lot of positive effects such as an antioxidative, antihyperlipidemic, anti-inflammatory, and antihepatotoxic agent. The aim of this study was to research the protective effect of C. ovata on 6-mercaptopurine (6-MP) induced to hepatotoxicity and oxidative stress in rats. The rats were divided into 4 groups: control, 6-MP, C. ovataovate, and 6-MP + C. ovata. A complete blood count was performed, liver function test and antioxidant enzymes levels such as superoxide dismutase, glutathione peroxidase, catalase, and malondialdehyde were measured in blood before and after a 14-day test period. White blood cell and platelet counts were lower in the 6-MP group than other 3 groups (P < 0.005). Hepatic transaminase levels were higher in 6-MP group than the 3 groups (P < 0.05). Superoxide dismutase, glutathione peroxidase, and CAT levels were lower and malondialdehyde was higher in blood samples in 6-MP group than other 3 groups (P < 0.005). In conclusion, our tests were showed that C. ovata may be useful in patients receiving 6-MP therapy to prevent hepatotoxicity and in order to maintain uninterrupted therapy possibly reducing the risk of relapse. Although additional studies ensure that Capparis does not affect 6-MP antileukemic activity. We believe these results are important contribution to the literature.

Osteoporosis in thalassemia major: an update and the I-CET 2013 recommendations for surveillance and treatment.

In recent years, the issue of osteopenia/osteoporosis in children, adolescents and young adults with thalassaemia major (TM) has attracted much attention because it is a prominent cause of morbidity despite adequate transfusion and iron chelation therapy. The reported frequency of osteoporosis, even in well treated TM patients varies from 13.6% to 50% with an additional 45% affected by osteopenia. The pathogenesis of TM-induced osteoporosis is multifactorial. Genetic and acquired factors play role in demineralization of bones in thalassemia. Osteoporosis is characterized by low bone mass and disruption of bone architecture, resulting in reduced bone strength and increased risk of fractures. The significant predictors of fracture prevalence include male gender, hypothyroidism, age, lack of spontaneous puberty in females, active hepatitis, heart disease and diabetes. The early identification of osteopenia and osteoporosis is of paramount importance. This is because delayed diagnosis and inadequate treatment have led to severe osteoporosis, skeletal abnormalities, fractures, spinal deformities, nerve compression and growth failure. dequate hormonal replacement, has been posponed, Effective iron chelation adequate hormonal replacement, improvement of hemoglobin levels, calcium and vitamin D administration and physical activity are currently the main measures for the management of the disease. The use of bisphosphonates in TM patients with osteoporosis is increasing and their positive effect in improving bone mineral density is encouraging. The recommendations of the International Network on Growth Disorders and Endocrine Complications in Thalassaemia (I-CET) for diagnosis and management of osteoporosis in TM are also briefly included in this review.

Iron chelation with deferasirox in adult and pediatric patients with thalassemia major: efficacy and safety during 5 years' follow-up.

Patients with ß-thalassemia require lifelong iron chelation therapy from early childhood to prevent complications associated with transfusional iron overload. To evaluate long-term efficacy and safety of once-daily oral iron chelation with deferasirox, patients aged ≥ 2 years who completed a 1-year, phase 3, randomized trial entered a 4-year extension study, either continuing on deferasirox (deferasirox cohort) or switching from deferoxamine to deferasirox (crossover cohort). Of 555 patients who received ≥ 1 deferasirox dose, 66.8% completed the study; 43 patients (7.7%) discontinued because of adverse events. In patients with ≥ 4 years' deferasirox exposure who had liver biopsy, mean liver iron concentration significantly decreased by 7.8 ± 11.2 mg Fe/g dry weight (dw; n = 103; P < .001) and 3.1 ± 7.9 mg Fe/g dw (n = 68; P < .001) in the deferasirox and crossover cohorts, respectively. Median serum ferritin significantly decreased by 706 ng/mL (n = 196; P < .001) and 371 ng/mL (n = 147; P < .001), respectively, after ≥ 4 years' exposure. Investigator-assessed, drug-related adverse events, including increased blood creatinine (11.2%), abdominal pain (9.0%), and nausea (7.4%), were generally mild to moderate, transient, and reduced in frequency over time. No adverse effect was observed on pediatric growth or adolescent sexual development. This first prospective study of long-term deferasirox use in pediatric and adult patients with ß-thalassemia suggests treatment for ≤ 5 years is generally well tolerated and effectively reduces iron burden. This trial was registered at www.clinicaltrials.gov as #NCT00171210.