Macrocytosis secondary to hydroxyurea therapy.

PubMed

Conrado, Francisco O; Weeden, Amy L; Speas, Abbie L; Leissinger, Mary K

2017-09-01

A 10-year-old, male neutered Shetland Sheepdog was presented to the University of Florida for evaluation of a well-granulated mast cell tumor. Hydroxyurea therapy was instituted and serial CBCs showed persistent mild anemia and macrocytosis without a corresponding increase in polychromasia. The dog's MCV increased progressively, reaching its highest value of 100.0 fL after 6 months of treatment, and a diagnosis of macrocytosis associated with hydroxyurea therapy was made. The dog's increase in MCV was prominent, and rapidly decreased after the drug was discontinued, consistent with previous observations in human and canine subjects treated with hydroxyurea. Hydroxyurea is a cytotoxic chemotherapeutic agent used in a variety of conditions in human and veterinary medicine, and megaloblastic changes associated with its use have been described in multiple species. This report shows that hydroxyurea treatment is a differential diagnosis for prominent macrocytosis in dogs in the absence of other signs of erythrocyte regeneration. © 2017 American Society for Veterinary Clinical Pathology.

Assessment of genotoxicity associated with hydroxyurea therapy in children with sickle cell anemia

PubMed Central

Flanagan, Jonathan M.; Howard, Thad A.; Mortier, Nicole; Avlasevich, Svetlana L.; Smeltzer, Matthew P.; Wu, Song; Dertinger, Stephen D.; Ware, Russell E.

2018-01-01

Hydroxyurea induces fetal hemoglobin, improves laboratory parameters, and ameliorates clinical complications of sickle cell anemia (SCA), but its long-term efficacy and safety in this patient population remain incompletely defined. Although generally considered non-DNA reactive, an important safety concern is that hydroxyurea may indirectly cause genotoxic damage. To better address this safety issue of hydroxyurea in patients with SCA, we measured the production of micronuclei (MN) in red blood cells (RBC) as a marker of genotoxicity. Blood samples were collected from children with SCA enrolled in the Hydroxyurea Study of Long-term Effects (ClinicalTrials.gov NCT00305175). Flow cytometry quantified circulating MN-containing erythrocyte sub-populations before and during hydroxyurea exposure. The frequency of micronucleated reticulocytes (MN-CD71+) and micronucleated mature erythrocytes (MN-RBC) were then tested for associations with laboratory and clinical data. In cross-sectional analysis of 293 blood samples from 105 children with SCA and a median of 2 years of hydroxyurea therapy, exposure to hydroxyurea was associated with significantly increased frequencies of MN-CD71+ and MN-RBC compared to baseline. The increases were evident by 3 months of therapy, and did not escalate further with up to 12 years of continuous drug exposure. In prospective longitudinal analysis, substantial inter-individual variation in the effect of hydroxyurea on %MN-CD71+ was observed that was associated with the expected laboratory effects of hydroxyurea. In conclusion, clinically relevant exposure to hydroxyurea is associated with increased MN production consistent with erythroblast genotoxicity but with substantial inter-patient variability. Associations between increased %MN-CD71+ and laboratory benefits suggest that hydroxyurea effects on MN production may be related to individual patient sensitivity to hydroxyurea within the bone marrow. PMID:20230905

Therapeutic superiority and safety of combined hydroxyurea with recombinant human erythropoietin over hydroxyurea in young β-thalassemia intermedia patients.

PubMed

Elalfy, Mohsen S; Adly, Amira A M; Ismail, Eman A; Elhenawy, Yasmine I; Elghamry, Islam R

2013-12-01

To assess the efficacy and safety of combined hydroxyurea (HU) and recombinant human erythropoietin (rHuEPO) in β-thalassemia intermedia (TI) patients compared with single HU therapy. An interventional prospective randomized study registered in the ClinicalTrials.gov (NCT01624038) was performed on 80 TI patients (≤ 18 yr) divided into group A (40 patients received combined HU and rHuEPO) and group B (40 patients received single HU therapy). Baseline serum EPO levels were measured, and both groups were followed up for a mean period of 1 yr with regular assessment of transfusion requirements, blood pressure, ferritin, liver and renal functions, hemoglobin, and HbF. Quality of life (QoL) was assessed at the start and end of the study. Transfusion frequency and index were significantly decreased, while QoL was increased in group A compared with group B where 85% of patients showed improvement on combined therapy compared with 50% of patients on HU. Hemoglobin and HbF were significantly increased in both TI groups; however, this was more evident in group A than in group B. Also, 37.5% of patients in group A became transfusion-independent compared with 15% in group B. EPO levels were negatively related to increments of hemoglobin and HbF. Splenectomized patients and those with initial HbF% >40% had the best response to combined therapy. No serious adverse events necessitating discontinuation of therapy in both groups. HU was effective in management of TI; however, combination with rHuEPO gave a superior therapeutic effect resulting in the best clinical and hematological responses without adverse events. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Hydroxyurea Use in Young Children With Sickle Cell Anemia in New York State.

PubMed

Anders, David G; Tang, Fei; Ledneva, Tatania; Caggana, Michele; Green, Nancy S; Wang, Ying; Sturman, Lawrence S

2016-07-01

This study examined hydroxyurea usage in young children with sickle cell anemia within New York State (NYS). The cohort was 273 children with sickle cell anemia born in NYS in 2006-2009 and enrolled essentially continuously in Medicaid for the first 4 years of life. Medicaid data were used to examine hydroxyurea usage in this group by age at first prescription fill, persistence, region, treatment institution, and year. Log-binomial regression models were used to estimate the likelihood of receiving hydroxyurea treatment. Data from birth through 2014 for all members of the study group were assembled and analyzed in 2015. About 25% of the cohort had at least one filled hydroxyurea prescription by their fifth birthday, and nearly 40% by the end of the study period. The mean proportion of days covered for the first year of therapy was 56.3%. Adherence was also assessed by calculating medication possession ratios for individual treatment periods. Slightly more than one third of treated children showed 80% coverage by these measures. There was a consistent, but not statistically significant, trend toward younger age at first fill. Significant regional and treatment center differences in initiation of hydroxyurea use, but not in persistence after initiation, were noted among NYS centers. Subsequent to clinical studies demonstrating safety, current NYS-wide use of hydroxyurea in young children with sickle cell anemia appears to be widespread and increasing. However, practice differences between treatment centers and inadequate adherence may limit the full disease-modifying effects of hydroxyurea. Copyright © 2016 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

From Infancy to Adolescence: Fifteen Years of Continuous Treatment With Hydroxyurea in Sickle Cell Anemia

PubMed Central

Hankins, Jane S.; Aygun, Banu; Nottage, Kerri; Thornburg, Courtney; Smeltzer, Matthew P.; Ware, Russell E.; Wang, Winfred C.

2014-01-01

Abstract Despite documented laboratory and clinical benefits of hydroxyurea for children with sickle cell anemia (SCA), the drug's long-term safety and efficacy remains poorly defined. The HUSOFT trial and extension study examined feasibility, toxicity, and hematological efficacy of hydroxyurea in infants with SCA. This report describes HUSOFT participants who have continued hydroxyurea therapy for 15 years. With IRB approval, medical records were reviewed for clinical, laboratory, and growth parameters. Twenty-eight infants enrolled in the original 2-year HUSOFT study received open-label liquid hydroxyurea at 20 mg/kg/day; 17 completed the extension study with dose escalation to 30 mg/kg/day. Eight of these 17 (6 girls and 2 boys, all HbSS) have continued on daily hydroxyurea for at least 15 years (median age at last follow-up 17.6 years) without interruption. All hematologic indices (Hb concentration, mean corpuscular volume (MCV), fetal hemoglobin) showed sustained effect after 15 years. The median maximum tolerated dose of hydroxyurea has decreased from 30 to 26 mg/kg/day (range 19.5–31.2); neutropenia [absolute neutrophil count (ANC) < 1.0 × 109/L] prompting temporary drug discontinuation occurred a total of 10 times in 4 subjects and there was no severe neutropenia (ANC < 0.5 × 109/L). Growth rates over 15 years continued at the 50th percentile for both height and weight, and puberty occurred without delay (age range 10–14 years). There were 5.1 vaso-occlusive events (pain and acute chest syndrome)/100 patient years, 7.3 packed red blood cell transfusions/100 patient years. No malignancies, strokes, or deaths occurred. At last follow up, all subjects were at appropriate grade level (10–12 grade) with no history of repeated grades. A cohort of young teenagers with SCA who initiated treatment in infancy have had sustained and continued hematological benefits for a decade and a half. Growth and sexual development are normal and comparable to the general pediatric population. Continuous hydroxyurea therapy since infancy appears safe and efficacious in SCA. PMID:25526439

From infancy to adolescence: fifteen years of continuous treatment with hydroxyurea in sickle cell anemia.

PubMed

Hankins, Jane S; Aygun, Banu; Nottage, Kerri; Thornburg, Courtney; Smeltzer, Matthew P; Ware, Russell E; Wang, Winfred C

2014-12-01

Despite documented laboratory and clinical benefits of hydroxyurea for children with sickle cell anemia (SCA), the drug's long-term safety and efficacy remains poorly defined. The HUSOFT trial and extension study examined feasibility, toxicity, and hematological efficacy of hydroxyurea in infants with SCA. This report describes HUSOFT participants who have continued hydroxyurea therapy for 15 years. With IRB approval, medical records were reviewed for clinical, laboratory, and growth parameters. Twenty-eight infants enrolled in the original 2-year HUSOFT study received open-label liquid hydroxyurea at 20 mg/kg/day; 17 completed the extension study with dose escalation to 30 mg/kg/day. Eight of these 17 (6 girls and 2 boys, all HbSS) have continued on daily hydroxyurea for at least 15 years (median age at last follow-up 17.6 years) without interruption. All hematologic indices (Hb concentration, mean corpuscular volume (MCV), fetal hemoglobin) showed sustained effect after 15 years. The median maximum tolerated dose of hydroxyurea has decreased from 30 to 26 mg/kg/day (range 19.5-31.2); neutropenia [absolute neutrophil count (ANC)<1.0×10⁹/L] prompting temporary drug discontinuation occurred a total of 10 times in 4 subjects and there was no severe neutropenia (ANC<0.5×10⁹/L). Growth rates over 15 years continued at the 50th percentile for both height and weight, and puberty occurred without delay (age range 10-14 years). There were 5.1 vaso-occlusive events (pain and acute chest syndrome)/100 patient years, 7.3 packed red blood cell transfusions/100 patient years. No malignancies, strokes, or deaths occurred. At last follow up, all subjects were at appropriate grade level (10-12 grade) with no history of repeated grades. A cohort of young teenagers with SCA who initiated treatment in infancy have had sustained and continued hematological benefits for a decade and a half. Growth and sexual development are normal and comparable to the general pediatric population. Continuous hydroxyurea therapy since infancy appears safe and efficacious in SCA.

Busulfan is effective second-line therapy for older patients with Philadelphia-negative myeloproliferative neoplasms intolerant of or unresponsive to hydroxyurea.

PubMed

Douglas, Genevieve; Harrison, Claire; Forsyth, Cecily; Bennett, Michael; Stevenson, William; Hounsell, John; Ratnasingam, Sumita; Ritchie, David; Ross, David M; Grigg, Andrew

2017-01-01

Hydroxyurea (Hu) is widely used as first-line cytoreductive therapy for patients with high-risk Philadelphia-negative myeloproliferative neoplasms (Ph-neg MPN), but a small proportion of patients have refractory disease or experience adverse effects. Studies have demonstrated busulfan (Bu) to be an active first-line agent, but data on its role as second-line or later therapy are minimal. To evaluate its efficacy and safety in this context, we undertook a multicenter audit of Ph-neg MPN patients who had received Bu as therapy for Hu intolerance or failure. Of 51 patients identified, 38 (75%) achieved either complete or partial hematological response following at least one Bu cycle. Bu was generally well tolerated, with only 21/135 (15%) cycles complicated by adverse effects, predominantly cytopenia; only 6% of cycles were ceased due to treatment complications. Bu is an effective and well-tolerated agent in patients with Ph-neg MPN in the setting of Hu intolerance or unresponsiveness.

The effect of hydroxyurea on compound heterozygotes for sickle cell-hemoglobin D-Punjab--a single centre experience in eastern India.

PubMed

Patel, Siris; Purohit, Prasanta; Mashon, Ranjeet Singh; Dehury, Snehadhini; Meher, Satyabrata; Sahoo, Sulia; Dash, Subhransu Sekhar; Das, Kishalaya; Das, Padmalaya; Patel, Dilip Kumar

2014-08-01

Although hydroxyurea is the only effective agent for the treatment of sickle cell disease, published experience with this drug is limited to treatment of homozygous sickle cell anemia and HbS/β thalassemia. The role of hydroxyurea in the treatment of patients with HbSD-Punjab, a rare hemoglobinopathy with phenotypic expression similar to that of sickle cell anemia is unknown. Over a period of 10 years, we followed 42 patients with HbSD-Punjab, of which 20 presented with severe clinical manifestations (≥3 episodes of VOC and/or ≥2 units of blood transfusion in the previous 12 months). These 20 patients were enrolled for treatment with hydroxyurea at a dose of 10 mg/kg/day and followed prospectively for a period of 24 months. The frequency of VOC decreased significantly and none of them required blood transfusion while receiving hydroxyurea. The HbF, total hemoglobin, MCV, MCH, and MCHC levels increased significantly, whereas HbS, WBC, platelet count, total serum bilirubin, and LDH levels decreased significantly in all the patients. No short-term drug toxicity was observed. This study describes the use of hydroxyurea therapy in patients with HbSD-Punjab. Low dose hydroxyurea (10 mg/kg/day) was found to be effective in reducing the clinical severity in patients with HbSD-Punjab without any short-term toxicity. In view of easy affordability amongst poor patients, widespread acceptability by patients and doctors, the need of infrequent monitoring and its potential effectiveness, low dose hydroxyurea is suitable for treatment of patients with HbSD-Punjab. © 2014 Wiley Periodicals, Inc.

Hydroxyurea responses in clinically varied beta, HbE-beta thalassaemia and sickle cell anaemia patients of Eastern India.

PubMed

Chatterjee, Tridip; Chakravarty, Amit; Chakravarty, Sudipa

2018-05-01

The haematological and clinical response to hydroxyurea was estimated in HbE-beta, beta thalassaemia and sickle cell anaemia patients of Eastern India, with variable clinical severity and transfusion requirement to determine whether hydroxyurea can help these patients to maintain their steady haemoglobin level without blood transfusions. Three hundred patients (189 HbE-beta thalassaemia, 95 beta thalassaemia and 16 other haemoglobinopathies including sickle cell anaemia) were selected for hydroxyurea therapy and were followed up for 48-60 months. Results suggest significant response to hydroxyurea therapy in 19 beta and 99 HbE-beta patients in the transfusion-dependent group (GR-I). All of them became transfusion-independent while on hydroxyurea therapy. The majority of responding patients were IVS1-5(G-C) in one of their alleles in HbE-beta cases (83 out of 119). Though IVS1-5(G-C) was found to be the commonest mutation in our selected patients, the mutational background of the patients does not found to have any significant correlation with the response category towards hydroxyurea as per the results observed in our study. But, the drug works pretty well in most of the transfusion-dependent patients, as these patients were withdrawn from regular blood transfusion. At the same time, partial or no response to the drug hydroxyurea was also recorded in our study.

Acral keratoses and leucocytoclastic vasculitis occurring during treatment of essential thrombocythaemia with hydroxyurea.

PubMed

Worley, B; Glassman, S J

2016-03-01

Hydroxyurea is used in essential thrombocythaemia to lower thromboembolic risk. Cutaneous adverse effects from hydroxyurea are diverse. Small vessel vasculitis has been rarely reported, and the coexistence of several different morphologies has not been described. We report a case of acral keratoses, psoriasiform plaques and leucocytoclastic vasculitis (LCV) in a patient with essential thrombocythaemia. A 69-year-old woman developed a confusing array of skin lesions including keratotic papules, psoriasiform plaques and keratoderma 4 years after commencing hydroxyurea therapy. The initial diagnosis was hand and foot psoriasis, but lesions were resistant to therapy. With an increase in the dose of hydroxyurea, the lesions ulcerated. Skin biopsies taken from different sites indicated different diagnoses, including LCV. Discontinuation of hydroxyurea yielded rapid improvement. Although the most commonly reported cutaneous adverse effect from hydroxyurea is leg ulceration, this can be preceded or accompanied by less dramatic skin lesions. Unless recognized, delayed diagnosis and lesion progression can occur. © 2015 British Association of Dermatologists.

Patients with sickle cell disease taking hydroxyurea in the Hemocentro Regional de Montes Claros

PubMed Central

Santos, Fernanda Kelle de Souza; Maia, Caroline Nogueira

2011-01-01

Background The development of therapies for sickle cell disease has received special attention, particularly those that reduce the polymerization of hemoglobin S. Hydroxyurea is a commonly used medication because it has the ability to raise levels of fetal hemoglobin, decrease the frequency of vaso-occlusive episodes and thus improve the clinical course of sickle cell disease patients. Objective To study hematological data and the clinical profile of sickle cell disease patients taking hydroxyurea in a regional blood center. Methods From the charts of 20 patients with sickle cell anemia, the clinical outcomes and a number of hematological variables were analyzed before and during treatment with hydroxyurea. Results The patients' ages ranged from 6 to 41 years old, most were dark skinned and there was a predominance of women. The main symptom that defined whether patients were prescribed hydroxyurea was painful crises followed by hospitalizations. During treatment with hydroxyurea there were significant increases in hemoglobin, fetal hemoglobin, mean corpuscular volume and mean corpuscular hemoglobin. The reticulocyte and white blood cell counts dropped significantly with treatment. A positive correlation was found between fetal hemoglobin and mean corpuscular volume before and during treatment. Additionally, a correlation was found between the white blood cell and reticulocyte counts before treatment with hydroxyurea. Conclusion Most patients showed improvements with treatment as demonstrated by increases in hemoglobin, fetal hemoglobin and mean corpuscular volume, as well as by reductions in the reticulocyte and white blood cell counts. Clinically, more than 50% of patients had a significant reduction of events. PMID:23284256

Original Research: Use of hydroxyurea and phlebotomy in pediatric patients with hemoglobin SC disease

PubMed Central

Summarell, Carly C Ginter

2016-01-01

Hydroxyurea is an excellent therapeutic agent for the pharmacological induction of HbF in patients with sickle cell disease (SCD). However, all completed clinical trials of hydroxyurea have excluded patients with hemoglobin SC (HbSC) disease. HbSC differs significantly in pathophysiology from HbSS, as HbC does not sickle, but instead causes cellular dehydration which potentiates sickling of HbS. Many severely affected HbSC patients have been placed on hydroxyurea on a case by case basis, but there are no large scale prospective data on safety or efficacy of hydroxyurea in this subset of patients with SCD. Here, we report a case series of 14 pediatric patients with HbSC treated to maximum tolerated dose (MTD) with hydroxyurea. Those who failed to show clinical improvement after at least six months at MTD were offered phlebotomy in addition to hydroxyurea. Five out of 11 patients with HbSC who achieved MTD failed to demonstrate clinical improvement on hydroxyurea. Of the four placed on dual hydroxyurea and phlebotomy therapy, all showed at least partial clinical improvement. Percent dense red blood cells (%DRBC) were measured via an ADVIA hematology analyzer. A marked rise in percent dense cells preceded clinical complications in three patients. Dual therapy with hydroxyurea and phlebotomy may be an effective approach to patients with HbSC that do not experience improvement with hydroxyurea alone. Monitoring of %DRBC may predict adverse events and aid in assessing hydroxyurea compliance. Large scale clinical trials are needed to evaluate the safety and efficacy of hydroxyurea and hydroxyurea with phlebotomy in patients with HbSC disease. PMID:26993671

Original Research: Use of hydroxyurea and phlebotomy in pediatric patients with hemoglobin SC disease.

PubMed

Summarell, Carly C Ginter; Sheehan, Vivien A

2016-04-01

Hydroxyurea is an excellent therapeutic agent for the pharmacological induction of HbF in patients with sickle cell disease (SCD). However, all completed clinical trials of hydroxyurea have excluded patients with hemoglobin SC (HbSC) disease. HbSC differs significantly in pathophysiology from HbSS, as HbC does not sickle, but instead causes cellular dehydration which potentiates sickling of HbS. Many severely affected HbSC patients have been placed on hydroxyurea on a case by case basis, but there are no large scale prospective data on safety or efficacy of hydroxyurea in this subset of patients with SCD. Here, we report a case series of 14 pediatric patients with HbSC treated to maximum tolerated dose (MTD) with hydroxyurea. Those who failed to show clinical improvement after at least six months at MTD were offered phlebotomy in addition to hydroxyurea. Five out of 11 patients with HbSC who achieved MTD failed to demonstrate clinical improvement on hydroxyurea. Of the four placed on dual hydroxyurea and phlebotomy therapy, all showed at least partial clinical improvement. Percent dense red blood cells (%DRBC) were measured via an ADVIA hematology analyzer. A marked rise in percent dense cells preceded clinical complications in three patients. Dual therapy with hydroxyurea and phlebotomy may be an effective approach to patients with HbSC that do not experience improvement with hydroxyurea alone. Monitoring of %DRBC may predict adverse events and aid in assessing hydroxyurea compliance. Large scale clinical trials are needed to evaluate the safety and efficacy of hydroxyurea and hydroxyurea with phlebotomy in patients with HbSC disease. © 2016 by the Society for Experimental Biology and Medicine.

NTP-CERHR monograph on the potential human reproductive and developmental effects of hydroxyurea.

PubMed

2008-10-01

The National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR) conducted an evaluation of the potential for hydroxyurea to cause adverse effects on reproduction and development in humans. Hydroxyurea is a drug used to treat cancer, sickle cell disease, and thalassemia. It is the only treatment for sickle cell disease in children, aside from blood transfusion and, in severe cases, hematopoietic stem cell transplantation. Hydroxyurea is FDA-approved for use in adults with sickle cell anemia to reduce the frequency of painful crises and the need for blood transfusions. Hydroxyurea may be given to children and adults with sickle cell disease for an extended period of time or for repeated cycles of therapy. Treatment with hydroxyurea is associated with known side effects such as cytotoxicity and myelosuppression, and hydroxyurea is genotoxic (can damage DNA). CERHR selected hydroxyurea for evaluation because of: its increasing use for treatment of sickle cell disease in children and adults, knowledge that it inhibits DNA synthesis and is cytotoxic, and published evidence of reproductive and developmental toxicity in rodents. The results of this evaluation are published in the NTP-CERHR Monograph on Hydroxyurea, which includes the NTP Brief and Expert Panel Report on the Reproductive and Developmental Toxicity of Hydroxyurea. Additional information related to the evaluation process, including public comments received on the draft NTP Brief and the final expert panel report, are available on the CERHR website (http:// cerhr.niehs.nih.gov/). See hydroxyurea under "CERHR Chemicals" on the homepage or go directly to http://cerhr.niehs.nih.gov/chemicals/hydroxyurea/hydroxyurea-eval.html). The NTP reached the following conclusions on the possible effects of exposure to hydroxyurea on human reproduction or development. The possible levels of concern, from lowest to highest, are negligible concern, minimal concern, some concern, concern, and serious concern. The NTP expresses serious concern that exposure of men to therapeutic doses of hydroxyurea may adversely affect sperm production. This level of concern is for all males who have reached puberty. The NTP concurs with the Expert Panel that there is concern that exposure of pregnant women to hydroxyurea may result in birth defects, abnormalities of fetal growth, or abnormal postnatal development in offspring. The NTP concurs with the Expert Panel that there is minimal concern that exposure of children to therapeutic doses of hydroxyurea at 5 -15 years of age will adversely affect growth. NTP will transmit the NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Hydroxyurea to federal and state agencies, interested parties, and the public and make it available in electronic PDF format on the CERHR web site (http://cerhr niehs nih gov) and in printed text or CD from CERHR.

PREVENTION OF CONVERSION TO ABNORMAL TCD WITH HYDROXYUREA IN SICKLE CELL ANEMIA: A PHASE III INTERNATIONAL RANDOMIZED CLINICAL TRIAL

PubMed Central

Hankins, Jane S.; McCarville, M. Beth; Rankine-Mullings, Angela; Reid, Marvin E.; Lobo, Clarisse L.C.; Moura, Patricia G.; Ali, Susanna; Soares, Deanne; Aldred, Karen; Jay, Dennis W.; Aygun, Banu; Bennett, John; Kang, Guolian; Goldsmith, Jonathan C.; Smeltzer, Matthew P.; Boyett, James M.; Ware, Russell E.

2015-01-01

Children with sickle cell anemia (SCA) and conditional transcranial Doppler (TCD) ultrasound velocities (170-199 cm/sec) may develop stroke. However, with limited available clinical data, the current standard of care for conditional TCD velocities is observation. The efficacy of hydroxyurea in preventing conversion from conditional to abnormal TCD (≥200 cm/sec), which confers a higher stroke risk, has not been studied prospectively in a randomized trial. Sparing Conversion to Abnormal TCD Elevation (SCATE #NCT01531387) was an NHLBI-funded Phase III multicenter international clinical trial comparing alternative therapy (hydroxyurea) to standard care (observation) to prevent conversion from conditional to abnormal TCD velocity in children with SCA. SCATE enrolled 38 children from the United States, Jamaica, and Brazil [HbSS (36), HbSβ0-thalassemia (1), and HbSD (1), median age 5.4 years (range, 2.7-9.8)]. Due to slow patient accrual and administrative delays, SCATE was terminated early. In an intention-to-treat analysis, the cumulative incidence of abnormal conversion was 9% (95% CI 0 to 35%) in the hydroxyurea arm and 47% (95% CI 6 to 81%) in observation arm at 15 months (p=0.16). In post-hoc analysis according to treatment received, significantly fewer children on hydroxyurea converted to abnormal TCD velocities, compared to observation (0% versus 50%, p=0.02). After a mean of 10.1 months, a significant change in mean TCD velocity was observed with hydroxyurea treatment (−15.5 versus +10.2 cm/sec, p=0.02). No stroke events occurred in either arm. Hydroxyurea reduces TCD velocities in children with SCA and conditional velocities. PMID:26414435

Prevention of conversion to abnormal transcranial Doppler with hydroxyurea in sickle cell anemia: A Phase III international randomized clinical trial.

PubMed

Hankins, Jane S; McCarville, Mary Beth; Rankine-Mullings, Angela; Reid, Marvin E; Lobo, Clarisse L C; Moura, Patricia G; Ali, Susanna; Soares, Deanne P; Aldred, Karen; Jay, Dennis W; Aygun, Banu; Bennett, John; Kang, Guolian; Goldsmith, Jonathan C; Smeltzer, Matthew P; Boyett, James M; Ware, Russell E

2015-12-01

Children with sickle cell anemia (SCA) and conditional transcranial Doppler (TCD) ultrasound velocities (170-199 cm/sec) may develop stroke. However, with limited available clinical data, the current standard of care for conditional TCD velocities is observation. The efficacy of hydroxyurea in preventing conversion from conditional to abnormal TCD (≥200 cm/sec), which confers a higher stroke risk, has not been studied prospectively in a randomized trial. Sparing Conversion to Abnormal TCD Elevation (SCATE #NCT01531387) was a National Heart, Lung, and Blood Institute-funded Phase III multicenter international clinical trial comparing alternative therapy (hydroxyurea) to standard care (observation) to prevent conversion from conditional to abnormal TCD velocity in children with SCA. SCATE enrolled 38 children from the United States, Jamaica, and Brazil [HbSS (36), HbSβ(0) -thalassemia (1), and HbSD (1), median age = 5.4 years (range, 2.7-9.8)]. Because of the slow patient accrual and administrative delays, SCATE was terminated early. In an intention-to-treat analysis, the cumulative incidence of abnormal conversion was 9% (95% CI = 0-35%) in the hydroxyurea arm and 47% (95% CI = 6-81%) in observation arm at 15 months (P = 0.16). In post hoc analysis according to treatment received, significantly fewer children on hydroxyurea converted to abnormal TCD velocities when compared with observation (0% vs. 50%, P = 0.02). After a mean of 10.1 months, a significant change in mean TCD velocity was observed with hydroxyurea treatment (-15.5 vs. +10.2 cm/sec, P = 0.02). No stroke events occurred in either arm. Hydroxyurea reduces TCD velocities in children with SCA and conditional velocities. © 2015 Wiley Periodicals, Inc.

Pharmacokinetics, pharmacodynamics, and pharmacogenetics of hydroxyurea treatment for children with sickle cell anemia

PubMed Central

Despotovic, Jenny M.; Mortier, Nicole A.; Flanagan, Jonathan M.; He, Jin; Smeltzer, Matthew P.; Kimble, Amy C.; Aygun, Banu; Wu, Song; Howard, Thad; Sparreboom, Alex

2011-01-01

Hydroxyurea therapy has proven laboratory and clinical efficacies for children with sickle cell anemia (SCA). When administered at maximum tolerated dose (MTD), hydroxyurea increases fetal hemoglobin (HbF) to levels ranging from 10% to 40%. However, interpatient variability of percentage of HbF (%HbF) response is high, MTD itself is variable, and accurate predictors of hydroxyurea responses do not currently exist. HUSTLE (NCT00305175) was designed to provide first-dose pharmacokinetics (PK) data for children with SCA initiating hydroxyurea therapy, to investigate pharmacodynamics (PD) parameters, including HbF response and MTD after standardized dose escalation, and to evaluate pharmacogenetics influences on PK and PD parameters. For 87 children with first-dose PK studies, substantial interpatient variability was observed, plus a novel oral absorption phenotype (rapid or slow) that influenced serum hydroxyurea levels and total hydroxyurea exposure. PD responses in 174 subjects were robust and similar to previous cohorts; %HbF at MTD was best predicted by 5 variables, including baseline %HbF, whereas MTD was best predicted by 5 variables, including serum creatinine. Pharmacogenetics analysis showed single nucleotide polymorphisms influencing baseline %HbF, including 5 within BCL11A, but none influencing MTD %HbF or dose. Accurate prediction of hydroxyurea treatment responses for SCA remains a worthy but elusive goal. PMID:21876119

Ruxolitinib versus standard therapy for the treatment of polycythemia vera.

PubMed

Vannucchi, Alessandro M; Kiladjian, Jean Jacques; Griesshammer, Martin; Masszi, Tamas; Durrant, Simon; Passamonti, Francesco; Harrison, Claire N; Pane, Fabrizio; Zachee, Pierre; Mesa, Ruben; He, Shui; Jones, Mark M; Garrett, William; Li, Jingjin; Pirron, Ulrich; Habr, Dany; Verstovsek, Srdan

2015-01-29

Ruxolitinib, a Janus kinase (JAK) 1 and 2 inhibitor, was shown to have a clinical benefit in patients with polycythemia vera in a phase 2 study. We conducted a phase 3 open-label study to evaluate the efficacy and safety of ruxolitinib versus standard therapy in patients with polycythemia vera who had an inadequate response to or had unacceptable side effects from hydroxyurea. We randomly assigned phlebotomy-dependent patients with splenomegaly, in a 1:1 ratio, to receive ruxolitinib (110 patients) or standard therapy (112 patients). The primary end point was both hematocrit control through week 32 and at least a 35% reduction in spleen volume at week 32, as assessed by means of imaging. The primary end point was achieved in 21% of the patients in the ruxolitinib group versus 1% of those in the standard-therapy group (P<0.001). Hematocrit control was achieved in 60% of patients receiving ruxolitinib and 20% of those receiving standard therapy; 38% and 1% of patients in the two groups, respectively, had at least a 35% reduction in spleen volume. A complete hematologic remission was achieved in 24% of patients in the ruxolitinib group and 9% of those in the standard-therapy group (P=0.003); 49% versus 5% had at least a 50% reduction in the total symptom score at week 32. In the ruxolitinib group, grade 3 or 4 anemia occurred in 2% of patients, and grade 3 or 4 thrombocytopenia occurred in 5%; the corresponding percentages in the standard-therapy group were 0% and 4%. Herpes zoster infection was reported in 6% of patients in the ruxolitinib group and 0% of those in the standard-therapy group (grade 1 or 2 in all cases). Thromboembolic events occurred in one patient receiving ruxolitinib and in six patients receiving standard therapy. In patients who had an inadequate response to or had unacceptable side effects from hydroxyurea, ruxolitinib was superior to standard therapy in controlling the hematocrit, reducing the spleen volume, and improving symptoms associated with polycythemia vera. (Funded by Incyte and others; RESPONSE ClinicalTrials.gov number, NCT01243944.).

The case for and against initiating either hydroxyurea therapy, blood transfusion therapy or hematopoietic stem cell transplant in asymptomatic children with sickle cell disease.

PubMed

Kassim, Adetola A; DeBaun, Michael R

2014-02-01

The perception of an asymptomatic sickle cell disease (SCD) state is a misnomer. Children without overt symptoms, likely have subclinical disease beginning in infancy with progression into adulthood. Predictive models of SCD severity are unable to predict a subgroup of asymptomatic children likely to develop severe SCD. The introduction of penicillin prophylaxis, conjugated pneumococcal and Haemophilus influenzae type B vaccines have dramatically decreased the rate of life-threatening infections, while use of hydroxyurea in children has decreased pain and acute chest syndrome events. Use of transcranial Doppler coupled with regular blood transfusion therapy has decreased the rate of overt strokes and premature death associated with strokes. Currently, therapy for asymptomatic children includes hydroxyurea, regular blood transfusion or allogeneic hematopoietic stem cell transplant (allo-HSCT). The pros and cons of initiating hydroxyurea, regular blood transfusion or allo-HSCT in asymptomatic children with SCD. Emerging evidence from observational studies indicates that hydroxyurea prolongs survival in children and adults with sickle cell anemia. Regular blood transfusions reduce incidence of strokes, acute chest and pain episodes, but is associated with the burden of monthly visits and excessive iron stores. Although curative, the perceived risk:benefit ratio associated with allo-HSCT limits its use in asymptomatic children.

Novel use Of Hydroxyurea in an African Region with Malaria (NOHARM): a trial for children with sickle cell anemia.

PubMed

Opoka, Robert O; Ndugwa, Christopher M; Latham, Teresa S; Lane, Adam; Hume, Heather A; Kasirye, Phillip; Hodges, James S; Ware, Russell E; John, Chandy C

2017-12-14

Hydroxyurea treatment is recommended for children with sickle cell anemia (SCA) living in high-resource malaria-free regions, but its safety and efficacy in malaria-endemic sub-Saharan Africa, where the greatest sickle-cell burden exists, remain unknown. In vitro studies suggest hydroxyurea could increase malaria severity, and hydroxyurea-associated neutropenia could worsen infections. NOHARM (Novel use Of Hydroxyurea in an African Region with Malaria) was a randomized, double-blinded, placebo-controlled trial conducted in malaria-endemic Uganda, comparing hydroxyurea to placebo at 20 ± 2.5 mg/kg per day for 12 months. The primary outcome was incidence of clinical malaria. Secondary outcomes included SCA-related adverse events (AEs), clinical and laboratory effects, and hematological toxicities. Children received either hydroxyurea (N = 104) or placebo (N = 103). Malaria incidence did not differ between children on hydroxyurea (0.05 episodes per child per year; 95% confidence interval [0.02, 0.13]) vs placebo (0.07 episodes per child per year [0.03, 0.16]); the hydroxyurea/placebo malaria incidence rate ratio was 0.7 ([0.2, 2.7]; P = .61). Time to infection also did not differ significantly between treatment arms. A composite SCA-related clinical outcome (vaso-occlusive painful crisis, dactylitis, acute chest syndrome, splenic sequestration, or blood transfusion) was less frequent with hydroxyurea (45%) than placebo (69%; P = .001). Children receiving hydroxyurea had significantly increased hemoglobin concentration and fetal hemoglobin, with decreased leukocytes and reticulocytes. Serious AEs, sepsis episodes, and dose-limiting toxicities were similar between treatment arms. Three deaths occurred (2 hydroxyurea, 1 placebo, and none from malaria). Hydroxyurea treatment appears safe for children with SCA living in malaria-endemic sub-Saharan Africa, without increased severe malaria, infections, or AEs. Hydroxyurea provides SCA-related laboratory and clinical efficacy, but optimal dosing and monitoring regimens for Africa remain undefined. This trial was registered at www.clinicaltrials.gov as #NCT01976416. © 2017 by The American Society of Hematology.

Ruxolitinib for the treatment of inadequately controlled polycythemia vera without splenomegaly: 80-week follow-up from the RESPONSE-2 trial.

PubMed

Griesshammer, Martin; Saydam, Guray; Palandri, Francesca; Benevolo, Giulia; Egyed, Miklos; Callum, Jeannie; Devos, Timothy; Sivgin, Serdar; Guglielmelli, Paola; Bensasson, Caroline; Khan, Mahmudul; Ronco, Julian Perez; Passamonti, Francesco

2018-05-27

RESPONSE-2 is a phase 3 study comparing the efficacy and safety of ruxolitinib with the best available therapy (BAT) in hydroxyurea-resistant/hydroxyurea-intolerant polycythemia vera (PV) patients without palpable splenomegaly. This analysis evaluated the durability of the efficacy and safety of ruxolitinib after patients completed the visit at week 80 or discontinued the study. Endpoints included proportion of patients achieving hematocrit control (< 45%), proportion of patients achieving complete hematologic remission (CHR) at week 28, and the durability of hematocrit control and CHR. At the time of analysis, 93% (69/74) of patients randomized to ruxolitinib were receiving ruxolitinib; while in the BAT arm, 77% (58/75) of patients crossed over to ruxolitinib after week 28. No patient remained on BAT by week 80. Among patients who achieved a hematocrit response at week 28, the probability of maintaining response up to week 80 was 78% in the ruxolitinib arm. At week 80, durable CHR was achieved in 18 patients (24%) in the ruxolitinib arm versus 2 patients (3%) in the BAT arm. The safety profile of ruxolitinib was consistent with previous reports. These data support that ruxolitinib treatment should be considered also as a standard of care for hydroxyurea-resistant/hydroxyurea-intolerant PV patients without palpable splenomegaly.

Cutaneous ulcers associated with hydroxyurea therapy.

PubMed

Quattrone, Filippo; Dini, Valentina; Barbanera, Sabrina; Zerbinati, Nicola; Romanelli, Marco

2013-11-01

Hydroxyurea is an antitumoral drug mainly used in the treatment of Philadelphia chromosome-negative myeloproliferative syndromes and sickle-cell disease. Ulcers represent a rare but severe long-term adverse effect of hydroxyurea therapy. Hydroxyurea-induced ulcers are often multiple and bilateral, typically developing in the perimalleolar region, although any cutaneous district is potentially affected. They generally look small, well-defined, shallow with an adherent, yellow, fibrinous necrotic base. A constant finding is also an extremely intense, treatment-resistant pain accompanying these ulcerations. Withdrawal of the drug generally leads to spontaneous healing of these lesions. Care providers tend to show insufficient awareness of this highly debilitating cutaneous side effect, and late or missed diagnoses are frequent. Instead, regular dermatologic screening should be performed on hydroxyurea-treated patients. This article will present a comprehensive review of indexed case reports and clinical studies, followed by a discussion about treatment options aiming at increasing knowledge about this specific topic. Copyright © 2013 Tissue Viability Society. Published by Elsevier Ltd. All rights reserved.

A predictable but life-threatening complication of hydroxyurea in a patient with sickle cell anaemia: an experience learned from a Jehovah's Witness.

PubMed

Tun, Aung Myint; Naing, Ei Ei; Tun, Nay Min; Guevara, Elizabeth

2015-09-30

It is well known that hydroxyurea can cause pancytopaenia secondary to bone marrow suppression, which is reversible with short-term discontinuation of the therapy. However, it is important to note that bone marrow suppressive effects caused by hydroxyurea could be easily potentiated in patients with sickle cell anaemia complicated by chronic kidney disease (CKD). We present a case of a Jehovah's Witness with sickle cell anaemia, who developed severe bone marrow suppression due to the combined effects of hydroxyurea and CKD, resulting in a prolonged recovery period after discontinuation of hydroxyurea. 2015 BMJ Publishing Group Ltd.

Improved hydroxyurea effect with the use of text messaging in children with sickle cell anemia.

PubMed

Estepp, Jeremie H; Winter, Bryan; Johnson, Margery; Smeltzer, Matthew P; Howard, Scott C; Hankins, Jane S

2014-11-01

In children with sickle cell anemia (SCA), hydroxyurea reduces morbidity, but adherence is frequently suboptimal. Because most families of children with SCA have access to cellular telephone services, we assessed the impact of text messaged reminders as a tool to improve adherence to hydroxyurea. All patients <19 years of age with HbSS or HbSβ(0) thalassemia who were treated with hydroxyurea at a maximal tolerated dosage (MTD) at St. Jude Children's Research Hospital Comprehensive Pediatric Sickle Cell Program and who received automated text message reminders (SIMON®) were retrospectively identified. Laboratory parameters, hospitalizations, and medication possession ratios (MPR) prior to and after initiation of SIMON® were compared to assess the impact of SIMON®. Of the 97.3% of families with access to a cell phone, 91% elected to receive text message reminders. Among 55 children receiving hydroxyurea at MTD, laboratory parameters reflected waning medication compliance during the 12 months prior to SIMON®. Following initiation of SIMON®, children had higher mean corpuscular volumes, hemoglobin levels and fetal hemoglobin percentages and lower absolute reticulocyte counts and bilirubin levels, suggesting improved medication adherence. Hospitalizations were uncommon before and after SIMON®, and medication possession ratios (MPRs) were high before and after SIMON®, neither was significantly changed. SIMON® was feasible and improved hematologic parameters in children with SCA receiving hydroxyurea at a MTD. Future work will include extension of this technology to children with other chronic medical conditions who require daily use of medication. © 2014 Wiley Periodicals, Inc.

Impact of hydroxyurea on clinical events in the BABY HUG trial

PubMed Central

Files, Beatrice A.; Luo, Zhaoyu; Miller, Scott T.; Kalpatthi, Ram; Iyer, Rathi; Seaman, Phillip; Lebensburger, Jeffrey; Alvarez, Ofelia; Thompson, Bruce; Ware, Russell E.; Wang, Winfred C.

2012-01-01

The Pediatric Hydroxyurea Phase 3 Clinical Trial (BABY HUG) was a phase 3 multicenter, randomized, double-blind, placebo-controlled clinical trial of hydroxyurea in infants (beginning at 9-18 months of age) with sickle cell anemia. An important secondary objective of this study was to compare clinical events between the hydroxyurea and placebo groups. One hundred and ninety-three subjects were randomized to hydroxyurea (20 mg/kg/d) or placebo; there were 374 patient-years of on-study observation. Hydroxyurea was associated with statistically significantly lower rates of initial and recurrent episodes of pain, dactylitis, acute chest syndrome, and hospitalization; even infants who were asymptomatic at enrollment had less dactylitis as well as fewer hospitalizations and transfusions if treated with hydroxyurea. Despite expected mild myelosuppression, hydroxyurea was not associated with an increased risk of bacteremia or serious infection. These data provide important safety and efficacy information for clinicians considering hydroxyurea therapy for very young children with sickle cell anemia. This clinical trial is registered with the National Institutes of Health (NCT00006400, www.clinicaltrials.gov). PMID:22915643

Cyclical thrombocytosis, acquired von Willebrand syndrome and aggressive non-melanoma skin cancers are common in patients with Philadelphia-negative myeloproliferative neoplasms treated with hydroxyurea.

PubMed

Verner, Emma; Forsyth, Cecily; Grigg, Andrew

2014-05-01

Abstract Cyclical thrombocytosis, acquired von Willebrand syndrome, aggressive non-melanoma skin cancers and other hydroxyurea complications have been reported in Philadelphia-negative myeloproliferative neoplasms (MPNs), but their incidence and clinical consequences have not been defined in a large cohort of patients. We conducted a retrospective analysis of 188 consecutive patients with MPNs specifically addressing the incidence of these complications. Cyclical thrombocytosis was documented in 29 patients (15%), the majority of whom were receiving hydroxyurea. Acquired von Willebrand syndrome was identified in 17 of the 84 screened patients (20%), but was not associated with any major bleeding complications. Non-melanoma skin cancers were reported in 51 patients (27%). Hydroxyurea-related fever occurred in nine of 149 patients (6%) who received hydroxyurea. Seventy-three patients (39%) experienced a total of 98 major thrombotic events, with the majority of these occurring prior to or within 3 months of the diagnosis. Cyclical thrombocytosis, acquired von Willebrand syndrome, aggressive non-melanoma skin cancers and other hydroxyurea-related complications are not infrequent in MPNs and have important clinical consequences for management.

Massive Accidental Overdose of Hydroxyurea in a Young Child with Sickle Cell Anemia

PubMed Central

Miller, Scott T.; Rey, Kathy; He, Jin; Flanagan, Jonathan; Fish, Billie J.; Rogers, Zora R.; Wang, Winfred C.; Ware, Russell E.

2011-01-01

The Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) confirmed safety and efficacy of hydroxyurea therapy for infants with sickle cell anemia. Treatment was associated with reduction in rates of pain, acute chest syndrome, hospitalizations and blood transfusions; improved hematologic values; and, perhaps, preservation of organ function. During the study, a two year-old ingested at one time an entire 35-day supply of hydroxyurea (612 mg/kg body-weight). Despite a serum level of 7,756 μM four hours post-ingestion, the only toxicity was transient mild myelosuppression. With wider usage of hydroxyurea anticipated, conservative management of future overdoses seems reasonable. (ClinicalTrials.gov NCT00006400) PMID:21744485

Inpatient management of sickle cell pain: a 'snapshot' of current practice.

PubMed

Miller, Scott T; Kim, Hae-Young; Weiner, Debra; Wager, Carrie G; Gallagher, Dianne; Styles, Lori; Dampier, Carlton D

2012-03-01

The Sickle Cell Disease Clinical Research Network (SCDCRN) designed the PROACTIVE Feasibility Study (ClinicalTrials.gov NCT00951808) to determine whether elevated serum levels of secretory phospholipase A2 (sPLA2) during hospitalization for pain would permit preemptive therapy of sickle cell acute chest syndrome (ACS) by blood transfusion. While PROACTIVE was not designed to assess pain management and was terminated early due to inadequate patient accrual, collection of clinical data allowed a "snapshot" of current care by expert providers. Nearly half the patients admitted for pain were taking hydroxyurea; hydroxyurea did not affect length of stay. Providers commonly administered parenteral opioid analgesia, usually morphine or hydromorphone, to adults and children, generally by patient-controlled analgesia (PCA). Adult providers were more likely to prescribe hydromorphone and did so at substantially higher morphine equivalent doses than were given to adults receiving morphine; the latter received doses similar to children who received either medication. All subjects treated with PCA received higher daily doses of opioids than those treated by time-contingent dosing. Physicians often restricted intravenous fluids to less than a maintenance rate and underutilized incentive spirometry, which reduces ACS in patients hospitalized for pain.

Inpatient Management of Sickle Cell Pain: a Snapshot of Current Practice

PubMed Central

Miller, Scott T.; Kim, Hae-Young; Weiner, Debra; Wager, Carrie G.; Gallagher, Dianne; Styles, Lori; Dampier, Carlton D.

2012-01-01

The Sickle Cell Disease Clinical Research Network (SCDCRN) designed the PROACTIVE Feasibility Study (ClinicalTrials.gov NCT00951808) to determine whether elevated serum levels of secretory phospholipase A2 (sPLA2) during hospitalization for pain would permit preemptive therapy of sickle cell acute chest syndrome (ACS) by blood transfusion. [1, 2] While PROACTIVE was not designed to assess pain management and terminated early due to inadequate patient accrual, collection of clinical data allowed a “snapshot” of current care by expert providers. Nearly half the patients admitted for pain were taking hydroxyurea; hydroxyurea did not affect length of stay. Providers commonly administered parenteral opioid analgesia, usually morphine or hydromorphone, to adults and children, generally by patient-controlled analgesia (PCA). Adult providers were more likely to prescribe hydromorphone and did so at substantially higher morphine equivalent doses than were given to adults receiving morphine; the latter received doses similar to children who received either medication. All subjects treated with PCA received higher daily doses of opioids than those treated by time-contingent dosing. Physicians often restricted intravenous fluids to less than a maintenance rate and underutilized incentive spirometry, which reduces ACS in patients hospitalized for pain. [3] PMID:22231150

Twenty-Nail Transverse Melanonychia Induced by Hydroxyurea: Case Report and Review of the Literature.

PubMed

Osemwota, Osamuede; Uhlemann, John; Rubin, Adam

2017-08-01

Twenty-nail transverse melanonychia from hydroxyurea is a rare phenomenon, only reported four times previously. Here we describe a 51-year-old female who presented with 20-nail transverse melanonychia 3 months after initiating hydroxyurea therapy. Transverse melanonychia is a benign process but can cause patients significant distress, and thus is an entity with which dermatologists should recognize. We then review the cutaneous manifestations, differential diagnosis, and clinical considerations when evaluating patients with transverse melanonychia from hydroxyurea or other causes.

J Drugs Dermatol. 2017;16(8):814-815.

Hydroxyurea Therapy for Children With Sickle Cell Anemia in Sub‐Saharan Africa: Rationale and Design of the REACH Trial

PubMed Central

Tshilolo, Léon; Santos, Brigida; Tomlinson, George A.; Stuber, Susan; Latham, Teresa; Aygun, Banu; Obaro, Stephen K.; Olupot‐Olupot, Peter; Williams, Thomas N.; Odame, Isaac; Ware, Russell E.

2015-01-01

Background Sickle cell anemia (SCA) is an inherited hematological disorder that causes a large but neglected global health burden, particularly in Africa. Hydroxyurea represents the only available disease‐modifying therapy for SCA, and has proven safety and efficacy in high‐resource countries. In sub‐Saharan Africa, there is minimal use of hydroxyurea, due to lack of data, absence of evidence‐based guidelines, and inexperience among healthcare providers. Procedure A partnership was established between investigators in North America and sub‐Saharan Africa, to develop a prospective multicenter research protocol designed to provide data on the safety, feasibility, and benefits of hydroxyurea for children with SCA. Results The Realizing Effectiveness Across Continents with Hydroxyurea (REACH, ClinicalTrials.gov NCT01966731) trial is a prospective, phase I/II open‐label dose escalation study of hydroxyurea that will treat a total of 600 children age 1–10 years with SCA: 150 at each of four different clinical sites within sub‐Saharan Africa (Angola, Democratic Republic of Congo, Kenya, and Uganda). The primary study endpoint will be severe hematological toxicities that occur during the fixed‐dose treatment phase. REACH has an adaptive statistical design that allows for careful assessment of toxicities to accurately identify a safe hydroxyurea dose. Conclusions REACH will provide data that address critical gaps in knowledge for the treatment of SCA in sub‐Saharan Africa. By developing local expertise with the use of hydroxyurea and helping to establish treatment guidelines, the REACH trial results will have the potential to transform care for children with SCA in Africa. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc. PMID:26275071

Hydroxyurea Therapy for Children With Sickle Cell Anemia in Sub-Saharan Africa: Rationale and Design of the REACH Trial.

PubMed

McGann, Patrick T; Tshilolo, Léon; Santos, Brigida; Tomlinson, George A; Stuber, Susan; Latham, Teresa; Aygun, Banu; Obaro, Stephen K; Olupot-Olupot, Peter; Williams, Thomas N; Odame, Isaac; Ware, Russell E

2016-01-01

Sickle cell anemia (SCA) is an inherited hematological disorder that causes a large but neglected global health burden, particularly in Africa. Hydroxyurea represents the only available disease-modifying therapy for SCA, and has proven safety and efficacy in high-resource countries. In sub-Saharan Africa, there is minimal use of hydroxyurea, due to lack of data, absence of evidence-based guidelines, and inexperience among healthcare providers. A partnership was established between investigators in North America and sub-Saharan Africa, to develop a prospective multicenter research protocol designed to provide data on the safety, feasibility, and benefits of hydroxyurea for children with SCA. The Realizing Effectiveness Across Continents with Hydroxyurea (REACH, ClinicalTrials.gov NCT01966731) trial is a prospective, phase I/II open-label dose escalation study of hydroxyurea that will treat a total of 600 children age 1-10 years with SCA: 150 at each of four different clinical sites within sub-Saharan Africa (Angola, Democratic Republic of Congo, Kenya, and Uganda). The primary study endpoint will be severe hematological toxicities that occur during the fixed-dose treatment phase. REACH has an adaptive statistical design that allows for careful assessment of toxicities to accurately identify a safe hydroxyurea dose. REACH will provide data that address critical gaps in knowledge for the treatment of SCA in sub-Saharan Africa. By developing local expertise with the use of hydroxyurea and helping to establish treatment guidelines, the REACH trial results will have the potential to transform care for children with SCA in Africa. © 2015 The Authors. Pediatric Blood & Cancer Published by Wiley Periodicals, Inc.

Assessment of rotation thromboelastometry parameters in patients with essential thrombocythemia at diagnosis and after hydroxyurea therapy.

PubMed

Treliński, Jacek; Okońska, Marta; Robak, Marta; Chojnowski, Krzysztof

2016-03-01

Patients with essential thrombocythemia suffer from thrombotic complications that are the main source of mortality. Due to its complex pathogenesis, no existing single laboratory method is able to identify the patients at highest risk for developing thrombosis. Twenty patients with essential thrombocythemia at diagnosis, 15 healthy volunteers and 20 patients treated with hydroxyurea were compared with regard to certain rotation thromboelastometry parameters. Clotting time (CT), clot formation time (CFT), α-angle, and maximum clot firmness (MCF) were assessed by using the INTEM, EXTEM, FIBTEM, and NATEM tests. Patients with essential thrombocythemia at diagnosis demonstrated significantly higher mean platelet count and markedly lower mean red blood count than controls. CT and CFT readings were found to be markedly lower in essential thrombocythemia patients at diagnosis than in the control group according to the EXTEM test. Patients at diagnosis had markedly lower CT values (EXTEM, FIBTEM) than patients on hydroxyurea therapy. Alpha angle values were markedly higher in essential thrombocythemia patients at diagnosis than in controls, according to the EXTEM, FIBTEM and NATEM tests. MCF readings were significantly higher in essential thrombocythemia patients at diagnosis than in controls according to EXTEM, INTEM, FIBTEM, and NATEM tests. Patients on hydroxyurea therapy had markedly lower MCF values according to EXTEM test than patients at diagnosis. Patients with essential thrombocythemia demonstrate a prothrombotic state at the time of diagnosis, which is reflected in changes by certain rotation thromboelastometry parameters. The hydroxyurea therapy induces downregulation of the prothrombotic features seen in essential thrombocythemia patients at diagnosis.

Pre-treatment with oral hydroxyurea prior to intensive chemotherapy improves early survival of patients with high hyperleukocytosis in acute myeloid leukemia.

PubMed

Mamez, Anne-Claire; Raffoux, Emmanuel; Chevret, Sylvie; Lemiale, Virginie; Boissel, Nicolas; Canet, Emmanuel; Schlemmer, Benoît; Dombret, Hervé; Azoulay, Elie; Lengliné, Etienne

2016-10-01

Acute myeloid leukemia with high white blood cell count (WBC) is a medical emergency. A reduction of tumor burden with hydroxyurea may prevent life-threatening complications induced by straight chemotherapy. To evaluate this strategy, we reviewed medical charts of adult patients admitted to our institution from 1997 to 2011 with non-promyelocytic AML and WBC over 50 G/L. One hundred and sixty patients were included with a median WBC of 120 G/L (range 50-450), 107 patients received hydroxyurea prior to chemotherapy, and 53 received emergency induction chemotherapy (CT). Hospital mortality was lower for patients treated with hydroxyurea (34% versus 19%, p = 0.047) even after adjusting for age (p < 0.01) and initial WBC count (p = 0.02). No evidence of any difference between treatment groups in terms of WBC decline kinetics and disease free survival (p = 0.87) was found. Oral hydroxyurea prior to chemotherapy seems a safe and efficient strategy to reduce early death of hyperleukocytic AML patients.

Changes in quality of life and disease-related symptoms in patients with polycythemia vera receiving ruxolitinib or standard therapy.

PubMed

Mesa, Ruben; Verstovsek, Srdan; Kiladjian, Jean-Jacques; Griesshammer, Martin; Masszi, Tamas; Durrant, Simon; Passamonti, Francesco; Harrison, Claire N; Pane, Fabrizio; Zachee, Pierre; Zhen, Huiling; Jones, Mark M; Parasuraman, Shreekant; Li, Jingjin; Côté, Isabelle; Habr, Dany; Vannucchi, Alessandro M

2016-08-01

Polycythemia vera (PV)-related symptoms may not be adequately controlled with conventional therapy. This current analysis of the RESPONSE trial evaluated the effects of ruxolitinib compared with standard therapy on quality of life (QoL) and symptoms in patients with PV who were hydroxyurea resistant/intolerant. In the previously reported primary analysis, ruxolitinib achieved the primary composite endpoint of hematocrit control and ≥35% reduction in spleen volume at Week 32. The current analysis evaluated patient-reported outcomes using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF), the Pruritus Symptom Impact Scale (PSIS), and the Patient Global Impression of Change (PGIC). Compared with standard therapy, ruxolitinib was associated with greater improvements in global health status/QoL, functional subscales, and individual symptom scores of the EORTC QLQ-C30. At Week 32, more patients in the ruxolitinib arm (44%) achieved a ≥10-point improvement in global health status/QoL vs. standard therapy (9%). Improvements in MPN-SAF symptom scores were consistent with improvements in EORTC QLQ-C30, PSIS, and PGIC scores. Ruxolitinib provides clinically relevant improvements in QoL and ameliorates symptom burden in patients with PV who are hydroxyurea resistant/intolerant. © 2016 The Authors. European Journal of Haematology Published by John Wiley & Sons Ltd.

Hydroxyurea Effectiveness in Children and Adolescents with Sickle Cell Anemia: A Large Retrospective, Population-Based Cohort

PubMed Central

Quarmyne, Maa-Ohui; Dong, Wei; Theodore, Rodney; Anand, Sonia; Barry, Vaughn; Adisa, Olufolake; Buchanan, Iris D.; Bost, James; Brown, Robert C.; Joiner, Clinton H.; Lane, Peter A.

2016-01-01

The clinical efficacy of hydroxyurea in patients with sickle cell anemia (SCA) has been well established. However, data about its clinical effectiveness in practice is limited. We evaluated the clinical effectiveness of hydroxyurea in a large pediatric population using a retrospective cohort, pre-post treatment study design to control for disease severity selection bias. The cohort included children with SCA (SS, S β 0thalassemia) who received care at Children's Healthcare of Atlanta (CHOA) and who initiated hydroxyurea in 2009-2011. Children on chronic transfusions, or children with inadequate follow up data and/or children who had taken hydroxyurea in the 3 years prior were excluded. For each patient, healthcare utilization, laboratory values and clinical outcomes for the 2-year period prior to hydroxyurea initiation were compared to those 2 years after initiation. Of 211 children with SCA who initiated hydroxyurea in 2009-2011, 134 met eligibility criteria. After initiation of hydroxyurea, rates of hospitalizations, pain encounters, and emergency department visits were reduced by 47% (<0.0001), 36% (p=0.0001) and 43% (p<0.0001), respectively. Average hemoglobin levels increased by 0.7g/dl (p<0.0001). Hydroxyurea effectiveness was similar across gender, insurance types and age, although there was a slightly greater reduction in hospitalizations in younger children. PMID:27761932

Epigenetic and molecular profiles of erythroid cells after hydroxyurea treatment in sickle cell anemia

PubMed Central

Steward, Shirley; Howard, Thad A.; Mortier, Nicole; Smeltzer, Matthew; Wang, Yong-Dong; Ware, Russell E.

2011-01-01

Hydroxyurea has been shown to be efficacious for the treatment of sickle cell anemia (SCA), primarily through the induction of fetal hemoglobin (HbF). However, the exact mechanisms by which hydroxyurea can induce HbF remain incompletely defined, although direct transcriptional effects and altered cell cycle kinetics have been proposed. In this study, we investigated potential epigenetic and alternative molecular mechanisms of hydroxyurea-mediated HbF induction by examining methylation patterns within the Gγ-globin promoter and miRNA expression within primary CD71+ erythrocytes of patients with SCA, both at baseline before beginning hydroxyurea therapy and after reaching maximum tolerated dose (MTD). Using both cross-sectional analysis and paired-sample analysis, we found that the highly methylated Gγ-globin promoter was inversely correlated to baseline HbF levels, but only slightly altered by hydroxyurea treatment. Conversely, expression of several specific miRNAs was significantly increased after hydroxyurea treatment, and expression of miR-26b and miR-151-3p were both associated with HbF levels at MTD. The significant associations identified in these studies suggest that methylation may be important for regulation of baseline HbF, but not after hydroxyurea treatment, whereas changes in miRNA expression may be associated with hydroxyurea-mediated HbF induction. This study was registered at ClinicalTrials.gov (NCT00305175). PMID:21921042

Anagrelide compared with hydroxyurea in essential thrombocythemia: a meta-analysis.

PubMed

Samuelson, Bethany; Chai-Adisaksopha, Chatree; Garcia, David

2015-11-01

Cytoreductive therapy, with or without low-dose aspirin, is the mainstay of thrombotic risk reduction in patients with essential thrombocythemia (ET), but the optimal choice of agent remains unclear. The aim of this study was to meta-analyze currently available data comparing anagrelide to hydroxyurea for reduction of rates of thrombosis, bleeding and death among patients with ET. A literature search for randomized, controlled trials comparing anagrelide to hydroxyurea among patients with ET revealed two published studies. Statistical analysis was performed using fixed effects meta-analysis. Rates of thrombosis were similar between patients treated with hydroxyurea vs anagrelide (RR 0.86, 95 % CI 0.64-1.16). Rates of major bleeding were lower in patients treated with hydroxyurea (RR 0.37, 95 % CI 0.18-0.75). Rates of progression to acute myeloid leukemia were not statistically different (RR 1.50, 95 % CI 0.43-5.29). The composite of thrombosis, major bleeding and death favored hydroxyurea (RR 0.78, 95 % CI 0.63-0.97). In conclusion, our analysis supports use of hydroxyurea as a first-line cytoreductive agent for patients with ET, based largely on decreased rates of major bleeding. Anagrelide appears to be equally effective for protection against thrombotic events and may be an appropriate alternative for patients who are intolerant of hydroxyurea.

Candidate Sequence Variants and Fetal Hemoglobin in Children with Sickle Cell Disease Treated with Hydroxyurea

PubMed Central

Green, Nancy S.; Ender, Katherine L.; Pashankar, Farzana; Driscoll, Catherine; Giardina, Patricia J.; Mullen, Craig A.; Clark, Lorraine N.; Manwani, Deepa; Crotty, Jennifer; Kisselev, Sergey; Neville, Kathleen A.; Hoppe, Carolyn; Barral, Sandra

2013-01-01

Background Fetal hemoglobin level is a heritable complex trait that strongly correlates swith the clinical severity of sickle cell disease. Only few genetic loci have been identified as robustly associated with fetal hemoglobin in patients with sickle cell disease, primarily adults. The sole approved pharmacologic therapy for this disease is hydroxyurea, with effects largely attributable to induction of fetal hemoglobin. Methodology/Principal Findings In a multi-site observational analysis of children with sickle cell disease, candidate single nucleotide polymorphisms associated with baseline fetal hemoglobin levels in adult sickle cell disease were examined in children at baseline and induced by hydroxyurea therapy. For baseline levels, single marker analysis demonstrated significant association with BCL11A and the beta and epsilon globin loci (HBB and HBE, respectively), with an additive attributable variance from these loci of 23%. Among a subset of children on hydroxyurea, baseline fetal hemoglobin levels explained 33% of the variance in induced levels. The variant in HBE accounted for an additional 13% of the variance in induced levels, while variants in the HBB and BCL11A loci did not contribute beyond baseline levels. Conclusions/Significance These findings clarify the overlap between baseline and hydroxyurea-induced fetal hemoglobin levels in pediatric disease. Studies assessing influences of specific sequence variants in these and other genetic loci in larger populations and in unusual hydroxyurea responders are needed to further understand the maintenance and therapeutic induction of fetal hemoglobin in pediatric sickle cell disease. PMID:23409025

Development of a pharmacokinetic-guided dose individualization strategy for hydroxyurea treatment in children with sickle cell anaemia.

PubMed

Dong, Min; McGann, Patrick T; Mizuno, Tomoyuki; Ware, Russell E; Vinks, Alexander A

2016-04-01

Hydroxyurea has emerged as the primary disease-modifying therapy for patients with sickle cell anaemia (SCA). The laboratory and clinical benefits of hydroxyurea are optimal at maximum tolerated dose (MTD), but the current empirical dose escalation process often takes up to 12 months. The purpose of this study was to develop a pharmacokinetic-guided dosing strategy to reduce the time required to reach hydroxyurea MTD in children with SCA. Pharmacokinetic (PK) data from the HUSTLE trial (NCT00305175) were used to develop a population PK model using non-linear mixed effects modelling (nonmem 7.2). A D-optimal sampling strategy was developed to estimate individual PK and hydroxyurea exposure (area under the concentration-time curve (AUC)). The initial AUC target was derived from HUSTLE clinical data and defined as the mean AUC at MTD. PK profiles were best described by a one compartment with Michaelis-Menten elimination and a transit absorption model. Body weight and cystatin C were identified as significant predictors of hydroxyurea clearance. The following clinically feasible sampling times are included in a new prospective protocol: pre-dose (baseline), 15-20 min, 50-60 min and 3 h after an initial 20 mg kg(-1) oral dose. The mean target AUC(0,∞) for initial dose titration was 115 mg l(-1)  h. We developed a PK model-based individualized dosing strategy for the prospective Therapeutic Response Evaluation and Adherence Trial (TREAT, ClinicalTrials.gov NCT02286154). This approach has the potential to optimize the dose titration of hydroxyurea therapy for children with SCA, such that the clinical benefits at MTD are achieved more quickly. © 2015 The British Pharmacological Society.

Development of a pharmacokinetic‐guided dose individualization strategy for hydroxyurea treatment in children with sickle cell anaemia

PubMed Central

Dong, Min; McGann, Patrick T.; Mizuno, Tomoyuki; Ware, Russell E.

2016-01-01

AIMS Hydroxyurea has emerged as the primary disease‐modifying therapy for patients with sickle cell anaemia (SCA). The laboratory and clinical benefits of hydroxyurea are optimal at maximum tolerated dose (MTD), but the current empirical dose escalation process often takes up to 12 months. The purpose of this study was to develop a pharmacokinetic‐guided dosing strategy to reduce the time required to reach hydroxyurea MTD in children with SCA. Methods Pharmacokinetic (PK) data from the HUSTLE trial (NCT00305175) were used to develop a population PK model using non‐linear mixed effects modelling (nonmem 7.2). A D‐optimal sampling strategy was developed to estimate individual PK and hydroxyurea exposure (area under the concentration–time curve (AUC)). The initial AUC target was derived from HUSTLE clinical data and defined as the mean AUC at MTD. Results PK profiles were best described by a one compartment with Michaelis–Menten elimination and a transit absorption model. Body weight and cystatin C were identified as significant predictors of hydroxyurea clearance. The following clinically feasible sampling times are included in a new prospective protocol: pre‐dose (baseline), 15–20 min, 50–60 min and 3 h after an initial 20 mg kg–1 oral dose. The mean target AUC(0,∞) for initial dose titration was 115 mg l–1 h. Conclusion We developed a PK model‐based individualized dosing strategy for the prospective Therapeutic Response Evaluation and Adherence Trial (TREAT, ClinicalTrials.gov NCT02286154). This approach has the potential to optimize the dose titration of hydroxyurea therapy for children with SCA, such that the clinical benefits at MTD are achieved more quickly. PMID:26615061

Hydroxyurea therapy requires HbF induction for clinical benefit in a sickle cell mouse model

PubMed Central

Lebensburger, Jeffrey D.; Pestina, Tamara I.; Ware, Russell E.; Boyd, Kelli L.; Persons, Derek A.

2010-01-01

Hydroxyurea has proven clinical efficacy in patients with sickle cell disease. Potential mechanisms for the beneficial effects include fetal hemoglobin induction and the reduction of cell adhesive properties, inflammation and hypercoagulability. Using a murine model of sickle cell disease in which fetal hemoglobin induction does not occur, we evaluated whether hydroxyurea administration would still yield improvements in hematologic parameters and reduce end-organ damage. Animals given a maximally tolerated dose of hydroxyurea that resulted in significant reductions in the neutrophil and platelet counts showed no improvement in hemolytic anemia and end-organ damage compared to control mice. In contrast, animals having high levels of fetal hemoglobin due to gene transfer with a γ-globin lentiviral vector showed correction of anemia and organ damage. These data suggest that induction of fetal hemoglobin by hydroxyurea is an essential mechanism for its clinical benefits. PMID:20378564

Hydroxyurea effectiveness in children and adolescents with sickle cell anemia: A large retrospective, population-based cohort.

PubMed

Quarmyne, Maa-Ohui; Dong, Wei; Theodore, Rodney; Anand, Sonia; Barry, Vaughn; Adisa, Olufolake; Buchanan, Iris D; Bost, James; Brown, Robert C; Joiner, Clinton H; Lane, Peter A

2017-01-01

The clinical efficacy of hydroxyurea in patients with sickle cell anemia (SCA) has been well established. However, data about its clinical effectiveness in practice is limited. We evaluated the clinical effectiveness of hydroxyurea in a large pediatric population using a retrospective cohort, pre-post treatment study design to control for disease severity selection bias. The cohort included children with SCA (SS, Sβ 0 thalassemia) who received care at Children's Healthcare of Atlanta (CHOA) and who initiated hydroxyurea in 2009-2011. Children on chronic transfusions, or children with inadequate follow up data and/or children who had taken hydroxyurea in the 3 years prior were excluded. For each patient healthcare utilization, laboratory values, and clinical outcomes for the 2-year period prior to hydroxyurea initiation were compared to those 2 years after initiation. Of 211 children with SCA who initiated hydroxyurea in 2009-2011, 134 met eligibility criteria. After initiation of hydroxyurea, rates of hospitalizations, pain encounters, and emergency department visits were reduced by 47% (<0.0001), 36% (P = 0.0001) and 43% (P < 0.0001), respectively. Average hemoglobin levels increased by 0.7 g/dl (P < 0.0001). Hydroxyurea effectiveness was similar across gender, insurance types and age, although there was a slightly greater reduction in hospitalizations in younger children. Am. J. Hematol. 92:77-81, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Low and fixed dose of hydroxyurea is effective and safe in patients with HbSβ(+) thalassemia with IVS1-5(G→C) mutation.

PubMed

Dehury, Snehadhini; Purohit, Prasanta; Patel, Siris; Meher, Satyabrata; Kullu, Bipin Kishore; Sahoo, Lulup Kumar; Patel, Nayan Kumar; Mohapatra, Alok Kumar; Das, Kishalaya; Patel, Dilip Kumar

2015-06-01

Despite compelling evidence that hydroxyurea is safe and effective in sickle cell disease, it is prescribed sparingly due to several barriers like knowledge gaps in certain genotypes, apprehension about its safety and toxicity, and limited resources. We undertook this study to find out the efficacy and safety of HU in patients with HbSβ(+) -thalassemia with IVS1-5(G→C) mutation. We registered 318 patients with HbSβ(+) -thalassemia with IVS1-5(G→C) mutation. Of these, 203 were enrolled for hydroxyurea treatment at a low and fixed dose of 10 mg/kg/day. One hundred four patients (Group-I: 37 children and Group-II: 67 adults) with ≥2 years of hydroxyurea treatment were studied. The rate of vaso-occlusive crises, requirement of blood transfusion and rate of hospitalization reduced from 3 to 0.5, 1 to 0 and 1 to 0 in Group-I and 3 to 0, 1 to 0 and 0.5 to 0 in Group-II respectively after HU therapy (P < 0.0001). %HbF level, hemoglobin, MCV and MCH increased significantly, whereas HbS, WBC, platelet count, serum-bilirubin and LDH levels decreased significantly after HU therapy. It has been observed that along with fairly subtle hematological changes following HU therapy, there was a substantial clinical improvement occurred in these patients. Transient myelotoxicity was observed in 4.8%. There was minimal gonadal toxicity without affecting reproductive function. In view of easy affordability, better acceptability, minimal toxicity, the need of infrequent monitoring and its potential effectiveness, low and fixed dose of hydroxyurea is suitable for treatment of patients with HbSβ(+) -thalassemia in resource poor setting. © 2014 Wiley Periodicals, Inc.

Analysis of oxidative status and biochemical parameters in adult patients with sickle cell anemia treated with hydroxyurea, Ceará, Brazil

PubMed Central

Teixeira Neto, Paulo Florentino; Gonçalves, Romélia Pinheiro; Elias, Darcielle Bruna Dias; de Araújo, Cleiton Pinheiro; Magalhães, Hemerson Iury Ferreira

2011-01-01

Background Sickle cell anemia is a hemoglobinopathy caused by a mutation that results in the production of an abnormal hemoglobin molecule, hemoglobin S (Hb S). This is responsible for profound physiological changes, such as the sickling of red blood cells. Several studies have shown that hydroxyurea protects against vaso-occlusive crises. Objective The aim of this study was to evaluate the oxidative stress associated with biochemical parameters in patients with sickle cell anemia treated with hydroxyurea. Methods The study was conducted with 20 male and 25 female patients at the Hospital Universitário Walter Cantídio. The patients were divided into two groups: a study group (n = 12), patients with sickle cell anemia who were receiving hydroxyurea and a control group (n = 33) of sickle cell anemia patients not submitted to hydroxyurea treatment. The biochemical parameters analyzed were ferritin, transferrin, and serum iron. Glutathione was measured in its reduced form to analyze the oxidative state. Results The results showed insignificant increases in the levels of serum iron, transferrin and ferritin in patients treated with hydroxyurea when compared with those who did not take the medication. However, the glutathione levels were significantly higher in patients taking hydroxyurea than in controls. Conclusions These results indicate that hydroxyurea possibly acts as an antioxidant by increasing glutathione levels. PMID:23049297

Hydroxyurea is associated with lower prevalence of albuminuria in adults with sickle cell disease

PubMed Central

Laurin, Louis-Philippe; Nachman, Patrick H.; Desai, Payal C.; Ataga, Kenneth I.; Derebail, Vimal K.

2014-01-01

Background Albuminuria is an early manifestation of sickle cell nephropathy. Prior small case series suggests benefit of hydroxyurea in reducing albuminuria, with a similar trend noted in pediatric studies. We aimed to comprehensively evaluate hydroxyurea use and prevalence of albuminuria in adult sickle cell patients. Methods We performed a cross-sectional study of 149 adult patients followed between 2000 and 2011 in a comprehensive sickle cell clinic. All patients were assessed for albuminuria either by direct measurement or by urinary chemical strip (dipstick) testing. Urinary albumin-to-creatinine ratios (UACRs) were available for 112 patients. Hydroxyurea exposure was defined as ≥3 months of therapy before the assessment of albuminuria. Albuminuria was defined as either UACR ≥30 mg/g or ≥1+ proteinuria on two separate dipsticks. We constructed a multivariate logistic regression model to assess the association between hydroxyurea and albuminuria. Results The prevalence of albuminuria was lower among patients on hydroxyurea (34.7 versus 55.4%; P = 0.01) as was median albumin excretion (17.9 versus 40.5 mg/g; P = 0.04). In multivariate analysis, hydroxyurea was associated with a lower likelihood of albuminuria (odds ratio 0.28, 95% CI: 0.11–0.75, P = 0.01), adjusting for age, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use, tricuspid regurgitant jet velocity, hypertension and acute chest syndrome. Conclusions In our population of sickle cell patients, those using hydroxyurea were less than one-third as likely to exhibit albuminuria. Hydroxyurea use may prevent development of overt nephropathy or the progression of sickle cell disease nephropathy to end-stage renal disease, and its use for this indication merits further investigation. PMID:24084325

Hydroxyurea is associated with lower prevalence of albuminuria in adults with sickle cell disease.

PubMed

Laurin, Louis-Philippe; Nachman, Patrick H; Desai, Payal C; Ataga, Kenneth I; Derebail, Vimal K

2014-06-01

Albuminuria is an early manifestation of sickle cell nephropathy. Prior small case series suggests benefit of hydroxyurea in reducing albuminuria, with a similar trend noted in pediatric studies. We aimed to comprehensively evaluate hydroxyurea use and prevalence of albuminuria in adult sickle cell patients. We performed a cross-sectional study of 149 adult patients followed between 2000 and 2011 in a comprehensive sickle cell clinic. All patients were assessed for albuminuria either by direct measurement or by urinary chemical strip (dipstick) testing. Urinary albumin-to-creatinine ratios (UACRs) were available for 112 patients. Hydroxyurea exposure was defined as ≥3 months of therapy before the assessment of albuminuria. Albuminuria was defined as either UACR ≥30 mg/g or ≥1+ proteinuria on two separate dipsticks. We constructed a multivariate logistic regression model to assess the association between hydroxyurea and albuminuria. The prevalence of albuminuria was lower among patients on hydroxyurea (34.7 versus 55.4%; P = 0.01) as was median albumin excretion (17.9 versus 40.5 mg/g; P = 0.04). In multivariate analysis, hydroxyurea was associated with a lower likelihood of albuminuria (odds ratio 0.28, 95% CI: 0.11-0.75, P = 0.01), adjusting for age, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use, tricuspid regurgitant jet velocity, hypertension and acute chest syndrome. In our population of sickle cell patients, those using hydroxyurea were less than one-third as likely to exhibit albuminuria. Hydroxyurea use may prevent development of overt nephropathy or the progression of sickle cell disease nephropathy to end-stage renal disease, and its use for this indication merits further investigation. © The Author 2013. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Survival and mortality among users and non-users of hydroxyurea with sickle cell disease

PubMed Central

de Araujo, Olinda Maria Rodrigues; Ivo, Maria Lúcia; Ferreira, Marcos Antonio; Pontes, Elenir Rose Jardim Cury; Bispo, Ieda Maria Gonçalves Pacce; de Oliveira, Eveny Cristine Luna

2015-01-01

OBJECTIVE: to estimate survival, mortality and cause of death among users or not of hydroxyurea with sickle cell disease. METHOD: cohort study with retrospective data collection, from 1980 to 2010 of patients receiving inpatient treatment in two Brazilian public hospitals. The survival probability was determined using the Kaplan-Meier estimator, survival calculations (SPSS version 10.0), comparison between survival curves, using the log rank method. The level of significance was p=0.05. RESULTS: of 63 patients, 87% had sickle cell anemia, with 39 using hydroxyurea, with a mean time of use of the drug of 20.0±10.0 years and a mean dose of 17.37±5.4 to 20.94±7.2 mg/kg/day, raising the fetal hemoglobin. In the comparison between those using hydroxyurea and those not, the survival curve was greater among the users (p=0.014). A total of 10 deaths occurred, with a mean age of 28.1 years old, and with Acute Respiratory Failure as the main cause. CONCLUSION: the survival curve is greater among the users of hydroxyurea. The results indicate the importance of the nurse incorporating therapeutic advances of hydroxyurea in her care actions. PMID:25806633

Survival and mortality among users and non-users of hydroxyurea with sickle cell disease.

PubMed

de Araujo, Olinda Maria Rodrigues; Ivo, Maria Lúcia; Ferreira Júnior, Marcos Antonio; Pontes, Elenir Rose Jardim Cury; Bispo, Ieda Maria Gonçalves Pacce; de Oliveira, Eveny Cristine Luna

2015-01-01

to estimate survival, mortality and cause of death among users or not of hydroxyurea with sickle cell disease. cohort study with retrospective data collection, from 1980 to 2010 of patients receiving inpatient treatment in two Brazilian public hospitals. The survival probability was determined using the Kaplan-Meier estimator, survival calculations (SPSS version 10.0), comparison between survival curves, using the log rank method. The level of significance was p=0.05. of 63 patients, 87% had sickle cell anemia, with 39 using hydroxyurea, with a mean time of use of the drug of 20.0±10.0 years and a mean dose of 17.37±5.4 to 20.94±7.2 mg/kg/day, raising the fetal hemoglobin. In the comparison between those using hydroxyurea and those not, the survival curve was greater among the users (p=0.014). A total of 10 deaths occurred, with a mean age of 28.1 years old, and with Acute Respiratory Failure as the main cause. the survival curve is greater among the users of hydroxyurea. The results indicate the importance of the nurse incorporating therapeutic advances of hydroxyurea in her care actions.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liebelt, E.L.; Balk, S.J.; Faber, W.

The National Toxicology Program (NTP) and the National Institute of Environmental Health Sciences (NIEHS) established the NTP Center for the Evaluation of Risks to Human Reproduction (CERHR) in June 1998. The purpose of CERHR is to provide timely, unbiased, scientifically sound evaluations of human and experimental evidence for adverse effects on reproduction and development caused by agents to which humans may be exposed. Hydroxyurea was selected for evaluation by a CERHR expert panel because of (1) its increasing use in the treatment of sickle cell disease in children and adults, (2) knowledge that it inhibits DNA synthesis and is cytotoxic,more » and (3) published evidence of its reproductive and developmental toxicity in rodents. Hydroxyurea is FDA-approved for reducing the frequency of painful crises and the need for blood transfusions in adults with sickle cell anemia who experience recurrent moderate-to-severe crises. Hydroxyurea is used in the treatment of cancer, sickle cell disease, and thalassemia. It is the only treatment for sickle cell disease aside from blood transfusion used in children. Hydroxyurea may be used in the treatment of children and adults with sickle cell disease for an extended period of time or for repeated cycles of therapy. Treatment with hydroxyurea may be associated with cytotoxic and myelosuppressive effects, and hydroxyurea is mutagenic.« less

Phase II study of Gleevec® plus hydroxyurea in adults with progressive or recurrent low-grade glioma1

PubMed Central

Reardon, David A.; Desjardins, Annick; Vredenburgh, James J.; Herndon, James E.; Coan, April; Gururangan, Sridharan; Peters, Katherine B.; McLendon, Roger; Sathornsumetee, Sith; Rich, Jeremy N.; Lipp, Eric S.; Janney, Dorothea; Friedman, Henry S.

2013-01-01

Background We evaluated the efficacy of imatinib plus hydroxyurea in patients with progressive/recurrent low-grade glioma. Methods A total of 64 patients with recurrent/progressive low-grade glioma were enrolled in this single-center study that stratified patients into astrocytoma and oligodendroglioma cohorts. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 400 mg per day for patients not on EIAEDs and at 500 mg twice a day if on EIAEDs. The primary endpoint was progression-free survival at 12 months (PFS-12) and secondary endpoints were safety, median progression-free survival and radiographic response rate. Results Thirty-two patients were enrolled into each cohort. Eleven patients (17%) had prior radiotherapy and 24 (38%) had received prior chemotherapy. The median PFS and PFS-12 were 11 months and 39%, respectively. Outcome did not differ between the histologic cohorts. No patient achieved a radiographic response. The most common grade 3 or greater adverse events were neutropenia (11%), thrombocytopenia (3%) and diarrhea (3%). Conclusions Imatinib plus hydroxyurea was well tolerated among recurrent/progressive LGG patients but this regimen demonstrated negligible anti-tumor activity. PMID:22371319

A patient case highlighting the myriad of cutaneous adverse effects of prolonged use of hydroxyurea.

PubMed

Neill, Brett; Ryser, Ted; Neill, John; Aires, Daniel; Rajpara, Anand

2017-11-15

Hydroxyurea is an antimetabolite primarily used to treat myeloproliferative disorders, and chronic treatment is associated with many cutaneous adverse effects ranging in severity from ichthyosis to aggressive nonmelanoma skin cancer. We report a 67-year-oldman with a history of polycythemia vera who was referred for management of progressively worsening dorsal hand lesions. The patient presented withhyperpigmentation, ichthyosis, plantar keratoderma, dermatomyositis-like eruptions, two squamous cell carcinomas, and actinic keratoses. The adversereactions observed were acknowledged to be related to chronic hydroxyurea use. The patient underwent Mohs excision of the squamous cell carcinomas and thehydroxyurea was promptly discontinued; subsequent cutaneous improvement of the dermatomyositislike lesions ensued. Another clinically suspicious aggressive squamous cell carcinoma was suspected and the patient was referred to the plastic surgery department for complete excision because of the size of the lesion. The patient remains on periodic dermatology follow up. We report a case that exemplifies the cutaneous adverse effects of chronic hydroxyurea therapy. Although many cases improve after drug discontinuation, strict photoprotection and ongoing surveillance are indicated given the recently proposed premalignant potential of dermatomyositis-like eruptions and the aggressive nature of hydroxyurea-induced nonmelanoma skin cancer.

Can hydroxyurea serve as a free radical scavenger and reduce iron overload in β-thalassemia patients?

PubMed

Italia, Khushnooma; Chandrakala, S; Ghosh, Kanjaksha; Colah, Roshan

2016-09-01

In this study, we hypothesize that hydroxyurea could provide an additional benefit as a free radical scavenger and/or iron chelator in β-thalassemia patients with iron overload. Twenty-one β-thalassemia intermedia patients who presented between 3 and 17 years but later required regular blood transfusions were enrolled for hydroxyurea therapy for a year. Fourteen patients responded to the therapy with hemoglobin levels maintained above 7.5 g/dl without transfusions. Hydroxyurea was discontinued after 6 months in seven patients who did not respond to the therapy and had to be continued on regular blood transfusions. We observed a statistically significant decrease in serum ferritin levels from 4194 ± 4850 ng/ml to 2129 ± 2380 ng/ml among the responders and from 2955 ± 2909 ng/ml to 2040 ± 2432 ng/ml among the non-responders and statistically significant decrease in labile iron pool from 18678.7 ± 10067.4 mean fluorescence intensity (MFI) to 14888.5 ± 5284.0 MFI among responders and from 17986.3 ± 9079.8 MFI to 15634.8 ± 8976.9 MFI among the non-responders after therapy. Phosphatidylserine externalization also showed a statistically significant decrease from 44.2 ± 22.2 MFI to 16.6 ± 6.7 MFI among the responders and from 46.9 ± 33.1 MFI to 39.8 ± 7.4 MFI among the non-responders along with a statistically significant decrease in the levels of reactive oxygen species from 72.8 ± 35.5 MFI to 29.0 ± 8.3 MFI among the responders and from 80.9 ± 41.4 MFI to 40.5 ± 15.8 MFI among the non-responders after therapy. A statistically significant increase in reduced glutathione levels was also observed from 430.8 ± 201.1 MFI to 715.5 ± 292.4 MFI among the responders and from 359.6 ± 165.6 MFI to 450.3 ± 279.5 MFI among the non-responders after therapy. This suggests the possible additional role of hydroxyurea as a free radical scavenger and/or iron chelator but requires a larger study for substantiation.

Alpha-thalassaemia and response to hydroxyurea in sickle cell anaemia.

PubMed

Darbari, Deepika S; Nouraie, Mehdi; Taylor, James G; Brugnara, Carlo; Castro, Oswaldo; Ballas, Samir K

2014-04-01

Hydroxyurea (HU) reduces vaso-occlusive crises (VOC) and other complications of sickle cell anaemia (SCA). Alpha-thalassaemia is a known modifier of SCA. Studies on the efficacy of HU in SCA patients with α-thalassaemia have yielded varying results. To determine the effect of α-thalassaemia in response to HU therapy in the Multicenter Study of Hydroxyurea (MSH) cohort. We compared the laboratory parameters and VOC incidence in the MSH cohort stratified by the presence or the absence of α-thalassaemia. Hydroxyurea showed significant (P = 0.001 for all baseline vs. follow-up comparisons) treatment effect on red cell indices irrespective of α-globin gene deletion. The magnitude of the HU-related changes was similar for mean corpuscular volume (MCV) (no α-thalassaemia 13 fl and α-thalassaemia 13 fl) and mean corpuscular haemoglobin (MCH) (no α-thalassaemia 4 pg and α-thalassaemia 4 pg) in both groups. Foetal haemoglobin (HbF) and F-cells also increased significantly with HU treatment in both groups. Total haemoglobin increased after HU treatment in both groups, but the increase was smaller and not statistically significant in patients with α-thalassaemia. In contrast, HU-related reduction in VOCs was more pronounced in patients with α-thalassaemia (VOC incidence rate ratio HU/placebo: 0.63 for α-thalassaemia and 0.54 for no α-thalassaemia (P for interaction 0.003). Hydroxyurea decreases VOCs in SCA patients with and without α-thalassaemia, and the degree of VOC reduction was more pronounced in the patients with alpha-thalassaemia. Despite the lower baseline values, changes in standard laboratory parameters such as MCV and HbF percent remain useful in monitoring HU therapy in the presence of α-thalassaemia. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Severe excessive daytime sleepiness induced by hydroxyurea.

PubMed

Revol, Bruno; Joyeux-Faure, Marie; Albahary, Marie-Victoire; Gressin, Remy; Mallaret, Michel; Pepin, Jean-Louis; Launois, Sandrine H

2017-06-01

Excessive daytime sleepiness (EDS) has been reported with many drugs, either as an extension of a hypnotic effect (e.g. central nervous system depressants) or as an idiosyncratic response of the patient. Here, we report unexpected and severe subjective and objective EDS induced by hydroxyurea therapy, with a favorable outcome after withdrawal. Clinical history, sleep log, polysomnography, and multiple sleep latency tests confirming the absence of other EDS causes are presented. © 2016 Société Française de Pharmacologie et de Thérapeutique.

Hydroxyurea for Treatment of Nephrotic Syndrome Associated With Polycythemia Vera.

PubMed

Hundemer, Gregory L; Rosales, Ivy A; Chen, Yi-Bin; Colvin, Robert B; Tolkoff-Rubin, Nina E

2016-09-01

Myeloproliferative disorders are a rare cause of focal segmental glomerulosclerosis (FSGS), although the mechanism is unclear. Hydroxyurea is commonly used in these disorders for its cytoreductive properties; however, the effect of this treatment on proteinuria or kidney function remains unclear in cases of myeloproliferative disorder-associated FSGS. We describe the clinical course of a patient with polycythemia vera and nephrotic-range proteinuria, demonstrated to have FSGS on biopsy. The patient had a distant history of granulomatosis with polyangiitis (Wegener's), for which he routinely had his kidney function and proteinuria measured, allowing for early detection of nephrotic syndrome soon after being diagnosed with polycythemia vera. Treatment with hydroxyurea resulted in rapid improvement in proteinuria that correlated with a decrease in hematocrit. This response was replicated 2 additional times when the patient was taken off and then restarted on hydroxyurea therapy. He now maintains a steady dose of hydroxyurea with favorable kidney measures (proteinuria with <1g/d of protein excretion and serum creatinine of 1.27mg/dL [corresponding to estimated glomerular filtration rate of 56mL/min/1.73 m(2)]). This case suggests that early screening and treatment for myeloproliferative disorder-associated FSGS may lead to improved long-standing kidney function. Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Hydroxyurea with or without imatinib in the treatment of recurrent or progressive meningiomas: a randomized phase II trial by Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO).

PubMed

Mazza, Elena; Brandes, Alba; Zanon, Silvia; Eoli, Marika; Lombardi, Giuseppe; Faedi, Marina; Franceschi, Enrico; Reni, Michele

2016-01-01

Hydroxyurea (HU) is among the most widely used salvage therapies in progressive meningiomas. Platelet-derived growth factor receptors are expressed in virtually all meningiomas. Imatinib sensitizes transformed cells to the cytotoxic effects of chemotherapeutic agents that interfere with DNA metabolism. The combination of HU with imatinib yielded intriguing results in recurrent malignant glioma. The current trial addressed the activity of this association against meningioma. Patients with recurrent or progressive WHO grade I-III meningioma, without therapeutic indication for surgery, radiotherapy, or stereotactic radiosurgery, aged 18-75 years, ECOG performance status 0-2, and not on enzyme-inducing anti-epileptic drugs were randomized to receive HU 500 mg BID ± imatinib 400 mg QD until progression, unacceptable toxicity, or patient's refusal. The primary endpoint was progression-free survival rate at 9 months (PFS-9). Between September 2009 and February 2012, 15 patients were randomized to receive HU + imatinib (N = 7; Arm A) or HU alone (N = 8; Arm B). Afterward the trial was prematurely closed due to slow enrollment rate. PFS-9 (A/B) was 0/75%, and median PFS was 4/19.5 months. Median and 2-year overall survival (A/B) rates were: 6/27.5 months; 28.5/75%, respectively. Main G3-4 toxicities were: G3 neutropenia in 1/0, G4 headache in 1/1, and G3 vomiting in 1/0. The conduction of a study in recurrent or progressive meningioma remains a challenge. Given the limited number of patients enrolled, no firm conclusions can be drawn about the combination of imatinib and HU. The optimal systemic therapy for meningioma failing surgery and radiation has yet to be identified.

Hydroxyurea-Increased Fetal Hemoglobin Is Associated with Less Organ Damage and Longer Survival in Adults with Sickle Cell Anemia.

PubMed

Fitzhugh, Courtney D; Hsieh, Matthew M; Allen, Darlene; Coles, Wynona A; Seamon, Cassie; Ring, Michael; Zhao, Xiongce; Minniti, Caterina P; Rodgers, Griffin P; Schechter, Alan N; Tisdale, John F; Taylor, James G

2015-01-01

Adults with sickle cell anemia (HbSS) are inconsistently treated with hydroxyurea. We retrospectively evaluated the effects of elevating fetal hemoglobin with hydroxyurea on organ damage and survival in patients enrolled in our screening study between 2001 and 2010. An electronic medical record facilitated development of a database for comparison of study parameters based on hydroxyurea exposure and dose. This study is registered with ClinicalTrials.gov, number NCT00011648. Three hundred eighty-three adults with homozygous sickle cell disease were analyzed with 59 deaths during study follow-up. Cox regression analysis revealed deceased subjects had more hepatic dysfunction (elevated alkaline phosphatase, Hazard Ratio = 1.005, 95% CI 1.003-1.006, p<0.0.0001), kidney dysfunction (elevated creatinine, Hazard Ratio = 1.13, 95% CI 1.00-1.27, p = 0.043), and cardiopulmonary dysfunction (elevated tricuspid jet velocity on echocardiogram, Hazard Ratio = 2.22, 1.23-4.02, p = 0.0082). Sixty-six percent of subjects were treated with hydroxyurea, although only 66% of those received a dose within the recommended therapeutic range. Hydroxyurea use was associated with improved survival (Hazard Ratio = 0.58, 95% CI 0.34-0.97, p = 0.040). This effect was most pronounced in those taking the recommended dose of 15-35 mg/kg/day (Hazard Ratio 0.36, 95% CI 0.17-0.73, p = 0.0050). Hydroxyurea use was not associated with changes in organ function over time. Further, subjects with higher fetal hemoglobin responses to hydroxyurea were more likely to survive (p = 0.0004). While alkaline phosphatase was lowest in patients with the best fetal hemoglobin response (95.4 versus 123.6, p = 0.0065 and 96.1 versus 113.6U/L, p = 0.041 at first and last visits, respectively), other markers of organ damage were not consistently improved over time in patients with the highest fetal hemoglobin levels. Our data suggest that adults should be treated with the maximum tolerated hydroxyurea dose, ideally before organ damage occurs. Prospective studies are indicated to validate these findings.

Hydroxyurea-Increased Fetal Hemoglobin Is Associated with Less Organ Damage and Longer Survival in Adults with Sickle Cell Anemia

PubMed Central

Fitzhugh, Courtney D.; Hsieh, Matthew M.; Allen, Darlene; Coles, Wynona A.; Seamon, Cassie; Ring, Michael; Zhao, Xiongce; Minniti, Caterina P.; Rodgers, Griffin P.; Schechter, Alan N.; Tisdale, John F.; Taylor, James G.

2015-01-01

Background Adults with sickle cell anemia (HbSS) are inconsistently treated with hydroxyurea. Objectives We retrospectively evaluated the effects of elevating fetal hemoglobin with hydroxyurea on organ damage and survival in patients enrolled in our screening study between 2001 and 2010. Methods An electronic medical record facilitated development of a database for comparison of study parameters based on hydroxyurea exposure and dose. This study is registered with ClinicalTrials.gov, number NCT00011648. Results Three hundred eighty-three adults with homozygous sickle cell disease were analyzed with 59 deaths during study follow-up. Cox regression analysis revealed deceased subjects had more hepatic dysfunction (elevated alkaline phosphatase, Hazard Ratio = 1.005, 95% CI 1.003–1.006, p<0.0.0001), kidney dysfunction (elevated creatinine, Hazard Ratio = 1.13, 95% CI 1.00–1.27, p = 0.043), and cardiopulmonary dysfunction (elevated tricuspid jet velocity on echocardiogram, Hazard Ratio = 2.22, 1.23–4.02, p = 0.0082). Sixty-six percent of subjects were treated with hydroxyurea, although only 66% of those received a dose within the recommended therapeutic range. Hydroxyurea use was associated with improved survival (Hazard Ratio = 0.58, 95% CI 0.34–0.97, p = 0.040). This effect was most pronounced in those taking the recommended dose of 15–35 mg/kg/day (Hazard Ratio 0.36, 95% CI 0.17–0.73, p = 0.0050). Hydroxyurea use was not associated with changes in organ function over time. Further, subjects with higher fetal hemoglobin responses to hydroxyurea were more likely to survive (p = 0.0004). While alkaline phosphatase was lowest in patients with the best fetal hemoglobin response (95.4 versus 123.6, p = 0.0065 and 96.1 versus 113.6U/L, p = 0.041 at first and last visits, respectively), other markers of organ damage were not consistently improved over time in patients with the highest fetal hemoglobin levels. Conclusions Our data suggest that adults should be treated with the maximum tolerated hydroxyurea dose, ideally before organ damage occurs. Prospective studies are indicated to validate these findings. PMID:26576059

A clinically meaningful fetal hemoglobin threshold for children with sickle cell anemia during hydroxyurea therapy.

PubMed

Estepp, Jeremie H; Smeltzer, Matthew P; Kang, Guolian; Li, Chen; Wang, Winfred C; Abrams, Christina; Aygun, Banu; Ware, Russell E; Nottage, Kerri; Hankins, Jane S

2017-12-01

Hydroxyurea has proven clinical benefits and is recommended to be offered to all children with sickle cell anemia (SCA), but the optimal dosing regimen remains controversial. Induction of red blood cell fetal hemoglobin (HbF) by hydroxyurea appears to be dose-dependent. However, it is unknown whether maximizing HbF% improves clinical outcomes. HUSTLE (NCT00305175) is a prospective observational study with a primary goal of describing the long-term clinical effects of hydroxyurea escalated to maximal tolerated dose (MTD) in children with SCA. In 230 children, providing 610 patient-years of follow up, the mean attained HbF% at MTD was >20% for up to 4 years of follow-up. When HbF% values were ≤20%, children had twice the odds of hospitalization for any reason (P < .0001), including vaso-occlusive pain (P < .01) and acute chest syndrome (ACS) (P < .01), and more than four times the odds of admission for fever (P < .001). Thirty day readmission rates were not affected by HbF%. Neutropenia (ANC <1000 × 10 6 /L) was rare (2.3% of all laboratory monitoring), transient, and benign. Therefore, attaining HbF >20% was associated with fewer hospitalizations without significant toxicity. These data support the use of hydroxyurea in children, and suggest that the preferred dosing strategy is one that targets a HbF endpoint >20%. © 2017 Wiley Periodicals, Inc.

An Evaluation of Treatment Patterns and Outcomes in Elderly Patients Newly Diagnosed With Acute Myeloid Leukemia: A Retrospective Analysis of Electronic Medical Records From US Community Oncology Practices.

PubMed

Ma, Esprit; Bonthapally, Vijayveer; Chawla, Anita; Lefebvre, Patrick; Swords, Ronan; Lafeuille, Marie-Hélène; Fortier, Jonathan; Emond, Bruno; Duh, Mei Sheng; Dezube, Bruce J

2016-11-01

Many elderly patients with acute myeloid leukemia (AML) are considered ineligible for standard intensive induction therapy due to performance status and comorbidities. We analyzed treatment patterns and outcomes among elderly patients newly diagnosed with AML in the US community oncology setting. A retrospective observational study was conducted using patient-level data from a network of US community oncology practices provided by Altos Solutions. Patients aged ≥ 60 years, diagnosed with AML between November 2005 and February 2014, with ≥ 1 recorded visit and ≥ 6 months between diagnosis and data cutoff, were included. Only patients who received active treatment or best supportive care (BSC) per National Comprehensive Cancer Network (NCCN) AML Guidelines were analyzed. Of 1139 patients meeting the inclusion criteria, 922 (median age 76 years) received NCCN-recommended treatments: standard induction (n = 5), low-intensity therapy (n = 425), BSC with hydroxyurea (HU) (n = 36), or BSC without HU (n = 455). For the low-intensity therapy cohort, median time from diagnosis to treatment initiation was 17 days; median duration of therapy was 5.1 months. Median overall survival (OS) from diagnosis in the low-intensity, BSC with HU, and BSC without HU groups was 12.3, 7.0, and 49.4 months, respectively. Median time to next therapy/death was 10.1 months in patients receiving low-intensity therapy. A higher proportion of patients receiving low-intensity therapy required transfusion or other supportive care versus those receiving BSC. As expected, OS in patients receiving low-intensity therapy or BSC with HU is poor for elderly patients with AML. Remarkably, intensive induction strategies are rarely used for older patients in community oncology practice. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Multicentre phase II studies evaluating imatinib plus hydroxyurea in patients with progressive glioblastoma.

PubMed

Reardon, D A; Dresemann, G; Taillibert, S; Campone, M; van den Bent, M; Clement, P; Blomquist, E; Gordower, L; Schultz, H; Raizer, J; Hau, P; Easaw, J; Gil, M; Tonn, J; Gijtenbeek, A; Schlegel, U; Bergstrom, P; Green, S; Weir, A; Nikolova, Z

2009-12-15

We evaluated the efficacy of imatinib mesylate in addition to hydroxyurea in patients with recurrent glioblastoma (GBM) who were either on or not on enzyme-inducing anti-epileptic drugs (EIAEDs). A total of 231 patients with GBM at first recurrence from 21 institutions in 10 countries were enrolled. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 600 mg per day for patients not on EIAEDs and at 500 mg twice a day if on EIAEDs. The primary end point was radiographic response rate and secondary end points were safety, progression-free survival at 6 months (PFS-6), and overall survival (OS). The radiographic response rate after centralised review was 3.4%. Progression-free survival at 6 months and median OS were 10.6% and 26.0 weeks, respectively. Outcome did not appear to differ based on EIAED status. The most common grade 3 or greater adverse events were fatigue (7%), neutropaenia (7%), and thrombocytopaenia (7%). Imatinib in addition to hydroxyurea was well tolerated among patients with recurrent GBM but did not show clinically meaningful anti-tumour activity.

Clinical and hematological response to hydroxyurea in a patient with Hb Lepore/beta-thalassemia.

PubMed

Rigano, P; Manfré, L; La Galla, R; Renda, D; Renda, M C; Calabrese, A; Calzolari, R; Maggio, A

1997-05-01

The possibility of increasing Hb F in vivo using drugs like 5-azacytidine, hydroxyurea, and butyrate has been established. However, in many cases this does not entail an increase in total hemoglobin. We report on a patient with Hb Lepore/beta-thalassemia being treated with hydroxyurea (30 mg/Kg/day) because of the presence of erythroid extramedullary masses with severe neurological abnormalities. During therapy the patient showed a remarkable improvement in neurological signs due to the reduction in extra-medullary masses, a significant increase in both total hemoglobin (from 5.8 to 9.7 g/dl) and Hb F (from 4.9 g/dl to 9.1 g/dl). The marked improvement in hemoglobin level in our patient with Hb Lepore/beta-thalassemia suggests gamma-globin gene activation due to the DNA structure determined by the crossover event.

Immunological role of CD4+CD28null T lymphocytes, natural killer cells, and interferon-gamma in pediatric patients with sickle cell disease: relation to disease severity and response to therapy.

PubMed

ElAlfy, Mohsen Saleh; Adly, Amira Abdel Moneam; Ebeid, Fatma Soliman ElSayed; Eissa, Deena Samir; Ismail, Eman Abdel Rahman; Mohammed, Yasser Hassan; Ahmed, Manar Elsayed; Saad, Aya Sayed

2018-06-20

Sickle cell disease (SCD) is associated with alterations in immune phenotypes. CD4 + CD28 null T lymphocytes have pro-inflammatory functions and are linked to vascular diseases. To assess the percentage of CD4 + CD28 null T lymphocytes, natural killer cells (NK), and IFN-gamma levels, we compared 40 children and adolescents with SCD with 40 healthy controls and evaluated their relation to disease severity and response to therapy. Patients with SCD steady state were studied, focusing on history of frequent vaso-occlusive crisis, hydroxyurea therapy, and IFN-gamma levels. Analysis of CD4 + CD28 null T lymphocytes and NK cells was done by flow cytometry. Liver and cardiac iron overload were assessed. CD4 + CD28 null T lymphocytes, NK cells, and IFN-gamma levels were significantly higher in patients than controls. Patients with history of frequent vaso-occlusive crisis and those with vascular complications had higher percentage of CD4 + CD28 null T lymphocytes and IFN-gamma while levels were significantly lower among hydroxyurea-treated patients. CD4 + CD28 null T lymphocytes were positively correlated to transfusional iron input while these cells and IFN-gamma were negatively correlated to cardiac T2* and duration of hydroxyurea therapy. NK cells were correlated to HbS and indirect bilirubin. Increased expression of CD4 + CD28 null T lymphocytes highlights their role in immune dysfunction and pathophysiology of SCD complications.

Real-life experience with hydroxyurea in sickle cell disease: A multicenter study in a cohort of patients with heterogeneous descent.

PubMed

Rigano, Paolo; De Franceschi, Lucia; Sainati, Laura; Piga, Antonio; Piel, Frédéric B; Cappellini, Maria Domenica; Fidone, Carmelo; Masera, Nicoletta; Palazzi, Giovanni; Gianesin, Barbara; Forni, Gian Luca

2018-03-01

We conducted the first nation-wide cohort study of sickle cell disease (SCD) in Italy, a Southern European country exposed to intense recent flux migration from endemic areas for SCD. We evaluate the impact of hydroxyurea on a total of 652 pediatric and adult patients from 33 Reference Centers for SCD (mean age 24.5±15years, 51.4% males). Hydroxyurea median treatment duration was 7years (range: <1year to 29years) at a mean therapeutic dose of 18±4.7mg/kg/day. Hydroxyurea was associated with a significant increase in mean total and fetal hemoglobin and a significant decrease in mean hemoglobin S, white blood and platelet counts, and lactate dehydrogenase levels. Hydroxyurea was associated with a significant reduction in the incidence of acute chest syndrome (-29.3%, p<0.001), vaso-occlusive crisis (-34.1%, p<0.001), hospitalization (-53.2%, p<0.001), and bone necrosis (-6.9%, p<0.001). New silent cerebral infarction (SCI) occurred during treatment (+42.4%, p<0.001) but not stroke (+0.5%, p=0.572). These observations were generally consistent upon stratification for age, descent (Caucasian or African), genotype (βS/βS, βS/β 0 or βS/β + ) and duration of treatment (< or ≥10years). There were no new safety concerns observed compared to those commonly reported in the literature. Our study, conducted on a large population of patients with different descent and compound state supports the benefits of hydroxyurea therapy as a treatment option. Registered at clinical trials.gov (NCT02709681). Copyright © 2017 Elsevier Inc. All rights reserved.

Phase I Pharmacokinetic Study of the VEGFR Tyrosine Kinase Inhibitor Vatalanib (PTK787) plus Imatinib and Hydroxyurea for Malignant Glioma

PubMed Central

Reardon, David A.; Egorin, Merrill J.; Desjardins, Annick; Vredenburgh, James J.; Beumer, Jan H.; Lagattuta, Theodore F.; Gururangan, Sridharan; Herndon, James E.; Salvado, August J.; Friedman, Henry S.

2009-01-01

Background We determined the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of the oral vascular endothelial growth factor receptor (VEGFR) inhibitor, vatalanib, when administered with imatinib and hydroxyurea on a continuous daily schedule among recurrent malignant glioma patients. Methods All patients received 500 mg of hydroxyurea twice daily. Imatinib was dosed at 400 mg per day for patients not taking enzyme-inducing antiepileptic drugs (EIAEDs; stratum A) and at 500 mg twice-a-day for patients taking EIAEDs (stratum B). Vatalanib was escalated from 500 mg to 1250 mg twice daily in successive cohorts, independently for each stratum. Pharmacokinetics of each drug were assessed. Results Thirty-seven recurrent patients, including 34 (92%) with glioblastoma and 3 (8%) with grade 3 malignant glioma, were enrolled. Nineteen patients (51%) were taking EIAEDs. The MTD of vatalanib for all patients was 1000 mg twice-a-day. DLTs were hematologic, gastrointestinal, renal and hepatic. No patients developed intracranial hemorrhage. Concurrent administration of imatinib and hydroxyurea did not affect vatalanib exposure, but EIAEDs decreased vatalanib and imatinib plasma exposures. Conclusion Vatalanib doses up to 1000 mg twice-a-day combined with imatinib and hydroxyurea are well tolerated. Strategies to target tumor blood vessel endothelial cells and pericytes by inhibiting VEGFR and PDGFR, respectively, are safe among recurrent malignant glioma patients and may enhance anti-angiogenesis activity. PMID:19248046

P11.10 Role of hydroxyurea as an adjuvant treatment after gamma knife radiosurgery for atypical (WHO grade II) meningiomas

PubMed Central

Abdel Karim, K.; El Shehaby, A.; Emad, R.; Reda, W.; El Mahdy, M.; Ghali, R.; Nabeel, A.

2016-01-01

Abstract Objective: The use of gamma knife radiosurgery in the treatment of atypical (WHO grade II) meningiomas has been reported in the past with highly variable degrees of success. The use of hydroxyurea as a radiation sensitizer as well as salvage chemotherapy in cancer patients is well established and was also used for treatment of recurrent and malignant meningiomas. In this study we investigated the effect of hydroxyurea administration after gamma knife radiosurgery for atypical (grade II) meningiomas on local tumor control and patient survival. Patients and methods: Between November 2008 and April 2014, thirty-five patients with pathologically proven atypical meningiomas were treated by gamma knife radiosurgery. We excluded patients who had received previous external beam radiotherapy. Twenty-three patients were given hydroxyurea after gamma knife treatment. The rest of the patients refused to take the treatment or were incompliant (were not included in the study). Of these 23, nineteen patients harboring 20 tumors were available for radiological and clinical follow up for a minimum of 2 years. Four patients were lost from follow up. Twenty tumors underwent 26 gamma knife procedures. Five tumors underwent staged treatment. The tumor volume was 0.6–38.3 cc (median 12.7 cc). The prescription dose/session ranged from 10 to 16 Gy (mean 14 Gy). The patients received a course of hydroxyurea (1000 mg/day) for one year after gamma knife treatment. The mean follow up period was 43 months (14–76 months). Results: Tumor control was achieved in 18 out of 20 tumors where 15 tumors shrank and 3 tumors remained stable with a tumor control rate of 90%. Tumor progression occurred in 2 patients (at 14 and 15 months). Transient edema was observed with 6 tumors which was temporary, and no G3 or G4 myelosuppression were recorded. Two patients died from progression of other tumors not included in the study after 3 and 6 years. Distant tumor progression (in another intracranial location or outside the radiation field) was observed in 5 patients. In 3 patients new tumors developed at the edge of previous craniotomy, in one patient tumor progression occurred after receiving radiosurgery alone for another lesion after the end of adjuvant treatment and in one patient progression occurred in an untreated tumor that was under observation. The actuarial progression free survival and overall survival at 3 years were 89.5% and 94% respectively. Conclusion: Preliminary results suggest good tumor control and shrinkage of atypical (grade II) meningiomas treated with Gamma Knife radiosurgery followed by one year of adjuvant hydroxyurea. Further larger randomized and double-arm studies are required to confirm the potential role of hydroxyurea in those tumors.

Hydroxyurea (hydroxycarbamide) for sickle cell disease.

PubMed

Nevitt, Sarah J; Jones, Ashley P; Howard, Jo

2017-04-20

Sickle cell disease (SCD) is one of the most common inherited diseases worldwide. It is associated with lifelong morbidity and a reduced life expectancy. Hydroxyurea (hydroxycarbamide), an oral chemotherapeutic drug, ameliorates some of the clinical problems of SCD, in particular that of pain, by raising fetal haemoglobin. This is an update of a previously published Cochrane Review. To assess the effects of hydroxyurea therapy in people with SCD (all genotypes), of any age, regardless of setting. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Register, comprising of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched online trial registries.Date of the most recent search: 16 January 2017. Randomised and quasi-randomised controlled trials, of one month or longer, comparing hydroxyurea with placebo, standard therapy or other interventions for people with SCD. Authors independently assessed studies for inclusion, carried out data extraction and assessed the risk of bias. Seventeen studies were identified in the searches; eight randomised controlled trials were included, recruiting 899 adults and children with SCD (haemoglobin SS (HbSS), haemoglobin SC (HbSC) or haemoglobin Sβºthalassaemia (HbSβºthal) genotypes). Studies lasted from six to 30 months.Four studies (577 adults and children with HbSS or HbSβºthal) compared hydroxyurea to placebo; three recruited individuals with only severe disease and one recruited individuals with all disease severities. There were statistically significant improvements in terms of pain alteration (using measures such as pain crisis frequency, duration, intensity, hospital admissions and opoid use), measures of fetal haemoglobin and neutrophil counts and fewer occurrences of acute chest syndrome and blood transfusions in the hydroxyurea groups. There were no consistent statistically significant differences in terms of quality of life and adverse events (including serious or life-threatening events). Seven deaths occurred during the studies, but the rates by treatment group were not statistically significantly different.Two studies (254 children with HbSS or HbSβºthal also with risk of primary or secondary stroke) compared hydroxyurea and phlebotomy to transfusion and chelation; there were statistically significant improvements in terms of measures of fetal haemoglobin and neutrophil counts, but more occurrences of acute chest syndrome and infections in the hydroxyurea and phlebotomy group. There were no consistent statistically significant differences in terms of pain alteration and adverse events (including serious or life-threatening events). Two deaths occurred during the studies (one in a the hydroxyurea treatment arm and one in the control arm), but the rates by treatment group were not statistically significantly different. In the primary prevention study, no strokes occurred in either treatment group but in the secondary prevention study, seven strokes occurred in the hydroxyurea and phlebotomy group (none in the transfusion and chelation group) and the study was terminated early.The quality of the evidence for the above two comparisons was judged as moderate to low as the studies contributing to these comparisons were mostly large and well designed (and at low risk of bias); however evidence was limited and imprecise for some outcomes such as quality of life, deaths during the studies and adverse events and results are applicable only to individuals with HbSS and HbSβºthal genotypes.Of the remaining two studies, one (22 children with HbSS or HbSβºthal also at risk of stoke) compared hydroxyurea to observation; there were statistically significant improvements in terms of measures of fetal haemoglobin and neutrophil counts but no statistically significant differences in terms of adverse events (including serious or life-threatening events).The final study (44 adults and children with HbSC) compared treatment regimens with and without hydroxyurea - there was statistically significant improvement in terms of measures of fetal haemoglobin, but no statistically significant differences in terms of adverse events (including serious or life-threatening events). No participants died in either of these studies and other outcomes relevant to the review were not reported.The quality of the evidence for the above two comparisons was judged to be very low due to the limited number of participants, the lack of statistical power (as both studies were terminated early with approximately only 20% of their target sample size recruited) and the lack of applicability to all age groups and genotypes. There is evidence to suggest that hydroxyurea is effective in decreasing the frequency of pain episodes and other acute complications in adults and children with sickle cell anaemia of HbSS or HbSβºthal genotypes and in preventing life-threatening neurological events in those with sickle cell anaemia at risk of primary stroke by maintaining transcranial doppler velocities. However, there is still insufficient evidence on the long-term benefits of hydroxyurea, particularly in preventing chronic complications of SCD, recommending a standard dose or dose escalation to maximum tolerated dose. There is also insufficient evidence about the long-term risks of hydroxyurea, including its effects on fertility and reproduction. Evidence is also limited on the effects of hydroxyurea on individuals with HbSC genotype. Future studies should be designed to address such uncertainties.

Laser Photobiomodulation for a Complex Patient with Severe Hydroxyurea-Induced Oral Ulcerations.

PubMed

Cabras, Marco; Cafaro, Adriana; Gambino, Alessio; Broccoletti, Roberto; Romagnoli, Ercole; Marina, Davide; Arduino, Paolo G

2016-01-01

Patients affected by polycythemia vera (PV), a myeloproliferative neoplasm characterized by an elevated red blood cell mass, are at high risk of vascular and thrombotic complications. Conventional therapeutic options aim at reducing vascular and thrombotic risk; low-dose aspirin and phlebotomy are first-line recommendations, for patients at low risk of thrombotic events, whereas cytoreductive therapy, usually hydroxyurea (HU) or interferon alpha, is recommended for high-risk patients. In the present study, we report the case of a patient with persistent oral ulcerations, possibly related to long-lasting HU treatment, firstly treated with topic and systemic corticosteroids and then more effectively with the addition of low-level laser therapy. Laser photobiomodulation has achieved pain control and has contributed to the healing of oral ulcers without any adverse effect; this has permitted a reduction in the dose of systemic corticosteroids and the suspension of the use of the topic ones, due to the long-term stability of oral health, even after the interruption of low-level laser therapy sessions.

Laser Photobiomodulation for a Complex Patient with Severe Hydroxyurea-Induced Oral Ulcerations

PubMed Central

Cabras, Marco; Cafaro, Adriana; Broccoletti, Roberto; Romagnoli, Ercole; Marina, Davide

2016-01-01

Patients affected by polycythemia vera (PV), a myeloproliferative neoplasm characterized by an elevated red blood cell mass, are at high risk of vascular and thrombotic complications. Conventional therapeutic options aim at reducing vascular and thrombotic risk; low-dose aspirin and phlebotomy are first-line recommendations, for patients at low risk of thrombotic events, whereas cytoreductive therapy, usually hydroxyurea (HU) or interferon alpha, is recommended for high-risk patients. In the present study, we report the case of a patient with persistent oral ulcerations, possibly related to long-lasting HU treatment, firstly treated with topic and systemic corticosteroids and then more effectively with the addition of low-level laser therapy. Laser photobiomodulation has achieved pain control and has contributed to the healing of oral ulcers without any adverse effect; this has permitted a reduction in the dose of systemic corticosteroids and the suspension of the use of the topic ones, due to the long-term stability of oral health, even after the interruption of low-level laser therapy sessions. PMID:27957350

A Case of Recurrent Anaplastic Meningioma of the Skull Base with Radiologic Response to Hydroxyurea

PubMed Central

Gurberg, Joshua; Bouganim, Nathaniel; Shenouda, George; Zeitouni, Anthony

2014-01-01

Anaplastic meningiomas are rare and aggressive tumors with a high propensity for local recurrence. Surgical resection and postoperative radiotherapy are the standard of care for primary disease and local recurrences. Refractory disease is managed with chemotherapy with limited success. A highly efficacious, well-tolerated chemotherapeutic agent has yet to be found for this disease entity. Hydroxyurea is currently receiving renewed attention because of its efficacy in inducing apoptosis of meningioma cells in vitro and its favorable side-effect profile. Thus far, in humans, this agent has only induced stable disease. We describe the first patient showing a near complete/partial clinical and radiological regression after 5 months of 25 mg/kg of hydroxyurea once daily, given within 1 month after stereotactic fractionated reirradiation of a previously irradiated and operated anaplastic meningioma of the skull base. Magnetic resonance imaging showed a significant and sustained response with tumor shrinkage and cavitation. PMID:25083390

Multicentre phase II studies evaluating imatinib plus hydroxyurea in patients with progressive glioblastoma

PubMed Central

Reardon, D A; Dresemann, G; Taillibert, S; Campone, M; van den Bent, M; Clement, P; Blomquist, E; Gordower, L; Schultz, H; Raizer, J; Hau, P; Easaw, J; Gil, M; Tonn, J; Gijtenbeek, A; Schlegel, U; Bergstrom, P; Green, S; Weir, A; Nikolova, Z

2009-01-01

Background: We evaluated the efficacy of imatinib mesylate in addition to hydroxyurea in patients with recurrent glioblastoma (GBM) who were either on or not on enzyme-inducing anti-epileptic drugs (EIAEDs). Methods: A total of 231 patients with GBM at first recurrence from 21 institutions in 10 countries were enrolled. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 600 mg per day for patients not on EIAEDs and at 500 mg twice a day if on EIAEDs. The primary end point was radiographic response rate and secondary end points were safety, progression-free survival at 6 months (PFS-6), and overall survival (OS). Results: The radiographic response rate after centralised review was 3.4%. Progression-free survival at 6 months and median OS were 10.6% and 26.0 weeks, respectively. Outcome did not appear to differ based on EIAED status. The most common grade 3 or greater adverse events were fatigue (7%), neutropaenia (7%), and thrombocytopaenia (7%). Conclusions: Imatinib in addition to hydroxyurea was well tolerated among patients with recurrent GBM but did not show clinically meaningful anti-tumour activity. PMID:19904263

Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme.

PubMed

Reardon, David A; Egorin, Merrill J; Quinn, Jennifer A; Rich, Jeremy N; Rich, Jeremy N; Gururangan, Sridharan; Gururangan, Idharan; Vredenburgh, James J; Desjardins, Annick; Sathornsumetee, Sith; Provenzale, James M; Herndon, James E; Dowell, Jeannette M; Badruddoja, Michael A; McLendon, Roger E; Lagattuta, Theodore F; Kicielinski, Kimberly P; Dresemann, Gregor; Sampson, John H; Friedman, Allan H; Salvado, August J; Friedman, Henry S

2005-12-20

We performed a phase II study to evaluate the combination of imatinib mesylate, an adenosine triphosphate mimetic, tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, in patients with recurrent glioblastoma multiforme (GBM). Patients with GBM at any recurrence received imatinib mesylate plus hydroxyurea (500 mg twice a day) orally on a continuous, daily schedule. The imatinib mesylate dose was 500 mg twice a day for patients on enzyme-inducing antiepileptic drugs (EIAEDs) and 400 mg once a day for those not on EIAEDs. Assessments were performed every 28 days. The primary end point was 6-month progression-free survival (PFS). Thirty-three patients enrolled with progressive disease after prior radiotherapy and at least temozolomide-based chemotherapy. With a median follow-up of 58 weeks, 27% of patients were progression-free at 6 months, and the median PFS was 14.4 weeks. Three patients (9%) achieved radiographic response, and 14 (42%) achieved stable disease. Cox regression analysis identified concurrent EIAED use and no more than one prior progression as independent positive prognostic factors of PFS. The most common toxicities included grade 3 neutropenia (16%), thrombocytopenia (6%), and edema (6%). There were no grade 4 or 5 events. Concurrent EIAED use lowered imatinib mesylate exposure. Imatinib mesylate clearance was decreased at day 28 compared with day 1 in all patients, suggesting an effect of hydroxyurea. Imatinib mesylate plus hydroxyurea is well tolerated and associated with durable antitumor activity in some patients with recurrent GBM.

Hydroxycarbamide treatment and brain MRI/MRA findings in children with sickle cell anaemia.

PubMed

Nottage, Kerri A; Ware, Russell E; Aygun, Banu; Smeltzer, Matthew; Kang, Guolian; Moen, Joseph; Wang, Winfred C; Hankins, Jane S; Helton, Kathleen J

2016-10-01

Silent cerebral infarction (SCI) is the most common neurological abnormality among children with sickle cell anaemia (SCA). The effect of hydroxycarbamide (also termed hydroxyurea) on the development and progression of SCI is unclear. We evaluated brain magnetic resonance imaging/angiography (MRI/MRA) in children with SCA receiving long-term hydroxycarbamide therapy. Fifty participants (median 9·4 years, range 1·1-17·3) enrolled in the Hydroxyurea Study of Long-Term Effects (HUSTLE; NCT00305175) underwent brain MRI/MRA and laboratory evaluations before hydroxycarbamide initiation and after 3 and 6 years of treatment to maximum tolerated dose. SCI and vascular stenosis were evaluated. At baseline, 3 and 6 years, SCI were present in 19/50 (38%), 20/49 (41%), and 7/17 (41%), respectively. At 3 years, one child developed a SCI lesion, and another progressed (single lesion to multiple). Lower haemoglobin (Hb) (80 g/l vs. 86 g/l, P = 0·049), fetal Hb (5·0% vs. 10·4%, P < 0·001) and oxygen saturation (97% vs. 98%, P = 0·027) before hydroxycarbamide initiation were associated with SCI. No patients had vascular stenosis identified on MRA, transient ischaemic attack or stroke. Our data indicate that children receiving hydroxycarbamide over a 3- to 6-year period have a low rate of new or worsening cerebrovascular disease. Further studies are needed to confirm that hydroxycarbamide can prevent the onset and progression of SCI. © 2016 John Wiley & Sons Ltd.

TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, randomised controlled trial

PubMed Central

Ware, Russell E.; Davis, Barry R.; Schultz, William H.; Brown, R. Clark; Aygun, Banu; Sarnaik, Sharada; Odame, Isaac; Fuh, Beng; George, Alex; Owen, William; Luchtman-Jones, Lori; Rogers, Zora R.; Hilliard, Lee; Gauger, Cynthia; Piccone, Connie; Lee, Margaret T.; Kwiatkowski, Janet L.; Jackson, Sherron; Miller, Scott T.; Roberts, Carla; Heeney, Matthew M.; Kalfa, Theodosia A.; Nelson, Stephen; Imran, Hamayun; Nottage, Kerri; Alvarez, Ofelia; Rhodes, Melissa; Thompson, Alexis A.; Rothman, Jennifer A.; Helton, Kathleen J.; Roberts, Donna; Coleman, Jamie; Bonner, Melanie J.; Kutlar, Abdullah; Patel, Niren; Wood, John; Piller, Linda; Wei, Peng; Luden, Judy; Mortier, Nicole A.; Stuber, Susan E.; Luban, Naomi L. C.; Cohen, Alan R.; Pressel, Sara; Adams, Robert J.

2017-01-01

Background For children with sickle cell anaemia and elevated transcranial Doppler (TCD) flow velocities, regular blood transfusions effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxyurea in this setting is unknown. Methods TWiTCH was a multicentre Phase III randomised open label, non-inferiority trial comparing standard treatment (transfusions) to alternative treatment (hydroxyurea) in children with abnormal TCD velocities but no severe vasculopathy. Iron overload was managed with chelation (Standard Arm) and serial phlebotomy (Alternative Arm). The primary study endpoint was the 24-month TCD velocity calculated from a general linear mixed model, with non-inferiority margin = 15 cm/sec. Findings Among 121 randomised participants (61 transfusions, 60 hydroxyurea), children on transfusions maintained <30% sickle haemoglobin, while those taking hydroxyurea (mean 27 mg/kg/day) averaged 25% fetal haemoglobin. The first scheduled interim analysis demonstrated non-inferiority, and the sponsor terminated the study. Final model-based TCD velocities (mean ± standard error) on Standard versus Alternative Arm were 143 ± 1.6 and 138 ± 1.6 cm/sec, respectively, with difference (95% CI) = 4.54 (0.10, 8.98), non-inferiority p=8.82 × 10−16 and post-hoc superiority p=0.023. Among 29 new neurological events adjudicated centrally by masked reviewers, no strokes occurred but there were 3 transient ischaemic attacks per arm. Exit brain MRI/MRA revealed no new cerebral infarcts in either arm, but worse vasculopathy in one participant (Standard Arm). Iron burden decreased more in the Alternative Arm, with ferritin difference −1047 ng/mL (−1524, −570), p<0.001 and liver iron difference −4.3 mg Fe/gm dry weight (−6.1, −2.5), p=0.001. Interpretation For high-risk children with sickle cell anaemia and abnormal TCD velocities, after four years of transfusions and without severe MRA vasculopathy, hydroxyurea therapy can substitute for chronic transfusions to maintain TCD velocities and help prevent primary stroke. PMID:26670617

Where to Turn for Second-Line Cytoreduction After Hydroxyurea in Polycythemia Vera?

PubMed

Nazha, Aziz; Gerds, Aaron T

2016-04-01

The goals of therapy in patients with polycythemia vera (PV) are to improve disease-related symptoms, prevent the incidence or recurrence of thrombosis, and possibly delay or prevent the transformation into myelofibrosis or acute myeloid leukemia (AML). Cytoreductive therapies have been used in older patients and those with a history of thrombosis to achieve these goals. Hydroxyurea (HU) remains the first-line cytoreductive choice; however, up to one in four patients treated with HU over time will develop resistance or intolerance to HU. More importantly, patients who fail HU have a 5.6-fold increase in mortality and a 6.8-fold increase risk of transformation to myelofibrosis or AML; therefore, alternative therapies are needed for these patients. Interferon-α has been used in PV and has shown significant activity in achieving hematologic responses and decreasing JAK2 V617F mutation allele burden. JAK inhibition has also been investigated and recently garnered regulatory approval for this indication. In this review, we will discuss the current treatment options that are available for patients after HU and the novel therapies that are currently under investigation. The outcomes of PV patients who fail or who are intolerant of hydroxyurea are poor. Although pegylated interferon can be considered in younger patients, currently, ruxolitinib is the only U.S. Food and Drug Administration-approved agent in this setting, representing a viable option, leading to hematocrit control and a reduction in spleen size and constitutional symptoms. Although a small number of patients will achieve a molecular response with continuous treatment, the implications of such response on the clinical outcomes are still unknown. Patients whose disease is not adequately controlled with ruxolitinib, or who lose their response, can be treated with low-dose busulfan or pipobroman; however, they should be encouraged to participate in trials with novel therapies. ©AlphaMed Press.

[Is therapeutic progress in the management of sickle cell disease applicable in sub-Saharan Africa?].

PubMed

De Montalembert, M; Tshilolo, L

2007-12-01

The life expectancy of patients with sickle cell disease has improved in the United States and Europe thanks to the use of penicillin prophylaxis, appropriate immunizations, neonatal screening, implementation of a quality transfusional policy, hydroxyurea therapy, detection and treatment of cerebral vasculopathy, recognition of situations that can benefit from allogenic marrow transplantation, and improvements in bone marrow transplantation techniques. The cost of almost all these techniques is far beyond the means of health care systems in Africa where they cannot be used. However at least three, i.e., penicillin, vaccines, and hydroxyurea, could be easily accessible in the framework of defined therapeutic strategies. If daily penicillin and pneumococcal vaccine Pneumo 23 are required, it would likely be necessary to select a conjugated vaccine other than Prevenar that does not provide protection against all strains present in Africa. Neonatal screening is still a rare procedure in sub-Saharan countries. Periodic transfusion is steadily improving but exchange transfusion programs aimed in particular at preventing neurological complications are still unfeasible. Indications for hydroxyurea therapy in Africa are more common due to the lack of access to chronic transfusion and must be based on consensus decision. Use of bone marrow transplantation, i.e., the only currently available curative treatment, is still possible only in northern hemisphere countries where it is still restricted to children with severe forms and an HLA-compatible family donor.

A Cutaneous Lupus Erythematosus-Like Eruption Induced by Hydroxyurea.

PubMed

Yanes, Daniel A; Mosser-Goldfarb, Joy L

2017-01-01

Hydroxyurea is a medication with many well-described cutaneous side effects, notably the dermatomyositis-like eruption known as hydroxyurea dermopathy. Although systemic lupus erythematosus has been reported with hydroxyurea use, cutaneous lupus has not. We report a novel case of chronic cutaneous lupus induced by hydroxyurea and propose that this is a side effect that is distinct from hydroxyurea dermopathy. © 2016 Wiley Periodicals, Inc.

Phase II study of Gleevec® plus hydroxyurea (HU) in adults with progressive or recurrent meningioma.

PubMed

Reardon, David A; Norden, Andrew D; Desjardins, Annick; Vredenburgh, James J; Herndon, James E; Coan, April; Sampson, John H; Gururangan, Sridharan; Peters, Katherine B; McLendon, Roger E; Norfleet, Julie A; Lipp, Eric S; Drappatz, Jan; Wen, Patrick Y; Friedman, Henry S

2012-01-01

We prospectively evaluated the efficacy and safety of imatinib plus hydroxyurea in patients with progressive/recurrent meningioma. A total of 21 patients with progressive/recurrent meningioma were enrolled in this dual center, single-arm, phase II trial. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 400 mg/day for patients not on CYP3A enzyme inducing anti-epileptic drugs (EIAEDs) and at 500 mg twice a day for patients on EIAEDs. The primary endpoint was progression-free survival at 6 months (PFS-6) and secondary endpoints were safety, radiographic response rate, and overall survival (OS). Best radiographic response was stable disease and was observed in 14 patients (67%). PFS-6 for all patients, those with grade I tumors (n = 8) and those with grade II or III tumors (n = 13) was 61.9, 87.5 and 46.2%, respectively. Patients with grade II or III tumors had poorer PFS and OS than those with grade I tumors, (P = 0.025 and P = 0.018) respectively. The only grade 3 or greater adverse event occurring in ≥ 10% of patients was anemia (10%). Imatinib plus hydroxyurea is well tolerated among patients with meningioma but has modest anti-tumor activity for this indication.

Phase II study of Gleevec® plus hydroxyurea (HU) in adults with progressive or recurrent meningioma

PubMed Central

Norden, Andrew D.; Desjardins, Annick; Vredenburgh, James J.; Herndon, James E.; Coan, April; Sampson, John H.; Gururangan, Sridharan; Peters, Katherine B.; McLendon, Roger E.; Norfleet, Julie A.; Lipp, Eric S.; Drappatz, Jan; Wen, Patrick Y.; Friedman, Henry S.

2011-01-01

We prospectively evaluated the efficacy and safety of imatinib plus hydroxyurea in patients with progressive/recurrent meningioma. A total of 21 patients with progressive/recurrent meningioma were enrolled in this dual center, single-arm, phase II trial. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 400 mg/day for patients not on CYP3A enzyme inducing anti-epileptic drugs (EIAEDs) and at 500 mg twice a day for patients on EIAEDs. The primary endpoint was progression-free survival at 6 months (PFS-6) and secondary endpoints were safety, radiographic response rate, and overall survival (OS). Best radiographic response was stable disease and was observed in 14 patients (67%). PFS-6 for all patients, those with grade I tumors (n = 8) and those with grade II or III tumors (n = 13) was 61.9, 87.5 and 46.2%, respectively. Patients with grade II or III tumors had poorer PFS and OS than those with grade I tumors, (P = 0.025 and P = 0.018) respectively. The only grade 3 or greater adverse event occurring in ≥10% of patients was anemia (10%). Imatinib plus hydroxyurea is well tolerated among patients with meningioma but has modest anti-tumor activity for this indication. PMID:21938530

Transfusional iron overload in children with sickle cell anemia on chronic transfusion therapy for secondary stroke prevention.

PubMed

Kwiatkowski, Janet L; Cohen, Alan R; Garro, Julian; Alvarez, Ofelia; Nagasubramanian, Ramamorrthy; Sarnaik, Sharada; Thompson, Alexis; Woods, Gerald M; Schultz, William; Mortier, Nicole; Lane, Peter; Mueller, Brigitta; Yovetich, Nancy; Ware, Russell E

2012-02-01

Chronic transfusion reduces the risk of recurrent stroke in children with sickle cell anemia (SCA) but leads to iron loading. Management of transfusional iron overload in SCA has been reported as suboptimal [1], but studies characterizing monitoring and treatment practices for iron overload in children with SCA, particularly in recent years with the expansion of chelator options, are lacking. We investigated the degree of iron loading and treatment practices of 161 children with SCA receiving transfusions for a history of stroke who participated in the Stroke with Transfusions Changing to Hydroxyurea (SWiTCH) trial. Data obtained during screening, including past and entry liver iron concentration (LIC) measurements, ferritin values, and chelation were analyzed. The mean age at enrollment was 12.9 ± 4 years and the mean duration of transfusion was 7 ± 3.8 years. Baseline LIC (median 12.94 mg/g dw) and serum ferritin (median 3,164 ng/mL) were elevated. Chelation therapy was initiated after a mean of 2.6 years of transfusions. At study entry, 137 were receiving chelation, most of whom (90%) were receiving deferasirox. This study underscores the need for better monitoring of iron burden with timely treatment adjustments in chronically transfused children with SCA.

Effects of hydroxyurea on blood rheology in sickle cell anemia: A two-years follow-up study.

PubMed

Lemonne, Nathalie; Möckesch, Berenike; Charlot, Keyne; Garnier, Yohann; Waltz, Xavier; Lamarre, Yann; Antoine-Jonville, Sophie; Etienne-Julan, Maryse; Hardy-Dessources, Marie-Dominique; Romana, Marc; Connes, Philippe

2017-01-01

The aim of the present study was to test the effects of hydroxyurea (HU) therapy on clinical, hematological and hemorheological parameters in adult patients with sickle cell anemia (SCA). Hematological and hemorheological parameters were measured in 28 SCA patients before HU therapy (i.e., baseline) and at 6, 12 and 24 months of treatment. RBC deformability was determined by ektacytometry at 30 Pa. RBC aggregation properties were investigated by light-backscatter method. Blood viscosity was measured at 225 s-1 by a cone-plate viscometer. The rates of vaso-occlusive crises and acute chest syndrome were lower at 1 and 2 years of HU therapy compared to baseline. The proportion of patients with leg ulcers tended to decrease after 2 years of treatment. Hemoglobin oxygen saturation improved with HU therapy. HU therapy induced a decrease of platelet and white blood cell counts and a rise in fetal hemoglobin level and mean cell volume. While hemoglobin concentrations increased under HU, blood viscosity remained unchanged all along the study. RBC deformability increased over baseline values at 6 months of HU therapy and continued to rise until the end of the follow-up period. In conclusion, the improvement in RBC deformability probably compensates the increase of hemoglobin on blood viscosity and participates to the improvement of the clinical status of patients.

Clinical Course of Two Children with Unstable Hemoglobins: The Effect of Hydroxyurea Therapy.

PubMed

Loovers, Harriët M; Tamminga, Nienke; Mulder, André B; Tamminga, Rienk Y J

2016-09-01

Case reports on the effect of hydroxyurea (HU) therapy for unstable hemoglobins (Hbs) are sparse; only three adult cases have been reported. We report for the first time on the effect of HU therapy in children carrying unstable Hbs. The first case concerns a female child with a familial history of chronic hemolytic anemia. She was diagnosed with Hb Volga (HBB: c.83C>A) at the age of 7 months. At age 6, treatment options were reconsidered due to increasing fatigue and decreasing Hb concentration. The second case also concerns a female child with chronic hemolytic anemia and icterus since the age of 5. She was diagnosed with Hb Köln (HBB: c.295G>A) at the age of 9. At age 10, treatment options were reconsidered due to decreased general condition and poor school performance. Both children were started on HU therapy. The child with Hb Volga showed reduced clinical symptoms and increased average Hb concentrations. She has been on HU therapy for over 7 years at preparation of this manuscript. The child with Hb Köln showed decreasing Hb concentrations upon start of therapy; clinical symptoms did not improve. Therapy was discontinued after 3½ months. The Hb Volga case report suggests that HU therapy could improve clinical symptoms in some patients with unstable Hbs. Based on these and previously published cases, it was speculated that response can be predicted by the percentage of Hb F and reticulocyte counts.

Cyanide, Peroxide and Nitric Oxide Formation in Solutions of Hydroxyurea Causes Cellular Toxicity and May Contribute to its Therapeutic Potency

PubMed Central

Kuong, Kawai J.; Kuzminov, Andrei

2009-01-01

Hydroxyurea is a potent remedy against a variety of ailments and an efficient inhibitor of DNA synthesis, yet its pharmacology is unclear. Hydroxyurea acts in Escherichia coli by the same mechanism as it does in eukaryotes, via inhibition of ribonucleotide reductase. When examining a controversy about concentrations of hydroxyurea that prevent thymineless death in E. coli, we found instability in hydroxyurea solutions which avoided prior detection due to its peculiar nature. In contrast to freshly dissolved hydroxyurea, which did not affect respiration and was bacteriostatic, one-day-old hydroxyurea solutions inhibited respiration and were immediately bactericidal. Respiration was inhibited by two gasses, hydrogen cyanide (HCN) and nitric oxide (NO), whose appearance we detected in “aged” hydroxyurea stocks by GC-MS; however, neither gas was bactericidal. While determining the cause of toxicity, we found that hydroxyurea damages DNA directly. We also demonstrated accumulation of peroxides in hydroxyurea solutions by enzymatic assays, which explains the toxicity, as both NO and HCN are known to kill bacteria when combined with hydrogen peroxide. Remarkably, we found that bactericidal effects of NO + H2O2 and HCN + H2O2 mixtures were further synergistic. Accumulation of decomposition products in solutions of hydroxyurea may explain the broad therapeutic effects of this drug. PMID:19467244

HABIT, a Randomized Feasibility Trial to Increase Hydroxyurea Adherence, Suggests Improved Health-Related Quality of Life in Youths with Sickle Cell Disease.

PubMed

Smaldone, Arlene; Findley, Sally; Manwani, Deepa; Jia, Haomiao; Green, Nancy S

2018-06-01

To examine the effect of a community health worker (CHW) intervention, augmented by tailored text messages, on adherence to hydroxyurea therapy in youths with sickle cell disease, as well as on generic and disease-specific health-related quality of life (HrQL) and youth-parent self-management responsibility concordance. We conducted a 2-site randomized controlled feasibility study (Hydroxyurea Adherence for Personal Best in Sickle Cell Treatment [HABIT]) with 2:1 intervention allocation. Youths and parents participated as dyads. Intervention dyads received CHW visits and text message reminders. Data were analyzed using descriptive statistics, the Wilcoxon signed-rank test, and growth models adjusting for group assignment, time, and multiple comparisons. Changes in outcomes from 0 to 6 months were compared with their respective minimal clinically important differences. A total of 28 dyads (mean age of youths, 14.3 ± 2.6 years; 50% Hispanic) participated (18 in the intervention group, 10 in the control group), with 10.7% attrition. Accounting for group assignment, time, and multiple comparisons, at 6 months intervention youths reported improved generic HrQL total score (9.8 points; 95% CI, 0.4-19.2) and Emotions subscale score (15.0 points; 95% CI, 1.6-28.4); improved disease-specific subscale scores for Worry I (30.0 points; 95% CI, 8.5-51.5), Emotions (37.0 points, 95% CI, 9.4-64.5), and Communication I (17.8 points; 95% CI, 0.5-35.1); and 3-month dyad self-management responsibility concordance (3.5 points; 95% CI, -0.2 to 7.1). There were no differences in parent proxy-reported HrQL measures at 6 months. These findings add to research examining effects of behavioral interventions on HrQL outcomes in youths with sickle cell disease. ClinicalTrials.gov: NCT02029742. Copyright © 2018 Elsevier Inc. All rights reserved.

A phase 2 study of ruxolitinib, an oral JAK1 and JAK2 Inhibitor, in patients with advanced polycythemia vera who are refractory or intolerant to hydroxyurea.

PubMed

Verstovsek, Srdan; Passamonti, Francesco; Rambaldi, Alessandro; Barosi, Giovanni; Rosen, Peter J; Rumi, Elisa; Gattoni, Elisabetta; Pieri, Lisa; Guglielmelli, Paola; Elena, Chiara; He, Shui; Contel, Nancy; Mookerjee, Bijoyesh; Sandor, Victor; Cazzola, Mario; Kantarjian, Hagop M; Barbui, Tiziano; Vannucchi, Alessandro M

2014-02-15

Polycythemia vera (PV) is a myeloproliferative neoplasm associated with somatic gain-of-function mutations of Janus kinase-2 (JAK2). Therapeutic options are limited in patients with advanced disease. Ruxolitinib, an oral JAK1/JAK2 inhibitor, is active in preclinical models of PV. The long-term efficacy and safety of ruxolitinib in patients with advanced PV who are refractory or intolerant to hydroxyurea were studied in a phase 2 trial. Response was assessed using modified European LeukemiaNet criteria, which included a reduction in hematocrit to <45% without phlebotomy, resolution of palpable splenomegaly, normalization of white blood cell and platelet counts, and reduction in PV-associated symptoms. Thirty-four patients received ruxolitinib for a median of 152 weeks (range, 31 weeks-177 weeks) or 35.0 months (range, 7.1 months-40.7 months). Hematocrit <45% without phlebotomy was achieved in 97% of patients by week 24.Only 1 patient required a phlebotomy after week 4. Among patients with palpable splenomegaly at baseline, 44% and 63%, respectively, achieved nonpalpable spleen measurements at weeks 24 and 144. Clinically meaningful improvements in pruritus, night sweats, and bone pain were observed within 4 weeks of the initiation of therapy and maintained with continued treatment. Ruxolitinib treatment also reduced elevated levels of inflammatory cytokines and granulocyte activation. Thrombocytopenia and anemia were the most common adverse events.Thrombocytopenia of grade 3 or anemia of grade 3 (according to National Cancer Institute Common Terminology Criteria for Adverse Events,version 3.0) occurred in 3 patients each (9%) (1 patient had both) and were managed with dose modification. Ruxolitinib was generally well tolerated and provided rapid and durable clinical benefits in patients with advanced PV who were refractory or intolerant to hydroxyurea.

Organic anion transporting polypeptide 1B transporters modulate hydroxyurea pharmacokinetics.

PubMed

Walker, Aisha L; Lancaster, Cynthia S; Finkelstein, David; Ware, Russell E; Sparreboom, Alex

2013-12-15

Hydroxyurea is currently the only FDA-approved drug that ameliorates the pathophysiology of sickle cell anemia. Unfortunately, substantial interpatient variability in the pharmacokinetics (PK) of hydroxyurea may result in variation of the drug's efficacy. However, little is known about mechanisms that modulate hydroxyurea PK. Recent in vitro studies identifying hydroxyurea as a substrate for organic anion transporting polypeptide (OATP1B) transporters prompted the current investigation assessing the role of OATP1B transporters in modulating hydroxyurea PK. Using wild-type and Oatp1b knockout (Oatp1b(-/-)) mice, hydroxyurea PK was analyzed in vivo by measuring [(14)C]hydroxyurea distribution in plasma, kidney, liver, urine, or the exhaled (14)CO2 metabolite. Plasma levels were significantly reduced by 20% in Oatp1b(-/-) mice compared with wild-type (area under the curve of 38.64 or 48.45 μg·h(-1)·ml(-1), respectively) after oral administration, whereas no difference was observed between groups following intravenous administration. Accumulation in the kidney was significantly decreased by twofold in Oatp1b(-/-) mice (356.9 vs. 748.1 pmol/g), which correlated with a significant decrease in urinary excretion. Hydroxyurea accumulation in the liver was also decreased (136.6 vs. 107.3 pmol/g in wild-type or Oatp1b(-/-) mice, respectively) correlating with a decrease in exhaled (14)CO2. These findings illustrate that deficiency of Oatp1b transporters alters the absorption, distribution, and elimination of hydroxyurea thus providing the first in vivo evidence that cell membrane transporters may play a significant role in modulating hydroxyurea PK. Future studies to investigate other transporters and their role in hydroxyurea disposition are warranted for understanding the sources of variation in hydroxyurea's PK.

Organic anion transporting polypeptide 1B transporters modulate hydroxyurea pharmacokinetics

PubMed Central

Lancaster, Cynthia S.; Finkelstein, David; Ware, Russell E.; Sparreboom, Alex

2013-01-01

Hydroxyurea is currently the only FDA-approved drug that ameliorates the pathophysiology of sickle cell anemia. Unfortunately, substantial interpatient variability in the pharmacokinetics (PK) of hydroxyurea may result in variation of the drug's efficacy. However, little is known about mechanisms that modulate hydroxyurea PK. Recent in vitro studies identifying hydroxyurea as a substrate for organic anion transporting polypeptide (OATP1B) transporters prompted the current investigation assessing the role of OATP1B transporters in modulating hydroxyurea PK. Using wild-type and Oatp1b knockout (Oatp1b−/−) mice, hydroxyurea PK was analyzed in vivo by measuring [14C]hydroxyurea distribution in plasma, kidney, liver, urine, or the exhaled 14CO2 metabolite. Plasma levels were significantly reduced by 20% in Oatp1b−/− mice compared with wild-type (area under the curve of 38.64 or 48.45 μg·h−1·ml−1, respectively) after oral administration, whereas no difference was observed between groups following intravenous administration. Accumulation in the kidney was significantly decreased by twofold in Oatp1b−/− mice (356.9 vs. 748.1 pmol/g), which correlated with a significant decrease in urinary excretion. Hydroxyurea accumulation in the liver was also decreased (136.6 vs. 107.3 pmol/g in wild-type or Oatp1b−/− mice, respectively) correlating with a decrease in exhaled 14CO2. These findings illustrate that deficiency of Oatp1b transporters alters the absorption, distribution, and elimination of hydroxyurea thus providing the first in vivo evidence that cell membrane transporters may play a significant role in modulating hydroxyurea PK. Future studies to investigate other transporters and their role in hydroxyurea disposition are warranted for understanding the sources of variation in hydroxyurea's PK. PMID:23986199

Study of alpha hemoglobin stabilizing protein expression in patients with β thalassemia and sickle cell anemia and its impact on clinical severity.

PubMed

Mahmoud, Hanan Mohamed; Shoeib, Ahmed Al-Saiid Hamed; Abd El Ghany, Shereen Mohamed; Reda, Marwa Mohamed; Ragab, Iman Ahmed

2015-12-01

The α hemoglobin stabilizing protein (AHSP) binds α-Hb and prevents its precipitation limiting free α-Hb toxicities. Our aim was to study AHSP expression in β thalassemia syndromes in relation to their clinical severity and to compare it with its level in sickle cell anemia. We compared patients with β-thalassemia (n=37) (β-thalassemia major (BTM) (n=19) and β-thalassemia intermedia (BTI) (n=18)) with 12 patients with sickle cell anemia as regards clinical severity, age at presentation, transfusion dependency, mean pre-transfusion hemoglobin level, use of hydroxyurea and AHSP expression by real time quantitative PCR. Median (and IQR) AHSP expression was significantly higher in patients with sickle cell anemia 2275 (3898) compared to thalassemia 283 (718), P=0.001, with no significant difference between BTM and BTI (P=0.346). It was also significantly higher in non-transfusion dependent patients with β thalassemia (NTDT) compared to transfusion dependent ones (P=0.019), and in patients on hydroxyurea therapy (P<0.001). However, there was no significant difference in its level according to clinical severity score (P=0.946) or splenectomy status (P=0.145). AHSP expression was higher in patients with sickle cell anemia versus thalassemia, with no significant difference between BTM and BTI. Expression was higher in patients with NTDT and on hydroxyurea therapy. Copyright © 2015 Elsevier Inc. All rights reserved.

L-glutamine for sickle cell anemia: more questions than answers.

PubMed

Quinn, Charles T

2018-06-12

In 2017, the Food and Drug Administration (FDA) approved two medications for sickle cell anemia (SCA): hydroxyurea for children (≥2 years of age) and L-glutamine for children and adults (≥5 years). The approval of hydroxyurea for children was long overdue, having been authorized by the FDA for adults in 1998 and by the European Medicines Agency for adults and children in 2007, but the approval of L-glutamine was a surprise to many in the field. There are few published studies of L-glutamine as a treatment for SCA, so all can be reviewed in this brief manuscript. Accordingly, there are many unanswered questions about L-glutamine and its role in current therapy for SCA. Copyright © 2018 American Society of Hematology.

Fertility challenges for women with sickle cell disease.

PubMed

Ghafuri, Djamila L; Stimpson, Sarah-Jo; Day, Melissa E; James, Andra; DeBaun, Michael R; Sharma, Deva

2017-10-01

Sickle cell disease (SCD) represents one of the most common monogenic blood disorders worldwide, with an incidence of over 300,000 newborns affected per year. Reproductive challenges for men and women with SCD have been previously reviewed; however, evidence-based strategies to prevent and manage infertility and increase fecundity are lacking in women with SCD, which is one of the most important factors for quality of life. Areas covered: This review article summarizes the known risk factors for infertility, low fecundity, and premature menopause related to SCD. Expert commentary: Women with SCD have unique risk factors that may impact their ability to conceive, including chronic inflammation, oxidative stress, transfusion-related hemochromatosis, and ovarian sickling, causing ischemia and reperfusion injury to the ovary. Contraception is strongly recommended while on hydroxyurea therapy during reproductive years and discontinuing hydroxyurea for family planning and during pregnancy based on teratogenicity in animal studies. Hematopoietic stem cell transplantation (HSCT), the only curative therapy, sometimes involves conditioning regimens containing alkylating agents and total body irradiation that contribute to infertility and premature ovarian failure. Prior to HSCT or gene therapy, we strongly recommend referral to a reproductive endocrinologist to discuss fertility preservation and surrogacy options for all women with SCD.

Stable-Isotope Dilution HPLC-Electrospray Ionization Tandem Mass Spectrometry Method for Quantifying Hydroxyurea in Dried Blood Samples.

PubMed

Marahatta, Anu; Megaraj, Vandana; McGann, Patrick T; Ware, Russell E; Setchell, Kenneth D R

2016-12-01

Sickle cell anemia (SCA) is a life-threatening blood disorder characterized by the presence of sickle-shaped erythrocytes. Hydroxyurea is currently the only US Food and Drug Administration-approved treatment and there is a need for a convenient method to monitor compliance and hydroxyurea concentrations, especially in pediatric SCA patients. We describe a novel approach to the determination of hydroxyurea concentrations in dried whole blood collected on DMPK-C cards or volumetric absorptive microsampling (VAMS) devices. Hydroxyurea was quantified by electrospray ionization LC-MS/MS using [ 13 C 15 N 2 ]hydroxyurea as the internal standard. Calibrators were prepared in whole blood applied to DMPK-C cards or VAMS devices. Calibration curves for blood hydroxyurea measured from DMPK-C cards and VAMS devices were linear over the range 0.5-60 μg/mL. Interassay and intraassay CVs were <15% for blood collected by both methods, and the limit of detection was 5 ng/mL. Whole blood hydroxyurea was stable for up to 60 days on DMPK-C cards and VAMS devices when frozen at -20 °C or -80 °C. Whole blood hydroxyurea concentrations in samples collected on DMPK-C cards or VAMS devices from SCA patients were in close agreement. This tandem mass spectrometry method permits measurement of hydroxyurea concentrations in small volumes of dried blood applied to either DMPK-C cards or VAMS devices with comparable performance. This method for measuring hydroxyurea from dried blood permits the evaluation of therapeutic drug monitoring, individual pharmacokinetics, and medication adherence using heel/finger-prick samples from pediatric patients with SCA treated with hydroxyurea. © 2016 American Association for Clinical Chemistry.

[Hydroxyurea-induced pneumonia].

PubMed

Girard, A; Ricordel, C; Poullot, E; Claeyssen, V; Decaux, O; Desrues, B; Delaval, P; Jouneau, S

2014-05-01

Hydroxyurea is an antimetabolite drug used in the treatment of myeloproliferative disorders. Common adverse effects include haematological, gastrointestinal cutaneous manifestations, and fever. Hydroxyurea-induced pneumonitis is unusual. A female patient was treated with hydroxyurea for polycythemia vera. She was admitted 20 days after commencing treatment with a high fever, productive cough, clear sputum and nausea. A chest CT-scan showed diffuse ground-glass opacities. Microbiological investigations were negative. The symptoms disappeared a few days after discontinuation of the drug and rechallenge led to a relapse of symptoms. Our case and 15 earlier cases of hydroxyurea-induced pneumonitis are reviewed. Two patterns of this disease may exist: an acute febrile form occurring within 1 month of introduction of hydroxyurea and a subacute form without fever. Even if uncommon, one should be aware of this complication of hydroxyurea. Copyright © 2013. Published by Elsevier Masson SAS.

Immunologic effects of hydroxyurea in sickle cell anemia.

PubMed

Lederman, Howard M; Connolly, Margaret A; Kalpatthi, Ram; Ware, Russell E; Wang, Winfred C; Luchtman-Jones, Lori; Waclawiw, Myron; Goldsmith, Jonathan C; Swift, Andrea; Casella, James F

2014-10-01

Susceptibility to encapsulated bacteria is well known in sickle cell disease (SCD). Hydroxyurea use is common in adults and children with SCD, but little is known about hydroxyurea's effects on immune function in SCD. Because hydroxyurea inhibits ribonucleotide reductase, causing cell cycle arrest at the G1-S interface, we postulated that hydroxyurea might delay transition from naive to memory T cells, with inhibition of immunologic maturation and vaccine responses. T-cell subsets, naive and memory T cells, and antibody responses to pneumococcal and measles, mumps, and rubella vaccines were measured among participants in a multicenter, randomized, double-blind, placebo-controlled trial of hydroxyurea in infants and young children with SCD (BABY HUG). Compared with placebo, hydroxyurea treatment resulted in significantly lower total lymphocyte, CD4, and memory T-cell counts; however, these numbers were still within the range of historical healthy controls. Antibody responses to pneumococcal vaccination were not affected, but a delay in achieving protective measles antibody levels occurred in the hydroxyurea group. Antibody levels to measles, mumps, and rubella showed no differences between groups at exit, indicating that effective immunization can be achieved despite hydroxyurea use. Hydroxyurea does not appear to have significant deleterious effects on the immune function of infants and children with SCD. Additional assessments of lymphocyte parameters of hydroxyurea-treated children may be warranted. No changes in current immunization schedules are recommended; however, for endemic disease or epidemics, adherence to accelerated immunization schedules for the measles, mumps, and rubella vaccine should be reinforced. Copyright © 2014 by the American Academy of Pediatrics.

Polycythemia Vera Management and Challenges in the Community Health Setting

PubMed Central

Gerds, Aaron T.; Dao, Kim-Hien

2017-01-01

Patients with polycythemia vera (PV) experience shortened survival, increased risk of thromboembolic and hemorrhagic events, and burdensome symptoms. For all patients with PV, treatment with aspirin and hematocrit control with phlebotomy are recommended. In addition, patients with high-risk status or poor hematocrit control benefit from cytoreductive therapy with hydroxyurea, although approximately 1 in 4 patients develops resistance or intolerance. For patients who are resistant to or intolerant of hydroxyurea, studies have shown that ruxolitinib, a Janus kinase 1/2 inhibitor, provides hematocrit control, reduces spleen size, normalizes blood counts, and improves PV-related symptoms. For many patients, PV is managed in a community health setting, and it is important that community hematologists, oncologists, and internists are familiar with the contemporary management of PV to improve patient outcomes, including management for patients who present with unique health-care needs. This review provides an overview of current treatment options for patients with PV and discusses challenging circumstances encountered by community providers in the management of PV, including symptom assessment, identification of hydroxyurea resistance/intolerance, pregnancy, elective surgeries, concomitant immunosuppressants, and managing patients in areas with limited access to specialized hematologic care. PMID:28095380

Secondary benefit of maintaining normal transcranial Doppler velocities when using hydroxyurea for prevention of severe sickle cell anemia.

PubMed

Ghafuri, Djamila Labib; Chaturvedi, Shruti; Rodeghier, Mark; Stimpson, Sarah-Jo; McClain, Brandi; Byrd, Jeannie; DeBaun, Michael R

2017-07-01

In a retrospective cohort study, we tested the hypothesis that when prescribing hydroxyurea (HU) to children with sickle cell anemia (SCA) to prevent vaso-occlusive events, there will be a secondary benefit of maintaining low transcranial Doppler (TCD) velocity, measured by imaging technique (TCDi). HU was prescribed for 90.9% (110 of 120) of children with SCA ≥5 years of age and followed for a median of 4.4 years, with 70% (n = 77) receiving at least one TCDi evaluation after starting HU. No child prescribed HU had a conditional or abnormal TCDi measurement. HU initiation for disease severity prevention decreases the prevalence of abnormal TCDi velocities. © 2016 Wiley Periodicals, Inc.

Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet.

PubMed

Barbui, Tiziano; Barosi, Giovanni; Birgegard, Gunnar; Cervantes, Francisco; Finazzi, Guido; Griesshammer, Martin; Harrison, Claire; Hasselbalch, Hans Carl; Hehlmann, Rudiger; Hoffman, Ronald; Kiladjian, Jean-Jacques; Kröger, Nicolaus; Mesa, Ruben; McMullin, Mary F; Pardanani, Animesh; Passamonti, Francesco; Vannucchi, Alessandro M; Reiter, Andreas; Silver, Richard T; Verstovsek, Srdan; Tefferi, Ayalew

2011-02-20

We present a review of critical concepts and produce recommendations on the management of Philadelphia-negative classical myeloproliferative neoplasms, including monitoring, response definition, first- and second-line therapy, and therapy for special issues. Key questions were selected according the criterion of clinical relevance. Statements were produced using a Delphi process, and two consensus conferences involving a panel of 21 experts appointed by the European LeukemiaNet (ELN) were convened. Patients with polycythemia vera (PV) and essential thrombocythemia (ET) should be defined as high risk if age is greater than 60 years or there is a history of previous thrombosis. Risk stratification in primary myelofibrosis (PMF) should start with the International Prognostic Scoring System (IPSS) for newly diagnosed patients and dynamic IPSS for patients being seen during their disease course, with the addition of cytogenetics evaluation and transfusion status. High-risk patients with PV should be managed with phlebotomy, low-dose aspirin, and cytoreduction, with either hydroxyurea or interferon at any age. High-risk patients with ET should be managed with cytoreduction, using hydroxyurea at any age. Monitoring response in PV and ET should use the ELN clinicohematologic criteria. Corticosteroids, androgens, erythropoiesis-stimulating agents, and immunomodulators are recommended to treat anemia of PMF, whereas hydroxyurea is the first-line treatment of PMF-associated splenomegaly. Indications for splenectomy include symptomatic portal hypertension, drug-refractory painful splenomegaly, and frequent RBC transfusions. The risk of allogeneic stem-cell transplantation-related complications is justified in transplantation-eligible patients whose median survival time is expected to be less than 5 years.

Philadelphia-Negative Classical Myeloproliferative Neoplasms: Critical Concepts and Management Recommendations From European LeukemiaNet

PubMed Central

Barbui, Tiziano; Barosi, Giovanni; Birgegard, Gunnar; Cervantes, Francisco; Finazzi, Guido; Griesshammer, Martin; Harrison, Claire; Hasselbalch, Hans Carl; Hehlmann, Rudiger; Hoffman, Ronald; Kiladjian, Jean-Jacques; Kröger, Nicolaus; Mesa, Ruben; McMullin, Mary F.; Pardanani, Animesh; Passamonti, Francesco; Vannucchi, Alessandro M.; Reiter, Andreas; Silver, Richard T.; Verstovsek, Srdan; Tefferi, Ayalew

2011-01-01

We present a review of critical concepts and produce recommendations on the management of Philadelphia-negative classical myeloproliferative neoplasms, including monitoring, response definition, first- and second-line therapy, and therapy for special issues. Key questions were selected according the criterion of clinical relevance. Statements were produced using a Delphi process, and two consensus conferences involving a panel of 21 experts appointed by the European LeukemiaNet (ELN) were convened. Patients with polycythemia vera (PV) and essential thrombocythemia (ET) should be defined as high risk if age is greater than 60 years or there is a history of previous thrombosis. Risk stratification in primary myelofibrosis (PMF) should start with the International Prognostic Scoring System (IPSS) for newly diagnosed patients and dynamic IPSS for patients being seen during their disease course, with the addition of cytogenetics evaluation and transfusion status. High-risk patients with PV should be managed with phlebotomy, low-dose aspirin, and cytoreduction, with either hydroxyurea or interferon at any age. High-risk patients with ET should be managed with cytoreduction, using hydroxyurea at any age. Monitoring response in PV and ET should use the ELN clinicohematologic criteria. Corticosteroids, androgens, erythropoiesis-stimulating agents, and immunomodulators are recommended to treat anemia of PMF, whereas hydroxyurea is the first-line treatment of PMF-associated splenomegaly. Indications for splenectomy include symptomatic portal hypertension, drug-refractory painful splenomegaly, and frequent RBC transfusions. The risk of allogeneic stem-cell transplantation–related complications is justified in transplantation-eligible patients whose median survival time is expected to be less than 5 years. PMID:21205761

Isotope-dilution gas chromatography-mass spectrometry method for the analysis of hydroxyurea.

PubMed

Garg, Uttam; Scott, David; Frazee, Clint; Kearns, Gregory; Neville, Kathleen

2015-06-01

Hydroxyurea is used in the treatment of various malignancies and sickle cell disease. There are limited studies on the pharmacokinetics of hydroxyurea, particularly in pediatric patients. An accurate, precise, and sensitive method is needed to support such studies and to monitor therapeutic adherence. We describe a novel gas chromatography-mass spectrometry (GC-MS) method for the determination of hydroxyurea concentration in plasma using stable labeled hydroxyurea C N2 as an internal standard. The method involved an organic extraction followed by the preparation of trimethylsilyl (TMS) derivatives of hydroxyurea for GC-MS selected ion-monitoring analysis. The following mass-to-charge (m/z) ratio ions for silated hydroxyurea and hydroxyurea C N2 were monitored: hydroxyurea-quantitative ion 277, qualifier ions 292 and 249; hydroxyurea C N2-quantitative ion 280, qualifier ion 295. This method was evaluated for reportable range, accuracy, within-run and between-run imprecisions, and limits of quantification. The reportable range for the method was 0.1-100 mcg/mL. All results were accurate within an allowable error of 15%. Within-run and between-run imprecisions were <15%. Samples were stable for at least 4 hours at room temperature, 2 months at -20°C, and 6 months at -70°C, and after 3 freeze/thaw cycles. Extraction efficiency for 1-, 5-, 10-, and 50-mcg/mL samples averaged 2.2%, 1.8%, 1.6%, and 1.4%, respectively. The isotope-dilution GC-MS method for analysis of hydroxyurea described here is accurate, sensitive, precise, and robust. Its characteristics make the method suitable for supporting pharmacokinetic studies and/or clinical therapeutic monitoring.

Hydroxyurea-induced oral ulceration.

PubMed

Badawi, Maha; Almazrooa, Soulafa; Azher, Fatima; Alsayes, Fatin

2015-12-01

Hydroxyurea is an antimetabolite that is widely used in the treatment of many benign and malignant conditions. This drug is usually well tolerated but has a number of side effects that vary in incidence. In cases of clinically significant adverse events, hydroxyurea is usually discontinued either temporarily or permanently, depending on treatment need versus harm caused by side effects. Here, we report a case of oral ulceration associated with hydroxyurea treatment in a patient who had chronic myelogenous leukemia. The patient rapidly developed an oral ulcer 12 days after administration of the drug. Hydroxyurea was discontinued, and the oral lesion appreciably decreased in size and severity. Physicians and dentists should be aware of the association between hydroxyurea and oral lesions. Copyright © 2015 Elsevier Inc. All rights reserved.

Immunologic Effects of Hydroxyurea in Sickle Cell Anemia

PubMed Central

Lederman, Howard M.; Connolly, Margaret A.; Kalpatthi, Ram; Ware, Russell E.; Wang, Winfred C.; Luchtman-Jones, Lori; Waclawiw, Myron; Goldsmith, Jonathan C.; Swift, Andrea

2014-01-01

BACKGROUND AND OBJECTIVE: Susceptibility to encapsulated bacteria is well known in sickle cell disease (SCD). Hydroxyurea use is common in adults and children with SCD, but little is known about hydroxyurea’s effects on immune function in SCD. Because hydroxyurea inhibits ribonucleotide reductase, causing cell cycle arrest at the G1–S interface, we postulated that hydroxyurea might delay transition from naive to memory T cells, with inhibition of immunologic maturation and vaccine responses. METHODS: T-cell subsets, naive and memory T cells, and antibody responses to pneumococcal and measles, mumps, and rubella vaccines were measured among participants in a multicenter, randomized, double-blind, placebo-controlled trial of hydroxyurea in infants and young children with SCD (BABY HUG). RESULTS: Compared with placebo, hydroxyurea treatment resulted in significantly lower total lymphocyte, CD4, and memory T-cell counts; however, these numbers were still within the range of historical healthy controls. Antibody responses to pneumococcal vaccination were not affected, but a delay in achieving protective measles antibody levels occurred in the hydroxyurea group. Antibody levels to measles, mumps, and rubella showed no differences between groups at exit, indicating that effective immunization can be achieved despite hydroxyurea use. CONCLUSIONS: Hydroxyurea does not appear to have significant deleterious effects on the immune function of infants and children with SCD. Additional assessments of lymphocyte parameters of hydroxyurea-treated children may be warranted. No changes in current immunization schedules are recommended; however, for endemic disease or epidemics, adherence to accelerated immunization schedules for the measles, mumps, and rubella vaccine should be reinforced. PMID:25180279

Transcellular movement of hydroxyurea is mediated by specific solute carrier transporters

PubMed Central

Walker, Aisha L.; Franke, Ryan M.; Sparreboom, Alex; Ware, Russell E.

2015-01-01

Objective Hydroxyurea has proven laboratory and clinical therapeutic benefits for sickle cell anemia (SCA) and other diseases, yet many questions remain regarding its in vivo pharmacokinetic and pharmacodynamic profiles. Previous reports suggest that hydroxyurea passively diffuses across cells, but its observed rapid absorption and distribution are more consistent with facilitated or active transport. We investigated the potential role of solute carrier (SLC) transporters in cellular uptake and accumulation of hydroxyurea. Materials and Methods Passive diffusion of hydroxyurea across cell membranes was determined using the parallel artificial membrane permeability assay. SLC transporter screens were conducted using in vitro intracellular drug accumulation and transcellular transport assays in cell lines and oocytes overexpressing SLC transporters. Gene expression of SLC transporters was measured by real-time PCR in human tissues and cell lines. Results Hydroxyurea had minimal diffusion across a lipid bilayer but was a substrate for 5 different SLC transporters belonging to the OCTN and OATP families of transporters and urea transporters A and B. Further characterization of hydroxyurea transport revealed that cellular uptake by OATP1B3 is time and temperature dependent and inhibited by known substrates of OATP1B3. Urea transporters A and B are expressed differentially in human tissues and erythroid cells, and transport hydroxyurea bidirectionally via facilitated diffusion. Conclusions These studies provide new insight into drug transport proteins that may be involved in the in vivo absorption, cellular distribution, and elimination of hydroxyurea. Elucidation of hydroxyurea transcellular movement should improve our understanding of its pharmacokinetics and pharmacodynamics, and may help explain some of the inter-patient drug variability observed in patients with SCA. PMID:21256917

Phase II study of imatinib mesylate and hydroxyurea for recurrent grade III malignant gliomas.

PubMed

Desjardins, Annick; Quinn, Jennifer A; Vredenburgh, James J; Sathornsumetee, Sith; Friedman, Allan H; Herndon, James E; McLendon, Roger E; Provenzale, James M; Rich, Jeremy N; Sampson, John H; Gururangan, Sridharan; Dowell, Jeannette M; Salvado, August; Friedman, Henry S; Reardon, David A

2007-05-01

Recent reports demonstrate the activity of imatinib mesylate, an ATP-mimetic, tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, in patients with recurrent glioblastoma multiforme. We performed the current phase 2 study to evaluate this regimen among patients with recurrent WHO grade III malignant glioma (MG). Patients with grade III MG at any recurrence, received imatinib mesylate plus hydroxyurea (500 mg twice a day) orally on a continuous, daily schedule. The imatinib mesylate dose was 500 mg twice a day for patients on enzyme inducing anti-epileptic drugs (EIAEDs) and 400 mg once a day for those not on EIAEDs. Clinical assessments were performed monthly and radiographic assessments were obtained at least every 2 months. The primary endpoint was 6-month progression-free survival (PFS) rate. Thirty-nine patients were enrolled. All patients had progressive disease after prior radiotherapy and at least temozolomide-based chemotherapy. The median number of episodes of prior progression was 2 (range, 1-7) and the median number of prior treatment regimens was 3 (range, 1-8). With a median follow-up of 82.9 weeks, 24% of patients were progression-free at 6 months. The radiographic response rate was 10%, while 33% achieved stable disease. Among patients who achieved at least stable disease at first evaluation, the 6-month and 12-month PFS rates were 53% and 29%, respectively. The most common grade 3 or greater toxicities were hematologic and complicated less than 4% of administered courses. Imatinib mesylate plus hydroxyurea, is well tolerated and associated with anti-tumor activity in some patients with recurrent grade 3 MG.

Hydroxyurea for sickle cell anemia: What have we learned and what questions still remain?

PubMed Central

McGann, Patrick T.; Ware, Russell E.

2011-01-01

Purpose of review Sickle cell anemia (SCA) is a well-characterized severe hematological disorder with substantial morbidity and early mortality. Hydroxyurea is a potent inducer of fetal hemoglobin, and evidence over the past 25 years has documented its laboratory and clinical efficacy for both adults and children with SCA. Recent findings The Phase III study of hydroxyurea in infants (BABY HUG) has just been completed and preliminary results indicate equivocal benefits for organ protection during the two-year treatment period, but significant benefits for pain, acute chest syndrome, hospitalizations, and transfusions. Three new reports document the benefits of hydroxyurea on reducing mortality in SCA: two adult trials (LaSHS and MSH) and one pediatric study (Brazilian cohort). Recent results from the HUSTLE protocol suggest minimal genotoxicity or carcinogenicity with long-term hydroxyurea exposure. Summary The potential utility of hydroxyurea for all patients with SCA is clear and indisputable. With decades of accumulated evidence and documented efficacy with an acceptable long-term safety profile, it is time to consider hydroxyurea treatment the standard of care for all young patients with SCA. Exporting our knowledge and experience with hydroxyurea to developing nations with large medical burdens from SCA can help relieve global suffering from this condition. PMID:21372708

Key endothelial cell angiogenic mechanisms are stimulated by the circulating milieu in sickle cell disease and attenuated by hydroxyurea

PubMed Central

Lopes, Flavia C. M.; Traina, Fabiola; Almeida, Camila B.; Leonardo, Flavia C.; Franco-Penteado, Carla F.; Garrido, Vanessa T.; Colella, Marina P.; Soares, Raquel; Olalla-Saad, Sara T.; Costa, Fernando F.; Conran, Nicola

2015-01-01

As hypoxia-induced inflammatory angiogenesis may contribute to the manifestations of sickle cell disease, we compared the angiogenic molecular profiles of plasma from sickle cell disease individuals and correlated these with in vitro endothelial cell-mediated angiogenesis-stimulating activity and in vivo neovascularization. Bioplex demonstrated that plasma from patients with steady-state sickle cell anemia contained elevated concentrations of pro-angiogenic factors (angiopoietin-1, basic fibroblast growth factor, vascular endothelial growth factor, vascular endothelial growth factor-D and placental growth factor) and displayed potent pro-angiogenic activity, significantly increasing endothelial cell proliferation, migration and capillary-like structure formation. In vivo neovascularization of Matrigel plugs was significantly greater in sickle cell disease mice than in non-sickle cell disease mice, consistent with an up-regulation of angiogenesis in the disease. In plasma from patients with hemoglobin SC disease without proliferative retinopathy, anti-angiogenic endostatin and thrombospondin-2 were significantly elevated. In contrast, plasma from hemoglobin SC individuals with proliferative retinopathy had a pro-angiogenic profile and more significant effects on endothelial cell proliferation and capillary formation than plasma from patients without retinopathy. Hydroxyurea therapy was associated with significant reductions in plasma angiogenic factors and inhibition of endothelial cell-mediated angiogenic mechanisms and neovascularization. Thus, individuals with sickle cell anemia or hemoglobin SC disease with retinopathy present a highly angiogenic circulating milieu, capable of stimulating key endothelial cell-mediated angiogenic mechanisms. Combination anti-angiogenic therapy to prevent the progression of unregulated neovascularization and associated manifestations in sickle cell disease, such as pulmonary hypertension, may be indicated; furthermore, the benefits and drawbacks of the potent anti-angiogenic effects of hydroxyurea should be clarified. PMID:25769545

Amphiphilic lipid derivatives of 3'-hydroxyurea-deoxythymidine: preparation, properties, molecular self-assembly, simulation and in vitro anticancer activity.

PubMed

Li, Miao; Qi, Shuo; Jin, Yiguang; Yao, Weishang; Zhang, Sa; Zhao, Jingyu

2014-11-01

Lipid derivatives of nucleoside analogs and their nanoassemblies have become the research hotspot due to their unique function in cancer therapy. Six lipid derivatives of 3'-hydroxyurea-deoxythymidine were prepared with zidovudine as the raw material. The 5'-substituted lipid chains in the derivatives were from the various fatty acids including octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid, hexadecanoic acid and octadecanoic acid corresponding to the derivatives OHT, DHT, DDHT, TDHT, HDHT and ODHT. The amphiphilic derivatives formed Langmuir monolayers at the air/water interface with different surface pressure-molecular area isotherms depending on the length of lipid chains. The nanoassemblies of OHT, DHT, DDHT, TDHT and HDHT and the nanoscale precipitates of ODHT were obtained after we injected their tetrahydrofuran solutions doped with hydrophilic long chained polymers into water. Electron microscopy showed that the morphology of nanoassemblies may be vesicles or nanotubes depending on the length of lipid chains. The shorter the lipid chains were, the softer the nanoassemblies. Computer simulation supported the experimental results. The nanoassemblies and the nanoscale precipitates showed much higher anticancer effects on SW620 cells than the parent drug hydroxyurea. The nanostructures of the derivatives are promising anticancer nanomedicines. Copyright © 2014 Elsevier B.V. All rights reserved.

Adherence to hydroxyurea, health-related quality of life domains, and patients' perceptions of sickle cell disease and hydroxyurea: a cross-sectional study in adolescents and young adults.

PubMed

Badawy, Sherif M; Thompson, Alexis A; Lai, Jin-Shei; Penedo, Frank J; Rychlik, Karen; Liem, Robert I

2017-07-05

Sickle cell disease (SCD) patients have impaired domains of health-related quality of life (HRQOL). Hydroxyurea is safe and efficacious in SCD; however, adherence is suboptimal, and patients' perceptions are poorly understood amongst adolescents and young adults (AYA). Study objectives were to: (1) examine patients' perceptions of SCD and hydroxyurea; and (2) explore the relationship of their perceptions to clinical characteristics, HRQOL domains and hydroxyurea adherence. Thirty-four SCD patients on hydroxyurea (≥6 months) participated in a single-institution study. Study measures included Brief-Illness Perceptions Questionnaire, ©Modified Morisky Adherence Scale 8-items, and Patient Reported Outcomes Measurement Information System (PROMIS®). We assessed the relationship of patients' perceptions to hydroxyurea adherence using Wilcoxon rank-sum test, the number of hospitalizations using Kruskal-Wallis test, and the number of ED visits, adherence level, HRQOL domain scores using Spearman's rho correlations. We conducted a sub-analysis in HbSS patients to evaluate the relationship of patients' perceptions to laboratory markers of hydroxyurea adherence. Participants were 59% male and 91% Black, and had a median age of 13.5 (range 12-18) years. Participants with ≥4 hospitalizations over 1-year prior (using electronic medical chart review) reported more negative perceptions of SCD-related symptoms and emotional response, and perceived hydroxyurea as less beneficial; all p-values ≤0.01. Most participants (74%) reported low hydroxyurea adherence. Participants with higher hydroxyurea adherence perceived more hydroxyurea benefits (r s  = 0.44, p < 0.01) and had better emotional response to SCD (r s  = -0.44, p = 0.01). In a sub-analysis of HbSS patients, perceived benefits of hydroxyurea positively correlated with HbF (r s  = 0.37, p = 0.05) and MCV values (r s  = 0.35, p = 0.05). Participants with more negative perceptions of SCD-related consequences, concerns, and emotional response, and fewer perceived hydroxyurea benefits reported worse fatigue (r s  = 0.68; r s  = 0.44; r s  = 0.74; r s  = -0.60), pain (r s  = 0.56; r s  = 0.54; r s  = 0.63; r s  = -0.39), anxiety (r s  = 0.55; r s  = 0.58; r s  = 0.56; r s  = -0.47), and depression (r s  = 0.64; r s  = 0.49; r s  = 0.70; r s  = -0.62), respectively, all p-values <0.05. Dynamics influencing hydroxyurea adherence are multifactorial, and understanding patients' perceptions is critical to overcoming adherence barriers. Patients' favorable perceptions correlated with greater adherence and better HRQOL domain scores. Prospective evaluation of patients' perceptions of SCD and hydroxyurea in relation adherence, HRQOL domains and clinical outcomes is warranted.

Soluble fms-Like Tyrosine Kinase 1 as a Link Between Angiogenesis and Endothelial Dysfunction in Pediatric Patients With β-Thalassemia Intermedia.

PubMed

Tantawy, Azza Abdel Gawad; Adly, Amira Abdel Moneam; Ismail, Eman Abdel Rahman; Youssef, Omneya Ibrahim; Ali, Mohamed ElSayed

2017-11-01

Endothelial damage has been implicated in the pathogenesis of vascular complications in β-thalassemia intermedia (β-TI). Soluble fms-like tyrosine kinase 1 (sFLT-1) is a member of the vascular endothelial growth factor receptor (VEGFR) family. Soluble fms-like tyrosine kinase 1 is an antiangiogenic protein that induces endothelial dysfunction by adhering to and inhibiting VEGF and placenta growth factor. The aim of this study was to assess the level of sFLT-1 in 35 children and adolescents with β-TI, correlating it with markers of hemolysis and iron overload as well as cardiopulmonary complications. Patients were studied focusing on the history of cardiac disease, splenectomy, transfusion, chelation/hydroxyurea therapy, serum ferritin, and sFLT-1 levels. Echocardiography and measurement of carotid intima-media thickness (CIMT) were done for all participants. Soluble fms-like tyrosine kinase 1 was significantly higher in TI patients compared to the control group (median [interquartile range], 110 [80-155] pg/mL versus 70 [60-90] pg/mL; P < .001). Splenectomized patients and those who had pulmonary hypertension risk or heart disease had higher sFLT-1 levels than those without ( P < .001). The sFLT-1 cutoff value that differentiates patients with and without pulmonary hypertension risk or heart disease was determined. Soluble fms-like tyrosine kinase 1 was lower among patients who received chelation therapy and/or hydroxyurea. Significant positive relations were observed between sFLT-1 and lactate dehydrogenase, serum ferritin, liver iron concentration, tricuspid regurgitant jet velocity, and CIMT. We suggest that sFLT-1 represents a link between angiogenesis, endothelial dysfunction, and subclinical atherosclerosis. Measurement of sFLT-1 as a marker of vascular dysfunction in β-TI may provide utility for early identification of patients at increased risk of cardiopulmonary complications.

ARQ 092, an orally-available, selective AKT inhibitor, attenuates neutrophil-platelet interactions in sickle cell disease

PubMed Central

Kim, Kyungho; Li, Jing; Barazia, Andrew; Tseng, Alan; Youn, Seock-Won; Abbadessa, Giovanni; Yu, Yi; Schwartz, Brian; Andrews, Robert K.; Gordeuk, Victor R.; Cho, Jaehyung

2017-01-01

Previous studies identified the Ser/Thr protein kinase, AKT, as a therapeutic target in thrombo-inflammatory diseases. Here we report that specific inhibition of AKT with ARQ 092, an orally-available AKT inhibitor currently in phase Ib clinical trials as an anti-cancer drug, attenuates the adhesive function of neutrophils and platelets from sickle cell disease patients in vitro and cell-cell interactions in a mouse model of sickle cell disease. Studies using neutrophils and platelets isolated from sickle cell disease patients revealed that treatment with 50–500 nM ARQ 092 significantly blocks αMβ2 integrin function in neutrophils and reduces P-selectin exposure and glycoprotein Ib/IX/V-mediated agglutination in platelets. Treatment of isolated platelets and neutrophils with ARQ 092 inhibited heterotypic cell-cell aggregation under shear conditions. Intravital microscopic studies demonstrated that short-term oral administration of ARQ 092 or hydroxyurea, a major therapy for sickle cell disease, diminishes heterotypic cell-cell interactions in venules of sickle cell disease mice challenged with tumor necrosis factor-α. Co-administration of hydroxyurea and ARQ 092 further reduced the adhesive function of neutrophils in venules and neutrophil transmigration into alveoli, inhibited expression of E-selectin and intercellular adhesion molecule-1 in cremaster vessels, and improved survival in these mice. Ex vivo studies in sickle cell disease mice suggested that co-administration of hydroxyurea and ARQ 092 efficiently blocks neutrophil and platelet activation and that the beneficial effect of hydroxyurea results from nitric oxide production. Our results provide important evidence that ARQ 092 could be a novel drug for the prevention and treatment of acute vaso-occlusive complications in patients with sickle cell disease. PMID:27758820

Effect of Hydroxyurea on Staphylococcus epidermidis and Micrococcus lysodeikticus: Thickening of the Cell Wall

PubMed Central

Feiner, Rose R.; Coward, Joe E.; Rosenkranz, Herbert S.

1973-01-01

Hydroxyurea-sensitive strains of Staphylococcus epidermidis and Micrococcus lysodeikticus showed marked thickening of cell walls and reduction in deoxyribonucleic acid synthesis when grown in the presence of hydroxyurea. Images PMID:4790602

Deprenyl Enhances the Teratogenicity of Hydroxyurea in Organogenesis Stage Mouse Embryos

PubMed Central

Schlisser, Ava E.; Hales, Barbara F.

2013-01-01

Hydroxyurea, an antineoplastic drug, is a model teratogen. The administration of hydroxyurea to CD1 mice on gestation day 9 induces oxidative stress, increasing the formation of 4-hydroxy-2-nonenal adducts to redox-sensitive proteins such as glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in the caudal region of the embryo. GAPDH catalytic activity is reduced, and its translocation into the nucleus is increased. Because the nuclear translocation of GAPDH is associated with oxidative stress–induced cell death, we hypothesized that this translocation plays a role in mediating the teratogenicity of hydroxyurea. Deprenyl (also known as selegiline), a drug used as a neuroprotectant in Parkinson’s disease, inhibits the nuclear translocation of GAPDH. Hence, timed pregnant CD1 mice were treated with deprenyl (10mg/kg) on gestation day 9 followed by the administration of hydroxyurea (400 or 600mg/kg). Deprenyl treatment significantly decreased the hydroxyurea-induced nuclear translocation of GAPDH in the caudal lumbosacral somites. Deprenyl enhanced hydroxyurea-mediated caudal malformations, inducing specifically limb reduction, digit anomalies, tail defects, and lumbosacral vertebral abnormalities. Deprenyl did not augment the hydroxyurea-induced inhibition of glycolysis or alter the ratio of oxidized to reduced glutathione. However, it did dramatically increase cleaved caspase-3 in embryos. These data suggest that nuclear GAPDH plays an important, region-specific, role in teratogen-exposed embryos. Deprenyl exacerbated the developmental outcome of hydroxyurea exposure by a mechanism that is independent of oxidative stress. Although the administration of deprenyl alone did not affect pregnancy outcome, this drug may have adverse consequences when combined with exposures that increase the risk of malformations. PMID:23696560

Original Research: Parvovirus B19 infection in children with sickle cell disease in the hydroxyurea era

PubMed Central

Penkert, Rhiannon R; Lavoie, Paul; Tang, Li; Sun, Yilun; Hurwitz, Julia L

2016-01-01

Parvovirus B19 infection causes transient aplastic crisis in sickle cell disease (SCD) due to a temporary interruption in the red blood cell production. Toxicity from hydroxyurea includes anemia and reticulocytopenia, both of which also occur during a transient aplastic crisis event. Hydroxyurea inhibits proliferation of hematopoietic cells and may be immunosuppressive. We postulated that hydroxyurea could exacerbate parvovirus B19-induced aplastic crisis and inhibit the development of specific immune responses in children with SCD. We conducted a retrospective review of parvovirus B19 infection in 330 children with SCD. Altogether there were 120 known cases of aplastic crisis attributed to parvovirus B19 infection, and 12% of children were on hydroxyurea treatment during the episode. We evaluated hematological and immune responses. Children with HbSS or HbSβ0-thalassemia treated with hydroxyurea, when compared with untreated children, required fewer transfusions and had higher Hb concentration nadir during transient aplastic crisis. Duration of hospital stays was no different between hydroxyurea-treated and untreated groups. Children tested within a week following aplastic crisis were positive for parvovirus-specific IgG. Immune responses lasted for the duration of the observation period, up to 13 years after transient aplastic crisis, and there were no repeat aplastic crisis episodes. The frequencies of parvovirus-specific antibodies in all children with SCD increased with age, as expected due to the increased likelihood of a parvovirus exposure, and were comparable to frequencies reported for healthy children. Approximately one-third of children had a positive parvovirus B19-specific IgG test without a documented history of transient aplastic crisis, and 64% of them were treated with hydroxyurea. Hydroxyurea may reduce requirements for blood transfusions and may attenuate symptoms during transient aplastic crisis episodes caused by parvovirus B19 infections. Children with SCD, whether treated or untreated with hydroxyurea, generate sustained and protective parvovirus B19-specific immune responses. PMID:26940953

Original Research: Parvovirus B19 infection in children with sickle cell disease in the hydroxyurea era.

PubMed

Hankins, Jane S; Penkert, Rhiannon R; Lavoie, Paul; Tang, Li; Sun, Yilun; Hurwitz, Julia L

2016-04-01

Parvovirus B19 infection causes transient aplastic crisis in sickle cell disease (SCD) due to a temporary interruption in the red blood cell production. Toxicity from hydroxyurea includes anemia and reticulocytopenia, both of which also occur during a transient aplastic crisis event. Hydroxyurea inhibits proliferation of hematopoietic cells and may be immunosuppressive. We postulated that hydroxyurea could exacerbate parvovirus B19-induced aplastic crisis and inhibit the development of specific immune responses in children with SCD. We conducted a retrospective review of parvovirus B19 infection in 330 children with SCD. Altogether there were 120 known cases of aplastic crisis attributed to parvovirus B19 infection, and 12% of children were on hydroxyurea treatment during the episode. We evaluated hematological and immune responses. Children with HbSS or HbSβ(0)-thalassemia treated with hydroxyurea, when compared with untreated children, required fewer transfusions and had higher Hb concentration nadir during transient aplastic crisis. Duration of hospital stays was no different between hydroxyurea-treated and untreated groups. Children tested within a week following aplastic crisis were positive for parvovirus-specific IgG. Immune responses lasted for the duration of the observation period, up to 13 years after transient aplastic crisis, and there were no repeat aplastic crisis episodes. The frequencies of parvovirus-specific antibodies in all children with SCD increased with age, as expected due to the increased likelihood of a parvovirus exposure, and were comparable to frequencies reported for healthy children. Approximately one-third of children had a positive parvovirus B19-specific IgG test without a documented history of transient aplastic crisis, and 64% of them were treated with hydroxyurea. Hydroxyurea may reduce requirements for blood transfusions and may attenuate symptoms during transient aplastic crisis episodes caused by parvovirus B19 infections. Children with SCD, whether treated or untreated with hydroxyurea, generate sustained and protective parvovirus B19-specific immune responses. © 2016 by the Society for Experimental Biology and Medicine.

[Hydroxyurea (hydroxycarbamide)-induced hepatic dysfunction confirmed by drug-induced lymphocyte stimulation test].

PubMed

Shimizu, Takayuki; Mori, Takehiko; Karigane, Daiki; Kikuchi, Taku; Koda, Yuya; Toyama, Takaaki; Nakajima, Hideaki; Okamoto, Shinichiro

2014-01-01

A 62-year-old man with refractory leukemia transformed from myelodysplastic syndrome was placed on hydroxyurea (hydroxycarbamide) at a daily dose of 500 mg. Because of insufficient cytoreductive efficacy, the dose was increased to 1,500 mg five days later. Eight days after the initiation of hydroxyurea, the patient started complaining of chills, fever, and vomiting. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were markedly elevated to 5,098 and 3,880 IU/l from 44 and 59 IU/l in one day, respectively. Tests for hepatitis viruses were all negative. With the discontinuation of hydroxyurea, AST and ALT returned to their former levels within two weeks. A drug-induced lymphocyte stimulation test for hydroxyurea was positive with a stimulating index of 2.0. Hepatic dysfunction has been recognized as one of the side effects of hydroxyurea. However, there have been only a limited number of reports demonstrating drug allergy to have a role in hepatic dysfunction accompanied by fever and gastrointestinal symptoms. The findings of our case strongly suggest that all presentations could be explained by drug allergy. Physicians should be mindful of the potential for acute and severe hepatic dysfunction due to allergic reaction against hydroxyurea.

Splanchnic vein thrombosis in myeloproliferative neoplasms: treatment algorithm 2018.

PubMed

Finazzi, Guido; De Stefano, Valerio; Barbui, Tiziano

2018-06-26

Myeloproliferative neoplasms (MPNs) are a leading cause of splanchnic vein thrombosis (SVT). SVT is observed in all MPNs and frequently affects young patients. Therapy should be addressed to three main goals: preventing thrombosis recurrence, managing the underlying MPN, and supporting liver dysfunction. Life-long oral anticoagulation with vitamin K antagonists is the cornerstone of the antithrombotic treatment. However, recurrences of SVT or other thrombosis may occur in 15-20% of patients. Direct oral anticoagulants can represent an alternative and preliminary data encourage comparative studies. Survival of patients with SVT in MPN is primarily influenced by the natural history of the underlying neoplasms, rather than the SVT event. An aggressive management is recommended and a treatment algorithm based on the different MPN subtypes is proposed. Hydroxyurea is the cytoreductive drug of choice in polycythemia vera and essential thrombocythemia, whereas ruxolitinib is indicated in intermediate and high-risk patients with myelofibrosis and in PV patients resistant or intolerant to hydroxyurea. The management of SVT in MPNs requires a multidisciplinary approach that may include a hematologist, a gastroenterologist, an interventional radiologist, and a surgeon. In the case of clinical deterioration despite pharmacological therapy, patients with SVT should be considered for invasive procedures or liver transplantation.

Use patterns of first-line inhibitors of tyrosine kinase and time to change to second-line therapy in chronic myeloid leukemia.

PubMed

Machado-Alba, Jorge Enrique; Machado-Duque, Manuel Enrique

2017-08-01

Background Chronic myeloid leukemia (CML) has a low incidence but a high burden of disease, and is treated with high-cost tyrosine kinase inhibitors (TKI). Objective To determine the time from the start of a first-line TKI until it passes to second-line, and to establish the reasons for the change of therapy time. Setting Patients with Philadelphia-positive CML treated with some TKI. Methods Retrospective cohort study, between January 1 2007 and July 31 2015, with information obtained from medical records, the time to change initial drugs to secondline therapy, and the reasons for change, were identified. Kaplan-Meier survival analysis was carried out. Main outcome measure A change in therapy to the secondline TKI and the final reason for the change of therapy. Results A total of 247 patients treated were found in 22 cities in Colombia with a mean age of 53.2 ± 15.2 years. The drug most used as initial therapy was imatinib; 53.8% of cases had to change to another TKI. 50% of patients changed therapy in 42 months, men in 24 and women in 67 months (95% CI 14.314-33.686; p = 0.001). Being male (OR 2.23; 95% CI 1.291-3.854; p = 0.004) and receiving hydroxyurea (OR 3.65; 95% CI 1.601-8.326; p = 0.002) were associated with a higher probability of switching to nilotinib or dasatinib, while receiving a new-generation TKI (OR 0.15; 95% CI 0.071-0.341; p < 0.001) reduced this risk. Conclusions A high proportion of patients needed to change to a second line with nilotinib and dasatinib management. It is necessary to obtain more real world evidence, to improve the effectiveness, adherence and safety of the treatment.

Survival among children and adults with sickle cell disease in Belgium: Benefit from hydroxyurea treatment.

PubMed

Lê, Phu Quoc; Gulbis, Béatrice; Dedeken, Laurence; Dupont, Sophie; Vanderfaeillie, Anna; Heijmans, Catherine; Huybrechts, Sophie; Devalck, Christine; Efira, André; Dresse, Marie-Françoise; Rozen, Laurence; Benghiat, Fleur Samantha; Ferster, Alina

2015-11-01

To evaluate the survival of patients with sickle cell disease (SCD) recorded in the Belgian SCD Registry and to assess the impact of disease-modifying treatments (DMT). The Registry created in 2008 included patients of eight centers. All available data in 2008 were retrospectively encoded in the database. After 2008 and until 2012, all data were recorded prospectively for already registered patients as well as newly diagnosed subjects. Data were registered from neonatal screening or from diagnosis (first contact) until last follow-up or death. Data included diagnosis, demography, and outcome data. We collected data from 469 patients over a 5,110 patient years (PY) follow-up period. The global mortality rate was low (0.25/100 PY), although 13 patients died (2.8%) and was similar between children, adolescents (10-18 years), and young adults (P = 0.76). Out of the cohort, 185 patients received hydroxyurea at last follow-up (median duration of treatment: 10.3 years), 90 underwent hematopoietic stem cell transplantation (HSCT), 24 were chronically transfused, and 170 had never had any DMT. Hydroxyurea showed significant benefit on patients outcome as reflected by a lower mortality rate compared to transplanted individuals or people without DMT (0.14, 0.36, and 0.38 per 100 PY, respectively) and by higher Kaplan-Meier estimates of 15 year survival (99.4%) compared to HSCT (93.8%; P = 0.01) or no DMT groups (95.4%; P = 0.04). SCD mortality in Belgium is low with no increase observed in young adults. Patients treated with hydroxyurea demonstrate a significant benefit in survival when compared to those without DMT or transplanted. © 2015 Wiley Periodicals, Inc.

Blood transfusion versus hydroxyurea in beta-thalassemia in Iran: a cost-effectiveness study.

PubMed

Ravangard, Ramin; Mirzaei, Zahra; Keshavarz, Khosro; Haghpanah, Sezaneh; Karimi, Mehran

2017-11-21

Thalassemia intermedia is a type of anemia which has several treatments modalities. We aimed to study the cost effectiveness of two treatments, including blood transfusion and hydroxyurea, in patients with beta-thalassemia intermedia in south of Iran referred to a referral center affiliated to Iran, Shiraz University of Medical Sciences in 2015. This was a cost-effectiveness study which was conducted on 122 patients with beta-thalassemia intermedia. The indicator of effectiveness in this study was the reduction of growth disorder (normal BMI). Data analysis was done using SPSS 21, Excel 2010 and Treeage 2011. Finally, the one-way sensitivity analysis was performed to determine the robustness of the results. The average annual costs of blood transfusion and the use of hydroxyurea in 2015 were 20733.27 purchasing power parity (PPP)$ and 7040.29 PPP$, respectively. The effectiveness of blood transfusion was57.4% while in hydroxyurea group was 60.7%. The results showed that the cost effectiveness of using hydroxyurea was more than that of blood transfusion. Therefore, it is recommended that the use of hydroxyurea in the treatment of patients with beta-thalassemia intermedia would become the first priority, and more basic and supplementary insurance coverage for treating such patients using hydroxyurea should be considered.

Widespread Natural Occurrence of Hydroxyurea in Animals.

PubMed

Fraser, David I; Liu, Kyle T; Reid, Bryan J; Hawkins, Emily; Sevier, Andrew; Pyle, Michelle; Robinson, Jacob W; Ouellette, Pierre H R; Ballantyne, James S

2015-01-01

Here we report the widespread natural occurrence of a known antibiotic and antineoplastic compound, hydroxyurea in animals from many taxonomic groups. Hydroxyurea occurs in all the organisms we have examined including invertebrates (molluscs and crustaceans), fishes from several major groups, amphibians and mammals. The species with highest concentrations was an elasmobranch (sharks, skates and rays), the little skate Leucoraja erinacea with levels up to 250 μM, high enough to have antiviral, antimicrobial and antineoplastic effects based on in vitro studies. Embryos of L. erinacea showed increasing levels of hydroxyurea with development, indicating the capacity for hydroxyurea synthesis. Certain tissues of other organisms (e.g. skin of the frog (64 μM), intestine of lobster (138 μM) gills of the surf clam (100 μM)) had levels high enough to have antiviral effects based on in vitro studies. Hydroxyurea is widely used clinically in the treatment of certain human cancers, sickle cell anemia, psoriasis, myeloproliferative diseases, and has been investigated as a potential treatment of HIV infection and its presence at high levels in tissues of elasmobranchs and other organisms suggests a novel mechanism for fighting disease that may explain the disease resistance of some groups. In light of the known production of nitric oxide from exogenously applied hydroxyurea, endogenous hydoxyurea may play a hitherto unknown role in nitric oxide dynamics.

Widespread Natural Occurrence of Hydroxyurea in Animals

PubMed Central

Fraser, David I.; Liu, Kyle T.; Reid, Bryan J.; Hawkins, Emily; Sevier, Andrew; Pyle, Michelle; Robinson, Jacob W.; Ouellette, Pierre H. R.; Ballantyne, James S.

2015-01-01

Here we report the widespread natural occurrence of a known antibiotic and antineoplastic compound, hydroxyurea in animals from many taxonomic groups. Hydroxyurea occurs in all the organisms we have examined including invertebrates (molluscs and crustaceans), fishes from several major groups, amphibians and mammals. The species with highest concentrations was an elasmobranch (sharks, skates and rays), the little skate Leucoraja erinacea with levels up to 250 μM, high enough to have antiviral, antimicrobial and antineoplastic effects based on in vitro studies. Embryos of L. erinacea showed increasing levels of hydroxyurea with development, indicating the capacity for hydroxyurea synthesis. Certain tissues of other organisms (e.g. skin of the frog (64 μM), intestine of lobster (138 μM) gills of the surf clam (100 μM)) had levels high enough to have antiviral effects based on in vitro studies. Hydroxyurea is widely used clinically in the treatment of certain human cancers, sickle cell anemia, psoriasis, myeloproliferative diseases, and has been investigated as a potential treatment of HIV infection and its presence at high levels in tissues of elasmobranchs and other organisms suggests a novel mechanism for fighting disease that may explain the disease resistance of some groups. In light of the known production of nitric oxide from exogenously applied hydroxyurea, endogenous hydoxyurea may play a hitherto unknown role in nitric oxide dynamics. PMID:26600157

Serum Paraoxonase Activity and Malondialdehyde Serum Concentrations Remain Unaffected in Response to Hydroxyurea Therapy in β-Thalassemia Patients.

PubMed

Zohaib, Muhammad; Ansari, Saqib H; Hashim, Zehra; Shamsi, Tahir S; Zarina, Shamshad

2016-07-01

β-Thalassemia is the most common hereditary disorder characterized by reduced production of β-globin chains of hemoglobin A (HbA). In recent years, hydroxyurea (HU) has shown promising therapeutic benefits in patients with β-thalassemia by fetal hemoglobin augmentation. We have analyzed effects of hydroxyurea treatment on oxidative stress in β-thalassemia patients by assessing activities of paraoxonase (PON) and arylesterase along with malondialdehyde (MDA) and total reactive oxygen species (ROS) concentrations. Blood samples from 159 individuals including 56 HU-treated and 58 untreated β-thalassemia patients and 45 healthy controls were analyzed. PON activity was found to be highest in healthy individuals (177.76 ± 4.44 U/mL) as compared to treated (52.67 ± 3.65 U/mL) and untreated (55.11 ± 3.26 U/mL) patients. A similar trend was observed in the case of arylesterase activity in normal, β-thalassemia-treated, and untreated (210.0 ± 11.25 U/mL, 163.03 ± 9.04 U/mL, 139.77 ± 10.10 U/mL) subjects. Serum MDA concentrations (2.59 ± 0.09 nmol/mL, 2.45 ± 0.08 nmol/mL, and 1.15 ± 0.05 nmol/mL) and total ROS concentrations (3.73 ± 0.20 nmol/mL, 3.54 ± 0.23 nmol/mL, and 2.45 ± 0.14 nmol/mL) were significantly elevated in both groups (untreated and treated) as compared to healthy individuals (P < .01). Oxidative stress was found to be markedly elevated in β-thalassemia patients as compared to healthy controls. Insignificant differences were, however, observed in mean concentrations of PON1 paraoxonase and arylesterase activities, serum MDA concentration and total ROS concentrations between HU-treated and untreated patients. We propose that HU therapy alone seems to be ineffective in managing oxidative stress and is likely to offer a better clinical outcome when supplemented with efficient iron chelation therapy and antioxidants. © 2015, The American College of Clinical Pharmacology.

Hydroxyurea-Lactose Interaction Study: In Silico and In Vitro Evaluation.

PubMed

Bachchhao, Kunal B; Patil, R R; Patil, C R; Patil, Dipak D

2017-11-01

The Maillard reaction between hydroxyurea (a primary amine-containing drug) and lactose (used as an excipient) was explored. The adduct of these compounds was synthesized by heating hydroxyurea with lactose monohydrate at 60 °C in borate buffer (pH 9.2) for 12 h. Synthesis of the adduct was confirmed using UV-visible spectroscopy and Fourier transform infrared, differential scanning calorimetry, high-pressure liquid chromatography, and liquid chromatography-mass spectrometry studies. An in silico investigation of how the adduct formation affected the interactions of hydroxyurea with its biological target oxyhemoglobin, to which it binds to generate nitric oxide and regulates fetal hemoglobin synthesis, was carried out. The in silico evaluations were complemented by an in vitro assay of the anti-sickling activity. Co-incubation of hydroxyurea with deoxygenated blood samples reduced the percentage of sickled cells from 38% to 12 ± 1.6%, whereas the percentage of sickled cells in samples treated with the adduct was 17 ± 1.2%. This indicated loss of anti-sickling activity in the case of the adduct. This study confirmed that hydroxyurea can participate in a Maillard reaction if lactose is used as a diluent. Although an extended study at environmentally feasible temperatures was not carried out in the present investigation, the partial loss of the anti-sickling activity of hydroxyurea was investigated along with the in silico drug-target interactions. The results indicated that the use of lactose in hydroxyurea formulations needs urgent reconsideration and that lactose must be replaced by other diluents that do not form Maillard adducts.

Changes in urine albumin to creatinine ratio with the initiation of hydroxyurea therapy among children and adolescents with sickle cell disease.

PubMed

Tehseen, Sarah; Joiner, Clinton H; Lane, Peter A; Yee, Marianne E

2017-12-01

Renal damage is a progressive complication of sickle cell disease (SCD) that begins in childhood and may progress to renal failure and early mortality in 12% of adults with hemoglobin SS (HbSS) SCD. Early sickle nephropathy is characterized by hyperfiltration and microalbuminuria; therefore, urine albumin to creatinine ratio (ACR) is an effective screening tool for its detection. This study investigated the effect of hydroxyurea (HU) therapy on urine ACR levels among children with SCD. A retrospective review was conducted to identify all patients with HbSS or HbSβ 0 thalassemia of age 7-18 years who began HU therapy in 2011-2013; a control group of patients not on HU were matched by age and baseline hemoglobin. All urine ACR measurements ≤24 months prior to and ≥24 months after HU initiation were recorded. There were 63 eligible patients on HU and 13 (25%) with albuminuria prior to HU initiation. Among those with baseline albuminuria, the median ACR was 96 mg/g prior to HU, 39 mg/g at 1 year (P = 0.02), and 25 mg/g at 2 years (P = 0.03). Albuminuria normalized in 37.5% (6/16) after 1 year and 61% (8/13) after 2 years of HU therapy. Among those without albuminuria prior to HU, 13% (6/47) developed albuminuria during HU therapy. Sixteen percent (13/80) of control patients had albuminuria in the beginning of study period, which normalized in 15% (two of 13) of patients at 1-year follow up. Introduction of HU is associated with significant decreases in urine ACR in children with SCD and albuminuria. © 2017 Wiley Periodicals, Inc.

Whole exome sequencing identifies novel genes for fetal hemoglobin response to hydroxyurea in children with sickle cell anemia.

PubMed

Sheehan, Vivien A; Crosby, Jacy R; Sabo, Aniko; Mortier, Nicole A; Howard, Thad A; Muzny, Donna M; Dugan-Perez, Shannon; Aygun, Banu; Nottage, Kerri A; Boerwinkle, Eric; Gibbs, Richard A; Ware, Russell E; Flanagan, Jonathan M

2014-01-01

Hydroxyurea has proven efficacy in children and adults with sickle cell anemia (SCA), but with considerable inter-individual variability in the amount of fetal hemoglobin (HbF) produced. Sibling and twin studies indicate that some of that drug response variation is heritable. To test the hypothesis that genetic modifiers influence pharmacological induction of HbF, we investigated phenotype-genotype associations using whole exome sequencing of children with SCA treated prospectively with hydroxyurea to maximum tolerated dose (MTD). We analyzed 171 unrelated patients enrolled in two prospective clinical trials, all treated with dose escalation to MTD. We examined two MTD drug response phenotypes: HbF (final %HbF minus baseline %HbF), and final %HbF. Analyzing individual genetic variants, we identified multiple low frequency and common variants associated with HbF induction by hydroxyurea. A validation cohort of 130 pediatric sickle cell patients treated to MTD with hydroxyurea was genotyped for 13 non-synonymous variants with the strongest association with HbF response to hydroxyurea in the discovery cohort. A coding variant in Spalt-like transcription factor, or SALL2, was associated with higher final HbF in this second independent replication sample and SALL2 represents an outstanding novel candidate gene for further investigation. These findings may help focus future functional studies and provide new insights into the pharmacological HbF upregulation by hydroxyurea in patients with SCA.

Modeling and Proposed Molecular Mechanism of Hydroxyurea Through Docking and Molecular Dynamic Simulation to Curtail the Action of Ribonucleotide Reductase.

PubMed

Iman, Maryam; Khansefid, Zeynab; Davood, Asghar

2016-01-01

Ribonucleotide Reductase (RNR) is an important anticancer chemotherapy target. It has main key role in DNA synthesis and cell growth. Therefore several RNR inhibitors, such as hydroxyurea, have entered the clinical trials. Based on our proposed mechanism, radical site of RNR protein reacts with hydroxyurea in which hydroxyurea is converted into its oxidized form compound III, and whereby the tyrosyl radical is converted into a normal tyrosine residue. In this study, docking and molecular dynamics simulations were used for proposed molecular mechanism of hydroxyurea in RNR inhibition as anticancer agent. The binding affinity of hydroxyurea and compound III to RNR was studied by docking method. The docking study was performed for the crystal structure of human RNR with the radical scavenger Hydroxyurea and its oxidized form to inhibit the human RNR. hydroxyurea and compound III bind at the active site with Tyr-176, which are essential for free radical formation. This helps to understand the functional aspects and also aids in the development of novel inhibitors for the human RNR2. To confirm the binding mode of inhibitors, the molecular dynamics (MD) simulations were performed using GROMACS 4.5.5, based upon the docked conformation of inhibitors. Both of the studied compounds stayed in the active site. The results of MD simulations confirmed the binding mode of ligands, accuracy of docking and the reliability of active conformations which were obtained by AutoDock. MD studies confirm our proposed mechanism in which compound III reacts with the active site residues specially Tyr-176, and inhibits the radical generation and subsequently inhibits the RNR enzyme.

Editor's Highlight: Hydroxyurea Exposure Activates the P53 Signaling Pathway in Murine Organogenesis-Stage Embryos

PubMed Central

El Husseini, Nazem; Schlisser, Ava E.; Hales, Barbara F.

2016-01-01

Hydroxyurea, an anticancer agent and potent teratogen, induces oxidative stress and activates a DNA damage response pathway in the gestation day (GD) 9 mouse embryo. To delineate the stress response pathways activated by this drug, we investigated the effect of hydroxyurea exposure on the transcriptome of GD 9 embryos. Timed pregnant CD-1 mice were treated with saline or hydroxyurea (400 mg/kg or 600 mg/kg) on GD 9; embryonic gene and protein expression were examined 3 h later. Microarray analysis revealed that the expression of 1346 probe sets changed significantly in embryos exposed to hydroxyurea compared with controls; the P53 signaling pathway was highly affected. In addition, P53 related family members, P63 and P73, were predicted to be activated and had common and unique downstream targets. Western blot analysis revealed that active phospho-P53 was significantly increased in drug-exposed embryos; confocal microscopy showed that the translocation of phospho-P53 to the nucleus was widespread in the embryo. Furthermore, qRT-PCR showed that the expression of P53-regulated genes (Cdkn1A, Fas, and Trp53inp1) was significantly upregulated in hydroxyurea-exposed embryos; the concentration of the redox sensitive P53INP1 protein was also increased in a hydroxyurea dose-dependent fashion. Thus, hydroxyurea elicits a significant effect on the transcriptome of the organogenesis stage murine embryo, activating several key developmental signaling pathways related to DNA damage and oxidative stress. We propose that the P53 pathway plays a central role in the embryonic stress response and the developmental outcome after teratogen exposure. PMID:27208086

Organ iron accumulation in chronically transfused children with sickle cell anaemia: baseline results from the TWiTCH trial.

PubMed

Wood, John C; Cohen, Alan R; Pressel, Sara L; Aygun, Banu; Imran, Hamayun; Luchtman-Jones, Lori; Thompson, Alexis A; Fuh, Beng; Schultz, William H; Davis, Barry R; Ware, Russell E

2016-01-01

Transcranial Doppler (TCD) With Transfusions Changing to Hydroxyurea (TWiTCH) trial is a randomized, open-label comparison of hydroxycarbamide (also termed hydroxyurea) versus continued chronic transfusion therapy for primary stroke prevention in patients with sickle cell anaemia (SCA) and abnormal TCD. Severity and location of iron overload is an important secondary outcome measure. We report the baseline findings of abdominal organ iron burden in 121 participants. At enrollment, patients were young (9·8 ± 2·9 years), predominantly female (60:40), and previously treated with transfusions (4·1 ± 2·4 years) and iron chelation (3·1 ± 2·1 years). Liver iron concentration (LIC; 9·0 ± 6·6 mg/g dry weight) and serum ferritin were moderately elevated (2696 ± 1678 μg/l), but transferrin was incompletely saturated (47·2 ± 23·6%). Spleen R2* was 509 ± 399 Hz (splenic iron ~13·9 mg/g) and correlated with LIC (r(2)  = 0·14, P = 0·0008). Pancreas R2* was increased in 38·3% of patients but not to levels associated with endocrine toxicity. Kidney R2* was increased in 80·7% of patients; renal iron correlated with markers of intravascular haemolysis and was elevated in patients with increased urine albumin-creatinine ratios. Extra-hepatic iron deposition is common among children with SCA who receive chronic transfusions, and could potentiate oxidative stress caused by reperfusion injury and decellularized haemoglobin. © 2015 John Wiley & Sons Ltd.

A reappraisal of the benefit-risk profile of hydroxyurea in polycythemia vera: A propensity-matched study.

PubMed

Barbui, Tiziano; Vannucchi, Alessandro Maria; Finazzi, Guido; Finazzi, Maria Chiara; Masciulli, Arianna; Carobbio, Alessandra; Ghirardi, Arianna; Tognoni, Gianni

2017-11-01

The use of hydroxyurea (HU) as first line therapy in polycythemia vera (PV) has been criticized because no solid demonstration that this drug prevents thrombosis or prolongs survival has been so far produced. Here we present the outcomes of a large cohort of patients with PV included in the European Collaborative Low-dose Aspirin (ECLAP) study. We selected 1,042 patients who, during the follow-up, had received only phlebotomy (PHL) or HU to maintain the hematocrit level < 45%. To assure comparability, we conducted a propensity score matching analysis. The two groups (PHL n = 342 and HU n = 681) were well balanced for the parameters included in the propensity score (overall balance: χ 2  = 2.44, P = 0.964). Over a comparable period of follow-up (PHL = 29.9 vs. HU = 34.7 months), we documented an advantage of HU over PHL consistently significant with respect to the incidence of fatal/non-fatal cardiovascular (CV) events (5.8 vs. 3.0 per 100 person-years in PHL vs. HU group, P = 0.002) and myelofibrosis transformation that was only experienced by patients of PHL group. Evolution to acute leukemia was registered in three patients (two in PHL and one in HU group). The excess of mortality and total CV events in the PHL patients was restricted to the high-risk group, and, compared with HU cases, was significant higher in the PHL patients who failed to reach the hematocrit target < 0.45% (P = 0.000). In conclusion, this analysis provides reliable and qualified estimates of the therapeutic profile of HU and PHL treatments for future experimental studies and for the management of PV in clinical practice. © 2017 Wiley Periodicals, Inc.

Blood mononuclear cell gene expression profiles characterize the oxidant, hemolytic, and inflammatory stress of sickle cell disease

PubMed Central

Jison, Maria L.; Munson, Peter J.; Barb, Jennifer J.; Suffredini, Anthony F.; Talwar, Shefali; Logun, Carolea; Raghavachari, Nalini; Beigel, John H.; Shelhamer, James H.; Danner, Robert L.; Gladwin, Mark T.

2016-01-01

In sickle cell disease, deoxygenation of intra-erythrocytic hemoglobin S leads to hemoglobin polymerization, erythrocyte rigidity, hemolysis, and microvascular occlusion. Ischemia-reperfusion injury, plasma hemoglobin-mediated nitric oxide consumption, and free radical generation activate systemic inflammatory responses. To characterize the role of circulating leukocytes in sickle cell pathogenesis we performed global transcriptional analysis of blood mononuclear cells from 27 patients in steady-state sickle cell disease (10 patients treated and 17 patients untreated with hydroxyurea) compared with 13 control subjects. We used gender-specific gene expression to validate human microarray experiments. Patients with sickle cell disease demonstrated differential gene expression of 112 genes involved in heme metabolism, cell-cycle regulation, antioxidant and stress responses, inflammation, and angiogenesis. Inducible heme oxygenase-1 and downstream proteins biliverdin reductase and p21, a cyclin-dependent kinase, were up-regulated, potentially contributing to phenotypic heterogeneity and absence of atherosclerosis in patients with sickle cell disease despite endothelial dysfunction and vascular inflammation. Hydroxyurea therapy did not significantly affect leukocyte gene expression, suggesting that such therapy has limited direct anti-inflammatory activity beyond leukoreduction. Global transcriptional analysis of circulating leukocytes highlights the intense oxidant and inflammatory nature of steady-state sickle cell disease and provides insight into the broad compensatory responses to vascular injury. PMID:15031206

Hydroxyurea prescription, availability and use for children with sickle cell disease in Italy: Results of a National Multicenter survey.

PubMed

Colombatti, Raffaella; Palazzi, Giovanni; Masera, Nicoletta; Notarangelo, Lucia Dora; Bonetti, Elisa; Samperi, Piera; Barone, Angelica; Perrotta, Silverio; Facchini, Elena; Miano, Maurizio; Del Vecchio, Giovanni Carlo; Guerzoni, Maria Elena; Corti, Paola; Menzato, Federica; Cesaro, Simone; Casale, Maddalena; Rigano, Paolo; Forni, Gian Luca; Russo, Giovanna; Sainati, Laura

2018-02-01

The number of patients with sickle cell disease (SCD) has increased in Italy in the past decade due to immigration. In spite of the established efficacy of hydroxyurea (HU) in childhood, population-based data regarding its prescription and effectiveness come mainly from studies performed in adults or outside Europe. The Hydroxyurea in SCD: A Large Nation-wide Cohort Study from Italy was a retrospective cohort study of adult and pediatric patients with SCD attending 32 centers. Pediatric data are analyzed separately. Out of 504 children followed in 11 centers, 206 (40%) were on HU (194 SS/Sβ°, 12 SC/Sß+); 74% came from Sub-Saharian Africa and 18% from Europe. HU therapy indications for SS/Sβ° patients were as follows: 57% painful vaso-occlusive crisis, acute chest syndrome or both, 24% anemia, 8% anemia, and other reasons (the majority had Hb ≤ 8-8.5 g/dl, revealing scarce acceptance of low Hb values by pediatric hematologist). Mean starting dose was 15.5 mg/kg, and dose at full regimen was 17.1 mg/kg. Mean age at HU therapy was 7.68 years, although it was lower for SS/Sβ° patients. Only 10% started HU before 3 years. In 92%, 500 mg capsule was used; in 6%, the galenic was used; and in 2%, 100 mg tablet was used. Significant reduction of clinical events and inpatients admissions, with improvement in hematological parameters, was observed for SS/Sβ° patients and a trend toward improvement for SC/Sß+ patients was also observed. HU effectiveness is demonstrated in a national cohort of children with SCD living in Italy, even at a lower dose than recommended, revealing good adherence to a treatment program by a socially vulnerable group of patients such as immigrants. © 2017 Wiley Periodicals, Inc.

Whole Exome Sequencing Identifies Novel Genes for Fetal Hemoglobin Response to Hydroxyurea in Children with Sickle Cell Anemia

PubMed Central

Sheehan, Vivien A.; Crosby, Jacy R.; Sabo, Aniko; Mortier, Nicole A.; Howard, Thad A.; Muzny, Donna M.; Dugan-Perez, Shannon; Aygun, Banu; Nottage, Kerri A.; Boerwinkle, Eric; Gibbs, Richard A.; Ware, Russell E.; Flanagan, Jonathan M.

2014-01-01

Hydroxyurea has proven efficacy in children and adults with sickle cell anemia (SCA), but with considerable inter-individual variability in the amount of fetal hemoglobin (HbF) produced. Sibling and twin studies indicate that some of that drug response variation is heritable. To test the hypothesis that genetic modifiers influence pharmacological induction of HbF, we investigated phenotype-genotype associations using whole exome sequencing of children with SCA treated prospectively with hydroxyurea to maximum tolerated dose (MTD). We analyzed 171 unrelated patients enrolled in two prospective clinical trials, all treated with dose escalation to MTD. We examined two MTD drug response phenotypes: HbF (final %HbF minus baseline %HbF), and final %HbF. Analyzing individual genetic variants, we identified multiple low frequency and common variants associated with HbF induction by hydroxyurea. A validation cohort of 130 pediatric sickle cell patients treated to MTD with hydroxyurea was genotyped for 13 non-synonymous variants with the strongest association with HbF response to hydroxyurea in the discovery cohort. A coding variant in Spalt-like transcription factor, or SALL2, was associated with higher final HbF in this second independent replication sample and SALL2 represents an outstanding novel candidate gene for further investigation. These findings may help focus future functional studies and provide new insights into the pharmacological HbF upregulation by hydroxyurea in patients with SCA. PMID:25360671

Evidence review of hydroxyurea for the prevention of sickle cell complications in low-income countries.

PubMed

Mulaku, Mercy; Opiyo, Newton; Karumbi, Jamlick; Kitonyi, Grace; Thoithi, Grace; English, Mike

2013-11-01

Hydroxyurea is widely used in high-income countries for the management of sickle cell disease (SCD) in children. In Kenyan clinical guidelines, hydroxyurea is only recommended for adults with SCD. Yet many deaths from SCD occur in early childhood, deaths that might be prevented by an effective, disease modifying intervention. The aim of this review was to summarise the available evidence on the efficacy, effectiveness and safety of hydroxyurea in the management of SCD in children below 5 years of age to support guideline development in Kenya. We undertook a systematic review and used the Grading of Recommendations Assessment, Development and Evaluation system to appraise the quality of identified evidence. Overall, available evidence from 1 systematic review (n=26 studies), 2 randomised controlled trials (n=354 children), 14 observational studies and 2 National Institute of Health reports suggest that hydroxyurea may be associated with improved fetal haemoglobin levels, reduced rates of hospitalisation, reduced episodes of acute chest syndrome and decreased frequency of pain events in children with SCD. However, it is associated with adverse events (eg, neutropenia) when high to maximum tolerated doses are used. Evidence is lacking on whether hydroxyurea improves survival if given to young children. Majority of the included studies were of low quality and mainly from high-income countries. Overall, available limited evidence suggests that hydroxyurea may improve morbidity and haematological outcomes in SCD in children aged below 5 years and appears safe in settings able to provide consistent haematological monitoring.

Low-burden TP53 mutations in chronic phase of myeloproliferative neoplasms: association with age, hydroxyurea administration, disease type and JAK2 mutational status

PubMed Central

Kubesova, B; Pavlova, S; Malcikova, J; Kabathova, J; Radova, L; Tom, N; Tichy, B; Plevova, K; Kantorova, B; Fiedorova, K; Slavikova, M; Bystry, V; Kissova, J; Gisslinger, B; Gisslinger, H; Penka, M; Mayer, J; Kralovics, R; Pospisilova, S; Doubek, M

2018-01-01

The multistep process of TP53 mutation expansion during myeloproliferative neoplasm (MPN) transformation into acute myeloid leukemia (AML) has been documented retrospectively. It is currently unknown how common TP53 mutations with low variant allele frequency (VAF) are, whether they are linked to hydroxyurea (HU) cytoreduction, and what disease progression risk they carry. Using ultra-deep next-generation sequencing, we examined 254 MPN patients treated with HU, interferon alpha-2a or anagrelide and 85 untreated patients. We found TP53 mutations in 50 cases (0.2–16.3% VAF), regardless of disease subtype, driver gene status and cytoreduction. Both therapy and TP53 mutations were strongly associated with older age. Over-time analysis showed that the mutations may be undetectable at diagnosis and slowly increase during disease course. Although three patients with TP53 mutations progressed to TP53-mutated or TP53-wild-type AML, we did not observe a significant age-independent impact on overall survival during the follow-up. Further, we showed that complete p53 inactivation alone led to neither blast transformation nor HU resistance. Altogether, we revealed patient's age as the strongest factor affecting low-burden TP53 mutation incidence in MPN and found no significant age-independent association between TP53 mutations and hydroxyurea. Mutations may persist at low levels for years without an immediate risk of progression. PMID:28744014

Maintaining Genome Stability: The Role of Helicases and Deaminases

DTIC Science & Technology

2006-07-01

functional for replication. Then, we screened the surviving transformants for sensitivity to hydroxyurea . Our first screen was conducted under conditions...that are lethal for checkpoint mutants such as ∆rad3. We did not observe any hydroxyurea -sensitive MCM clones. However, following the old genetics...this kinase. In particular, we observe that an mcm4ts mutant blocked in hydroxyurea , and then released to restrictive temperature, is competent to

Maintaining Genome Stability: The Role of Helicases and Deaminases

DTIC Science & Technology

2007-07-01

transformants for sensitivity to hydroxyurea . Our first screen was conducted under conditions that are lethal for checkpoint mutants such as ∆rad3...We did not observe any hydroxyurea -sensitive MCM clones. However, following the old genetics adage “absence of evidence is not evidence of... hydroxyurea , and then released to restrictive temperature, is competent to complete replication and go on to divide. In contrast, this mutant shifted

The influence of hydroxyurea on oxidative stress in sickle cell anemia

PubMed Central

Torres, Lidiane de Souza; da Silva, Danilo Grünig Humberto; Belini Junior, Edis; de Almeida, Eduardo Alves; Lobo, Clarisse Lopes de Castro; Cançado, Rodolfo Delfini; Ruiz, Milton Artur; Bonini-Domingos, Claudia Regina

2012-01-01

Objective The oxidative stress in 20 sickle cell anemia patients taking hydroxyurea and 13 sickle cell anemia patients who did not take hydroxyurea was compared with a control group of 96 individuals without any hemoglobinopathy. Methods Oxidative stress was assessed by thiobarbituric acid reactive species production, the Trolox-equivalent antioxidant capacity and plasma glutathione levels. Results Thiobarbituric acid reactive species values were higher in patients without specific medication, followed by patients taking hydroxyurea and the Control Group (p < 0.0001). The antioxidant capacity was higher in patients taking hydroxyurea and lower in the Control Group (p = 0.0002 for Trolox-equivalent antioxidant capacity and p < 0.0292 for plasma glutathione). Thiobarbituric acid reactive species levels were correlated with higher hemoglobin S levels (r = 0.55; p = 0.0040) and lower hemoglobin F concentrations(r = -0.52; p = 0.0067). On the other hand, plasma glutathione levels were negatively correlated with hemoglobin S levels (r = -0.49; p = 0.0111) and positively associated with hemoglobin F values (r = 0.56; p = 0.0031). Conclusion Sickle cell anemia patients have high oxidative stress and, conversely, increased antioxidant activity. The increase in hemoglobin F levels provided by hydroxyurea and its antioxidant action may explain the reduction in lipid peroxidation and increased antioxidant defenses in these individuals. PMID:23323065

Editor's Highlight: Hydroxyurea Exposure Activates the P53 Signaling Pathway in Murine Organogenesis-Stage Embryos.

PubMed

El Husseini, Nazem; Schlisser, Ava E; Hales, Barbara F

2016-08-01

Hydroxyurea, an anticancer agent and potent teratogen, induces oxidative stress and activates a DNA damage response pathway in the gestation day (GD) 9 mouse embryo. To delineate the stress response pathways activated by this drug, we investigated the effect of hydroxyurea exposure on the transcriptome of GD 9 embryos. Timed pregnant CD-1 mice were treated with saline or hydroxyurea (400 mg/kg or 600 mg/kg) on GD 9; embryonic gene and protein expression were examined 3 h later. Microarray analysis revealed that the expression of 1346 probe sets changed significantly in embryos exposed to hydroxyurea compared with controls; the P53 signaling pathway was highly affected. In addition, P53 related family members, P63 and P73, were predicted to be activated and had common and unique downstream targets. Western blot analysis revealed that active phospho-P53 was significantly increased in drug-exposed embryos; confocal microscopy showed that the translocation of phospho-P53 to the nucleus was widespread in the embryo. Furthermore, qRT-PCR showed that the expression of P53-regulated genes (Cdkn1A, Fas, and Trp53inp1) was significantly upregulated in hydroxyurea-exposed embryos; the concentration of the redox sensitive P53INP1 protein was also increased in a hydroxyurea dose-dependent fashion. Thus, hydroxyurea elicits a significant effect on the transcriptome of the organogenesis stage murine embryo, activating several key developmental signaling pathways related to DNA damage and oxidative stress. We propose that the P53 pathway plays a central role in the embryonic stress response and the developmental outcome after teratogen exposure. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Implementation of the Southwestern Oncology Group Committee on Women’s Health Research Agenda: A Special Sabbatical for the Chairperson.

DTIC Science & Technology

1996-07-01

phase II study 1987-1989 Principal Investigator, Loyola/Hines pilot study of cisplatin preceded by concurrent cytarabine and oral hydroxyurea in...Investigator, Loyola/Hines pilot study of cisplatin preceded by concurrent 31 5 intravenous hydroxyurea and cytarabine . 1989-1992 Primary Study Coordinator...Conference: Modulation of cisplatin resistance by cytarabine and hydroxyurea. Illinois Cancer Council Annual Symposium: Review of Breast Cancer Growth

Role of cdc25 Phosphatases in Human Breast Cancer

DTIC Science & Technology

2007-05-01

cellular response to 5-fluorouracil or hydroxyurea . MCF-10A cells were infected with the indicated adenoviruses for 24 hr and then treated with...doxorubicin, 5-fluorouracil, or hydroxyurea for 48 hr. Cells were stained with propidium iodide prior to flow-cytometry analyses. In order to investigate...of two chemotherapeutic agents, 5- fluorouracil (5-FU, 50 μM), an inhibitor of pyrimidine synthesis, or hydroxyurea (HU, 2mM), an inhibitor of both

Centrosome Amplification: A Potential Marker of Breast Cancer Agressiveness

DTIC Science & Technology

2006-07-01

centrosome amplification. Introduction of DNA damage in the MCF-7 cell line by treatment with hydroxyurea (HU) or daunorubicin (DR) resulted in the...cycles of DNA synthesis and mitotic division in hydroxyurea - arrested Chinese hamster ovary cells. J Cell Biol, 130: 105-115, 1995. 23. D’Assoro, A. B...from cycles of DNA synthesis and mitotic division in hydroxyurea -arrested Chinese hamster ovary cells. J Cell Biol, 1995. 130(1): p. 105-15. 22

The burden and quality of life of caregivers of sickle cell anemia patients taking hydroxyurea versus those not taking hydroxyurea

PubMed Central

da Silva, Luiz Bernardino Lima; Ivo, Maria Lúcia; de Souza, Albert Schiaveto; Pontes, Elenir Rose Jardim Cury; Pinto, Alexandra Maria Almeida Carvalho; de Araujo, Olinda Maria Rodrigues

2012-01-01

Objective To assess the burden and quality of life of caregivers of patients with sickle cell anemia taking hydroxyurea versus those of patients not taking hydroxyurea. Methods A cross-sectional study was performed of caregivers of outpatients with sickle cell anemia in two public hospitals in Campo Grande, MS, from January through June 2010. The World Health Organization Quality of Life-BREF Scale and the Caregiver Burden Scale were used. Results Of the 37 caregivers in this study, 81.1% were women, 73.0% were mothers, 59.5% were married, 54.1%were mulattos, 48.6% were housewives, 54.1% had family incomes of up to one minimum wage and 75.7% had onlycompleted elementary education. The mean duration of care provided (time after diagnosis) was 16.08 ± 9.88 yearsand 89.2% reported that they provided 24-hour care. Regarding health, 27.0% of study participants reported having physical and 13.5% emotional problems. There were no significant relationships between these variables either with the different domains or the total score of the WHOQOL-BREF comparing caregivers of patients taking hydroxyurea versusthose of patients not taking hydroxyurea. There was a moderate negative linear correlation between the WHOQOL-BREF and the Caregiver Burden Scale scores (linear correlation test of Pearson: p-value = 0.003, r = -0.477). The burden of caregivers of patients who did not take hydroxyurea was significantly higher than those of patients who took the medication in terms of general tension, disappointment, environment and total score (student t-test: p-value < 0.05). Conclusion In the perception of the caregiver, looking after sickle cell anemia patients represents a moderate negative burden. PMID:23049439

Cytologic Effects of Air Force Chemicals

DTIC Science & Technology

1978-09-01

pCi/ml, 60 Ci/mmole), hydroxyurea (10- 2M) to suppress replicative DNA synthesis, and with or without 4-nitroquinoline-l-oxide (4NQO, a DNA-damaging...organ cultures. The tissues were minced in cold, buffered saline and then incubated with 3 H-thymidine, hydroxyurea and 4NQO to damage cellular DNA...incorporation under these conditions is taken as an indication of DNA repair activity, and incorporation of 3H-thymidine in the absence of hydroxyurea and

Hydroxyurea inhibits parvovirus B19 replication in erythroid progenitor cells.

PubMed

Bonvicini, Francesca; Bua, Gloria; Conti, Ilaria; Manaresi, Elisabetta; Gallinella, Giorgio

2017-07-15

Parvovirus B19 (B19V) infection is restricted to erythroid progenitor cells (EPCs) of the human bone marrow, leading to transient arrest of erythropoiesis and severe complications mainly in subjects with underlying hematological disorders or with immune system deficits. Currently, there are no specific antiviral drugs for B19V treatment, but identification of compounds inhibiting B19V replication can be pursued by a drug repositioning strategy. In this frame, the present study investigates the activity of hydroxyurea (HU), the only disease-modifying therapy approved for sickle cell disease (SCD), towards B19V replication in the two relevant cellular systems, the UT7/EpoS1 cell line and EPCs. Results demonstrate that HU inhibits B19V replication with EC 50 values of 96.2µM and 147.1µM in UT7/EpoS1 and EPCs, respectively, providing experimental evidence of the antiviral activity of HU towards B19V replication, and confirming the efficacy of a drug discovery process by drug repositioning strategy. The antiviral activity occurs in vitro at concentrations lower than those affecting cellular DNA replication and viability, and at levels measured in plasma samples of SCD patients undergoing HU therapy. HU might determine a dual beneficial effect on SCD patients, not only for the treatment of the disease but also towards a virus responsible for severe complications. Copyright © 2017 Elsevier Inc. All rights reserved.

Interaction of N-hydroxyurea with strong proton donors: HCl and HF

NASA Astrophysics Data System (ADS)

Sałdyka, Magdalena

2014-11-01

An infrared spectroscopic and MP2/6-311++G(2d,2p) study of strong hydrogen bonded complexes of N-hydroxyurea (NH2CONHOH) with hydrogen halides (HCl and HF) trapped in solid argon matrices is reported. 1:1 and 1:2 complexes between N-hydroxyurea and hydrogen chloride, hydrogen fluoride have been identified in the NH2CONHOH/HCl/Ar, NH2CONHOH/HF/Ar matrices, respectively; their structures were determined by comparison of the spectra with the results of calculations. In the 1:1 complexes, identified for both hydrogen halide molecules, the cyclic structure stabilized by the X-H⋯O and N-H⋯X bonds is present; for the NH2CONHOH⋯HF system another isomeric 1:1 complex is also observed. Two 1:2 complexes were identified for the N-hydroxyurea-hydrogen chloride system characterised by the Cl-H⋯O and N-H⋯Cl bonds. The results of the study evidence that N-hydroxyurea is an oxygen base in the gas-phase with the carbonyl group as the strongest proton acceptor centre in the molecule.

Hydroxyurea for reducing blood transfusion in non-transfusion dependent beta thalassaemias.

PubMed

Foong, Wai Cheng; Ho, Jacqueline J; Loh, C Khai; Viprakasit, Vip

2016-10-18

Non-transfusion dependent beta thalassaemia is a subset of inherited haemoglobin disorders characterised by reduced production of the beta globin chain of the haemoglobin molecule leading to anaemia of varying severity. Although blood transfusion is not a necessity for survival, it is required when episodes of chronic anaemia occur. This chronic anaemia can impair growth and affect quality of life. People with non-transfusion dependent beta thalassaemia suffer from iron overload due to their body's increased capability of absorbing iron from food sources. Iron overload becomes more pronounced in those requiring blood transfusion. People with a higher foetal haemoglobin level have been found to require fewer blood transfusions. Hydroxyurea has been used to increase foetal haemoglobin level; however, its efficacy in reducing transfusion, chronic anaemia complications and its safety need to be established. To assess the effectiveness, safety and appropriate dose regimen of hydroxyurea in people with non-transfusion dependent beta thalassaemia (haemoglobin E combined with beta thalassaemia and beta thalassaemia intermedia). We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of relevant journals. We also searched ongoing trials registries and the reference lists of relevant articles and reviews.Date of last search: 30 April 2016. Randomised or quasi-randomised controlled trials of hydroxyurea in people with non-transfusion dependent beta thalassaemia comparing hydroxyurea with placebo or standard treatment or comparing different doses of hydroxyurea. Two authors independently applied the inclusion criteria in order to select trials for inclusion. Both authors assessed the risk of bias of trials and extracted the data. A third author verified these assessments. No trials comparing hydroxyurea with placebo or standard care were found. However, we included one randomised controlled trial (n = 61) comparing 20 mg/kg/day with 10 mg/kg/day of hydroxyurea for 24 weeks.Both haemoglobin and foetal haemoglobin levels were lower at 24 weeks in the 20 mg group compared with the 10 mg group, mean difference -2.39 (95% confidence interval - 2.8 to -1.98) and mean difference -1.5 (95% confidence interval -1.83 to -1.17), respectively. Major adverse effects were significantly more common in the 20 mg group, for neutropenia risk ratio 9.93 (95% confidence interval 1.34 to 73.97) and for thrombocytopenia risk ratio 3.68 (95% confidence interval 1.13 to 12.07). No difference was reported for minor adverse effects (gastrointestinal disturbances and raised liver enzymes). The effect of hydroxyurea on transfusion frequency was not reported.The overall quality for the outcomes reported was graded as very low mainly because the outcomes were derived from only one small study with an unclear method of allocation concealment. There is no evidence from randomised controlled trials to show whether hydroxyurea has any effect compared with controls on the need for blood transfusion. Administration of 10 mg/kg/day compared to 20 mg/kg/day of hydroxyurea resulted in higher haemoglobin levels and seems safer with fewer adverse effects. It has not been reported whether hydroxyurea is capable of reducing the need for blood transfusion. Large well-designed randomised controlled trials with sufficient duration of follow up are recommended.

Molecular Analysis of the Inheritance of Transcriptional Silencing

DTIC Science & Technology

2007-04-01

arrest, to synchronize the cells for hydroxyurea (HU) addition, and then released into an alpha factor/0.2M HU arrest (Fig. 1A). 2 hours after release...restrictive conditions to degrade both Sir1td and Asf1td proteins. Cells were then release for 4 hours into 0.2M hydroxyurea (HU), an early S phase arrest...on three experiments. The “Block” row describes the cell cycle inhibitor used in each time point (alpha factor, hydroxyurea and nocodozole). 24

Effects of antineoplastic drugs on Lactobacillus casei and radioisotopic assays for serum folate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carmel, R.

1978-02-01

Microbiologic assay, usually employing Lactobacillus casei, remains the standard assay for serum folate to date. Among its disadvantages have been falsely low results in patients receiving bacteriostatic agents such as antibiotics. This study examined whether commonly used antineoplastic drugs had similar effect. Methotrexate and 5-fluorouracil depressed microbiologic serum folate levels. No effect was found for adriamycin, bleomycin, BCNU, cyclophosphamide, cytosine arabinoside, vincristine, vinblastine, mechlorethamine, mithramycin, hydroxyurea, and hydrocortisone. None of the drugs affected radioassay except methotrexate, which produced falsely high folate results. Thus, it appears that L. casei assay for folate becomes unreliable in patients receiving 5-fluorouracil and radioisotopic assaymore » becomes unreliable in those receiving methotrexate.« less

Impact of a Clinical Pharmacy Service on the Management of Patients in a Sickle Cell Disease Outpatient Center.

PubMed

Han, Jin; Bhat, Shubha; Gowhari, Michel; Gordeuk, Victor R; Saraf, Santosh L

2016-11-01

Ambulatory care clinical pharmacy services have expanded beyond primary care settings, but literature supporting the benefits of clinical pharmacy involvement with patients who have rare diseases such as sickle cell disease (SCD) is lacking. Hydroxyurea is the only agent approved by the U.S. Food and Drug Administration for the treatment of SCD; full benefit in controlling pain episodes and other complications is achieved through monitored escalation to a maximum tolerated dose. The primary objective of this analysis was to evaluate the impact of a newly implemented clinical pharmacy service on the management of patients with SCD. We performed a retrospective cross-sectional analysis of 385 adults with SCD who received care between January 1, 2014, and December 31, 2014, at a single Sickle Cell Outpatient Center that implemented a clinical pharmacy service in August 2013. Data were collected on hydroxyurea dose escalation, immunization completion rates, and health maintenance metrics (screening for nephropathy with microalbuminuria testing, retinopathy with annual retinal examinations, and pulmonary hypertension with echocardiography). The impact of the clinical pharmacy service on quality measurements was evaluated by using univariate and multivariate analyses. The number of pharmacist encounters, defined as a clinic visit when a clinical pharmacist interacted with a patient as documented in the medical records, was associated with an improved hydroxyurea dose escalation rate (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.07-2.05, p=0.02). Immunization rates for the 23-valent pneumococcal polysaccharide vaccine, the 13-valent pneumococcal conjugate vaccine, and influenza vaccine were 66%, 47%, and 62%, respectively. The number of pharmacist encounters was associated with improved immunization completion rates (OR 1.38, 95% CI 1.17-1.62, p<0.001). Improved screening for microalbuminuria (OR 2.14, 95% CI 1.60-2.86, p<0.001) and sickle cell retinopathy (OR 1.16, 95% CI 1.00-1.35, p=0.05) were also associated with the number of pharmacist encounters. A new clinical pharmacy service implemented in managing a rare disease, SCD, was associated with an improved hydroxyurea dose escalation rate, immunization completion rates, and health maintenance metrics. © 2016 Pharmacotherapy Publications, Inc.

Predictors of splenic function preservation in children with sickle cell anemia treated with hydroxyurea.

PubMed

Nottage, Kerri A; Ware, Russell E; Winter, Bryan; Smeltzer, Matthew; Wang, Winfred C; Hankins, Jane S; Dertinger, Stephen D; Shulkin, Barry; Aygun, Banu

2014-11-01

More than 90% of children with sickle cell anemia (SCA) lose splenic function by the age of 2 yrs. Splenic function may improve with hydroxyurea, but previous studies are conflicting. We prospectively evaluated the effect of hydroxyurea on splenic filtrative function. Children with SCA enrolled in the Hydroxyurea Study of Long-Term Effects (HUSTLE-NCT00305175) underwent clinical evaluations including Tc(99) m liver-spleen (LS) scans before hydroxyurea initiation and after 3 yrs of treatment to maximum tolerated dose (MTD). LS scans were classified as follows: no uptake, <10% uptake, decreased but ≥10% uptake, and normal. Mean age (N = 40) was 9.1 yrs, range 2.3-17.0. After 3 yrs of treatment, 13 (33%) had uptake on LS scan. These 13 children were younger (median age 6.0 vs. 10.6 yrs, P = 0.008), had a higher HbF at baseline (mean 10.2% vs. 5.8%, P = 0.004) and after 3 yrs (22.9% vs. 13.9%, P < 0.001), achieved MTD more rapidly (median 288 vs. 358 d, P = 0.021), and were more likely to have baseline splenic uptake (P < 0.001). Hydroxyurea at MTD is associated with preserved or improved splenic filtrative function, with 33% demonstrating LS scan uptake after 3 yrs. Younger age, higher %HbF, and baseline splenic function are associated with a favorable outcome. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chronic transfusion practice for children with sickle cell anaemia and stroke.

PubMed

Aygun, Banu; McMurray, Marsha A; Schultz, William H; Kwiatkowski, Janet L; Hilliard, Lee; Alvarez, Ofelia; Heeney, Matthew; Kalinyak, Karen; Lee, Margaret T; Miller, Scott; Helms, Ronald W; Ware, Russell E

2009-05-01

Chronic transfusions to maintain haemoglobin S (HbS) < or =30% are the mainstay of treatment for children with sickle cell anaemia (SCA) and previous stroke. This HbS target is often hard to maintain, however, and values achieved in current practice are unknown. In preparation for the Phase III Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) trial, we collected data on 295 children with SCA and stroke who received transfusions at 23 institutions. The overall average pre-transfusion %HbS was 35 +/- 11% (institutional range 22-51%). Receiving scheduled transfusions on time was the most predictive variable for maintaining HbS at the < or =30% goal.

Comparison of MicroRNAs Mediated in Reactivation of the γ-Globin in β-Thalassemia Patients, Responders and Non-Responders to Hydroxyurea.

PubMed

Hojjati, Mohammad T; Azarkeivan, Azita; Pourfathollah, Ali A; Amirizadeh, Naser

2017-03-01

Drug induction of Hb F seems to be an ideal therapy for patients with hemoglobin (Hb) disorders, and many efforts have been made to reveal the mechanism behind it. Thus, we examined in vivo expression of some microRNAs (miRNAs) that are thought to be involved in this process. Among β-thalassemia (β-thal) patients who were undergoing hydroxyurea (HU) therapy in the past 3 months and five healthy individuals, five responders and five non-responders, were also included in the study. Erythroid progenitors were isolated by magnetic activated cell sorting (MACS) and miRNA expression analyzed using reverse transcription-polymerase chain reaction (RT-PCR). We showed that γ-globin, miR-210 and miR-486-3p had higher levels in the responders than the non-responders group. Moreover, miR-150 and miR-320 had higher levels in the healthy group than both non-responders and responders groups, but the expression of miR-96 did not show any significant difference between the study groups. To the best of our knowledge, this is the first study proposing that 'induction of cellular hypoxic condition by Hb F inducing agents' could be the milestone of possible mechanisms that explain why responders are able to reactivate γ-globin genes and subsequently, more production of Hb F, in response to these agents in comparison to non-responders. However, further investigations need to be performed to verify this hypothesis.

Inhibition of Mutation: A Novel Approach to Preventing and Treating Cancer

DTIC Science & Technology

2007-06-01

Hydroxyurea (HU) is a small molecule chemotherapeutic that is thought to slow tumor growth by inhibiting RNR and thus reducing dNTP...Identification of hydroxyurea as an inhibitor of induced mutation that presumably acts by inhibiting ribonucleotide reductase and thereby decreasing the

Markers of iron deficiency in patients with polycythemia vera receiving ruxolitinib or best available therapy.

PubMed

Verstovsek, Srdan; Harrison, Claire N; Kiladjian, Jean-Jacques; Miller, Carole; Naim, Ahmad B; Paranagama, Dilan C; Habr, Dany; Vannucchi, Alessandro M

2017-05-01

Polycythemia vera (PV) is characterized by erythropoiesis and JAK2-activating mutations, with increased risks of morbidity and mortality. Most patients with PV are iron deficient, and treatment often includes hematocrit control with phlebotomy, which may exacerbate iron deficiency-associated complications. The phase 3 RESPONSE trial evaluated the JAK1/JAK2 inhibitor ruxolitinib (n=110) versus best available therapy (BAT; n=112) in patients with PV who were hydroxyurea-resistant/intolerant. Ruxolitinib was superior to BAT for hematocrit control, reduction in splenomegaly, and blood count normalization. This exploratory analysis, the first to evaluate iron status in a prospective study of patients with PV, investigated ruxolitinib effects on 7 serum iron markers and iron deficiency-related patient-reported outcomes (PRO). Among patients with evidence of baseline iron deficiency, ruxolitinib was associated with normalization of iron marker levels, compared with lesser improvement with BAT. Iron levels remained stable in ruxolitinib patients with normal iron levels at baseline. Regardless of baseline iron status, treatment with ruxolitinib was associated with improvements in concentration problems, cognitive function, dizziness, fatigue, headaches, and inactivity, although improvements were generally greater among patients with baseline iron deficiency. The improvements in iron deficiency markers and PROs observed with ruxolitinib are suggestive of clinical benefits that warrant further exploration. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Multiple myeloma on polycythemia vera following radioactive phosphorus therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

West, W.O.

1976-11-01

A 74-year-old white man with established polycythemia vera was treated with radioactive phosphorus after phlebotomies alone failed to control his disease. About 2/sup 3///sub 4/ years later he died of multiple myeloma. The mutagenic effect of radioactive phosphorus may have caused or possibly accelerated preexisting myeloma. Basic nonmalignant disease deserves careful consideration before radiation or radiomimetic agents are used. One might consider a probably less mutagenic drug such as hydroxyurea in patients with polycythemia vera when phlebotomy alone does not give good control of red cell mass and thrombocytosis.

Hydroxyurea for the Treatment of Sickle Cell Disease: Efficacy, Barriers, Toxicity, and Management in Children

PubMed Central

Strouse, John J.; Heeney, Matthew M.

2012-01-01

Hydroxyurea is the only approved medication in the United States for the treatment of sickle cell anemia (HbSS) and is widely used in children despite an indication limited to adults. We review the evidence of efficacy and safety in children with reference to pivotal adult studies. This evidence and expert opinion form the basis for recommended guidelines for the use of hydroxyurea in children including indications, dosing, therapeutic and safety monitoring, and interventions to improve adherence. However, there are substantial gaps in our knowledge to be addressed by on-going and planned studies in children. PMID:22517797

Role of Merlin in the Growth and Transformation of Arachnoidal Cells

DTIC Science & Technology

2009-01-01

studies on the chemotherapeutic agent, hydroxyurea , were performed using meningioma cells grown in the galea (25), and tests on celecoxib were performed...Anders M, Kiesewetter F, Marschalek R, Koch UH, Fahlbusch R (1997) Hydroxyurea for treatment of unresectable and recurrent meningiomas. I. Inhibition of

Development of Hypercalcemia in a Patient Receiving Peginterferon alfa-2a Therapy for Polycythemia Vera.

PubMed

Karne, Sheetal; Mainor, Candace B; Baer, Maria R

2016-06-01

Peginterferon alfa-2a (PEG-IFN alfa-2a) is commonly used to treat hepatitis C virus infection and is also being used increasingly to treat myeloproliferative neoplasms including polycythemia vera. Sarcoidosis associated with IFN therapy for treatment of hepatitis C is well described, with hypercalcemia occurring as a rare manifestation. We describe a 25-year-old man with polycythemia vera who became resistant to hydroxyurea after 6 years of treatment, requiring therapeutic phlebotomy procedures with increasing frequency for elevated hemoglobin and hematocrit levels. PEG-IFN alfa-2a was then initiated at 90 μg subcutaneously once/week and was progressively increased to 180 μg/week over the next 11 months, with normalization of his hemoglobin and hematocrit. The patient then developed hypercalcemia with low parathyroid hormone, parathyroid hormone-related protein, and 25-hydroxyvitamin D levels, and high 1,25-dihydroxyvitamin D and angiotensin-converting enzyme levels, without other evidence of sarcoidosis. PEG-IFN alfa-2a was discontinued, treatment with intravenous fluids and zoledronic acid was initiated, and the hypercalcemia resolved 10 weeks later. Use of the Naranjo Adverse Drug Reaction Probability Scale indicated a probable relationship (score of 7) between the patient's development of hypercalcemia and PEG-IFN alfa-2a therapy; the relationship could not be considered as definite because the patient was not rechallenged with the drug. To our knowledge, this is the first case report of IFN-induced hypercalcemia without other manifestations of sarcoidosis. Practitioners should be aware of hypercalcemia as a potential complication of PEG-IFN alfa-2a therapy, as well as its protracted time course, in patients with myeloproliferative neoplasms. © 2016 Pharmacotherapy Publications, Inc.

The Combined Effects of Pulsed Magnetic Radiation (Diapulse) and Chemotherapy on Tumor Bearing Mice. The Measurement of Rodent Palatal Explants as a Device for Measurement of the Biologic Effects of Nonionic Radiation (EMR)

NASA Technical Reports Server (NTRS)

Regelson, W.; West, B.; Depaola, D. P.

1978-01-01

Simultaneous treatment utilizing pulsed radiowave and cancer chemotherapy significantly extended the life span of mice with Lewis lung transplanted carcinoma. In comparison with nontreated controls, the combination of hydroxyurea and whole body nonionizing EM radiation (at 27.12 MHz) produced differential enhancement of longevity depending on hydroxyurea combined with highest power output achieved by pulsing the radiation 600 times per second; at a 3.9% duty cycle, peak watts = 975 produced the mean extension of life 67% greater than that of the group treated with hydroxyurea alone.

Clinic Attendance of Youth With Sickle Cell Disease on Hydroxyurea Treatment.

PubMed

Ingerski, Lisa M; Arnold, Trisha L; Banks, Gabrielle; Porter, Jerlym S; Wang, Winfred C

2017-07-01

The objective of this study is to describe rates of clinic attendance of youth with sickle cell disease prescribed hydroxyurea and examine potential demographic and medical factors related to consistent clinic attendance. Participants included 148 youth diagnosed with sickle cell disease and prescribed hydroxyurea during a single calendar year. Clinic attendance and potential demographic and medical factors related to attendance were extracted via systematic retrospective medical chart review. Youth attended 90.3% of scheduled appointments and 85.1% of youth attended at least 80% of scheduled clinic appointments during the study window. Adjusting for other factors, multivariate analysis revealed families with fewer children in the household, families with private insurance, youth experiencing fever, and youth not experiencing pain during the calendar year were more likely to consistently attend clinic visits. Adherence to clinic appointments is critical to optimizing health outcomes for youth with sickle cell disease and integral for adequate monitoring of youth prescribed hydroxyurea, in particular. Findings may aid providers in appropriately identifying possible barriers to clinic attendance to develop attendance promotion interventions.

Hydroxyurea in Pediatric Patients With Sickle Cell Disease: What Nurses Need to Know.

PubMed

Rees, Allison L

2016-09-01

Sickle cell disease (SCD) is an inherited disorder in which sickled red blood cells occlude the small vessels of the body, reducing oxygen delivery to tissues and ultimately negatively affecting many of the body's major organs. Hydroxyurea has proven beneficial in the treatment of SCD and prevention of disease-related complications. The 2014 guidelines put forth by the National Heart, Lung, and Blood Institute recommend hydroxyurea treatment in infants 9 months and older, children, and adolescents with SCD-SS or SCD-Sβ(0) thalassemia regardless of clinical severity. This is a change from the 2002 guidelines in which hydroxyurea was recommended for adolescents and children with SCD-SS or SCD-Sβ(0) thalassemia with frequent episodes of pain, a history of acute chest syndrome, severe and symptomatic anemia or other severe vaso-occlusive events. Nurses play a critical role in working with patients and families to provide education, guidance, and support to improve compliance to mitigate the long-term effects of SCD. © 2015 by Association of Pediatric Hematology/Oncology Nurses.

PRIMARY STROKE PREVENTION IN CHILDREN WITH SICKLE CELL ANEMIA LIVING IN AFRICA: THE FALSE CHOICE BETWEEN PATIENT-ORIENTED RESEARCH AND HUMANITARIAN SERVICE

PubMed Central

DEBAUN, MICHAEL R.; GALADANCI, NAJIBAH A.; KASSIM, ADETOLA A.; JORDAN, LORI C.; PHILLIPS, SHARON; ALIYU, MUKTAR H.

2016-01-01

In the United States, primary stroke prevention in children with sickle cell anemia (SCA) is now the standard of care and includes annual transcranial Doppler ultrasound evaluation to detect elevated intracranial velocities; and for those at risk, monthly blood transfusion therapy for at least a year followed by the option of hydroxyurea therapy. This strategy has decreased stroke prevalence in children with SCA from approximately 11% to 1%. In Africa, where 80% of all children with SCA are born, no systematic approach exists for primary stroke prevention. The two main challenges for primary stroke prevention in children with SCA in Africa include: 1) identifying an alternative to blood transfusion therapy, because safe monthly blood transfusion therapy is not feasible; and 2) assembling a health care team to implement and expand this effort. We will emphasize early triumphs and challenges to decreasing the incidence of strokes in African children with SCA. PMID:28066035

Barriers to hydroxyurea adherence and health-related quality of life in adolescents and young adults with sickle cell disease.

PubMed

Badawy, Sherif M; Thompson, Alexis A; Penedo, Frank J; Lai, Jin-Shei; Rychlik, Karen; Liem, Robert I

2017-06-01

To identify barriers to hydroxyurea adherence (negative beliefs, access, and/or recall barriers), and their relationship to adherence rates and health-related quality of life (HRQOL) among adolescents and young adults (AYA) with sickle cell disease (SCD). A cross-sectional survey was administered to 34 AYAs (12-22 years old) in SCD clinics from January to December 2015. Study measures included Brief Medication Questionnaire, Modified Morisky Adherence Scale 8-items, visual analog scale, and Patient Reported Outcomes Measurement Information System. Participants (59% male; 91% Black) had a median age of 13.5 years (IQR 12-18). Participants reported negative beliefs (32%), recall barriers (44%), and access barriers (32%). Participants with recall barriers reported worse pain (P=.02), fatigue (P=.05), and depression (P=.05). The number of adherence barriers inversely correlated with adherence level using ©MMAS-8 (r s =-.38, P=.02) and VAS dose (r s =-.25, P=.14) as well as MCV (r s =-.45, P=.01) and HbF% (r s =-.36, P=.05), suggesting higher hydroxyurea adherence in patients with fewer barriers. Patients with fewer barriers to hydroxyurea adherence were more likely to have higher adherence rates and better HRQOL scores. Routine assessment of hydroxyurea adherence and its related barriers could provide actionable information to improve adherence rates, HRQOL, and other clinical outcomes. © 2017 The Authors. European Journal of Haematology Published by John Wiley & Sons Ltd.

An exceptional case of renal artery restenosis in a patient with polycythaemia vera.

PubMed

Gavriilaki, Eleni; Sampanis, Nikolaos; Kavlakoudis, Christos; Papaioannou, George; Vasileiou, Sotirios

2014-12-01

Polycythaemia vera represents a rare chronic myeloproliferative neoplasm characterized by an increased thrombotic risk. Previous case reports have documented a link between primary or secondary polycythemia and the presence of renal artery stenosis and renovascular hypertension. Herein, we report an exceptional case of renal artery restenosis leading to uncontrolled hypertension in a patient with PV and high haematocrit levels. A 52-year-old female patient with a history of polycythaemia vera under treatment with hydroxyurea and phlebotomy presented in our outpatient clinic with newly diagnosed hypertension caused by left renal artery stenosis. Six months after stenting, patient returned for a follow-up visit due to uncontrolled hypertension and high haematocrit levels. Total restenosis of the left renal artery was found. Patient received optical medical treatment and was prescribed to higher doses of hydroxyurea by her treating haematologist. Since then, blood pressure and Hct levels remain adequately controlled. As described by earlier case reports, renal artery stenosis, hypertension and polycythemia often coexist. However, renovascular hypertension may not only lead to secondary erythrocytosis but also be a thrombotic complication of primary erythrocytosis. Thus, patients with polycythaemia vera should be carefully evaluated and optimally managed when hypertension or impaired renal function coexist.

Realizing effectiveness across continents with hydroxyurea: Enrollment and baseline characteristics of the multicenter REACH study in Sub-Saharan Africa.

PubMed

McGann, Patrick T; Williams, Thomas N; Olupot-Olupot, Peter; Tomlinson, George A; Lane, Adam; Luís Reis da Fonseca, José; Kitenge, Robert; Mochamah, George; Wabwire, Ham; Stuber, Susan; Howard, Thad A; McElhinney, Kathryn; Aygun, Banu; Latham, Teresa; Santos, Brígida; Tshilolo, Léon; Ware, Russell E

2018-08-01

Despite its well-described safety and efficacy in the treatment of sickle cell anemia (SCA) in high-income settings, hydroxyurea remains largely unavailable in sub-Saharan Africa, where more than 75% of annual SCA births occur and many comorbidities exist. Realizing Effectiveness Across Continents with Hydroxyurea (REACH, ClinicalTrials.gov NCT01966731) is a prospective, Phase I/II open-label trial of hydroxyurea designed to evaluate the feasibility, safety, and benefits of hydroxyurea treatment for children with SCA in four sub-Saharan African countries. Following comprehensive training of local research teams, REACH was approved by local Ethics Committees and achieved full enrollment ahead of projections with 635 participants enrolled over a 30-month period, despite half of families living >12 km from their clinical site. At enrollment, study participants (age 5.4 ± 2.4 years) had substantial morbidity, including a history of vaso-occlusive pain (98%), transfusion (68%), malaria (85%), and stroke (6%). Significant differences in laboratory characteristics were noted across sites, with lower hemoglobin concentrations (P < .01) in Angola (7.2 ± 1.0 g/dL) and the DRC (7.0 ± 0.9 g/dL) compared to Kenya (7.4 ± 1.1 g/dL) and Uganda (7.5 ± 1.1 g/dL). Analysis of known genetic modifiers of SCA demonstrated a high frequency of α-thalassemia (58.4% with at least a single α-globin gene deletion) and G6PD deficiency (19.7% of males and 2.4% of females) across sites. The CAR β-globin haplotype was present in 99% of participants. The full enrollment to REACH confirms the feasibility of conducting high-quality SCA research in Africa; this study will provide vital information to guide safe and effective dosing of hydroxyurea for children with SCA living in Africa. © 2018 Wiley Periodicals, Inc.

Efficacy and Safety of Ruxolitinib in the Treatment of Patients with Myelofibrosis

PubMed Central

Yi, Cecilia Arana; Tam, Constantine S.; Verstovsek, Srdan

2016-01-01

The JAK 1 and JAK2 inhibitor ruxolitinib has approved indications in myelofibrosis, a BCR-ABL1-negative myeloproliferative neoplasm associated with progressive bone marrow fibrosis and shortened survival. In Phase III clinical studies, ruxolitinib provided rapid and durable improvement of myelofibrosis-related splenomegaly and symptoms irrespective of mutation status, and was associated with a survival advantage compared with placebo or best available therapy. Because of dose-dependent cytopenias, blood count monitoring and dose titration are important to optimize therapy. Specific precautions apply to the treatment of patients with or at risk of serious infections. Discontinuation of ruxolitinib generally leads to symptom return within 1 week. Ruxolitinib also is approved for treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea. PMID:25757677

Hydroxyurea enhances the activity of acyclovir and cidofovir against herpes simplex virus type 1 resistant strains harboring mutations in the thymidine kinase and/or the DNA polymerase genes.

PubMed

Sergerie, Yan; Boivin, Guy

2008-01-01

Drug-resistant herpes simplex virus type 1 (HSV-1) recombinant strains harboring mutations in the thymidine kinase and/or the DNA polymerase genes were evaluated for their susceptibility to various antivirals in the presence of 25 microg/ml of hydroxyurea (HyU). The latter compound decreased the 50% inhibitory concentrations of acyclovir by 1.5-3.8-fold and that of cidofovir by 2.7-14.4-fold. However, HyU did not affect the susceptibilities of the various recombinant mutants to foscarnet. Hydroxyurea, a ribonucleotide reductase inhibitor, can increase the activity of nucleoside/nucleotide analogues against drug-resistant viruses.

Relationship Between Some Single-nucleotide Polymorphism and Response to Hydroxyurea Therapy in Iranian Patients With β-Thalassemia Intermedia.

PubMed

Karimi, Mehran; Zarei, Tahereh; Haghpanah, Sezaneh; Moghadam, Mohamad; Ebrahimi, Ahmad; Rezaei, Narges; Heidari, Ghazaleh; Vazin, Afsaneh; Khavari, Maryam; Miri, Hamid R

2017-05-01

To evaluate the possible relationship between hydroxyurea (HU) response and some single-nucleotide polymorphism (SNP) in patients affected by β-thalassemia intermedia. In this cross-sectional study, 100 β-thalassemia intermedia patients who were taking HU with a dose of 8 to 15 mg/kg body weight per day for a period of at least 6 months were randomly selected between February 2013 and October 2014 in southern Iran. HU response was defined based on decrease or cessation of the blood transfusion need and evaluation of Hb level. In univariate analysis, from all evaluated SNPs, only rs10837814 SNP of olfactory receptors (ORs) OR51B2 showed a significant association with HU response (P=0.038) and from laboratory characteristics, only nucleated red blood cells showed significant associations (116%±183%) in good responders versus (264%±286%) in poor responders (P=0.045). In multiple logistic regression, neither laboratory variables nor different SNPs, showed significant association with HU response. Three novel nucleotide variations (-665 [A→C], -1301 [T→G],-1199 delA) in OR51B2 gene were found in good responders. None of the evaluated SNPs in our study showed significant association with HU response. Further larger studies and evaluation of other genes are suggested.

Pain management trend of vaso-occulsive crisis (VOC) at a community hospital emergency department (ED) for patients with sickle cell disease.

PubMed

Inoue, Susumu; Khan, Isra'a; Mushtaq, Rao; Sanikommu, Srinivasa Reddy; Mbeumo, Carline; LaChance, Jenny; Roebuck, Michael

2016-01-01

Pain management at the emergency department (ED) for vaso-occulsive crisis (VOC) for patients with sickle cell disease has not been optimum, with a long delay in giving the initial analgesic. We conducted a retrospective survey over a 7-year period to determine our ED's timing in giving pain medication to patients with VOC as a quality improvement project. We compared different periods, children vs adults, and the influence of gender in the analgesic administration timing. This is a retrospective chart review of three different periods: (1) years 2007-2008, (2) years 2011-2012, and (3) year 2013. We extracted relevant information from ED records. Data were analyzed using Student t test, chi-square analysis, and the Kruskal-Wallis test. There was a progressive improvement in the time interval to the 1st analgesic over these three periods. Children received analgesics more quickly than adults in all periods. Male adult patients received pain medication faster than female adult patients, although initial pain scores were higher in female than in male patients. Progressively fewer pediatric patients utilized ED over these three periods, but no difference for adult patients was observed. The proportion of pediatric patients admitted to the hospital increased with each period. The progressive decrease in both the number of patients and the number of visits to the ED by children suggested that the collective number of VOC in children has decreased, possibly secondary to the dissemination of hydroxyurea use. We failed to observe the same trend in adult patients. The need for IV access, and ordering laboratory tests or imaging studies tends to delay analgesic administration. Delay in administration of the first analgesic was more pronounced for female adult patients than male adult patients in spite of their higher pain score. Health care providers working in ED should make conscious efforts to respect pain in women as well as pain in men. Though not proven from this study, we believe that a significantly wider use of hydroxyurea by adult patients most likely would reduce their utilization of ED for the purpose of relief of pain, and further pediatric hematologists may be better positioned to increase hydroxyurea adherence by young adult patients, since they have had established rapport with them before transitioning to adult care.

[Symptomatic extramedullary haematopoiesis in β-thalassemia: A retrospective single centre study].

PubMed

Maazoun, F; Gellen Dautremer, J; Boutekadjirt, A; Pissard, S; Habibi, A; Bachir, D; Rahmouni, A; Bartolucci, P; Debbache, K; Lagrange, J-L; Michel, M; Galacteros, F

2016-01-01

Symptomatic extramedullary hematopoiesis (EH) is a rare but potentially severe phenomenon which occurs in β-thalassemia. There are no treatment guidelines. Retrospective single centre study including the cases of symptomatic EH encountered between 1997 and 2014 in a unit specialised in red blood cell genetic disorders. Description of clinical, biological and radiological characteristics of the patients, treatments received, and outcomes. Among 182 β-thalassemia patients followed during the study period, 7 cases of symptomatic EH were diagnosed. They were 5 men and 2 women, and their mean age was 37 years. Four patients were splenectomised, two patients were regularly transfused, and four patients had already received erythropoietin. EH was localised in intravertebral areas and responsible for dorsal spinal cord compression in 5 patients, in paravertebral dorsal area in 1 patient, and in presacral area in 1 patient. The mean hemoglobin level at diagnosis was 7.9 g/dL. Treatment administered included: red cell transfusion in 6 cases, associated with hydroxyurea in 5 cases and/or radiotherapy in 3 patients. One patient was treated with surgery and HU. After a median follow-up of 41 months, clinical recovery was complete in 2 patients and partial in 5 patients. EH must be suspected in β-thalassemia in patients presenting clinical signs of organ compression, and a typical radiological aspect. The functional prognosis depends on the rapidity of treatment, which includes red blood cell transfusion, hydroxyurea, radiotherapy, and rarely surgery. Long-term outcome is uncertain. Copyright © 2015. Published by Elsevier SAS.

Class I Histone Deacetylase HDAC1 and WRN RECQ Helicase Contribute Additively to Protect Replication Forks upon Hydroxyurea-induced Arrest.

PubMed

Kehrli, Keffy; Phelps, Michael; Lazarchuk, Pavlo; Chen, Eleanor; Monnat, Ray; Sidorova, Julia M

2016-11-18

The WRN helicase/exonuclease is mutated in Werner syndrome of genomic instability and premature aging. WRN-depleted fibroblasts, although remaining largely viable, have a reduced capacity to maintain replication forks active during a transient hydroxyurea-induced arrest. A strand exchange protein, RAD51, is also required for replication fork maintenance, and here we show that recruitment of RAD51 to stalled forks is reduced in the absence of WRN. We performed a siRNA screen for genes that are required for viability of WRN-depleted cells after hydroxyurea treatment, and identified HDAC1, a member of the class I histone deacetylase family. One of the functions of HDAC1, which it performs together with a close homolog HDAC2, is deacetylation of new histone H4 deposited at replication forks. We show that HDAC1 depletion exacerbates defects in fork reactivation and progression after hydroxyurea treatment observed in WRN- or RAD51-deficient cells. The additive WRN, HDAC1 loss-of-function phenotype is also observed with a catalytic mutant of HDAC1; however, it does not correlate with changes in histone H4 deacetylation at replication forks. On the other hand, inhibition of histone deacetylation by an inhibitor specific to HDACs 1-3, CI-994, correlates with increased processing of newly synthesized DNA strands in hydroxyurea-stalled forks. WRN co-precipitates with HDAC1 and HDAC2. Taken together, our findings indicate that WRN interacts with HDACs 1 and 2 to facilitate activity of stalled replication forks under conditions of replication stress. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Genomic variants in the ASS1 gene, involved in the nitric oxide biosynthesis and signaling pathway, predict hydroxyurea treatment efficacy in compound sickle cell disease/β-thalassemia patients.

PubMed

Chalikiopoulou, Constantina; Tavianatou, Anastasia-Gerasimoula; Sgourou, Argyro; Kourakli, Alexandra; Kelepouri, Dimitra; Chrysanthakopoulou, Maria; Kanelaki, Vasiliki-Kaliopi; Mourdoukoutas, Evangelos; Siamoglou, Stavroula; John, Anne; Symeonidis, Argyris; Ali, Bassam R; Katsila, Theodora; Papachatzopoulou, Adamantia; Patrinos, George P

2016-03-01

Hemoglobinopathies exhibit a remarkable phenotypic diversity that restricts any safe association between molecular pathology and clinical outcomes. Herein, we explored the role of genes involved in the nitric oxide biosynthesis and signaling pathway, implicated in the increase of fetal hemoglobin levels and response to hydroxyurea treatment, in 119 Hellenic patients with β-type hemoglobinopathies. We show that two ASS1 genomic variants (namely, rs10901080 and rs10793902) can serve as pharmacogenomic biomarkers to predict hydroxyurea treatment efficacy in sickle cell disease/β-thalassemia compound heterozygous patients. These markers may exert their effect by inducing nitric oxide biosynthesis, either via altering splicing and/or miRNA binding, as predicted by in silico analysis, and ultimately, increase γ-globin levels, via guanylyl cyclase targeting.

Clinical Features of β-Thalassemia and Sickle Cell Disease.

PubMed

McGann, Patrick T; Nero, Alecia C; Ware, Russell E

2017-01-01

Sickle cell disease (SCD) and β-thalassemia are among the most common inherited diseases, affecting millions of persons globally. It is estimated that 5-7% of the world's population is a carrier of a significant hemoglobin variant. Without early diagnosis followed by initiation of preventative and therapeutic care, both SCD and β-thalassemia result in significant morbidity and early mortality. Despite great strides in the understanding of the molecular basis and pathophysiology of these conditions, the burden of disease remains high, particularly in limited resource settings. Current therapy relies heavily upon the availability and safety of erythrocyte transfusions to treat acute and chronic complications of these conditions, but frequent transfusions results in significant iron overload, as well as challenges from acquired infections and alloimmunization. Hydroxyurea is a highly effective treatment for SCD but less so for β-thalassemia, and does not represent curative therapy. As technology and use of cellular and gene therapies expand, SCD and thalassemia should be among the highest disease priorities.

Bone marrow necrosis in a patient with acute promyelocytic leukemia during re-induction therapy with arsenic trioxide.

PubMed

Ishitsuka, Kenji; Shirahashi, Akihiko; Iwao, Yasuhiro; Shishime, Mikiko; Takamatsu, Yasushi; Takatsuka, Yoshifusa; Utsunomiya, Atae; Suzumiya, Junji; Hara, Syuji; Tamura, Kazuo

2004-04-01

Arsenic trioxide (As2O3) therapy at a daily dose of 0.15 mg/kg was given to a 60-yr-old Japanese male with refractory acute promyelocytic leukemia. White blood cell (WBC) of 6.6 x 10(3)/microl increased to 134 x 10(3)/microl following the administration of As2O3. Daily hydroxyurea (HU), and 6-mercaptopurine (6-MP) were added on days 7 and 19, respectively. Both HU and 6-MP were discontinued on day 28, when WBC declined to 54.0 x 10(3)/microl. He developed unexplained fever and profound cytopenia requiring multiple blood products transfusions. Bone marrow examination on day 42 revealed massive necrosis. Pharmacokinetics confirmed a mean maximum plasma arsenic concentration (Cpmax) and a half-life time (t1/2) of 6.9 microm and 3.2 h, respectively, in the therapeutic range. This is the first case of bone marrow necrosis after standard-dose As2O3 therapy.

Current and future treatment options for polycythemia vera.

PubMed

Griesshammer, Martin; Gisslinger, Heinz; Mesa, Ruben

2015-06-01

Patients with polycythemia vera (PV), a myeloproliferative neoplasm characterized by an elevated red blood cell mass, are at high risk of vascular and thrombotic complications and have reduced quality of life due to a substantial symptom burden that includes pruritus, fatigue, constitutional symptoms, microvascular disturbances, and bleeding. Conventional therapeutic options aim at reducing vascular and thrombotic risk, with low-dose aspirin and phlebotomy as first-line recommendations for patients at low risk of thrombotic events and cytoreductive therapy (usually hydroxyurea or interferon alpha) recommended for high-risk patients. However, long-term effective and well-tolerated treatments are still lacking. The discovery of mutations in Janus kinase 2 (JAK2) as the underlying molecular basis of PV has led to the development of several targeted therapies, including JAK inhibitors, and results from the first phase 3 clinical trial with a JAK inhibitor in PV are now available. Here, we review the current treatment landscape in PV, as well as therapies currently in development.

Exploring alternative Zn-binding groups in the design of HDAC inhibitors: squaric acid, N-hydroxyurea, and oxazoline analogues of SAHA.

PubMed

Hanessian, Stephen; Vinci, Valerio; Auzzas, Luciana; Marzi, Mauro; Giannini, Giuseppe

2006-09-15

Analogues of suberoylanilide hydroxamic acid (SAHA) were prepared by replacing the Zn-binding group with squaric acid, N-hydroxyurea, and 4-hydroxymethyl oxazoline units, also varying the length of the aliphatic chain. No inhibitory activity on HDAC was observed below 1.0 microM and no cytotoxic activity on different tumor cell lines was seen below 20.0 microM.

How We Identify and Manage Patients with Inadequately Controlled Polycythemia Vera.

PubMed

Reiter, Andreas; Harrison, Claire

2016-10-01

Polycythemia vera (PV) is a chronic myeloproliferative neoplasm (MPN) characterized by an overactive Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway through mutations in JAK2 exons 12 or 14 (JAK2 V617F). The dominant clinical characteristics include erythrocytosis (with or without leukocytosis/thrombocytosis), thrombotic events, and symptoms. Increased risk of mortality is mainly caused by thrombotic events and progression to post-polycythemia vera myelofibrosis (PPV-MF) or secondary acute myeloid leukemia (sAML). The most important prognostic factors include age and a history of thrombotic events, although recent evidence has indicated that leukocytosis and additional cytogenetic aberrations may also be of significant prognostic value. First-line therapies include aspirin and phlebotomies, which significantly reduce the incidence of thrombotic events and prolong survival. Cytoreductive treatment with hydroxyurea (approved) and conventional or pegylated interferon-α (effective, but not approved in many countries) is initiated for high-risk or inadequately controlled disease, e.g., uncontrolled hematocrit, leukocytosis, thrombocytosis, thrombotic events, splenomegaly, or symptoms. However, some patients may not receive initial benefit from first-line therapy or may become resistant or intolerant in due course. Although second-line treatment options are limited, clinical trials have shown the efficacy of ruxolitinib toward improving blood counts, enlarged spleen, and symptoms and potentially reducing thrombotic events. Identification of patients with uncontrolled PV is important for clinical care, as such patients have a high risk of complications, and future studies with JAK inhibitors or other agents alone or in combination are needed to test their potential to reduce rates of thrombotic events and transformation to PPV-MF or sAML.

Systemic mastocytosis in adults: 2013 update on diagnosis, risk stratification, and management.

PubMed

Pardanani, Animesh

2013-07-01

Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in one or more extracutaneous organs. The major criterion is presence of multifocal clusters of morphologically abnormal MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC expression of CD25 and/or CD2, and presence of KITD816V. The 2008 World Health Organization (WHO) classification of SM has been shown to be prognostically relevant. Classification of SM patients into indolent (SM), aggressive SM (ASM), SM associated with a clonal non-MC lineage disease (SM-AHNMD) and mast cell leukemia (MCL) subgroups is a useful first step in establishing prognosis. SM treatment is generally palliative. ISM patients have a normal life expectancy and receive symptom-directed therapy; infrequently, cytoreductive therapy may be indicated for refractory symptoms. ASM patients have disease-related organ dysfunction; interferon-α (±corticosteroids) can control dermatological, hematological, gastrointestinal, skeletal, and mediator-release symptoms, but is hampered by poor tolerability. Similarly, cladribine has broad therapeutic activity, with particular utility when rapid MC debulking is indicated; the main toxicity is myelosuppression. Imatinib has a therapeutic role in the presence of an imatinib-sensitive KIT mutation or in KITD816-unmutated patients. Treatment of SM-AHNMD is governed primarily by the non-MC neoplasm; hydroxyurea has modest utility in this setting. Dasatinib's in vitro anti- KITD816V activity has not translated into significant therapeutic activity in most SM patients. In contrast, recently updated data confirms Midostaurin's significant anti-MC activity in patients with advanced SM. Copyright © 2013 Wiley Periodicals, Inc.

Systemic mastocytosis in adults: 2012 Update on diagnosis, risk stratification, and management.

PubMed

Pardanani, Animesh

2012-04-01

Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in one or more extra-cutaneous organs. The major criterion is presence of multifocal clusters of morphologically abnormal MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC expression of CD25 and/or CD2, and presence of KITD816V. The prognostic relevance of the 2008 World Health Organization (WHO) classification of SM has recently been confirmed. Classification of SM patients into indolent (SM), aggressive SM (ASM), SM associated with a clonal non-MC lineage disease (SM-AHNMD) and mast cell leukemia (MCL) subgroups is a useful first step in establishing prognosis. SM treatment is generally palliative. ISM patients have a normal life expectancy and receive symptom-directed therapy; infrequently, cytoreductive therapy may be indicated for refractory symptoms. ASM patients have disease-related organ dysfunction; interferon-α (±corticosteroids) can control dermatological, hematological, gastrointestinal, skeletal, and mediator-release symptoms, but is hampered by poor tolerability. Similarly, cladribine has broad therapeutic activity, with particular utility when rapid MC debulking is indicated; the main toxicity is myelosuppression. Imatinib has a therapeutic role in the presence of an imatinib-sensitive KIT mutation or in KITD816-unmutated patients. Treatment of SM-AHNMD is governed primarily by the non-MC neoplasm; hydroxyurea has modest utility in this setting. Dasatinib's in vitro anti-KITD816V activity has not translated into significant therapeutic activity in most SM patients. In contrast, preliminary data suggest that Midostaurin may produce significant decreases in MC burden in some patients. Copyright © 2012 Wiley Periodicals, Inc.

Systemic mastocytosis in adults: 2015 update on diagnosis, risk stratification, and management.

PubMed

Pardanani, Animesh

2015-03-01

Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in one or more extracutaneous organs. The major criterion is presence of multifocal clusters of morphologically abnormal MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC expression of CD25 and/or CD2, and presence of KITD816V. The 2008 World Health Organization classification of SM has been shown to be prognostically relevant. Classification of SM patients into indolent SM (ISM), aggressive SM (ASM), SM associated with a clonal non-MC lineage disease (SM-AHNMD), and mast cell leukemia (MCL) subgroups is a useful first step in establishing prognosis. SM treatment is generally palliative. ISM patients have a normal life expectancy and receive symptom-directed therapy; infrequently, cytoreductive therapy may be indicated for refractory symptoms. ASM patients have disease-related organ dysfunction; interferon-α (+/-corticosteroids) can control dermatological, hematological, gastrointestinal, skeletal, and mediator-release symptoms, but is hampered by poor tolerability. Similarly, cladribine has broad therapeutic activity, with particular utility when rapid MC debulking is indicated; the main toxicity is myelosuppression. Imatinib has a therapeutic role in the presence of an imatinib-sensitive KIT mutation or in KITD816-unmutated patients. Treatment of SM-AHNMD is governed primarily by the non-MC neoplasm; hydroxyurea has modest utility in this setting; there is a role for allogeneic stem cell transplantation in select cases. Investigational Drugs: Recent data confirms midostaurin's significant anti-MC activity in patients with advanced SM. © 2015 Wiley Periodicals, Inc.

Systemic mastocytosis in adults: 2011 update on diagnosis, risk stratification, and management.

PubMed

Pardanani, Animesh

2011-04-01

Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in one or more extracutaneous organs. The major criterion is presence of multifocal clusters of morphologically abnormal MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC expression of CD25 and/or CD2, and presence of KITD816V. The prognostic relevance of the 2008 World Health Organization (WHO) classification of SM has recently been confirmed. Classification of SM patients into indolent (SM), aggressive SM (ASM), SM associated with a clonal non-MC lineage disease (SM-AHNMD), and mast cell leukemia (MCL) subgroups is a useful first step in establishing prognosis. SM treatment is generally palliative. ISM patients have a normal life expectancy and receive symptom-directed therapy; infrequently, cytoreductive therapy may be indicated for refractory symptoms. ASM patients have disease-related organ dysfunction; interferon-α (±corticosteroids) can control dermatological, hematological, gastrointestinal, skeletal, and mediator-release symptoms, but is hampered by poor tolerability. Similarly, cladribine has broad therapeutic activity, with particular utility when rapid MC debulking is indicated; the main toxicity is myelosuppression. Imatinib has a therapeutic role in the presence of an imatinib-sensitive KIT mutation or in KITD816-unmutated patients. Treatment of SM-AHNMD is governed primarily by the non-MC neoplasm; hydroxyurea has modest utility in this setting. Dasatinib's in vitro anti- KITD816V activity has not translated into significant therapeutic activity in most SM patients. In contrast, preliminary data suggest that Midostaurin may produce significant decreases in MC burden in some patients. Copyright © 2011 Wiley-Liss, Inc.

Blood transfusion for preventing primary and secondary stroke in people with sickle cell disease.

PubMed

Wang, Winfred C; Dwan, Kerry

2013-11-14

In sickle cell disease, a common inherited haemoglobin disorder, abnormal haemoglobin distorts red blood cells, causing anaemia, vaso-occlusion and dysfunction in most body organs. Without intervention, stroke affects around 10% of children with sickle cell anaemia (HbSS) and recurrence is likely. Chronic blood transfusion dilutes the sickled red blood cells, reducing the risk of vaso-occlusion and stroke. However, side effects can be severe. To assess risks and benefits of chronic blood transfusion regimens in people with sickle cell disease to prevent first stroke or recurrences. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and conference proceedings.Date of the latest search of the Group's Haemoglobinopathies Trials Register: 28 January 2013. Randomised and quasi-randomised controlled trials comparing blood transfusion as prophylaxis for stroke in people with sickle cell disease to alternative or no treatment. Both authors independently assessed the risk of bias of the included trials and extracted data. Searches identified three eligible randomised trials (n = 342). The first two trials addressed the use of chronic transfusion to prevent primary stroke; the third utilized the drug hydroxycarbamide (hydroxyurea) and phlebotomy to prevent both recurrent (secondary) stroke and iron overload in patients who had already experienced an initial stroke. In the first trial (STOP) a chronic transfusion regimen for maintaining sickle haemoglobin lower than 30% was compared with standard care in 130 children with sickle cell disease judged (through transcranial Doppler ultrasonography) as high-risk for first stroke. During the trial, 11 children in the standard care group suffered a stroke compared to one in the transfusion group, odds ratio 0.08 (95% confidence interval 0.01 to 0.66). This meant the trial was terminated early. The transfusion group had a high complications rate, including iron overload, alloimmunisation, and transfusion reactions. The second trial (STOP II) investigated risk of stroke when transfusion was stopped after at least 30 months in this population. The trial closed early due to a significant difference in risk of stroke between participants who stopped transfusion and those who continued as measured by reoccurrence of abnormal velocities on Doppler examination or the occurrence of overt stroke in the group that stopped transfusion. The third trial (SWiTCH) was a non-inferiority trial comparing transfusion and iron chelation (standard management) with hydroxyurea and phlebotomy (alternative treatment) with the combination endpoint of prevention of stroke recurrence and reduction of iron overload. This trial was stopped early after enrolment and follow up of 133 children because of analysis showing futility in reaching the composite primary endpoint. The stroke rate (seven strokes on hydroxyurea and phlebotomy, none on transfusion and chelation, odds ratio 16.49 (95% confidence interval 0.92 to 294.84)) was within the non-inferiority margin, but the liver iron content was not better in the alternative arm. The STOP trial demonstrated a significantly reduced risk of stroke in participants with abnormal transcranial Doppler ultrasonography velocities receiving regular blood transfusions. The follow-up trial (STOP 2) indicated that individuals may revert to former risk status if transfusion is discontinued. The degree of risk must be balanced against the burden of chronic transfusions. The combination of hydroxyurea and phlebotomy is not as effective as "standard" transfusion and chelation in preventing secondary stroke and iron overload. Ongoing multicentre trials are investigating the use of chronic transfusion to prevent silent infarcts, the use of hydroxyurea as an alternative to transfusion in children with abnormal transcranial Doppler ultrasonography velocities, and the use of hydroxyurea to prevent conversion of transcranial Doppler ultrasonography velocities from conditional (borderline) to abnormal values.

Centromere replication timing determines different forms of genomic instability in Saccharomyces cerevisiae checkpoint mutants during replication stress.

PubMed

Feng, Wenyi; Bachant, Jeff; Collingwood, David; Raghuraman, M K; Brewer, Bonita J

2009-12-01

Yeast replication checkpoint mutants lose viability following transient exposure to hydroxyurea, a replication-impeding drug. In an effort to understand the basis for this lethality, we discovered that different events are responsible for inviability in checkpoint-deficient cells harboring mutations in the mec1 and rad53 genes. By monitoring genomewide replication dynamics of cells exposed to hydroxyurea, we show that cells with a checkpoint deficient allele of RAD53, rad53K227A, fail to duplicate centromeres. Following removal of the drug, however, rad53K227A cells recover substantial DNA replication, including replication through centromeres. Despite this recovery, the rad53K227A mutant fails to achieve biorientation of sister centromeres during recovery from hydroxyurea, leading to secondary activation of the spindle assembly checkpoint (SAC), aneuploidy, and lethal chromosome segregation errors. We demonstrate that cell lethality from this segregation defect could be partially remedied by reinforcing bipolar attachment. In contrast, cells with the mec1-1 sml1-1 mutations suffer from severely impaired replication resumption upon removal of hydroxyurea. mec1-1 sml1-1 cells can, however, duplicate at least some of their centromeres and achieve bipolar attachment, leading to abortive segregation and fragmentation of incompletely replicated chromosomes. Our results highlight the importance of replicating yeast centromeres early and reveal different mechanisms of cell death due to differences in replication fork progression.

Population pharmacokinetics of hydroxyurea for children and adolescents with sickle cell disease.

PubMed

Wiczling, Paweł; Liem, Robert I; Panepinto, Julie A; Garg, Uttam; Abdel-Rahman, Susan M; Kearns, Gregory L; Neville, Kathleen A

2014-09-01

The objective of this study was to develop a population pharmacokinetic (PK) model sufficient to describe hydroxyurea (HU) concentrations in serum and urine following oral drug administration in pediatric patients with sickle cell disease. Additionally, the measured hydroxyurea concentrations for particular sampling time were correlated with exposure measures (AUC) to find the most predictive relationship. Hydroxyurea concentrations were determined in 21 subjects. Using a population nonlinear mixed-effect modeling, the HU PK was best described by a one-compartment model with two elimination pathways (metabolic and renal) and a transit compartment absorption. The typical mean absorption time was 0.222 hour. The typical apparent volume of distribution was 21.8 L and the apparent systemic clearance was 6.88 L/h for an average weight patient of 30.7 kg. The 50% of the HU dose was renally excreted. Linear correlations were apparent between the plasma HU concentration at 1, 1.5, 2, 4, and 6 hours post-dose and AUC with the most significant (R(2)  = 0.71) observed at 1.5 hours. A population PK model was successful in describing HU disposition in plasma and urine. Data from the model also demonstrated that HU plasma concentrations at 1.5 hours after an oral dose of the drug were highly predictive of systemic drug exposure. © 2014, The American College of Clinical Pharmacology.

In Vitro/In Vivo Evaluation of Radiolabeled [(99m)Tc(CO)3](+)-Hydroxyurea and Fluorescein Isothiocyanate-Hydroxyurea.

PubMed

Yilmaz, Baris; Teksoz, Serap; Kilcar, Ayfer Yurt; Ucar, Eser; Ichedef, Cigdem; Medine, Emin Ilker; Ari, Kadir

2016-02-01

The aim of current study is to examine hydroxyurea (HU), which is an antineoplastic drug used for the treatment of leukemia, sickle-cell disease, HIV, psoriasis, thrombocythemia, and various neoplastic diseases in two aspects. The active ingredient hydroxyurea was obtained by purification of the capsule form drug, commercially named as HYDREA. Then, [(99m)Tc(CO)3](+)core radiolabeling with HU was performed as first aspect. Quality control studies of (99m)Tc(CO)3-HU complex were performed by thin-layer radiochromatography and high-performance liquid radiochromatography methods. The results demonstrated that the radiolabeling yield was quite high (98.43% ± 2.29%). Also, (99m)Tc(CO)3-HU complex has good stability during the 24-hour period. Biological behavior of (99m)Tc(CO)3-HU complex is evaluated by biodistribution studies on Wistar Albino rats. Fluorescein isothiocyanate (FITC) labeling of HU was performed as second aspect. Fluorometric evaluation of binding efficacy and fluorescence imaging studies on MCF7 and Hela cell lines were carried out. It was thought that the knowledge achieved in this study would contribute to using (99m)Tc(CO)3-HU complex as an imaging agent, which inhibits the DNA synthesis selectively, by inhibiting ribonucleotide reductase enzyme. It was observed that FITC-HU has noteworthy incorporation on both cell lines.

Health-related quality of life and adherence to hydroxyurea in adolescents and young adults with sickle cell disease.

PubMed

Badawy, Sherif M; Thompson, Alexis A; Lai, Jin-Shei; Penedo, Frank J; Rychlik, Karen; Liem, Robert I

2017-06-01

Complications related to sickle cell disease (SCD) result in significant declines in health-related quality of life (HRQOL). While hydroxyurea reduces SCD complications, adherence remains suboptimal. The study's objectives were to assess the feasibility of Internet-based electronic assessment of HRQOL in SCD clinic and to examine the relationship between HRQOL and hydroxyurea adherence in adolescents and young adults (AYAs) with SCD. A cross-sectional survey was administered on tablets to 34 AYAs (12-22 years old) in a SCD clinic from January through December 2015. Study measures included Patient Reported Outcomes Measurement Information System (PROMIS ® ) computerized adaptive testing and ©Modified Morisky Adherence Scale 8-items (©MMAS-8). Participants (59% male, 91% Black) had median age of 13.5 (range 12-18) years. Ninety-one percent completed PROMIS® measures electronically in the clinic, meeting our feasibility criterion of ≥85% completion rate. ©MMAS-8 scores positively correlated with fetal hemoglobin (HbF) (r s = 0.34, P = 0.04) and mean corpuscular volume (MCV) (r s = 0.42, P = 0.01) and inversely correlated with fatigue (r s = -0.45, P = 0.01), depression (r s = -0.3, P = 0.08), and social isolation (r s = -0.78, P = 0.02). Low ©MMAS-8 scores, indicating poor adherence, were associated with worse fatigue (P = 0.001) and trended toward significance for pain (P = 0.07) and depression (P = 0.06). Homozygous hemoglobin S disease patients with low HbF (<16%) had worse social isolation (P = 0.04) and those with low MCV (<102 fl) reported worse fatigue (P = 0.001), pain (P = 0.01), mobility (P = 0.01), and social isolation (P = 0.04). HRQOL assessment in the SCD clinic is feasible. SCD patients with low hydroxyurea adherence and/or low HbF or MCV levels had worse HRQOL scores, particularly fatigue. Future prospective studies examining the relationship between HRQOL and hydroxyurea adherence are warranted. © 2016 Wiley Periodicals, Inc.

Sickle cell disease in children.

PubMed

Meier, Emily Riehm; Miller, Jeffery L

2012-05-07

Early identification of infants with sickle cell disease (SCD) by newborn screening, now universal in all 50 states in the US, has improved survival, mainly by preventing overwhelming sepsis with the early use of prophylactic penicillin. Routine transcranial Doppler screening with the institution of chronic transfusion decreases the risk of stroke from 10% to 1% in paediatric SCD patients. Hydroxyurea decreases the number and frequency of painful crises, acute chest syndromes and number of blood transfusions in children with SCD. Genetic research continues to be driven toward the prevention and ultimate cure of SCD before adulthood. This review focuses on clinical manifestations and therapeutic strategies for paediatric SCD as well as the evolving topic of gene-focused prevention and therapy.

Essential thrombocythaemia in two dogs.

PubMed

Favier, R P; van Leeuwen, M; Teske, E

2004-06-01

In this report two dogs with essential thrombocythaemia (ET) are described. Both dogs were presented more or less at the same time with a combination of reduced exercise tolerance and pale mucous membranes without any report of blood loss. Moderate-to-severe, Coomb's-negative anaemia and thrombocytosis (> 1249 x 10'/l) were present. In addition, the peripheral blood smear revealed the presence of basophilia and large numbers of abnormally shaped megakaryocytes in the bone marrow of both dogs. Treatment with vincristine (0.7 mg/m2 once intravenously) and hydroxyurea (500 mg/m2 p.o. per day) was started. Because of insufficient response to treatment after 3 weeks, the dosage of hydroxyurea was increased in both dogs to 2000 mg/m2 p.o. per day. The dogs deteriorated further, however, and were euthanized at 6 weeks after the start of treatment. Blood examination revealed pancytopenia in both dogs, most likely due to the myelosuppressive effects of high-dose hydroxyurea. A survey of veterinary literature on ET is presented, including a comparison of ET in humans.

Dissociative electron attachment to the radiosensitizing chemotherapeutic agent hydroxyurea

NASA Astrophysics Data System (ADS)

Huber, S. E.; Śmiałek, M. A.; Tanzer, K.; Denifl, S.

2016-06-01

Dissociative electron attachment to hydroxyurea was studied in the gas phase for electron energies ranging from zero to 9 eV in order to probe its radiosensitizing capabilities. The experiments were carried out using a hemispherical electron monochromator coupled with a quadrupole mass spectrometer. Diversified fragmentation of hydroxyurea was observed upon low energy electron attachment and here we highlight the major dissociation channels. Moreover, thermodynamic thresholds for various fragmentation reactions are reported to support the discussion of the experimental findings. The dominant dissociation channel, which was observed over a broad range of energies, is associated with formation of NCO-, water, and the amidogen (NH2) radical. The second and third most dominant dissociation channels are associated with formation of NCNH- and NHCONH2-, respectively, which are both directly related to formation of the highly reactive hydroxyl radical. Other ions observed with significant abundance in the mass spectra were NH2-/O-, OH-, CN-, HNOH-, NCONH2-, and ONHCONH2-.

Re-emergence of interferon-α in the treatment of chronic myeloid leukemia

PubMed Central

Talpaz, M; Hehlmann, R; Quintás-Cardama, A; Mercer, J; Cortes, J

2013-01-01

Treatment for chronic myeloid leukemia (CML) has evolved from chemotherapy (busulfan, hydroxyurea) to interferon-α (IFNα), and finally to tyrosine kinase inhibitors such as imatinib. Although imatinib has profoundly improved outcomes for patients with CML, it has limitations. Most significantly, imatinib cannot eradicate CML primitive progenitors, which likely accounts for the high relapse rate when imatinib is discontinued. IFNα, unlike imatinib, preferentially targets CML stem cells. Early studies with IFNα in CML demonstrated its ability to induce cytogenetic remission. Moreover, a small percentage of patients treated with IFNα were able to sustain durable remissions after discontinuing therapy and were probably cured. The mechanisms by which IFNα exerts its antitumor activity in CML are not well understood; however, activation of leukemia-specific immunity may have a role. Some clinical studies have demonstrated that the combination of imatinib and IFNα is superior to either therapy alone, perhaps because of their different mechanisms of action. Nonetheless, the side effects of IFNα often impede its administration, especially in combination therapy. Here, we review the role of IFNα in CML treatment and the recent developments that have renewed interest in this once standard therapy for patients with CML. PMID:23238589

NEK8 regulates DNA damage-induced RAD51 foci formation and replication fork protection

PubMed Central

Abeyta, Antonio; Castella, Maria; Jacquemont, Celine; Taniguchi, Toshiyasu

2017-01-01

ABSTRACT Proteins essential for homologous recombination play a pivotal role in the repair of DNA double strand breaks, DNA inter-strand crosslinks and replication fork stability. Defects in homologous recombination also play a critical role in the development of cancer and the sensitivity of these cancers to chemotherapy. RAD51, an essential factor for homologous recombination and replication fork protection, accumulates and forms immunocytochemically detectable nuclear foci at sites of DNA damage. To identify kinases that may regulate RAD51 localization to sites of DNA damage, we performed a human kinome siRNA library screen, using DNA damage-induced RAD51 foci formation as readout. We found that NEK8, a NIMA family kinase member, is required for efficient DNA damage-induced RAD51 foci formation. Interestingly, knockout of Nek8 in murine embryonic fibroblasts led to cellular sensitivity to the replication inhibitor, hydroxyurea, and inhibition of the ATR kinase. Furthermore, NEK8 was required for proper replication fork protection following replication stall with hydroxyurea. Loading of RAD51 to chromatin was decreased in NEK8-depleted cells and Nek8-knockout cells. Single-molecule DNA fiber analyses revealed that nascent DNA tracts were degraded in the absence of NEK8 following treatment with hydroxyurea. Consistent with this, Nek8-knockout cells showed increased chromosome breaks following treatment with hydroxyurea. Thus, NEK8 plays a critical role in replication fork stability through its regulation of the DNA repair and replication fork protection protein RAD51. PMID:27892797

NEK8 regulates DNA damage-induced RAD51 foci formation and replication fork protection.

PubMed

Abeyta, Antonio; Castella, Maria; Jacquemont, Celine; Taniguchi, Toshiyasu

2017-02-16

Proteins essential for homologous recombination play a pivotal role in the repair of DNA double strand breaks, DNA inter-strand crosslinks and replication fork stability. Defects in homologous recombination also play a critical role in the development of cancer and the sensitivity of these cancers to chemotherapy. RAD51, an essential factor for homologous recombination and replication fork protection, accumulates and forms immunocytochemically detectable nuclear foci at sites of DNA damage. To identify kinases that may regulate RAD51 localization to sites of DNA damage, we performed a human kinome siRNA library screen, using DNA damage-induced RAD51 foci formation as readout. We found that NEK8, a NIMA family kinase member, is required for efficient DNA damage-induced RAD51 foci formation. Interestingly, knockout of Nek8 in murine embryonic fibroblasts led to cellular sensitivity to the replication inhibitor, hydroxyurea, and inhibition of the ATR kinase. Furthermore, NEK8 was required for proper replication fork protection following replication stall with hydroxyurea. Loading of RAD51 to chromatin was decreased in NEK8-depleted cells and Nek8-knockout cells. Single-molecule DNA fiber analyses revealed that nascent DNA tracts were degraded in the absence of NEK8 following treatment with hydroxyurea. Consistent with this, Nek8-knockout cells showed increased chromosome breaks following treatment with hydroxyurea. Thus, NEK8 plays a critical role in replication fork stability through its regulation of the DNA repair and replication fork protection protein RAD51.

Pulmonary hypertension as a risk factor for death in patients with sickle cell disease.

PubMed

Gladwin, Mark T; Sachdev, Vandana; Jison, Maria L; Shizukuda, Yukitaka; Plehn, Jonathan F; Minter, Karin; Brown, Bernice; Coles, Wynona A; Nichols, James S; Ernst, Inez; Hunter, Lori A; Blackwelder, William C; Schechter, Alan N; Rodgers, Griffin P; Castro, Oswaldo; Ognibene, Frederick P

2004-02-26

The prevalence of pulmonary hypertension in adults with sickle cell disease, the mechanism of its development, and its prospective prognostic significance are unknown. We performed Doppler echocardiographic assessments of pulmonary-artery systolic pressure in 195 consecutive patients (82 men and 113 women; mean [+/-SD] age, 36+/-12 years). Pulmonary hypertension was prospectively defined as a tricuspid regurgitant jet velocity of at least 2.5 m per second. Patients were followed for a mean of 18 months, and data were censored at the time of death or loss to follow-up. Doppler-defined pulmonary hypertension occurred in 32 percent of patients. Multiple logistic-regression analysis, with the use of the dichotomous variable of a tricuspid regurgitant jet velocity of less than 2.5 m per second or 2.5 m per second or more, identified a self-reported history of cardiovascular or renal complications, increased systolic blood pressure, high lactate dehydrogenase levels (a marker of hemolysis), high levels of alkaline phosphatase, and low transferrin levels as significant independent correlates of pulmonary hypertension. The fetal hemoglobin level, white-cell count, and platelet count and the use of hydroxyurea therapy were unrelated to pulmonary hypertension. A tricuspid regurgitant jet velocity of at least 2.5 m per second, as compared with a velocity of less than 2.5 m per second, was strongly associated with an increased risk of death (rate ratio, 10.1; 95 percent confidence interval, 2.2 to 47.0; P<0.001) and remained so after adjustment for other possible risk factors in a proportional-hazards regression model. Pulmonary hypertension, diagnosed by Doppler echocardiography, is common in adults with sickle cell disease. It appears to be a complication of chronic hemolysis, is resistant to hydroxyurea therapy, and confers a high risk of death. Therapeutic trials targeting this population of patients are indicated. Copyright 2004 Massachusetts Medical Society

Hydroxyurea derivatives of irofulven with improved antitumor efficacy.

PubMed

Staake, Michael D; Kashinatham, Alisala; McMorris, Trevor C; Estes, Leita A; Kelner, Michael J

2016-04-01

Irofulven is a semi-synthetic derivative of Illudin S, a toxic sesquiterpene isolated from the mushroom Omphalotus illudens. Irofulven has displayed significant antitumor activity in various clinical trials but displayed a limited therapeutic index. A new derivative of irofulven was prepared by reacting hydroxyurea with irofulven under acidic conditions. Acetylation of this new compound with acetic anhydride produced a second derivative. Both of these new derivatives displayed significant antitumor activity in vitro and in vivo comparable to or exceeding that of irofulven. Copyright © 2016 Elsevier Ltd. All rights reserved.

Fatal Disseminated Tuberculosis during Treatment with Ruxolitinib Plus Prednisolone in a Patient with Primary Myelofibrosis: A Case Report and Review of the Literature.

PubMed

Tsukamoto, Yasuhiro; Kiyasu, Junichi; Tsuda, Mariko; Ikeda, Motohiko; Shiratsuchi, Motoaki; Ogawa, Yoshihiro; Yufu, Yuji

2018-05-01

A 73-year-old man with primary myelofibrosis (PMF) was being treated with hydroxyurea, which was changed to ruxolitinib treatment because of worsening constitutional symptoms. Although ruxolitinib rapidly induced relief, he developed a high-grade fever. A comprehensive fever work-up found no apparent cause of the fever, except for PMF. Therefore, we increased the dose of ruxolitinib and added prednisolone, which was gradually withdrawn with resolution of the fever. However, the patient subsequently developed disseminated tuberculosis and died eight months after initiation of ruxolitinib. Our case highlights the importance of assessing and monitoring the immune status of patients receiving ruxolitinib.

Systemic mastocytosis in adults: 2017 update on diagnosis, risk stratification and management.

PubMed

Pardanani, Animesh

2016-11-01

Disease overview:Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in one or more extra-cutaneous organs. The major criterion is presence of multifocal clusters of morphologically abnormal MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC expression of CD25 and/or CD2, and presence of KITD816V. Risk stratification: The 2008 World Health Organization (WHO) classification of SM has been shown to be prognostically relevant. Classification of SM patients into indolent (SM), aggressive SM (ASM), SM associated with a clonal non-MC lineage disease (SM-AHNMD) and mast cell leukemia (MCL) subgroups is a useful first step in establishing prognosis. SM treatment is generally palliative. ISM patients have a normal life expectancy and receive symptom-directed therapy; infrequently, cytoreductive therapy may be indicated for refractory symptoms. ASM patients have disease-related organ dysfunction; interferon-α (±corticosteroids) can control dermatological, hematological, gastrointestinal, skeletal and mediator-release symptoms, but is hampered by poor tolerability. Similarly, cladribine has broad therapeutic activity, with particular utility when rapid MC debulking is indicated; the main toxicity is myelosuppression. Imatinib has a therapeutic role in the presence of an imatinib-sensitive KIT mutation or in KITD816-unmutated patients. Treatment of SM-AHNMD is governed primarily by the non-MC neoplasm; hydroxyurea has modest utility in this setting; there is a role for allogeneic stem cell transplantation in select cases. Investigational drugs: Recent data confirms midostaurin's significant anti-MC activity in patients with advanced SM. Am. J. Hematol. 91:1147-1159, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Role of XmnIgG Polymorphism in Hydroxyurea Treatment and Fetal Hemoglobin Level at Isfahanian Intermediate β-Thalassemia Patients.

PubMed

Motovali-Bashi, Majid; Ghasemi, Tayyebeh

2015-01-01

β-thalassemia is the most common monogenic disorder in human. The (C-->T) polymorphism at -158 upstream region of the γG-globin gene and pharmacological factors such as hydroxyurea have been reported to influence γ-globin gene expression and the severity of clinical symptoms of β-thalassemia. In the present study, 51 β-thalassemia intermediate patients were studied. Xmn1γG polymorphism genotype was determined using Tetra-Primer ARMS-PCR technique. Hemoglobin (Hb) and fetal hemoglobin (HbF) levels were determined by gel electrophoresis. Of 51 patients, 35 (68.6%) patients were heterozygous (CT) and 16 (31.4%) patients were homozygous (CC). Of 30 patients under treatment by hydroxyurea, 20 (66.7%) patients were heterozygous (CT) and 10 (33.3%) patients were homozygous (CC). Our results demonstrated that in the heterozygous (CT) genotype, the Hb (9.58 ± 1.25 gm/dl) and HbF (89.30 ± 21.87) levels were significantly higher in comparison with homozygous (CC) genotype (7.94 ± 1.34 gm/dl and 70.32 ± 40.56, respectively). Furthermore, we observed that after drug usage, the Hb and HbF levels in patients with heterozygous (CT) genotype (0.7 ± 1.26 gm/dl and 5.95 ± 14.8, respectively) raised more in comparison with homozygous (CC) genotype (0.26 ± 1.43 gm/dl and 0.8 ± 1.31, respectively). Hb and HbF levels in the patients carrying T allele are increased significantly, and they also response to hydroxyurea treatment.

Ruxolitinib: long-term management of patients with myelofibrosis and future directions in the treatment of myeloproliferative neoplasms.

PubMed

Yacoub, A; Odenike, O; Verstovsek, S

2014-12-01

Considerable clinical experience regarding the long-term efficacy and safety of ruxolitinib has been gathered since the drug was approved in the USA for patients with intermediate or high-risk myelofibrosis (MF) in November 2011. Findings from the pivotal phase 3 COMFORT studies showed that ruxolitinib-associated reductions in MF-related splenomegaly and symptom burden occur rapidly and in the majority of patients. Two- and 3-year follow-up data further suggest that the benefits of ruxolitinib are durable and associated with a survival advantage compared with conventional therapies. However, careful management of treatment-related thrombocytopenia and anemia with dose modifications and supportive care is critical to allow chronic therapy. Based on preliminary evidence, ruxolitinib also allows spleen size and symptom reduction before allogeneic stem cell transplantation without negative effect on engraftment or outcomes. In recent studies, ruxolitinib provided effective management of hematologic parameters and symptoms in patients with polycythemia vera refractory to or intolerant of hydroxyurea.

Dissociative electron attachment to the radiosensitizing chemotherapeutic agent hydroxyurea

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huber, S. E.; Tanzer, K.; Denifl, S.

Dissociative electron attachment to hydroxyurea was studied in the gas phase for electron energies ranging from zero to 9 eV in order to probe its radiosensitizing capabilities. The experiments were carried out using a hemispherical electron monochromator coupled with a quadrupole mass spectrometer. Diversified fragmentation of hydroxyurea was observed upon low energy electron attachment and here we highlight the major dissociation channels. Moreover, thermodynamic thresholds for various fragmentation reactions are reported to support the discussion of the experimental findings. The dominant dissociation channel, which was observed over a broad range of energies, is associated with formation of NCO{sup −}, water,more » and the amidogen (NH{sub 2}) radical. The second and third most dominant dissociation channels are associated with formation of NCNH{sup −} and NHCONH{sub 2}{sup −}, respectively, which are both directly related to formation of the highly reactive hydroxyl radical. Other ions observed with significant abundance in the mass spectra were NH{sub 2}{sup −}/O{sup −}, OH{sup −}, CN{sup −}, HNOH{sup −}, NCONH{sub 2}{sup −}, and ONHCONH{sub 2}{sup −}.« less

Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial.

PubMed

Ware, Russell E; Davis, Barry R; Schultz, William H; Brown, R Clark; Aygun, Banu; Sarnaik, Sharada; Odame, Isaac; Fuh, Beng; George, Alex; Owen, William; Luchtman-Jones, Lori; Rogers, Zora R; Hilliard, Lee; Gauger, Cynthia; Piccone, Connie; Lee, Margaret T; Kwiatkowski, Janet L; Jackson, Sherron; Miller, Scott T; Roberts, Carla; Heeney, Matthew M; Kalfa, Theodosia A; Nelson, Stephen; Imran, Hamayun; Nottage, Kerri; Alvarez, Ofelia; Rhodes, Melissa; Thompson, Alexis A; Rothman, Jennifer A; Helton, Kathleen J; Roberts, Donna; Coleman, Jamie; Bonner, Melanie J; Kutlar, Abdullah; Patel, Niren; Wood, John; Piller, Linda; Wei, Peng; Luden, Judy; Mortier, Nicole A; Stuber, Susan E; Luban, Naomi L C; Cohen, Alan R; Pressel, Sara; Adams, Robert J

2016-02-13

For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions. TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4-16 years and had abnormal TCD flow velocities (≥ 200 cm/s) but no severe vasculopathy. After screening, eligible participants were randomly assigned 1:1 to continue standard transfusions (standard group) or hydroxycarbamide (alternative group). Randomisation was done at a central site, stratified by site with a block size of four, and an adaptive randomisation scheme was used to balance the covariates of baseline age and TCD velocity. The study was open-label, but TCD examinations were read centrally by observers masked to treatment assignment and previous TCD results. Participants assigned to standard treatment continued to receive monthly transfusions to maintain 30% sickle haemoglobin or lower, while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day, which was escalated to each participant's maximum tolerated dose. The treatment period lasted 24 months from randomisation. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01425307. Between Sept 20, 2011, and April 17, 2013, 159 patients consented and enrolled in TWiTCH. 121 participants passed screening and were then randomly assigned to treatment (61 to transfusions and 60 to hydroxycarbamide). At the first scheduled interim analysis, non-inferiority was shown and the sponsor terminated the study. Final model-based TCD velocities were 143 cm/s (95% CI 140-146) in children who received standard transfusions and 138 cm/s (135-142) in those who received hydroxycarbamide, with a difference of 4·54 (0·10-8·98). Non-inferiority (p=8·82 × 10(-16)) and post-hoc superiority (p=0·023) were met. Of 29 new neurological events adjudicated centrally by masked reviewers, no strokes were identified, but three transient ischaemic attacks occurred in each group. Magnetic resonance brain imaging and angiography (MRI and MRA) at exit showed no new cerebral infarcts in either treatment group, but worsened vasculopathy in one participant who received standard transfusions. 23 severe adverse events in nine (15%) patients were reported for hydroxycarbamide and ten serious adverse events in six (10%) patients were reported for standard transfusions. The most common serious adverse event in both groups was vaso-occlusive pain (11 events in five [8%] patients with hydroxycarbamide and three events in one [2%] patient for transfusions). For high-risk children with sickle cell anaemia and abnormal TCD velocities who have received at least 1 year of transfusions, and have no MRA-defined severe vasculopathy, hydroxycarbamide treatment can substitute for chronic transfusions to maintain TCD velocities and help to prevent primary stroke. National Heart, Lung, and Blood Institute, National Institutes of Health. Copyright © 2016 Elsevier Ltd. All rights reserved.

Challenge of managing sickle cell disease in a pediatric population living in kinshasa, democratic republic of congo: a sickle cell center experience.

PubMed

Aloni, Michel Ntetani; Nkee, Leonard

2014-01-01

In the Democratic Republic of Congo (DRC), sickle cell disease is not yet really regarded as a health care priority. The patterns of sickle cell disease in patients living in Kinshasa, DRC are discussed and the difficulties encountered in their management are highlighted. The cross-sectional survey is of sickle cell patients and their families attending the Centre de Médecine Mixte et d'Anémie SS de Yolo (CMMASS), Kinshasa, DRC, between January and April 2009. Completed questionnaires were received from 168 respondents (111 girls; 57 boys). Seventy-one percent of the subjects were diagnosed before the age of 2 years but none in the neonatal period. Sickle cell disease was diagnosed in 54.8% of the patients after they had suffered pain crises. Of the 168 subjects, 74.0% had previously received blood transfusions. Seventy-five (45.0%) had more than three severe pain crises per year. A minority of 35.0% reported that they regularly took an antibioprophylaxis. Seventy-five (45.0%) subjects were eligible for hydroxyurea (HU) therapy but in all cases this drug was taken irregularly. Eighty-two percent of drugs were purchased by the parents. One hundred and sixty-three children (97.0%) were vaccinated according to the Expanded Programme on Immunization (EPI), 61.0% against Streptococcus pneumoniae and 16.0% against the Hepatitis B virus (HBV). No case of immunization against Hemophilus influenzae and Salmonella sp was reported. Neonatal screening programs, early educational detection programs for families, use of current method treatments and an implementation of a health insurance system for sickle cell disease will improve detection and management for these and future patients in our population.

Sickle cell disease caused by Hb S/Québec-CHORI: treatment with hydroxyurea and response.

PubMed

Tubman, Venée N; Bennett, Carolyn M; Luo, Hong-yuan; Chui, David H K; Heeney, Matthew M

2007-08-01

Sickle hemoglobin (Hb S;betaGlu 6 Val) is due to an A>T transversion in codon 6 of the beta-globin gene. Other variant hemoglobins mimic Hb A, S, or C on newborn screening and clinical laboratory diagnostic tools, thus making their correct identification potentially difficult. Sickling disorders can result in individuals who are compound heterozygous for beta-globin mutations (e.g., Hb SC, HbSO(Arab)). The authors report a second case of HbS/Québec-CHORI, a severe compound heterozygous sickling disorder and their experience managing this patient with hydroxyurea.

Oxidant-antioxidant status in Egyptian children with sickle cell anemia: a single center based study.

PubMed

El-Ghamrawy, Mona Kamal; Hanna, Wagdi Maurice; Abdel-Salam, Amina; El-Sonbaty, Marwa M; Youness, Eman R; Adel, Ahmed

2014-01-01

the present study was conducted to investigate the oxidant-antioxidant status in Egyptian children with sickle cell anemia. the serum levels of total antioxidant capacity (TAO), paraoxonase (PON), vitamin E, nitrite, and malondialdehyde (MDA) were measured in 40 steady state children with homozygous sickle cell anemia (24 males and 16 females) and 20 apparently healthy age- and gender-matched controls. mean serum TAO, PON, vitamin E, and nitrite levels were significantly lower in the group with sickle cell anemia, whereas mean serum MDA was significantly higher in these children compared to controls. No significant differences in mean levels of TAO, PON, nitrite, vitamin E, and MDA were found in sickle cell anemia patients receiving hydroxyurea when compared with those not receiving hydroxyurea. A significant negative correlation between serum nitrite and the occurrence of vaso-occlusive crises (VOC) was observed (r=-0.3, p=0.04). PON level was found to be positively correlated with patients' weight and BMI (r=-0.4, p=0.01; r=-0.7, p<0.001, respectively), but not with frequency of VOC. The area under the curve of serum nitrite in predicting occurrence of VOC was 0.782, versus 0.701 for PON, and 0.650 for TAO (p=0.006). Serum MDA was not correlated with nitrite, PON, TAO, or vitamin E levels. No significant correlations were detected between serum nitrite and hemoglobin or antioxidant enzymes. children with sickle cell anemia have chronic oxidative stress that may result in increased VOC, and decreased serum nitrite may be associated with increases in VOC frequency. A novel finding in this study is the decrease in PON level in these patients, which is an interesting subject for further research. Copyright © 2014 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

Potential of Three Ethnomedicinal Plants as Antisickling Agents.

PubMed

Nurain, Ismaila O; Bewaji, Clement O; Johnson, Jarrett S; Davenport, Robertson D; Zhang, Yang

2017-01-03

Sickle cell disease (SCD) is a genetic blood disorder that affects the shape and transportation of red blood cells (RBCs) in blood vessels, leading to various clinical complications. Many drugs that are available for treating the disease are insufficiently effective, toxic, or too expensive. Therefore, there is a pressing need for safe, effective, and inexpensive therapeutic agents from indigenous plants used in ethnomedicines. The potential of aqueous extracts of Cajanus cajan leaf and seed, Zanthoxylum zanthoxyloides leaf, and Carica papaya leaf in sickle cell disease management was investigated in vitro using freshly prepared 2% sodium metabisulfite for sickling induction. The results indicated that the percentage of sickled cells, which was initially 91.6% in the control, was reduced to 29.3%, 41.7%, 32.8%, 38.2%, 47.6%, in the presence of hydroxyurea, C. cajan seed, C. cajan leaf, Z. zanthoxyloides leaf, and C. papaya leaf extracts, respectively, where the rate of polymerization inhibition was 6.5, 5.9, 8.0, 6.6, and 6.0 (×10 -2 ) accordingly. It was also found that the RBC resistance to hemolysis was increased in the presence of the tested agents as indicated by the reduction of the percentage of hemolyzed cells from 100% to 0%. The phytochemical screening results indicated the presence of important phytochemicals including tannins, saponins, alkaloids, flavonoids, and glycosides in all the plant extracts. Finally, gas chromatography-mass spectrometry analysis showed the presence of important secondary metabolites in the plants. These results suggest that the plant extracts have some potential to be used as alternative antisickling therapy to hydroxyurea in SCD management.

Pharmacokinetics and bioequivalence of a liquid formulation of hydroxyurea in children with sickle cell anemia.

PubMed

Estepp, Jeremie H; Melloni, Chiara; Thornburg, Courtney D; Wiczling, Paweł; Rogers, Zora; Rothman, Jennifer A; Green, Nancy S; Liem, Robert; Brandow, Amanda M; Crary, Shelley E; Howard, Thomas H; Morris, Maurine H; Lewandowski, Andrew; Garg, Uttam; Jusko, William J; Neville, Kathleen A

2016-03-01

Hydroxyurea (HU) is a crucial therapy for children with sickle cell anemia, but its off-label use is a barrier to widespread acceptance. We found HU exposure is not significantly altered by liquid vs capsule formulation, and weight-based dosing schemes provide consistent exposure. HU is recommended for all children starting as young as 9 months of age with sickle cell anemia (SCA; HbSS and HbSβspan(0) thalassemia); however; a paucity of pediatric data exists regarding the pharmacokinetics (PK) or the exposure-response relationship of HU. This trial aimed to characterize the PK of HU in children and to evaluate and compare the bioavailability of a liquid vs capsule formulation. This multicenter; prospective; open-label trial enrolled 39 children with SCA who provided 682 plasma samples for PK analysis following administration of HU. Noncompartmental and population PK models are described. We report that liquid and capsule formulations of HU are bioequivalent; weight-based dosing schemes provide consistent drug exposure; and age-based dosing schemes are unnecessary. These data support the use of liquid HU in children unable to swallow capsules and in those whose weight precludes the use of fixed capsule formulations. Taken with existing safety and efficacy literature; these findings should encourage the use of HU across the spectrum of age and weight in children with SCA; and they should facilitate the expanded use of HU as recommended in the National Heart; Lung; and Blood Institute guidelines for individuals with SCA. © 2015, The American College of Clinical Pharmacology.

Comparison of hematologic measurements between local and central laboratories: data from the BABY HUG trial.

PubMed

Kalpatthi, Ram; Thompson, Bruce; Lu, Ming; Wang, Winfred C; Patel, Niren; Kutlar, Abdullah; Howard, Thomas; Luchtman-Jones, Lori; Miller, Scott T

2013-02-01

To investigate the concordance of blood count indices measured locally and at a central laboratory. In a multi-center clinical trial of hydroxyurea therapy in infants with sickle cell anemia (BABY HUG), the concordance between blood count indices measured locally and at a central laboratory was investigated. Local laboratory measurements of neutrophil and monocyte counts were significantly higher (44% and 37%, respectively) compared to the central measurements (p<0.0001), and mean corpuscular volume (MCV) was higher centrally. Overnight shipping with processing delay causes spurious reductions in absolute neutrophil count (ANC) and absolute monocyte count (AMC) that may result in incorrect monitoring decisions in multicenter clinical trials. Copyright © 2012 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Coagulation profile of Sudanese children with homozygous sickle cell disease and the effect of treatment with omega-3 fatty acid on the coagulation parameters.

PubMed

Awoda, Shiekh; Daak, Ahmed A; Husain, Nazik Elmalaika; Ghebremeskel, Kebreab; Elbashir, Mustafa I

2017-01-01

It has been reported that patients with SCD do have an abnormal coagulation profile. Coagulopathy is thought to be one of the key factors that contribute to the vaso-occlusive crisis that characterises sickle cell disease (SCD). In this study, we investigated whether Sudanese sickle cell patients have an abnormal coagulation profile. In addition, the effect of treatment with either omega-3 fatty acids or hydroxyurea on coagulation profile was assessed. Homozygous SCD patients untreated ( n  = 52), omega-3 treated ( n  = 44), hydroxyurea (HU) treated ( n  = 8) and healthy (HbAA) controls ( n  = 52) matched for age (4-20 years), gender and socioeconomic status were enrolled. Patients on omega-3 fatty acids, according to age, received one to four capsules containing 277.8 mg DHA and 39.0 mg eicosapentnoic. Patients on Hydroxyurea were in on dosage more than 20 mg/kg/day. The steady state levels of the coagulation parameters and the effect of the treatments with either HU or omega-3 fatty acids on markers of coagulation were investigated. Compared to the healthy controls, treated and untreated HbSS patients had lower hemoglobin, plasma Protein C, proteins S and higher white blood cell count (WBC), platelets count (PLTs) and plasma D-dimer levels,( p  < 0.05). In comparison to untreated HbSS, treatment with neither omega-3 nor HU had effect on the WBC, plasma proteins C and S, ( p  > 0.05). HU treated group had a lower PLTs count compared to HbSS untreated group ( p  < 0.5). The prothrombin and activated partial thromboplastin times and international normalized ratio (INR) of untreated patients are significantly higher than n-3 treated, HU-treated patients and health controls, ( p  < 0.05). Patients treated with omega-3 had lowered D-dimer levels in comparison to HU-treated and untreated HbSS patients, ( p  < 0.001). This study provides evidence that Sudanes patients have abnormal coagulation profile and treatment with either HU or omega-3 fatty acids might partially ameliorate SCD-associated chronic coagulopathic state.

World Health Organization-defined eosinophilic disorders: 2017 update on diagnosis, risk stratification, and management.

PubMed

Gotlib, Jason

2017-11-01

The eosinophilias encompass a broad range of nonhematologic (secondary or reactive) and hematologic (primary, clonal) disorders with potential for end-organ damage. Hypereosinophilia has generally been defined as a peripheral blood eosinophil count greater than 1500/mm 3 and may be associated with tissue damage. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of morphologic review of the blood and marrow, standard cytogenetics, fluorescent in situ-hybridization, flow immunocytometry, and T-cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic myeloid or lymphoproliferative disorder. Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2016 World Health Organization endorses a semi-molecular classification scheme of disease subtypes which includes the major category "myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2," and the "MPN subtype, chronic eosinophilic leukemia, not otherwise specified" (CEL, NOS). Lymphocyte-variant hypereosinophilia is an aberrant T-cell clone-driven reactive eosinophila, and idiopathic hypereosinophilic syndrome (HES) is a diagnosis of exclusion. The goal of therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (e.g., < 1500/mm 3 ) without symptoms or signs of organ involvement, a watch and wait approach with close-follow-up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Corticosteroids are first-line therapy for patients with lymphocyte-variant hypereosinophilia and HES. Hydroxyurea and interferon-alpha have demonstrated efficacy as initial treatment and steroid-refractory cases of HES. In addition to hydroxyurea, second line cytotoxic chemotherapy agents and hematopoietic cell transplant have been used for aggressive forms of HES and CEL with outcomes reported for limited numbers of patients. The use of antibodies against interleukin-5 (IL-5) (mepolizumab), the IL-5 receptor (benralizumab), and CD52 (alemtuzumab), as well as other targets on eosinophils remains an active area of investigation. © 2017 Wiley Periodicals, Inc.

Activity of single-agent decitabine in atypical chronic myeloid leukemia.

PubMed

Hausmann, Heidi; Bhatt, Vijaya R; Yuan, Ji; Maness, Lori J; Ganti, Apar K

2016-12-01

Atypical chronic myeloid leukemia is a rare entity that presents diagnostic and therapeutic challenges. Traditionally utilized therapeutic agents such as hydroxyurea or interferon result in a median survival of approximately two years, thus warranting identification of better options. We report a 49-year-old Caucasian female, who presented with extreme leukocytosis (white blood cells of 148,300/µL) with left shift, severe anemia, and thrombocytopenia. Following a diagnosis of atypical chronic myeloid leukemia, she was started on intravenous decitabine. She subsequently developed paraneoplastic vasculitis of large arteries, which responded to high-dose glucocorticoid. Decitabine therapy resulted in an excellent hematologic response, transfusion independence, and successful transition to an allogeneic peripheral stem cell transplantation. However, the patient subsequently succumbed to the complications of acute graft-versus-host-disease. This case illustrates an association between atypical chronic myeloid leukemia and steroid-responsive paraneoplastic vasculitis and highlights the single-agent disease activity of decitabine in atypical chronic myeloid leukemia, which may be utilized as a bridging therapy to allogeneic stem cell transplantation. © The Author(s) 2015.

Polycythemia Vera: An Appraisal of the Biology and Management 10 Years After the Discovery of JAK2 V617F

PubMed Central

Stein, Brady L.; Oh, Stephen T.; Berenzon, Dmitriy; Hobbs, Gabriela S.; Kremyanskaya, Marina; Rampal, Raajit K.; Abboud, Camille N.; Adler, Kenneth; Heaney, Mark L.; Jabbour, Elias J.; Komrokji, Rami S.; Moliterno, Alison R.; Ritchie, Ellen K.; Rice, Lawrence; Mascarenhas, John; Hoffman, Ronald

2015-01-01

Polycythemia vera (PV) is a chronic myeloproliferative neoplasm that is associated with a substantial symptom burden, thrombohemorrhagic complications, and impaired survival. A decade after the seminal discovery of an activating mutation in the tyrosine kinase JAK2 in nearly all patients with PV, new treatment options are finally beginning to emerge, necessitating a critical reappraisal of the underlying pathogenesis and therapeutic modalities available for PV. Herein, we comprehensively review clinical aspects of PV including diagnostic considerations, natural history, and risk factors for thrombosis. We summarize recent studies delineating the genetic basis of PV, including their implications for evolution to myelofibrosis and secondary acute myeloid leukemia. We assess the quality of evidence to support the use of currently available therapies, including aspirin, phlebotomy, hydroxyurea, and interferon. We analyze recent studies evaluating the safety and efficacy of JAK inhibitors, such as ruxolitinib, and evaluate their role in the context of other available therapies for PV. This review provides a framework for practicing hematologists and oncologists to make rational treatment decisions for patients with PV. PMID:26324368

Acute hemolytic vascular inflammatory processes are prevented by nitric oxide replacement or a single dose of hydroxyurea.

PubMed

Almeida, Camila Bononi; Souza, Lucas Eduardo Botelho; Leonardo, Flavia Costa; Costa, Fabio Trindade Maranhão; Werneck, Claudio C; Covas, Dimas Tadeu; Costa, Fernando Ferreira; Conran, Nicola

2015-08-06

Hemolysis and consequent release of cell-free hemoglobin (CFHb) impair vascular nitric oxide (NO) bioavailability and cause oxidative and inflammatory processes. Hydroxyurea (HU), a common therapy for sickle cell disease (SCD), induces fetal Hb production and can act as an NO donor. We evaluated the acute inflammatory effects of intravenous water-induced hemolysis in C57BL/6 mice and determined the abilities of an NO donor, diethylamine NONOate (DEANO), and a single dose of HU to modulate this inflammation. Intravenous water induced acute hemolysis in C57BL/6 mice, attaining plasma Hb levels comparable to those observed in chimeric SCD mice. This hemolysis resulted in significant and rapid systemic inflammation and vascular leukocyte recruitment within 15 minutes, accompanied by NO metabolite generation. Administration of another potent NO scavenger (2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide) to C57BL/6 mice induced similar alterations in leukocyte recruitment, whereas hemin-induced inflammation occurred over a longer time frame. Importantly, the acute inflammatory effects of water-induced hemolysis were abolished by the simultaneous administration of DEANO or HU, without altering CFHb, in an NO pathway-mediated manner. In vitro, HU partially reversed the Hb-mediated induction of endothelial proinflammatory cytokine secretion and adhesion molecule expression. In summary, pathophysiological levels of hemolysis trigger an immediate inflammatory response, possibly mediated by vascular NO consumption. HU presents beneficial anti-inflammatory effects by inhibiting rapid-onset hemolytic inflammation via an NO-dependent mechanism, independently of fetal Hb elevation. Data provide novel insights into mechanisms of hemolytic inflammation and further support perspectives for the use of HU as an acute treatment for SCD and other hemolytic disorders. © 2015 by The American Society of Hematology.

Current Management of Sickle Cell Anemia

PubMed Central

McGann, Patrick T.; Nero, Alecia C.; Ware, Russell E.

2013-01-01

Proper management of sickle cell anemia (SCA) begins with establishing the correct diagnosis early in life, ideally during the newborn period. The identification of affected infants by neonatal screening programs allows early initiation of prophylactic penicillin and pneumococcal immunizations, which help prevent overwhelming sepsis. Ongoing education of families promotes the early recognition of disease-released complications, which allows prompt and appropriate medical evaluation and therapeutic intervention. Periodic evaluation by trained specialists helps provide comprehensive care, including transcranial Doppler examinations to identify children at risk for primary stroke, plus assessments for other parenchymal organ damage as patients become teens and adults. Treatment approaches that previously highlighted acute vaso-occlusive events are now evolving to the concept of preventive therapy. Liberalized use of blood transfusions and early consideration of hydroxyurea treatment represent a new treatment paradigm for SCA management. PMID:23709685

Catalase and NO CATALASE ACTIVITY1 Promote Autophagy-Dependent Cell Death in Arabidopsis[C][W][OPEN

PubMed Central

Hackenberg, Thomas; Juul, Trine; Auzina, Aija; Gwiżdż, Sonia; Małolepszy, Anna; Van Der Kelen, Katrien; Dam, Svend; Bressendorff, Simon; Lorentzen, Andrea; Roepstorff, Peter; Lehmann Nielsen, Kåre; Jørgensen, Jan-Elo; Hofius, Daniel; Breusegem, Frank Van; Petersen, Morten; Andersen, Stig Uggerhøj

2013-01-01

Programmed cell death often depends on generation of reactive oxygen species, which can be detoxified by antioxidative enzymes, including catalases. We previously isolated catalase-deficient mutants (cat2) in a screen for resistance to hydroxyurea-induced cell death. Here, we identify an Arabidopsis thaliana hydroxyurea-resistant autophagy mutant, atg2, which also shows reduced sensitivity to cell death triggered by the bacterial effector avrRpm1. To test if catalase deficiency likewise affected both hydroxyurea and avrRpm1 sensitivity, we selected mutants with extremely low catalase activities and showed that they carried mutations in a gene that we named NO CATALASE ACTIVITY1 (NCA1). nca1 mutants showed severely reduced activities of all three catalase isoforms in Arabidopsis, and loss of NCA1 function led to strong suppression of RPM1-triggered cell death. Basal and starvation-induced autophagy appeared normal in the nca1 and cat2 mutants. By contrast, autophagic degradation induced by avrRpm1 challenge was compromised, indicating that catalase acted upstream of immunity-triggered autophagy. The direct interaction of catalase with reactive oxygen species could allow catalase to act as a molecular link between reactive oxygen species and the promotion of autophagy-dependent cell death. PMID:24285797

Cid1, a Fission Yeast Protein Required for S-M Checkpoint Control when DNA Polymerase δ or ɛ Is Inactivated

PubMed Central

Wang, Shao-Win; Toda, Takashi; MacCallum, Robert; Harris, Adrian L.; Norbury, Chris

2000-01-01

The S-M checkpoint is an intracellular signaling pathway that ensures that mitosis is not initiated in cells undergoing DNA replication. We identified cid1, a novel fission yeast gene, through its ability when overexpressed to confer specific resistance to a combination of hydroxyurea, which inhibits DNA replication, and caffeine, which overrides the S-M checkpoint. Cid1 overexpression also partially suppressed the hydroxyurea sensitivity characteristic of DNA polymerase δ mutants and mutants defective in the “checkpoint Rad” pathway. Cid1 is a member of a family of putative nucleotidyltransferases including budding yeast Trf4 and Trf5, and mutation of amino acid residues predicted to be essential for this activity resulted in loss of Cid1 function in vivo. Two additional Cid1-like proteins play similar but nonredundant checkpoint-signaling roles in fission yeast. Cells lacking Cid1 were found to be viable but specifically sensitive to the combination of hydroxyurea and caffeine and to be S-M checkpoint defective in the absence of Cds1. Genetic data suggest that Cid1 acts in association with Crb2/Rhp9 and through the checkpoint-signaling kinase Chk1 to inhibit unscheduled mitosis specifically when DNA polymerase δ or ɛ is inhibited. PMID:10757807

Blood transfusion for preventing primary and secondary stroke in people with sickle cell disease.

PubMed

Estcourt, Lise J; Fortin, Patricia M; Hopewell, Sally; Trivella, Marialena; Wang, Winfred C

2017-01-17

Sickle cell disease is one of the commonest severe monogenic disorders in the world, due to the inheritance of two abnormal haemoglobin (beta globin) genes. Sickle cell disease can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Stroke affects around 10% of children with sickle cell anaemia (HbSS). Chronic blood transfusions may reduce the risk of vaso-occlusion and stroke by diluting the proportion of sickled cells in the circulation.This is an update of a Cochrane Review first published in 2002, and last updated in 2013. To assess risks and benefits of chronic blood transfusion regimens in people with sickle cell disease for primary and secondary stroke prevention (excluding silent cerebral infarcts). We searched for relevant trials in the Cochrane Library, MEDLINE (from 1946), Embase (from 1974), the Transfusion Evidence Library (from 1980), and ongoing trial databases; all searches current to 04 April 2016.We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register: 25 April 2016. Randomised controlled trials comparing red blood cell transfusions as prophylaxis for stroke in people with sickle cell disease to alternative or standard treatment. There were no restrictions by outcomes examined, language or publication status. Two authors independently assessed trial eligibility and the risk of bias and extracted data. We included five trials (660 participants) published between 1998 and 2016. Four of these trials were terminated early. The vast majority of participants had the haemoglobin (Hb)SS form of sickle cell disease.Three trials compared regular red cell transfusions to standard care in primary prevention of stroke: two in children with no previous long-term transfusions; and one in children and adolescents on long-term transfusion.Two trials compared the drug hydroxyurea (hydroxycarbamide) and phlebotomy to long-term transfusions and iron chelation therapy: one in primary prevention (children); and one in secondary prevention (children and adolescents).The quality of the evidence was very low to moderate across different outcomes according to GRADE methodology. This was due to the trials being at a high risk of bias due to lack of blinding, indirectness and imprecise outcome estimates. Red cell transfusions versus standard care Children with no previous long-term transfusionsLong-term transfusions probably reduce the incidence of clinical stroke in children with a higher risk of stroke (abnormal transcranial doppler velocities or previous history of silent cerebral infarct), risk ratio 0.12 (95% confidence interval 0.03 to 0.49) (two trials, 326 participants), moderate quality evidence.Long-term transfusions may: reduce the incidence of other sickle cell disease-related complications (acute chest syndrome, risk ratio 0.24 (95% confidence interval 0.12 to 0.48)) (two trials, 326 participants); increase quality of life (difference estimate -0.54, 95% confidence interval -0.92 to -0.17) (one trial, 166 participants); but make little or no difference to IQ scores (least square mean: 1.7, standard error 95% confidence interval -1.1 to 4.4) (one trial, 166 participants), low quality evidence.We are very uncertain whether long-term transfusions: reduce the risk of transient ischaemic attacks, Peto odds ratio 0.13 (95% confidence interval 0.01 to 2.11) (two trials, 323 participants); have any effect on all-cause mortality, no deaths reported (two trials, 326 participants); or increase the risk of alloimmunisation, risk ratio 3.16 (95% confidence interval 0.18 to 57.17) (one trial, 121 participants), very low quality evidence. Children and adolescents with previous long-term transfusions (one trial, 79 participants)We are very uncertain whether continuing long-term transfusions reduces the incidence of: stroke, risk ratio 0.22 (95% confidence interval 0.01 to 4.35); or all-cause mortality, Peto odds ratio 8.00 (95% confidence interval 0.16 to 404.12), very low quality evidence.Several review outcomes were only reported in one trial arm (sickle cell disease-related complications, alloimmunisation, transient ischaemic attacks).The trial did not report neurological impairment, or quality of life. Hydroxyurea and phlebotomy versus red cell transfusions and chelationNeither trial reported on neurological impairment, alloimmunisation, or quality of life. Primary prevention, children (one trial, 121 participants)Switching to hydroxyurea and phlebotomy may have little or no effect on liver iron concentrations, mean difference -1.80 mg Fe/g dry-weight liver (95% confidence interval -5.16 to 1.56), low quality evidence.We are very uncertain whether switching to hydroxyurea and phlebotomy has any effect on: risk of stroke (no strokes); all-cause mortality (no deaths); transient ischaemic attacks, risk ratio 1.02 (95% confidence interval 0.21 to 4.84); or other sickle cell disease-related complications (acute chest syndrome, risk ratio 2.03 (95% confidence interval 0.39 to 10.69)), very low quality evidence. Secondary prevention, children and adolescents (one trial, 133 participants)Switching to hydroxyurea and phlebotomy may: increase the risk of sickle cell disease-related serious adverse events, risk ratio 3.10 (95% confidence interval 1.42 to 6.75); but have little or no effect on median liver iron concentrations (hydroxyurea, 17.3 mg Fe/g dry-weight liver (interquartile range 10.0 to 30.6)); transfusion 17.3 mg Fe/g dry-weight liver (interquartile range 8.8 to 30.7), low quality evidence.We are very uncertain whether switching to hydroxyurea and phlebotomy: increases the risk of stroke, risk ratio 14.78 (95% confidence interval 0.86 to 253.66); or has any effect on all-cause mortality, Peto odds ratio 0.98 (95% confidence interval 0.06 to 15.92); or transient ischaemic attacks, risk ratio 0.66 (95% confidence interval 0.25 to 1.74), very low quality evidence. There is no evidence for managing adults, or children who do not have HbSS sickle cell disease.In children who are at higher risk of stroke and have not had previous long-term transfusions, there is moderate quality evidence that long-term red cell transfusions reduce the risk of stroke, and low quality evidence they also reduce the risk of other sickle cell disease-related complications.In primary and secondary prevention of stroke there is low quality evidence that switching to hydroxyurea with phlebotomy has little or no effect on the liver iron concentration.In secondary prevention of stroke there is low-quality evidence that switching to hydroxyurea with phlebotomy increases the risk of sickle cell disease-related events.All other evidence in this review is of very low quality.

Blood transfusion for preventing primary and secondary stroke in people with sickle cell disease

PubMed Central

Estcourt, Lise J; Fortin, Patricia M; Hopewell, Sally; Trivella, Marialena; Wang, Winfred C

2017-01-01

Background Sickle cell disease is one of the commonest severe monogenic disorders in the world, due to the inheritance of two abnormal haemoglobin (beta globin) genes. Sickle cell disease can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Stroke affects around 10% of children with sickle cell anaemia (HbSS). Chronic blood transfusions may reduce the risk of vaso-occlusion and stroke by diluting the proportion of sickled cells in the circulation. This is an update of a Cochrane Review first published in 2002, and last updated in 2013. Objectives To assess risks and benefits of chronic blood transfusion regimens in people with sickle cell disease for primary and secondary stroke prevention (excluding silent cerebral infarcts). Search methods We searched for relevant trials in the Cochrane Library, MEDLINE (from 1946), Embase (from 1974), the Transfusion Evidence Library (from 1980), and ongoing trial databases; all searches current to 04 April 2016. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register: 25 April 2016. Selection criteria Randomised controlled trials comparing red blood cell transfusions as prophylaxis for stroke in people with sickle cell disease to alternative or standard treatment. There were no restrictions by outcomes examined, language or publication status. Data collection and analysis Two authors independently assessed trial eligibility and the risk of bias and extracted data. Main results We included five trials (660 participants) published between 1998 and 2016. Four of these trials were terminated early. The vast majority of participants had the haemoglobin (Hb)SS form of sickle cell disease. Three trials compared regular red cell transfusions to standard care in primary prevention of stroke: two in children with no previous long-term transfusions; and one in children and adolescents on long-term transfusion. Two trials compared the drug hydroxyurea (hydroxycarbamide) and phlebotomy to long-term transfusions and iron chelation therapy: one in primary prevention (children); and one in secondary prevention (children and adolescents). The quality of the evidence was very low to moderate across different outcomes according to GRADE methodology. This was due to the trials being at a high risk of bias due to lack of blinding, indirectness and imprecise outcome estimates. Red cell transfusions versus standard care Children with no previous long-term transfusions Long-term transfusions probably reduce the incidence of clinical stroke in children with a higher risk of stroke (abnormal transcranial doppler velocities or previous history of silent cerebral infarct), risk ratio 0.12 (95% confidence interval 0.03 to 0.49) (two trials, 326 participants), moderate quality evidence. Long-term transfusions may: reduce the incidence of other sickle cell disease-related complications (acute chest syndrome, risk ratio 0.24 (95% confidence interval 0.12 to 0.48)) (two trials, 326 participants); increase quality of life (difference estimate -0.54, 95% confidence interval -0.92 to -0.17) (one trial, 166 participants); but make little or no difference to IQ scores (least square mean: 1.7, standard error 95% confidence interval -1.1 to 4.4) (one trial, 166 participants), low quality evidence. We are very uncertain whether long-term transfusions: reduce the risk of transient ischaemic attacks, Peto odds ratio 0.13 (95% confidence interval 0.01 to 2.11) (two trials, 323 participants); have any effect on all-cause mortality, no deaths reported (two trials, 326 participants); or increase the risk of alloimmunisation, risk ratio 3.16 (95% confidence interval 0.18 to 57.17) (one trial, 121 participants), very low quality evidence. Children and adolescents with previous long-term transfusions (one trial, 79 participants) We are very uncertain whether continuing long-term transfusions reduces the incidence of: stroke, risk ratio 0.22 (95% confidence interval 0.01 to 4.35); or all-cause mortality, Peto odds ratio 8.00 (95% confidence interval 0.16 to 404.12), very low quality evidence. Several review outcomes were only reported in one trial arm (sickle cell disease-related complications, alloimmunisation, transient ischaemic attacks). The trial did not report neurological impairment, or quality of life. Hydroxyurea and phlebotomy versus red cell transfusions and chelation Neither trial reported on neurological impairment, alloimmunisation, or quality of life. Primary prevention, children (one trial, 121 participants) Switching to hydroxyurea and phlebotomy may have little or no effect on liver iron concentrations, mean difference -1.80 mg Fe/g dry-weight liver (95% confidence interval -5.16 to 1.56), low quality evidence. We are very uncertain whether switching to hydroxyurea and phlebotomy has any effect on: risk of stroke (no strokes); all-cause mortality (no deaths); transient ischaemic attacks, risk ratio 1.02 (95% confidence interval 0.21 to 4.84); or other sickle cell disease-related complications (acute chest syndrome, risk ratio 2.03 (95% confidence interval 0.39 to 10.69)), very low quality evidence. Secondary prevention, children and adolescents (one trial, 133 participants) Switching to hydroxyurea and phlebotomy may: increase the risk of sickle cell disease-related serious adverse events, risk ratio 3.10 (95% confidence interval 1.42 to 6.75); but have little or no effect on median liver iron concentrations (hydroxyurea, 17.3 mg Fe/g dry-weight liver (interquartile range 10.0 to 30.6)); transfusion 17.3 mg Fe/g dry-weight liver (interquartile range 8.8 to 30.7), low quality evidence. We are very uncertain whether switching to hydroxyurea and phlebotomy: increases the risk of stroke, risk ratio 14.78 (95% confidence interval 0.86 to 253.66); or has any effect on all-cause mortality, Peto odds ratio 0.98 (95% confidence interval 0.06 to 15.92); or transient ischaemic attacks, risk ratio 0.66 (95% confidence interval 0.25 to 1.74), very low quality evidence. Authors’ conclusions There is no evidence for managing adults, or children who do not have HbSS sickle cell disease. In children who are at higher risk of stroke and have not had previous long-term transfusions, there is moderate quality evidence that long-term red cell transfusions reduce the risk of stroke, and low quality evidence they also reduce the risk of other sickle cell disease-related complications. In primary and secondary prevention of stroke there is low quality evidence that switching to hydroxyurea with phlebotomy has little or no effect on the liver iron concentration. In secondary prevention of stroke there is low-quality evidence that switching to hydroxyurea with phlebotomy increases the risk of sickle cell disease-related events. All other evidence in this review is of very low quality. PMID:24226646

Selected terpenes from leaves of Ocimum basilicum L. induce hemoglobin accumulation in human K562 cells.

PubMed

Feriotto, Giordana; Marchetti, Nicola; Costa, Valentina; Torricelli, Piera; Beninati, Simone; Tagliati, Federico; Mischiati, Carlo

2018-06-01

Re-expression of fetal hemoglobin (HbF) was proposed as a possible therapeutic strategy for β-haemoglobinopathies. Although several inducers of HbF were tested in clinical trials, only hydroxyurea (HU) received FDA approval. Despite it produced adequate HbF levels only in half of HU-treated SCD patients, and was ineffective at all in β-thalassemia patients, beneficial effects of this approach suggested to continue in this direction identifying further molecules capable of inducing HbF. We tested the potential of essential oil isolated from Ocimum basilicum L. leaves (ObEO) in inducing hemoglobin biosynthesis. Initially, dose-dependent effect and kinetics of hemoglobin accumulation in K562 cells after treatment with ObEO were evaluated. ObEO induced dose-dependent hemoglobin accumulation superior to hydroxyurea and rapamycin and a strongest γ-globin mRNA expression. Terpenes composition of ObEO was studied by GC-MS. Three main constituents, linalool, eugenol and eucalyptol, represented about 75% of total. A blend of these three terpenes fully replicated the ObEO's biological effect, thus indicating that one of them or all together could be the active ingredients. When terpenes were tested individually, eugenol was the only one inducing stable hemoglobin accumulation, while eucalyptol and linalool produced only a small transient response. However, eugenol potential was strongly enhanced in the presence of eucalyptol and linalool, suggesting a synergistic effect on hemoglobin accumulation. By these results, the discovery of a new inducer and the interesting activity of a blend of major terpenes from ObOE on Hb accumulation could have positive fallouts on β-thalassemia and sickle cells anemia. Copyright © 2018 Elsevier B.V. All rights reserved.

Hydroxyurea Treatment and Development of the Rat Cerebellum: Effects on the Neurogenetic Profiles and Settled Patterns of Purkinje Cells and Deep Cerebellar Nuclei Neurons.

PubMed

Martí, Joaquín; Santa-Cruz, M C; Serra, Roger; Hervás, José P

2016-11-01

The current paper analyzes the development of the male and female rat cerebellum exposed to hydroxyurea (HU) (300 or 600 mg/kg) as embryo and collected at postnatal day 90. Our study reveals that the administration of this drug compromises neither the cytoarchitecture of the cerebellar cortex nor deep nuclei (DCN). However, in comparison with the saline group, we observed that several cerebellar parameters were lower in the HU injected groups. These parameters included area of the cerebellum, cerebellar cortex length, molecular layer area, Purkinje cell number, granule cell counts, internal granular layer, white matter and cerebellar nuclei areas, and number of deep cerebellar nuclei neurons. These features were larger in the rats injected with saline, smaller in those exposed to 300 mg/kg of HU and smallest in the group receiving 600 mg/kg of this agent. No sex differences in the effect of the HU were observed. In addition, we infer the neurogenetic timetables and the neurogenetic gradients of PCs and DCN neurons in rats exposed to either saline or HU as embryos. For this purpose, 5-bromo-2'-deoxyuridine was injected into pregnant rats previously administered with saline or HU. This thymidine analog was administered following a progressively delayed cumulative labeling method. The data presented here show that systematic differences exist in the pattern of neurogenesis and in the spatial location of cerebellar neurons between rats injected with saline or HU. No sex differences in the effect of the HU were observed. These findings have implications for the administration of this compound to women in gestation as the effects of HU on the development of the cerebellum might persist throughout their offsprings' life.

Sequential Oral Hydroxyurea and Intravenous Cytosine Arabinoside in Refractory Childhood Acute Leukemia: A Pediatric Oncology Group Phase I Study

PubMed Central

Dubowy, Ronald; Graham, Michael; Hakami, Nasrollah; Kletzel, Morris; Mahoney, Donald; Newman, Edward; Ravindranath, Yaddanapudi; Camitta, Bruce

2015-01-01

Summary At concentrations >0.1 mM, Hydroxyurea (HU) enhances the accumulation of cytosine arabinoside (ara-C) in leukemia cells in vitro. This study of children with refractory acute leukemia was designed to take advantage of this biochemical modulation. A fixed dose of HU and an escalating dose of ara-C were used. Oral HU, 1200 mg/m2 was followed 2 hours later by ara-C, 250-3100 mg/m2 intravenously in 15 minutes. The combination was given on days 1,2,3 and 8,9,10. Thirty-three children (26 ALL, 7 ANLL) were treated; 29 received at least one full course. All patients developed grade 4 cytopenias. Other grade 3-4 toxicities included: hyperbilirubinemia (2), elevated transaminases (3), transient gait disturbance (1), stomatitis (3), typhlitis (1), nausea/vomiting (9) and marrow aplasia >4 weeks (1). Three patients had intracranial bleeds while thrombocytopenic. Only liver toxicities and nausea/vomiting exhibited any dosage effect. The maximum tolerated dose of ara-C was 2400 mg/m2. There were 6 complete responses (5ALL), 5 partial responses (3 ALL), and 19 patients with no response or progressive disease. There was no dosage effect for response with 2 complete responses occurring at the lowest ara-C level. Responses were transient (1-3 months). 20/26 patients achieved a peak serum HU level >0.5 mM by 2 hours after the HU dose. The mean level at 2 hours was 0.57 mM (range 0.21-0.99 mM). This combination of HU and ara-C is tolerable and has efficacy in refractory leukemias. Responses at the lowest ara-C dose level suggests synergism. PMID:18458568

Sequential oral hydroxyurea and intravenous cytosine arabinoside in refractory childhood acute leukemia: a pediatric oncology group phase 1 study.

PubMed

Dubowy, Ronald; Graham, Michael; Hakami, Nasrollah; Kletzel, Morris; Mahoney, Donald; Newman, Edward; Ravindranath, Yaddanapudi; Camitta, Bruce

2008-05-01

At concentrations >0.1 mM, hydroxyurea (HU) enhances the accumulation of cytosine arabinoside (ara-C) in leukemia cells in vitro. This study of children with refractory acute leukemia was designed to take advantage of this biochemical modulation. A fixed dose of HU and an escalating dose of ara-C were used. Oral HU (1200 mg/m2) was followed 2 hours later by ara-C (250-3100 mg/m2) intravenously in 15 minutes. The combination was given on days 1, 2, 3 and 8, 9, 10. Thirty-three children [26 acute lymphocytic leukemia (ALL), 7 acute nonlymphocytic leukemia] were treated; 29 received at least 1 full course. All patients developed grade 4 cytopenias. Other grade 3 to 4 toxicities included hyperbilirubinemia (2), elevated transaminases (3), transient gait disturbance (1), stomatitis (3), typhlitis (1), nausea/vomiting (9), and marrow aplasia >4 weeks (1). Three patients had intracranial bleeds while thrombocytopenic. Only liver toxicities and nausea/vomiting exhibited any dosage effect. The maximum tolerated dose of ara-C was 2400 mg/m2. There were 6 complete responses (5 ALL), 5 partial responses (3 ALL), and 19 patients with no response or progressive disease. There was no dosage effect for response with 2 complete responses occurring at the lowest ara-C level. Responses were transient (1 to 3 mo). Twenty of twenty-six patients achieved a peak serum HU level >0.5 mM by 2 hours after the HU dose. The mean level at 2 hours was 0.57 mM (range: 0.21 to 0.99 mM). This combination of HU and ara-C is tolerable and has efficacy in refractory leukemias. Responses at the lowest ara-C dose level suggests synergism.

Comparing abstract numerical and visual depictions of risk in survey of parental assessment of risk in sickle cell hydroxyurea treatment.

PubMed

Patterson, Chavis A; Barakat, Lamia P; Henderson, Phyllis K; Nall, Faith; Westin, Anna; Dampier, Carlton D; Hsu, Lewis L

2011-01-01

Communicating risk is an important activity in medical decision-making; yet, numeracy is not a universal skill among the American public. We examined the hypothesis that numerical risk information about the use of hydroxyurea for children with sickle cell disease would elicit different risk assessment responses when visual depictions were used instead of abstract numbers and depending on the disease severity. Parents of 81 children with sickle cell disease participated in a survey in which hydroxyurea was first described as carrying a certain chance of risk for both birth defects and cancer. Then, the parents indicated the highest risk at which they would hypothetically consent to the treatment to help their child. Risk presentations were repeated with abstract numerical, pie graph, and 1000 people histogram formats. The χ analyses comparing high-risk to low-risk assessment across presentation formats showed high consistency between visual depictions but low consistency of abstract numerical with visual depictions. The parents of children with SC and other less severe types of SCD were less willing to accept higher risk than those with SS when the data were presented numerically. Given earlier concerns about poor "numeracy" in the US population, visual depictions of risk could be an effective tool for routine communication in health education and medical decision-making.

Toxicity of hydroxyurea in rats and dogs.

PubMed

Morton, Daniel; Reed, Lori; Huang, Wenhu; Marcek, John M; Austin-LaFrance, Robert; Northcott, Carrie A; Schelling, Scott H; Enerson, Bradley E; Tomlinson, Lindsay

2015-06-01

The toxicity of hydroxyurea, a treatment for specific neoplasms, sickle-cell disease, polycythemia, and thrombocytosis that kills cells in mitosis, was assessed in repeat-dose, oral gavage studies in rats and dogs and a cardiovascular study in telemetered dogs. Hydroxyurea produced hematopoietic, lymphoid, cardiovascular, and gastrointestinal toxicity with steep dose response curves. In rats dosed for 10 days, 50 mg/kg/day was tolerated; 500 mg/kg/day produced decreased body weight gain; decreased circulating leukocytes, erythrocytes, and platelets; decreased cellularity of thymus, lymph nodes, and bone marrow; and epithelial degeneration and/or dysplasia of the stomach and small intestine; 1,500 mg/kg/day resulted in deaths on day 5. In dogs, a single dose at ≥ 250 mg/kg caused prostration leading to unscheduled euthanasia. Dogs administered 50 mg/kg/day for 1 month had decreased circulating leukocytes, erythrocytes, and platelets; increased bone marrow cellularity with decreased maturing granulocytes; increased creatinine kinase activity; and increased iron pigment in bone marrow and hepatic sinusoidal cells. In telemetered dogs, doses ≥ 15 mg/kg decreased systolic blood pressure (BP); 50 mg/kg increased diastolic BP, heart rate, and change in blood pressure over time (+dP/dt), and decreased QT and PR intervals and maximum left ventricular systolic and end diastolic pressures with measures returning to control levels within 24 hr. © 2014 by The Author(s).

Exploiting the spatial locality of electron correlation within the parametric two-electron reduced-density-matrix method

NASA Astrophysics Data System (ADS)

DePrince, A. Eugene; Mazziotti, David A.

2010-01-01

The parametric variational two-electron reduced-density-matrix (2-RDM) method is applied to computing electronic correlation energies of medium-to-large molecular systems by exploiting the spatial locality of electron correlation within the framework of the cluster-in-molecule (CIM) approximation [S. Li et al., J. Comput. Chem. 23, 238 (2002); J. Chem. Phys. 125, 074109 (2006)]. The 2-RDMs of individual molecular fragments within a molecule are determined, and selected portions of these 2-RDMs are recombined to yield an accurate approximation to the correlation energy of the entire molecule. In addition to extending CIM to the parametric 2-RDM method, we (i) suggest a more systematic selection of atomic-orbital domains than that presented in previous CIM studies and (ii) generalize the CIM method for open-shell quantum systems. The resulting method is tested with a series of polyacetylene molecules, water clusters, and diazobenzene derivatives in minimal and nonminimal basis sets. Calculations show that the computational cost of the method scales linearly with system size. We also compute hydrogen-abstraction energies for a series of hydroxyurea derivatives. Abstraction of hydrogen from hydroxyurea is thought to be a key step in its treatment of sickle cell anemia; the design of hydroxyurea derivatives that oxidize more rapidly is one approach to devising more effective treatments.

Diagnosis and Management of Polycythemia Vera in a Ferret (Mustela putorius furo).

PubMed

Le, Kim; Beaufrère, Hugues; Bassel, Laura L; Wills, Sarah; Laniesse, Delphine; Blois, Shauna L; Smith, Dale A

2016-12-01

A 5-y-old female ferret (Mustela putorius furo) was evaluated for diarrhea, anorexia, and lethargy for 1 wk. Only mild dehydration was detected on physical examination. CBC analysis revealed marked erythrocytosis with an unremarkable plasma biochemistry panel; follow-up CBC analyses revealed a consistent primary erythrocytosis. Whole-body radiographs and abdominal ultrasonography were unremarkable except for a small nephrolith in the right kidney and a small cyst in the left kidney. The plasma erythropoietin level was 17.0 mIU/mL and considered normal. In light of the diagnostic work-up and consistent erythrocytosis, a diagnosis of polycythemia vera (primary erythrocytosis) was made. The initial presentation of diarrhea resolved after treatment with oral metronidazole (20 mg/kg PO BID for 7 d). Treatment for the polycythemia consisted of a phlebotomy initially followed by chemotherapy with hydroxyurea (10 mg/kg PO BID). During the subsequent 12 mo, the hydroxyurea dose adjusted according to follow-up CBC results, and finding an optimal dosage regimen proved to be challenging. One year after the initial diagnosis, the ferret presented to an emergency clinic for acute and severe hemorrhagic diarrhea and died shortly thereafter. The postmortem diagnosis was acute venous infarction of the small and large intestine. To our knowledge, this report is the first to describe the diagnosis and long-term management of polycythemia vera in a ferret and the use of hydroxyurea for this purpose.

Hydroxyurea

MedlinePlus

... on your response to treatment and any side effects that you may experience. Talk to your doctor ... a vitamin), to decrease some of the side effects of this medication. Take this medication exactly as ...

Sickle Cell Disease with Cyanotic Congenital Heart Disease: Long-Term Outcomes in 5 Children.

PubMed

Iannucci, Glen J; Adisa, Olufolake A; Oster, Matthew E; McConnell, Michael; Mahle, William T

2016-12-01

Sickle cell disease is a risk factor for cerebrovascular accidents in the pediatric population. This risk is compounded by hypoxemia. Cyanotic congenital heart disease can expose patients to prolonged hypoxemia. To our knowledge, the long-term outcome of patients who have combined sickle cell and cyanotic congenital heart disease has not been reported. We retrospectively reviewed patient records at our institution and identified 5 patients (3 girls and 2 boys) who had both conditions. Their outcomes were uniformly poor: 4 died (age range, 12 mo-17 yr); 3 had documented cerebrovascular accidents; and 3 developed ventricular dysfunction. The surviving patient had developmental delays. On the basis of this series, we suggest mitigating hypoxemia, and thus the risk of stroke, in patients who have sickle cell disease and cyanotic congenital heart disease. Potential therapies include chronic blood transfusions, hydroxyurea, earlier surgical correction to reduce the duration of hypoxemia, and heart or bone marrow transplantation.

Hydroxycarbamide-Induced Changes in E/beta Thalassemia Red Blood Cells

PubMed Central

Sylvia, Singer T.; Elliott, Vichinsky; Sandra, Larkin; Nancy, Olivieri; Nancy, Sweeters; Frans, Kuypers A.

2010-01-01

In thalassemia, fetal hemoglobin (HbF) augmentation with hydroxycarbamide (also known as hydroxyurea) is not always successful. The expected parallel effects on RBC membrane deformability, cell hydration and membrane phospholipid organization, all important for extending RBC life span and increasing Hb, have been infrequently examined. We analyzed these characteristics in 15 non-transfused E/β 0 thalassemia patients treated with HU (mean 10.2 months). Membrane deformability and cell hydration mildly improved in association with increased HbF levels approaching statistical significance (r = 0.51, p=0.06). All measures improved considerably splenectomized patients. These findings underscore the disappointing results of hydroxyurea treatment in clinical trials; and the importance of examining the effect on red cell characteristics for the development and understanding of HbF-enhancing agents. PMID:18821710

An origin-deficient yeast artificial chromosome triggers a cell cycle checkpoint.

PubMed

van Brabant, A J; Buchanan, C D; Charboneau, E; Fangman, W L; Brewer, B J

2001-04-01

Checkpoint controls coordinate entry into mitosis with the completion of DNA replication. Depletion of nucleotide precursors by treatment with the drug hydroxyurea triggers such a checkpoint response. However, it is not clear whether the signal for this hydroxyurea-induced checkpoint pathway is the presence of unreplicated DNA, or rather the persistence of single-stranded or damaged DNA. In a yeast artificial chromosome (YAC) we have engineered an approximately 170 kb region lacking efficient replication origins that allows us to explore the specific effects of unreplicated DNA on cell cycle progression. Replication of this YAC extends the length of S phase and causes cells to engage an S/M checkpoint. In the absence of Rad9 the YAC becomes unstable, undergoing deletions within the origin-free region.

[A rare case of myeloproliferative disease with t(8;13)(p11;q12) associated with eosinophilia and lymphadenopathy].

PubMed

Tsyba, N N; Turkina, A G; Chelysheva, E Yu; Nemchenko, I S; Kovrigina, A M; Obukhova, T N; Urnova, E S; Kuzmina, L A; Savchenko, V G

Myeloproliferative disease associated with FGFR1 rearrangement (8p11), which is included in the 2008 WHO Classification of Myeloid Neoplasms, is a rare and extremely aggressive abnormality. The paper describes a clinical case of a 39-year-old female patient who was detected to have leukocytosis (as high as 47.2·109/l), absolute eosinophilia (as high as 3.1·109/l), and enlarged peripheral lymph nodes during her visit to a doctor. The bone marrow (BM) showed the changes typically encountered in myeloproliferative disease with eosinophilia. The patient was found to have t(8;13)(p11;q12) translocation associated with the rearrangement of the FGFR1 gene located at the 8p11 locus. Molecular and cytogenetic examinations failed to reveal BCR-ABL chimeric transcript, Jak2 V617F mutation, and deletions and translocations involving PDGFRA (4q12) and PDGFRB (5q32-33). The similar changes in the karyotype were also found in the lymph node cells. The undertaken treatment with hydroxyurea and the tyrosine kinase inhibitor dasatinib turned out to be ineffective. The patient underwent allogeneic BM transplantation from a HLA-identical sibling. Graft rejection occurred 6 months later. Allogeneic BM transplantation from the same donor (100% donor chimerism; FGFR1/8р11 translocation was not detected), which was complicated by the development of chronic graft-versus-host reaction, was performed again in March 2015. The patient is being followed up and continues to receive immunosuppressive therapy.

Quality of life of chronic myeloid leukemia patients in Brazil: ability to work as a key factor.

PubMed

Hamerschlak, Nelson; de Souza, Carmino; Cornacchioni, Ana Lúcia; Pasquini, Ricardo; Tabak, Daniel; Spector, Nelson; Steagall, Merula

2014-08-01

The purpose of this study was to evaluate the quality of life (QOL) of patients receiving treatment by the public health system in Brazil for chronic myeloid leukemia (CML), a disease requiring daily and strict compliance to oral medication and regular blood and bone marrow controls, which are invasive exams. Between 2008 and 2010, patients with CML were surveyed by telephone. Quality of life was evaluated by the functional assessment of chronic illness therapy (FACIT) tool. The mean QOL among CML patients was 92.53 (out of 124 total points) in the trial outcome index, 78.50 (out of 108) in the general total score, and 130.43 (out of 176) in the leukemia total score. Patients who had the prescriptions recently changed anyway had better QOL general score (p = 0.012) and leukemia-specific score (p = 0.043) than those who remained with the same treatment. Imatinib was not associated with this change in QOL (p > 0.797). The more the patient felt able to work, the higher the scores in all three FACIT scales (p < 0.001, Spearman's correlation). The use of imatinib (p = 0.012) was associated with a better ability to work, while chemotherapy (p = 0.017) and the use of hydroxyurea (p = 0.001) were inversely associated with work capability. A recent change in medication can improve quality of life. The ability to work is an important component of quality of life of patients with CML. Ability to work should be specifically considered in CML treatment.

Hydroxyurea lowers transcranial Doppler flow velocities in children with sickle cell anaemia in a Nigerian cohort.

PubMed

Lagunju, IkeOluwa; Brown, Biobele J; Sodeinde, Olugbemiro

2015-09-01

Sickle cell anaemia (SCA) is the leading genetic disorder in Nigeria. Elevated velocities ≥170 cm/sec occur in about a third of Nigerian children with SCA. Chronic blood transfusion for stroke prevention is faced with a myriad of challenges in our practice. To evaluate the effectiveness of hydroxyurea (HU) in reducing flow velocities in a cohort of Nigerian children with SCA and elevated velocities treated with HU. An observational study was carried out on a cohort of Nigerian children with SCA and elevated velocities identified on routine transcranial Doppler (TCD) screening. HU was recommended in those with TCD velocities ≥ 170cm/sec as stipulated in our hospital protocol. Outcomes were compared after ≥12 months of observation. Fifty children with elevated TCD velocities were studied; 31 consented to HU therapy and 19 declined. Children on HU showed a statistically significant decline in mean velocities from 199.7 [17.1] cm/sec to 165.8 [20.7] cm/sec (P < 0.001) with a significant increase in mean packed cell volume from 21.1 [3.4] to 25.0 [2.8]%. Children without treatment had a significant rise in mean velocities from 190.2 [10.8] cm/sec to 199.7 [14.9] cm/sec (P = 0.003). Children with conditional risk velocities on HU were less likely to convert to abnormal risk (P < 0.001). Two stroke events occurred, one in each group. No adverse effects of HU were recorded in the cohort. HU appears to significantly reduce TCD velocities in Nigerian children with SCA and elevated velocities ≥170 cm/sec with beneficial effect on the haematological profile. HU may provide an effective approach to primary stroke prevention, particularly in Africa. © 2015 Wiley Periodicals, Inc.

Ruxolitinib for the Treatment of Patients With Polycythemia Vera

PubMed Central

Kiladjian, Jean-Jacques; Winton, Elliott F.; Talpaz, Moshe; Verstovsek, Srdan

2015-01-01

SUMMARY Polycythemia vera (PV) is a hematopoietic proliferative disorder associated with Janus-associated kinase (JAK)/signal transducer and activator of transcription (STAT) pathway dysregulation resulting in erythrocytosis and, possibly, leukocytosis and thrombocytosis. Patients diagnosed with PV experience a broad range of symptoms associated with a reduced quality of life, often develop splenomegaly, and have an increased risk of death compared to age-matched subjects without PV. Current treatment options, notably hydroxyurea, help with disease management; however, insufficient efficacy or progressive resistance occurs in some patients, highlighting the need for new treatment options. Ruxolitinib is an oral JAK1/JAK2 inhibitor that has been evaluated in phase 2 and 3 clinical trials in patients with PV who are intolerant of or resistant to hydroxyurea. In this setting, ruxolitinib treatment has demonstrated normalization of blood cell counts, reduction in splenomegaly, and improvements in PV-related symptom burden. PMID:25980454

Hydroxyurea-Mediated Cytotoxicity Without Inhibition of Ribonucleotide Reductase.

PubMed

Liew, Li Phing; Lim, Zun Yi; Cohen, Matan; Kong, Ziqing; Marjavaara, Lisette; Chabes, Andrei; Bell, Stephen D

2016-11-01

In many organisms, hydroxyurea (HU) inhibits class I ribonucleotide reductase, leading to lowered cellular pools of deoxyribonucleoside triphosphates. The reduced levels for DNA precursors is believed to cause replication fork stalling. Upon treatment of the hyperthermophilic archaeon Sulfolobus solfataricus with HU, we observe dose-dependent cell cycle arrest, accumulation of DNA double-strand breaks, stalled replication forks, and elevated levels of recombination structures. However, Sulfolobus has a HU-insensitive class II ribonucleotide reductase, and we reveal that HU treatment does not significantly impact cellular DNA precursor pools. Profiling of protein and transcript levels reveals modulation of a specific subset of replication initiation and cell division genes. Notably, the selective loss of the regulatory subunit of the primase correlates with cessation of replication initiation and stalling of replication forks. Furthermore, we find evidence for a detoxification response induced by HU treatment. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Structure and stability of the N-hydroxyurea dimer: Post-Hartree-Fock quantum mechanical study

NASA Astrophysics Data System (ADS)

Jabalameli, Ali; Venkatraman, Ramaiyer; Nowek, Andrzej; Sullivan, Richard H.

2000-10-01

The potential energy surface (PES) search of the N-hydroxyurea dimer was searched with second-order Møller-Plesset perturbation theory (MP2) and the 6-31G(d,p) basis set. Eight local minimum energy structures have been found. Four of them have relatively strong (ΔE˜-10 to -13 kcal/mol) intermolecular interactions and the others are moderately strongly interacting species (ΔE˜-3 to -7 kcal/mol). Final estimation of interaction energies was performed using the larger 6-311G(df,pd) and 6-311G(2df,2pd) basis sets. The predicted interaction energies are ΔE=-14.26 kcal/mol and -3.43 kcal/mol for the strongest and the weakest interacting forms of the studied complex, respectively, at the MP2/6-311G(2df,2pd)//MP2/6-31G(d,p) level of theory. The self-consistent field (SCF) interaction energy decomposition indicates the important influence of the deformation term magnitude on ΔE(SCF). The calculated electron correlation contribution to ΔE(MP2) depends on the geometry of the system and varies from -0.5 to -5 kcal/mol. The estimated influence of water on the stability (free energy of hydration) of N-hydroxyurea dimers using the self-consistent isodensity polarized continuum (SCI-PCM) model of solvation varies from ˜-11 kcal/mol to ˜-21 kcal/mol. The forms predicted to be more strongly interacting species in gas phase are less influenced by hydration than the more weakly interacting ones.

[Case of pediatric chronic myeloid leukemia with bilateral visual loss onset].

PubMed

Hara, Yusuke; Kamura, Yumi; Oikawa, Aki; Shichino, Hiroyuki; Mugishima, Hideo; Goto, Hiroshi

2010-05-01

Chronic myeloid leukemia (CML) during childhood is rare, and only been a few cases showed visual disturbances as an initial symptom. We report a pediatric CML case diagnosed by bilateral visual loss. An 11-year-old boy complained of visual loss in both eyes. His best corrected visual acuity was 0.5 in the right eye and 0.2 in the left. Fundus examination showed disc swelling, dilated and tortuous retinal veins and multiple elevated retinal lesions with hemorrhages of various size from one-forth to four disc diameters in both eyes. He was diagnosed as having CML by leucocytosis and systematic work-up including Philadelphia chromosome-positive, BCR-ABL kinase domain in peripheral blood and bone marrow. The ocular findings improved after treatment with hydroxyurea, leukocytaphresis and imatinib. His best corrected visual acuity improved to 0.7 in both eyes. Recent leukemia therapy including imatinib is effective not only for ocular lesions but also to induce hematological remission in childhood CML.

Treatment and management of myelofibrosis in the era of JAK inhibitors

PubMed Central

Keohane, Clodagh; Radia, Deepti H; Harrison, Claire N

2013-01-01

Myelofibrosis (MF) can present as a primary disorder or evolve from polycythemia vera (PV) or essential thrombocythemia (ET) to post-PV MF or post-ET MF, respectively. MF is characterized by bone marrow fibrosis, splenomegaly, leukoerythroblastosis, extramedullary hematopoiesis, and a collection of debilitating symptoms. Until recently, the therapeutic options for patients with MF consisted of allogeneic hematopoietic stem cell transplant (alloHSCT), the use of cytoreductive agents (ie, hydroxyurea), splenectomy and splenic irradiation for treatment of splenomegaly, and management of anemia with transfusions, erythropoiesis-stimulating agents (ESAs), androgens, and immunomodulatory agents. However, with increased understanding of the pathogenesis of MF resulting from dysregulated Janus kinase (JAK) signaling, new targeted JAK inhibitor therapies, such as ruxolitinib, are now available. The purpose of this article is to review the clinical features of MF, discuss the use and future of JAK inhibitors, reassess when and how to use conventional MF treatments in the context of JAK inhibitors, and provide a perspective on the future of MF treatment. PMID:23990704

Treatment and management of myelofibrosis in the era of JAK inhibitors.

PubMed

Keohane, Clodagh; Radia, Deepti H; Harrison, Claire N

2013-01-01

Myelofibrosis (MF) can present as a primary disorder or evolve from polycythemia vera (PV) or essential thrombocythemia (ET) to post-PV MF or post-ET MF, respectively. MF is characterized by bone marrow fibrosis, splenomegaly, leukoerythroblastosis, extramedullary hematopoiesis, and a collection of debilitating symptoms. Until recently, the therapeutic options for patients with MF consisted of allogeneic hematopoietic stem cell transplant (alloHSCT), the use of cytoreductive agents (ie, hydroxyurea), splenectomy and splenic irradiation for treatment of splenomegaly, and management of anemia with transfusions, erythropoiesis-stimulating agents (ESAs), androgens, and immunomodulatory agents. However, with increased understanding of the pathogenesis of MF resulting from dysregulated Janus kinase (JAK) signaling, new targeted JAK inhibitor therapies, such as ruxolitinib, are now available. The purpose of this article is to review the clinical features of MF, discuss the use and future of JAK inhibitors, reassess when and how to use conventional MF treatments in the context of JAK inhibitors, and provide a perspective on the future of MF treatment.

Elevated serum erythropoietin in a patient with polycythaemia vera presenting with Budd-Chiari syndrome

PubMed Central

Jones, Catherine; Levy, Yair; Tong, Alex W

2014-01-01

Polycythaemia vera (PV) is a clonal disorder of bone marrow stem cells characterised by erythrocytosis. Diagnosis of PV requires exclusion of secondary causes of polycythaemia. It has been held that an elevated erythropoietin (Epo) level strongly indicates secondary erythrocytosis and excludes PV diagnosis, to the extent that the reduced serum Epo level is currently listed as a minor criterion in the WHO classification scheme for PV. However, patients with PV who co-present with Budd-Chiari syndrome have been documented with elevated serum Epo levels. For these patients, identification of the Janus kinase 2 (JAK2) V617F point mutation along with the transient nature of the Epo elevation provides certainty of PV diagnosis, as illustrated by the proband. In this case report, the patient's positive response to cytoreductive therapy (hydroxyurea 500 mg daily) and phlebotomy (750 mL over three phlebotomies) further supports validity of PV diagnosis with elevated Epo. The patient remains on rivaroxaban (Xarelto) for treatment of her portal vein thrombosis. PMID:25452296

Correction of Murine Sickle Cell Disease Using γ-Globin Lentiviral Vectors to Mediate High-level Expression of Fetal Hemoglobin

PubMed Central

Pestina, Tamara I; Hargrove, Phillip W; Jay, Dennis; Gray, John T; Boyd, Kelli M; Persons, Derek A

2008-01-01

Increased levels of red cell fetal hemogloblin, whether due to hereditary persistence of expression or from induction with hydroxyurea therapy, effectively ameliorate sickle cell disease (SCD). Therefore, we developed erythroid-specific, γ-globin lentiviral vectors for hematopoietic stem cell (HSC)-targeted gene therapy with the goal of permanently increasing fetal hemoglobin (HbF) production in sickle red cells. We evaluated two different γ-globin lentiviral vectors for therapeutic efficacy in the BERK sickle cell mouse model. The first vector, V5, contained the γ-globin gene driven by 3.1 kb of β-globin regulatory sequences and a 130-bp β-globin promoter. The second vector, V5m3, was identical except that the γ-globin 3′-untranslated region (3′-UTR) was replaced with the β-globin 3′-UTR. Adult erythroid cells have β-globin mRNA 3′-UTR-binding proteins that enhance β-globin mRNA stability and we postulated this design might enhance γ-globin expression. Stem cell gene transfer was efficient and nearly all red cells in transplanted mice expressed human γ-globin. Both vectors demonstrated efficacy in disease correction, with the V5m3 vector producing a higher level of γ-globin mRNA which was associated with high-level correction of anemia and secondary organ pathology. These data support the rationale for a gene therapy approach to SCD by permanently enhancing HbF using a γ-globin lentiviral vector. PMID:19050697

Myeloid Blastic Transformation of Myeloproliferative Neoplasms – A Review of 112 Cases

PubMed Central

Noor, Syed J; Tan, Wei; Wilding, Gregory E; Ford, Laurie A; Barcos, Maurice; Sait, Sheila N J; Block, AnneMarie W; Thompson, James E; Wang, Eunice S; Wetzler, Meir

2010-01-01

Blastic transformation of myeloproliferative neoplasms (MPN) is still poorly understood. We describe a cohort of 23 Roswell Park Cancer Institute (RPCI) patients and 89 additional cases from the English literature for whom biologic features were described. We initially compared our 23 patients to the 89 cases from the literature. Our population had significantly less patients with prior history of polycythemia vera (PV), shorter time from MPN diagnosis to blastic transformation, <3 prior therapies, more frequent use of hydroxyurea and erythropoietin and less frequent use of alkylating agents. Interestingly, the overall survival of the two cohorts from the time of blastic transformation was similar. We therefore looked at the outcome of the entire cohort (n=112). Patients with prior history of essential thrombocythemia survived longer than patients with prior history of myelofibrosis or PV. Further, patients with <3 prior therapies, those who lacked complex karyotype and those <60 year old at MPN diagnosis had significantly longer survival. Among the PRCI population, 20/23 patients underwent induction treatment with cytarabine and an anthracycline containing regimens; 12 achieved remission and their overall survival was significantly longer than those who did not. Three patients underwent an allogeneic transplantation and their survival was significantly longer than those who did not. Patients with <3 prior therapies, those who lack complex karyotype and those <60 at MPN diagnosis have longer survival following blastic transformation. Finally, allogeneic transplantation represents the only chance for long-term survival in these patients. PMID:20727590

An altered REDOX environment, assisted by over-expression of fetal hemoglobins, protects from inflammatory colitis and reduces inflammatory cytokine expression.

PubMed

Gorczynski, R M; Alexander, C; Brandenburg, K; Chen, Z; Heini, A; Neumann, D; Mach, J P; Rietschel, E T; Tersikh, A; Ulmer, A J; Yu, Kai; Zahringer, U; Khatri, I

2017-09-01

C5BL/6 female mice receiving dextran sodium sulfate in their drinking water develop an acute inflammatory colitis within 7d, with weight loss, histopathologic signs of inflammation, and colonic expression of inflammatory cytokines. In previous studies we have reported that increased inflammatory cytokine expression in aged mice can be attenuated by oral gavage of a crude fetal extract containing glutathione (GSH), MPLA and fetal hemoglobin, or more specifically by injection of a combination of these purified reagents. We speculated that this combination led to an altered tissue redox environment in which the immune response developed, thus regulating inflammation. Accordingly, we used wild-type (WT) C57BL/6 mice, or mice lacking either murine beta Hemoglobin major (Hgbβ ma KO) or minor (Hgbβ mi KO) as recipients of DSS in their drinking water, and followed development of colitis both clinically and by inflammatory cytokine production, before/after oral treatment of mice with a crude fetal liver extract. Mice lacking an intact fetal hemoglobin chain (Hgbβ mi KO) developed severe colitis, with enhanced colonic expression of inflammatory cytokines, which could not be rescued by extract, unlike WT and Hgbβ ma KO animals. Moreover, disease in both WT and Hgbβ ma KO animals could also be attenuated by exposure to 5-hydroxymethyl furfural (5HMF), hydroxyurea or rapamycin. The former has been used as an alternative means of stabilizing the conformation of adult hemoglobin in a manner which mimicks the oxygen-affinity of fetal hemoglobin, while we show that both hydroxyurea and rapamycin augment expression of murine fetal hemoglobin chains. Our data suggests there may be a clinical value in exploring agents which alter local REDOX environments as an adjunctive treatment for colitis and attenuating inflammatory cytokine production. Copyright © 2017 Elsevier B.V. All rights reserved.

Distinct RAD51 Associations with RAD52 and BCCIP in Response to DNA Damage and Replication Stress

PubMed Central

Wray, Justin; Liu, Jingmei; Nickoloff, Jac A.; Shen, Zhiyuan

2009-01-01

RAD51 has critical roles in homologous recombination (HR) repair of DNA double-strand breaks (DSB) and restarting stalled or collapsed replication forks. In yeast, Rad51 function is facilitated by Rad52 and other “mediators.” Mammalian cells express RAD52, but BRCA2 may have supplanted RAD52 in mediating RAD51 loading onto ssDNA. BCCIP interacts with BRCA2, and both proteins are important for RAD51 focus formation after ionizing radiation and HR repair of DSBs. Nonetheless, mammalian RAD52 shares biochemical activities with yeast Rad52, including RAD51 binding and single-strand annealing, suggesting a conserved role in HR. Because RAD52 and RAD51 associate, and RAD51 and BCCIP associate, we investigated the colocalization of RAD51 with BCCIP and RAD52 in human cells. We found that RAD51 colocalizes with BCCIP early after ionizing radiation, with RAD52 later, and there was little colocalization of BCCIP and RAD52. RAD52 foci are induced to a greater extent by hydroxyurea, which stalls replication forks, than by ionizing radiation. Using fluorescence recovery after photo bleaching, we show that RAD52 mobility is reduced to a greater extent by hydroxyurea than ionizing radiation. However, BCCIP showed no changes in mobility after hydroxyurea or ionizing radiation. We propose that BCCIP-dependent repair of DSBs by HR is an early RAD51 response to ionizing radiation–induced DNA damage, and that RAD52-dependent HR occurs later to restart a subset of blocked or collapsed replication forks. RAD52 and BRCA2 seem to act in parallel pathways, suggesting that targeting RAD52 in BRCA2-deficient tumors may be effective in treating these tumors. PMID:18413737

Impact of cycling cells and cell cycle regulation on Hydra regeneration.

PubMed

Buzgariu, Wanda; Wenger, Yvan; Tcaciuc, Nina; Catunda-Lemos, Ana-Paula; Galliot, Brigitte

2018-01-15

Hydra tissues are made from three distinct populations of stem cells that continuously cycle and pause in G2 instead of G1. To characterize the role of cell proliferation after mid-gastric bisection, we have (i) used flow cytometry and classical markers to monitor cell cycle modulations, (ii) quantified the transcriptomic regulations of 202 genes associated with cell proliferation during head and foot regeneration, and (iii) compared the impact of anti-proliferative treatments on regeneration efficiency. We confirm two previously reported events: an early mitotic wave in head-regenerating tips, when few cell cycle genes are up-regulated, and an early-late wave of proliferation on the second day, preceded by the up-regulation of 17 cell cycle genes. These regulations appear more intense after mid-gastric bisection than after decapitation, suggesting a position-dependent regulation of cell proliferation during head regeneration. Hydroxyurea, which blocks S-phase progression, delays head regeneration when applied before but not after bisection. This result is consistent with the fact that the Hydra central region is enriched in G2-paused adult stem cells, poised to divide upon injury, thus forming a necessary constitutive pro-blastema. However a prolonged exposure to hydroxyurea does not block regeneration as cells can differentiate apical structures without traversing S-phase, and also escape in few days the hydroxyurea-induced S-phase blockade. Thus Hydra head regeneration, which is a fast event, is highly plastic, relying on large stocks of adult stem cells paused in G2 at amputation time, which immediately divide to proliferate and/or differentiate apical structures even when S-phase is blocked. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

A mutated dph3 gene causes sensitivity of Schizosaccharomyces pombe cells to cytotoxic agents.

PubMed

Villahermosa, Desirée; Knapp, Karen; Fleck, Oliver

2017-12-01

Dph3 is involved in diphthamide modification of the eukaryotic translation elongation factor eEF2 and in Elongator-mediated modifications of tRNAs, where a 5-methoxycarbonyl-methyl moiety is added to wobble uridines. Lack of such modifications affects protein synthesis due to inaccurate translation of mRNAs at ribosomes. We have discovered that integration of markers at the msh3 locus of Schizosaccharomyces pombe impaired the function of the nearby located dph3 gene. Such integrations rendered cells sensitive to the cytotoxic drugs hydroxyurea and methyl methanesulfonate. We constructed dph3 and msh3 strains with mutated ATG start codons (ATGmut), which allowed investigating drug sensitivity without potential interference by marker insertions. The dph3-ATGmut and a dph3::loxP-ura4-loxM gene disruption strain, but not msh3-ATGmut, turned out to be sensitive to hydroxyurea and methyl methanesulfonate, likewise the strains with cassettes integrated at the msh3 locus. The fungicide sordarin, which inhibits diphthamide modified eEF2 of Saccharomyces cerevisiae, barely affected survival of wild type and msh3Δ S. pombe cells, while the dph3Δ mutant was sensitive. The msh3-ATG mutation, but not dph3Δ or the dph3-ATG mutation caused a defect in mating-type switching, indicating that the ura4 marker at the dph3 locus did not interfere with Msh3 function. We conclude that Dph3 is required for cellular resistance to the fungicide sordarin and to the cytotoxic drugs hydroxyurea and methyl methanesulfonate. This is likely mediated by efficient translation of proteins in response to DNA damage and replication stress.

Technology Access and Smartphone App Preferences for Medication Adherence in Adolescents and Young Adults With Sickle Cell Disease.

PubMed

Badawy, Sherif M; Thompson, Alexis A; Liem, Robert I

2016-05-01

Hydroxyurea is the only Food and Drug Administration approved medication for sickle cell disease (SCD) with short- and long-term benefits for both morbidity and mortality. However, hydroxyurea underutilization and adherence remain challenges for patients with SCD. The objectives of this study were to determine access to technology among adolescents and young adults (AYA) with SCD and to identify their preferred technology-based strategies for improving medication adherence. A cross-sectional survey was administered in a variety of clinical settings from October 2014 through May 2015 to AYA (12-22 years) with SCD (all genotypes) followed in a Comprehensive Sickle Cell Program. Eighty of 107 eligible participants completed the survey for a 75% response rate. Participants (51% female, 94% Black) had a mean age of 15.3 ± 2.8 years. Most participants (75%) were on a daily medication with about half on hydroxyurea. Forgetfulness (67%) was the most common barrier to medication adherence. The majority of participants (85%) owned smartphones and either owned or had access to electronic tablets (83%), laptops (72%), or desktops (70%). Of the proposed smartphone app features, daily medication reminders were ranked first most frequently, followed by education about SCD, adherence text prompts, education about SCD medications, and medication log. The majority of our AYA with SCD owned smartphones and had access to other electronic devices. Our survey results provided valuable insight into the preferred app features and optimal strategies for developing technology-based interventions, such as a multicomponent app, to increase medication adherence for AYA with SCD or other chronic conditions. © 2016 Wiley Periodicals, Inc.

Contemporary approach to essential thrombocythemia and polycythemia vera.

PubMed

Aruch, Daniel; Mascarenhas, John

2016-03-01

Management of polycythemia vera and essential thrombocythemia requires understanding of the key concepts regarding diagnosis, risk stratification, and management. Essential thrombocythemia and polycythemia vera are among the Philadelphia chromosome negative myeloproliferative neoplasms. They are characterized by overproduction of blood cells and their complications include thrombosis, hemorrhage, and progression to myelofibrosis or acute myeloid leukemia (AML). Management of essential thrombocythemia/polycythemia vera requires recognition of the risk factors for thrombosis and hemorrhage. Risk stratification allows the clinician to make a treatment plan that may include antiplatelet therapy with aspirin alone or in combination with therapeutic phlebotomy in the case of polycythemia vera, or cytoreductive therapy for high-risk patients with either essential thrombocythemia or polycythemia vera. Hydroxyurea remains first-line therapy for high-risk patients with essential thrombocythemia/polycythemia vera, whereas second-line options include anagrelide, pegylated-IFNα-2a, and the JAK1/2 inhibitor ruxolitinib. The current evaluation of pegylated-IFNα-2a in global phase II and III studies will provide clarity to the potential long-term benefit and risks associated with this biologic in patients with essential thrombocythemia/polycythemia vera. Novel therapeutics aimed at prevention of disease progression to myelofibrosis/AML are the focus of current clinical trials. Risk stratification of patients with essential thrombocythemia/polycythemia vera by age and/or history of thrombosis provides the basis of risk adapted therapeutic intervention. Aggressive control of modifiable cardiovascular risk factors, the use of antiplatelet agents, control of the hematocrit less than 45% in polycythemia vera, and cytoreductive therapy in high-risk essential thrombocythemia/polycythemia vera patients is the focus of management. The exact role of IFN-α remains undefined and under active investigation, and the recent approval of ruxolitinib provides patients with polycythemia vera a second-line option.

Interventions for chronic kidney disease in people with sickle cell disease

PubMed Central

Roy, Noemi BA; Fortin, Patricia M; Bull, Katherine R; Doree, Carolyn; Trivella, Marialena; Hopewell, Sally; Estcourt, Lise J

2017-01-01

Background Sickle cell disease (SCD) is one of the commonest severe monogenic disorders in the world, due to the inheritance of two abnormal haemoglobin (beta-globin) genes. SCD can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Kidney disease is a frequent and potentially severe complication in people with SCD. Chronic kidney disease is defined as abnormalities of kidney structure or function, present for more than three months. Sickle cell nephropathy refers to the spectrum of kidney complications in SCD. Glomerular damage is a cause of microalbuminuria and can develop at an early age in children with SCD, and increases in prevalence in adulthood. In people with sickle cell nephropathy, outcomes are poor as a result of the progression to proteinuria and chronic kidney insufficiency. Up to 12% of people who develop sickle cell nephropathy will develop end-stage renal disease. Objectives To assess the effectiveness of any intervention in preventing or reducing kidney complications or chronic kidney disease in people with SCD (including red blood cell transfusions, hydroxyurea and angiotensin-converting enzyme inhibitor (ACEI)), either alone or in combination with each other. Search methods We searched for relevant trials in the Cochrane Library, MEDLINE (from 1946), Embase (from 1974), the Transfusion Evidence Library (from 1980), and ongoing trial databases; all searches current to 05 April 2016. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register: 13 April 2017. Selection criteria Randomised controlled trials comparing interventions to prevent or reduce kidney complications or chronic kidney disease in people with SCD. There were no restrictions by outcomes examined, language or publication status. Data collection and analysis Two authors independently assessed trial eligibility, extracted data and assessed the risk of bias. Main results We included two trials with 215 participants. One trial was published in 2011 and included 193 children aged 9 months to 18 months, and compared treatment with hydroxyurea to placebo. The second trial was published in 1998 and included 22 adults with normal blood pressure and microalbuminuria and compared ACEI to placebo. We rated the quality of evidence as low to very low across different outcomes according to GRADE methodology. This was due to trials having: a high or unclear risk of bias including attrition and detection bias; indirectness (the available evidence was for children aged 9 months to 18 months in one trial and a small and select adult sample size in a second trial); and imprecise outcome effect estimates of significant benefit or harm. Hydroxyurea versus placebo We are very uncertain if hydroxyurea reduces or prevents progression of kidney disease (assessed by change in glomerular filtration rate), or reduces hyperfiltration in children aged 9 to 18 months, mean difference (MD) 0.58 (95% confidence interval (CI) -14.60 to 15.76 (mL/min per 1.73 m2)) (one study; 142 participants; very low-quality evidence). In children aged 9 to 18 months, hydroxyurea may improve the ability to concentrate urine, MD 42.23 (95% CI 12.14 to 72.32 (mOsm/kg)) (one study; 178 participants; low-quality evidence). Hydroxyurea may make little or no difference to SCD-related serious adverse events including: incidence of acute chest syndrome, risk ratio (RR) 0.39 (99% CI 0.13 to 1.16); painful crisis, RR 0.68 (99% CI 0.45 to 1.02); and hospitalisations, RR 0.83 (99% CI 0.68 to 1.01) (one study, 193 participants; low-quality evidence). No deaths occurred in the trial. Quality of life was not reported. ACEI versus placebo We are very uncertain if ACEI reduces proteinuria in adults with SCD who have normal blood pressure and microalbuminuria, MD - 49.00 (95% CI -124.10 to 26.10 (mg per day)) (one study; 22 participants; very low-quality evidence). We are very uncertain if ACEI reduce or prevent kidney disease as measured by creatinine clearance. The authors state that creatinine clearance remained constant over six months in both groups, but no comparative data were provided (very low-quality evidence). All-cause mortality, serious adverse events and quality of life were not reported. Authors’ conclusions In young children aged 9 months to 18 months, we are very uncertain if hydroxyurea improves glomerular filtration rate or reduces hyperfiltration, but it may improve young children’s ability to concentrate urine and may make little or no difference on the incidence of acute chest syndrome, painful crises and hospitalisations. We are very uncertain if giving ACEI to adults with normal blood pressure and microalbuminuria has any effect on preventing or reducing kidney complications. This review identified no trials that looked at red cell transfusions nor any combinations of interventions to prevent or reduce kidney complications. Due to lack of evidence this review cannot comment on the management of either children aged over 18 months or adults with any known genotype of SCD. We have identified a lack of adequately-designed and powered studies, and no ongoing trials which address this critical question. Trials of hydroxyurea, ACEI or red blood cell transfusion in older children and adults are urgently needed to determine any effect on prevention or reduction kidney complications in people with SCD. PMID:28672087

Beyond hydroxyurea: new and old drugs in the pipeline for sickle cell disease

PubMed Central

2016-01-01

Despite Food and Drug Administration (FDA) approval of hydroxyurea to reduce the frequency of vaso-occlusive episodes, sickle cell disease (SCD) has continued to be treated primarily with analgesics for pain relief. However, elucidation of the multiple pathophysiologic mechanisms leading to vaso-occlusion and tissue injury in SCD has now resulted in a burgeoning effort to identify new treatment modalities to prevent or ameliorate the consequences of the disease. Development of new drugs as well as investigation of drugs previously used in other settings have targeted cell adhesion, inflammatory pathways, upregulation of hemoglobin F, hemoglobin polymerization and sickling, coagulation, and platelet activation. Although these efforts have not yet yielded drugs ready for FDA approval, several early studies have been extremely encouraging. Moreover, the marked increase in clinical pharmaceutical research addressing SCD and the new and old drugs in the pipeline make it reasonable to expect that we will soon have new treatments for SCD. PMID:26758919

Alpha-synuclein functions in the nucleus to protect against hydroxyurea-induced replication stress in yeast

PubMed Central

Liu, Xianpeng; Lee, Yong Joo; Liou, Liang-Chun; Ren, Qun; Zhang, Zhaojie; Wang, Shaoxiao; Witt, Stephan N.

2011-01-01

Hydroxyurea (HU) inhibits ribonucleotide reductase (RNR), which catalyzes the rate-limiting synthesis of deoxyribonucleotides for DNA replication. HU is used to treat HIV, sickle-cell anemia and some cancers. We found that, compared with vector control cells, low levels of alpha-synuclein (α-syn) protect S. cerevisiae cells from the growth inhibition and reactive oxygen species (ROS) accumulation induced by HU. Analysis of this effect using different α-syn mutants revealed that the α-syn protein functions in the nucleus and not the cytoplasm to modulate S-phase checkpoint responses: α-syn up-regulates histone acetylation and RNR levels, maintains helicase minichromosome maintenance protein complexes (Mcm2–7) on chromatin and inhibits HU-induced ROS accumulation. Strikingly, when residues 2–10 or 96–140 are deleted, this protective function of α-syn in the nucleus is abolished. Understanding the mechanism by which α-syn protects against HU could expand our knowledge of the normal function of this neuronal protein. PMID:21642386

Genomic mapping of single-stranded DNA in hydroxyurea-challenged yeasts identifies origins of replication.

PubMed

Feng, Wenyi; Collingwood, David; Boeck, Max E; Fox, Lindsay A; Alvino, Gina M; Fangman, Walton L; Raghuraman, Mosur K; Brewer, Bonita J

2006-02-01

During DNA replication one or both strands transiently become single stranded: first at the sites where initiation of DNA synthesis occurs (known as origins of replication) and subsequently on the lagging strands of replication forks as discontinuous Okazaki fragments are generated. We report a genome-wide analysis of single-stranded DNA (ssDNA) formation in the presence of hydroxyurea during DNA replication in wild-type and checkpoint-deficient rad53 Saccharomyces cerevisiae cells. In wild-type cells, ssDNA was first observed at a subset of replication origins and later 'migrated' bi-directionally, suggesting that ssDNA formation is associated with continuously moving replication forks. In rad53 cells, ssDNA was observed at virtually every known origin, but remained there over time, suggesting that replication forks stall. Telomeric regions seemed to be particularly sensitive to the loss of Rad53 checkpoint function. Replication origins in Schizosaccharomyces pombe were also mapped using our method.

Replication in hydroxyurea: it's a matter of time.

PubMed

Alvino, Gina M; Collingwood, David; Murphy, John M; Delrow, Jeffrey; Brewer, Bonita J; Raghuraman, M K

2007-09-01

Hydroxyurea (HU) is a DNA replication inhibitor that negatively affects both the elongation and initiation phases of replication and triggers the "intra-S phase checkpoint." Previous work with budding yeast has shown that, during a short exposure to HU, MEC1/RAD53 prevent initiation at some late S phase origins. In this study, we have performed microarray experiments to follow the fate of all origins over an extended exposure to HU. We show that the genome-wide progression of DNA synthesis, including origin activation, follows the same pattern in the presence of HU as in its absence, although the time frames are very different. We find no evidence for a specific effect that excludes initiation from late origins. Rather, HU causes S phase to proceed in slow motion; all temporal classes of origins are affected, but the order in which they become active is maintained. We propose a revised model for the checkpoint response to HU that accounts for the continued but slowed pace of the temporal program of origin activation.

Study on reduction and back extraction of Pu(IV) by urea derivatives in nitric acid conditions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ye, G.A.; Xiao, S.T.; Yan, T.H.

2013-07-01

The reduction kinetics of Pu(IV) by hydroxyl-semicarbazide (HSC), hydroxyurea (HU) and di-hydroxyurea (DHU) in nitric acid solutions were investigated separately with adequate kinetic equations. In addition, counter-current cascade experiments were conducted for Pu split from U in nitric acid media using three kinds of reductant, respectively. The results show that urea derivatives as a kind of novel salt-free reductant can reduce Pu(IV) to Pu(III) rapidly in the nitric acid solutions. The stripping experimental results showed that Pu(IV) in the organic phase can be stripped rapidly to the aqueous phase by the urea derivatives, and the separation factors of plutonium /uraniummore » can reach more than 10{sup 4}. This indicates that urea derivatives is a kind of promising salt-free agent for uranium/plutonium separation. In addition, the complexing effect of HSC with Np(IV) was revealed, and Np(IV) can be back-extracted by HSC with a separation factor of about 20.« less

Influence of Urea, Hydroxyurea, and Thiourea on Meloidogyne javanica and Infected Excised Tomato Roots in Culture

PubMed Central

Glazer, I.; Orion, D.

1984-01-01

Urea (U), hydroxyurea (HU), and thiourea (TU), in various concentrations, were added to chemically defined plant tissue culture medium on which Meloidogyne javanica was reared on excised tomato roots. Concentrations as low as 3 ppm HU or 12 ppm TU inhibited nematode maturation by 70-90% 4 weeks after inoculation, and the coenocytes in the parasitized tissue were poorly developed. Gall weight was also inhibited by 50% in cultures treated with 3 and 6 ppm HU. However, exposing juveniles of M. javanica and Tylenchulus semipenetrans or juveniles and adults of Pratylenchus thornei to increasing concentrations of HU or TU, up to 100 ppm, was not lethal. These two urea derivatives still inhibited nematode maturation when the infected region of the root was not in direct contact with the chemicals. Therefore, we suggest that these urea derivatives inhibit nematode development by affecting the plant metabolism essential to coenocyte formation, an occurrence similar to the hypersensitive reaction in a naturally resistant plant. PMID:19295888

Bilateral Proliferative Retinopathy as the Initial Presentation of Chronic Myeloid Leukemia

PubMed Central

Macedo, Mafalda S. F.; Figueiredo, Ana R. M.; Ferreira, Natália N.; Barbosa, Irene M. A.; Furtado, Maria João F. B. S.; Correia, Nuno F. C. B. A.; Gomes, Miguel P.; Lume, Miguel R. B.; Menéres, Maria João S.; Santos, Marinho M. N.; Meireles S., M. Angelina C.

2013-01-01

The authors report a rare case of a 48-year-old male with chronic myeloid leukemia (CML) who initially presented with a bilateral proliferative retinopathy. The patient complained of recent visual loss and floaters in both eyes (BE). Ophthalmologic evaluation revealed a best corrected visual acuity (BCVA) of 20/50 in the right eye and 20/200 in the left eye (LE). Fundoscopy showed the presence of bilateral peripheral capillary dropout with multiple retinal sea fan neovascularisations, which were confirmed on fluorescein angiography. Full blood count revealed hyperleukocytosis, thrombocytosis, anemia, and hyperuricemia. Bone marrow aspiration and biopsy showed the reciprocal chromosomal translocation t (9;22), diagnostic of CML. The patient was started on hydroxyurea, allopurinol and imatinib mesylate. He received bilateral panretinal laser photocoagulation and a vitrectomy was performed in the LE. The patient has been in complete hematologic, cytogenetic, and major molecular remission while on imatinib and his BCVA is 20/25 in BE. PMID:24339689

Cellular biophysical markers of hydroxyurea treatment in sickle cell disease

NASA Astrophysics Data System (ADS)

So, Peter T. C.; Hosseini, Poorya; Abidi, Sabia Z.; Du, E.; Papageorgiou, Dimitrios P.; Park, YongKeun; Higgins, John; Kato, Gregory J.; Suresh, Subra; Dao, Ming; Yaqoob, Zahid

2017-04-01

Using a common-path interferometric technique, we measure biomechanical and morphological properties of individual red blood cells in SCD patients as a function of cell density, and investigate the correlation of these biophysical properties with drug intake as well as other clinically measured parameters.

NTP-CERHR Expert Panel Report on the reproductive and developmental toxicity of hydroxyurea

EPA Science Inventory

The National Toxicology Program (NTP) and the National Institute of Environmental Health Sciences (NIEHS) established the NTP Center for the Evaluation of Risks to Human Reproduction (CERHR) in June 1998. The purpose of CERHR is to provide timely, unbiased, scientifically sound e...

Interventions for preventing silent cerebral infarcts in people with sickle cell disease

PubMed Central

Estcourt, Lise J; Fortin, Patricia M; Hopewell, Sally; Trivella, Marialena; Doree, Carolyn; Abboud, Miguel R

2017-01-01

This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the effectiveness of red blood transfusions and hydroxyurea alone or in combination and HSCT to reduce or prevent SCI in people with SCD. PMID:28344510

Role of ABCB5 P-Glycoprotein in Breast Cancer Multidrug Resistance

DTIC Science & Technology

2005-09-01

Hydroxyurea Doxorubicin Porfiromycin Mechlorethamine Fluorodopan Mitomycin Cytarabine (araC) Dianhydrogalactitol Gemcitabine Thiotepa N-N-Dibenzyl-daunomycin...0.0196 Mitomycin 0.4173 0.0318 Cytarabine (araC) 0.4163 0.0288 Dianhydrogalactitol 0.4105 0.0354 Gemcitabine 0.4088 0.0302 Thiotepa 0.4015 0.0232

Psychological therapies for thalassaemia.

PubMed

Anie, Kofi A; Massaglia, Pia

2014-03-06

Thalassaemia is a group of genetic blood disorders characterised by the absence or reduction in the production of haemoglobin. Severity is variable from less severe anaemia, through thalassaemia intermedia, to profound severe anaemia (thalassaemia major). In thalassaemia major other complications include growth retardation, bone deformation, and enlarged spleen. Blood transfusion is required to treat severe forms of thalassaemia, but this results in excessive accumulation of iron in the body (iron overload), removed mostly by a drug called desferrioxamine through 'chelation therapy'. Non-routine treatments are bone marrow transplantation (which is age restricted), and possibly hydroxyurea, designed to raise foetal haemoglobin level, thus reducing anaemia. In addition, psychological therapies seem appropriate to improving outcome and adherence to medical treatment. To examine the evidence that in people with thalassaemia, psychological treatments improve the ability to cope with the condition, and improve both medical and psychosocial outcomes. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register which comprises of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Searches on the Internet were also performed.Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 11 November 2013. All randomised or quasi-randomised controlled trials comparing the use of psychological intervention to no (psychological) intervention in people with thalassaemia. No trials of psychological therapies have been found in the literature for inclusion in this review. There are currently no results to be reported. As a chronic disease with a considerable role for self-management, psychological support seems appropriate for managing thalassaemia. However, from the information currently available, no conclusions can be made about the use of specific psychological therapies in thalassaemia. This systematic review has clearly identified the need for well-designed, adequately-powered, multicentre, randomised controlled trials assessing the effectiveness of specific psychological interventions for thalassaemia.

Inflammation in sickle cell disease.

PubMed

Conran, Nicola; Belcher, John D

2018-01-01

The primary β-globin gene mutation that causes sickle cell disease (SCD) has significant pathophysiological consequences that result in hemolytic events and the induction of the inflammatory processes that ultimately lead to vaso-occlusion. In addition to their role in the initiation of the acute painful vaso-occlusive episodes that are characteristic of SCD, inflammatory processes are also key components of many of the complications of the disease including autosplenectomy, acute chest syndrome, pulmonary hypertension, leg ulcers, nephropathy and stroke. We, herein, discuss the events that trigger inflammation in the disease, as well as the mechanisms, inflammatory molecules and cells that propagate these inflammatory processes. Given the central role that inflammation plays in SCD pathophysiology, many of the therapeutic approaches currently under pre-clinical and clinical development for the treatment of SCD endeavor to counter aspects or specific molecules of these inflammatory processes and it is possible that, in the future, we will see anti-inflammatory drugs being used either together with, or in place of, hydroxyurea in those SCD patients for whom hematopoietic stem cell transplants and evolving gene therapies are not a viable option.

Hydrogen Treatment Protects against Cell Death and Senescence Induced by Oxidative Damage.

PubMed

Han, A Lum; Park, Seong-Hoon; Park, Mi Sung

2017-02-28

Hydrogen has potential for preventive and therapeutic applications as an antioxidant. However, micro- and macroparticles of hydrogen in water disappear easily over time. In order to eliminate reactive oxygen species (ROS) related with the aging process, we used functional water containing nanoparticle hydrogen. Nanoparticle hydrogen does not disappear easily and collapse under water after long periods of time. We used murine embryonic fibroblasts that were isolated from 12.5-day embryos of C57BL/6 mice. We investigated the ability of nanoparticle hydrogen in water to suppress hydroxyurea-induced ROS production, cytotoxicity, and the accumulation of β-galactosidase (an indicator of aging), and promote cell proliferation. The accumulation of β-galactosidase in the cytoplasm and the appearance of abnormal nuclei were inhibited by daily treatment of cells with hydrogen water. When the aging process was accelerated by hydroxyurea-induced oxidative stress, the effect of hydrogen water was even more remarkable. Thus, this study showed the antioxidant and anti-senescence effects of hydrogen water. Nanoparticle hydrogen water is potentially a potent anti-aging agent.

A Systematic Review of Known Mechanisms of Hydroxyurea-induced Foetal Haemoglobin for Treatment of Sickle Cell Disease

PubMed Central

Pule, Gift D.; Mowla, Shaheen; Novitzky, Nicolas; Wiysonge, Charles S.; Wonkam, Ambroise

2016-01-01

Aims To report on molecular mechanisms of foetal haemoglobin (HbF) induction by hydroxyurea (HU) for the treatment of Sickle Cell Disease (SCD). Study Design Systematic review. Results Studies have provided consistent associations between genomic variations in HbF-promoting loci and variable HbF level in response to HU. Numerous signal transduction pathways have been implicated, through the identification of key genomic variants in BCL11A, HBS1L-MYB, SAR1 or XmnI polymorphism that predispose the response to the treatment, and signal transduction pathways, that modulate γ-globin expression (cAMP/cGMP; Giα/JNK/Jun; methylation and microRNA). Three main molecular pathways have been reported: 1) Epigenetic modifications, transcriptional events and signalling pathways involved in HU-mediated response, 2) Signalling pathways involving HU-mediated response and 3) Post-transcriptional pathways (regulation by microRNAs). Conclusions The complete picture of HU-mediated mechanisms of HbF production in SCD remains elusive. Research on post-transcriptional mechanisms could lead to therapeutic targets that may minimize alterations to the cellular transcriptome. PMID:26327494

A systematic review of known mechanisms of hydroxyurea-induced fetal hemoglobin for treatment of sickle cell disease.

PubMed

Pule, Gift D; Mowla, Shaheen; Novitzky, Nicolas; Wiysonge, Charles S; Wonkam, Ambroise

2015-10-01

To report on molecular mechanisms of fetal hemoglobin (HbF) induction by hydroxyurea (HU) for the treatment of sickle cell disease. Systematic review. Studies have provided consistent associations between genomic variations in HbF-promoting loci and variable HbF level in response to HU. Numerous signal transduction pathways have been implicated, through the identification of key genomic variants in BCL11A, HBS1L-MYB, SAR1 or XmnI polymorphism that predispose the response to the treatment, and signal transduction pathways that modulate γ-globin expression (cAMP/cGMP; Giα/c-Jun N-terminal kinase/Jun; methylation and miRNA). Three main molecular pathways have been reported: i) Epigenetic modifications, transcriptional events and signaling pathways involved in HU-mediated response, ii) Signaling pathways involving HU-mediated response and iii) Post-transcriptional pathways (regulation by miRNAs). The complete picture of HU-mediated mechanisms of HbF production in Sickle Cell Disease remains elusive. Research on post-transcriptional mechanisms could lead to therapeutic targets that may minimize alterations to the cellular transcriptome.

Post-Doctoral Research Award

DTIC Science & Technology

1988-12-01

day old tadpoles have completed most of organogenesis and, therefore, are usually not susceptible to malformation . An exception is limb development...antagonistic response may have b.een the result of poorer absorption of hydroxyurea by the severly malformed embryos, as isoniazid had a much greater...Short-chain carboxylic acids showed concentration additive joint actionsfor induction of malformation . Combinations of DNA synthesis inhibitors

Interventions for chronic kidney disease in people with sickle cell disease

PubMed Central

Roy, Noemi BA; Fortin, Patricia M; Bull, Katherine R; Doree, Carolyn; Trivella, Marialena; Hopewell, Sally; Estcourt, Lise J

2017-01-01

This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the effectiveness of any intervention in preventing or reducing kidney complications or CKD in people with SCD (including red blood cell transfusions, hydroxyurea and ACEI (either alone or in combination with each other)). PMID:28344511

Final Results of a Randomized Phase 2 Trial Investigating the Addition of Cetuximab to Induction Chemotherapy and Accelerated or Hyperfractionated Chemoradiation for Locoregionally Advanced Head and Neck Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Seiwert, Tanguy Y., E-mail: tseiwert@medicine.bsd.uchicago.edu; Melotek, James M.; Blair, Elizabeth A.

Purpose: The role of cetuximab in the treatment of locoregionally advanced head and neck squamous cell cancer (LA-HNSCC) remains poorly defined. In this phase 2 randomized study, we investigated the addition of cetuximab to both induction chemotherapy (IC) and hyperfractionated or accelerated chemoradiation. Methods and Materials: Patients with LA-HNSCC were randomized to receive 2 cycles of weekly IC (cetuximab, paclitaxel, carboplatin) and either Cetux-FHX (concurrent cetuximab, 5-fluorouracil, hydroxyurea, and 1.5 Gy twice-daily radiation therapy every other week to 75 Gy) or Cetux-PX (cetuximab, cisplatin, and accelerated radiation therapy with delayed concomitant boost to 72 Gy in 42 fractions). The primary endpoint was progression-freemore » survival (PFS), with superiority compared with historical control achieved if either arm had 2-year PFS ≥70%. Results: 110 patients were randomly assigned to either Cetux-FHX (n=57) or Cetux-PX (n=53). The overall response rate to IC was 91%. Severe toxicity on IC was limited to rash (23% grade ≥3) and myelosuppression (38% grade ≥3 neutropenia). The 2-year rates of PFS for both Cetux-FHX (82.5%) and Cetux-PX (84.9%) were significantly higher than for historical control (P<.001). The 2-year overall survival (OS) was 91.2% for Cetux-FHX and 94.3% for Cetux-PX. With a median follow-up time of 72 months, there were no significant differences in PFS (P=.35) or OS (P=.15) between the treatment arms. The late outcomes for the entire cohort included 5-year PFS, OS, locoregional failure, and distant metastasis rates of 74.1%, 80.3%, 15.7%, and 7.4%, respectively. The 5-year PFS and OS were 84.4% and 91.3%, respectively, among human papillomavirus (HPV)-positive patients and 65.9% and 72.5%, respectively, among HPV-negative patients. Conclusions: The addition of cetuximab to IC and chemoradiation was tolerable and produced long-term control of LA-HNSCC, particularly among poor-prognosis HPV-negative patients. Further investigation of cetuximab may be warranted in the neoadjuvant setting and with non–platinum-based chemoradiation.« less

Survival benefit of anti-HER2 therapy after whole-brain radiotherapy in HER2-positive breast cancer patients with brain metastasis.

PubMed

Zhang, Qian; Chen, Jian; Yu, Xiaoli; Cai, Gang; Yang, Zhaozhi; Cao, Lu; Hu, Chaosu; Guo, Xiaomao; Sun, Jing; Chen, Jiayi

2016-09-01

We aimed to assess the survival benefit of epidermal growth factor receptor 2 (HER2)-positive breast cancer patients with brain metastasis (BM) after whole-brain radiotherapy (WBRT) in combination with systemic treatments, especially anti-HER2 therapy. This retrospective study analyzed the overall survival (OS) of 60 HER2-positive breast cancer patients with BM after WBRT in combination with systemic treatments. Among them, 42 patients received chemotherapy while 18 patients did not receive after WBRT. With regard to anti-HER2 therapy, after WBRT, 17 patients received anti-HER2 treatment without prior adjuvant trastuzumab-based therapy, 7 patients received anti-HER2 treatment with prior adjuvant trastuzumab-based therapy, and 36 patients did not receive further anti-HER2 treatment. All patients were followed up regularly until January 23, 2013. The median OS of patients with BM was 12 months. Patients who received anti-HER2 therapy and chemotherapy after WBRT had significantly better survival compared with patients who did not receive further treatment. Patients who received anti-HER2 treatment after WBRT but did not receive adjuvant trastuzumab-based therapy for early breast cancer had better OS, followed by patients who received anti-HER2 agent both in adjuvant treatment and after WBRT and patients who did not receive anti-HER2 treatment. Multivariate analysis showed that Karnofsky Performance Status, control of extracranial metastases, chemotherapy after WBRT, and anti-HER2 therapy combined with WBRT were all independent predictors for OS. Both chemotherapy and anti-HER2 therapy after WBRT could improve OS. Moreover, patients without prior exposure to adjuvant anti-HER2 treatment may have survival benefit superior to those of patients with prior exposure.

Empirically-supported and non-empirically supported therapies for bulimia nervosa: retrospective patient ratings

PubMed Central

2013-01-01

Background Empirically supported therapies for bulimia nervosa include cognitive behaviour therapy and interpersonal therapy. Whilst these treatments have been shown to be effective in multiple randomised controlled trials, little research has investigated how they are perceived by patients who receive them. This study investigated whether empirically-supported psychological therapies (ESTs) are associated with superior self-rated treatment outcomes in clients with Bulimia Nervosa (BN). Results 98 adults who had received psychological therapy for BN in the United Kingdom completed a questionnaire which retrospectively assessed the specific contents of their psychological therapy and self-rated treatment outcomes. Around half the sample, fifty three participants reported receiving an EST. Fifty of these received Cognitive Behaviour Therapy (CBT) and three Interpersonal Therapy (IPT). Where therapy met expert criteria for Cognitive Behaviour Therapy for Bulimia Nervosa (CBT-BN, an EST) participants reported superior treatment outcomes than those who appeared to receive non-specialist cognitive-behavioural therapy. However, self-rated treatment outcomes were similar overall between those whose therapy met criteria for ESTs and those whose therapy did not. Conclusions The findings offer tentative support for the perceived helpfulness of CBT-BN as evaluated in controlled research trials. Cognitive-behavioural therapies for BN, as they are delivered in the UK, may not necessarily be perceived as more beneficial by clients with BN than psychological therapies which currently have less empirical support. PMID:24999419

Joint Actions of Developmental Toxicants.

DTIC Science & Technology

1991-06-01

antagonistic response may have been the result of poorer absorption of hydroxyurea by the severly malformed embryos, as isoniazid had a much greater...chain carboxylic acids showed concentration additive joint actions for induction of malformation . Combinations of DNA synthesis inhibitors showed...response additive to antagonistic joint actions at malformation -inducing con- centrations. Since each compound inhibits a different enzyme in the process of

Fetal hemoglobin in sickle cell anemia: The Arab-Indian haplotype and new therapeutic agents.

PubMed

Habara, Alawi H; Shaikho, Elmutaz M; Steinberg, Martin H

2017-11-01

Fetal hemoglobin (HbF) has well-known tempering effects on the symptoms of sickle cell disease and its levels vary among patients with different haplotypes of the sickle hemoglobin gene. Compared with sickle cell anemia haplotypes found in patients of African descent, HbF levels in Saudi and Indian patients with the Arab-Indian (AI) haplotype exceed that in any other haplotype by nearly twofold. Genetic association studies have identified some loci associated with high HbF in the AI haplotype but these observations require functional confirmation. Saudi patients with the Benin haplotype have HbF levels almost twice as high as African patients with this haplotype but this difference is unexplained. Hydroxyurea is still the only FDA approved drug for HbF induction in sickle cell disease. While most patients treated with hydroxyurea have an increase in HbF and some clinical improvement, 10 to 20% of adults show little response to this agent. We review the genetic basis of HbF regulation focusing on sickle cell anemia in Saudi Arabia and discuss new drugs that can induce increased levels of HbF. © 2017 Wiley Periodicals, Inc.

MOF Suppresses Replication Stress and Contributes to Resolution of Stalled Replication Forks.

PubMed

Singh, Dharmendra Kumar; Pandita, Raj K; Singh, Mayank; Chakraborty, Sharmistha; Hambarde, Shashank; Ramnarain, Deepti; Charaka, Vijaya; Ahmed, Kazi Mokim; Hunt, Clayton R; Pandita, Tej K

2018-03-15

The human MOF (hMOF) protein belongs to the MYST family of histone acetyltransferases and plays a critical role in transcription and the DNA damage response. MOF is essential for cell proliferation; however, its role during replication and replicative stress is unknown. Here we demonstrate that cells depleted of MOF and under replicative stress induced by cisplatin, hydroxyurea, or camptothecin have reduced survival, a higher frequency of S-phase-specific chromosome damage, and increased R-loop formation. MOF depletion decreased replication fork speed and, when combined with replicative stress, also increased stalled replication forks as well as new origin firing. MOF interacted with PCNA, a key coordinator of replication and repair machinery at replication forks, and affected its ubiquitination and recruitment to the DNA damage site. Depletion of MOF, therefore, compromised the DNA damage repair response as evidenced by decreased Mre11, RPA70, Rad51, and PCNA focus formation, reduced DNA end resection, and decreased CHK1 phosphorylation in cells after exposure to hydroxyurea or cisplatin. These results support the argument that MOF plays an important role in suppressing replication stress induced by genotoxic agents at several stages during the DNA damage response. Copyright © 2018 American Society for Microbiology.

Prasugrel hydrochloride for the treatment of sickle cell disease.

PubMed

Conran, Nicola; Rees, David C

2017-07-01

Therapeutic options for sickle cell disease (SCD) are limited and, currently, only one drug (hydroxyurea) has FDA approval for the treatment of adult SCD. While this genetic disease is caused by hemoglobin polymerization, subsequent downstream events trigger platelet activation, vaso-occlusion and the disease's complex pathophysiology. Areas covered: The oral thienopyridine, prasugrel hydrochloride, irreversibly inhibits the P2Y12 receptors, inhibiting ADP-dependent platelet activation. We discuss recent clinical trials evaluating the pharmokinetics of prasugrel and its potential for use in SCD. Expert opinion: Prasugrel administration in SCD appears to be well tolerated and safe. However, although this drug modestly inhibits platelet activity in these patients, administration of prasugrel to a large group of children and adolescents for up to 24 months failed to convincingly reduce vaso-occlusive complications. Speculatively, prasugrel may be of occasional use for off-license purposes in patients unable or unwilling to take hydroxyurea (particularly in 12-17-year olds). Although there is currently no prospect of prasugrel being licensed for use in SCD, the success of on-going trials of other antiplatelet agents in SCD might lead to further trials of prasugrel in SCD.

ESR studies on reactivity of protein-derived tyrosyl radicals formed by prostaglandin H synthase and ribonucleotide reductase.

PubMed

Lassmann, G; Curtis, J; Liermann, B; Mason, R P; Eling, T E

1993-01-01

Using ESR spectroscopy, the ability of enzyme inhibitors to quench protein-derived tyrosyl radicals was studied in two different enzymes, prostaglandin H synthase and ribonucleotide reductase. The prostaglandin H synthase inhibitors indomethacin, eugenol, and MK-410 effectively prevent the formation of tyrosyl radicals during the oxidation of arachidonic acid by prostaglandin H synthase from ram seminal vesicles. A direct reaction with preformed tyrosyl radicals was observed only with eugenol. The other prostaglandin H synthase inhibitors were ineffective. The ribonucleotide reductase inhibitors hydroxyurea and 4-hydroxyanisole, which effectively inactivate the tyrosyl radical in the active site of ribonucleotide reductase present in tumor cells, exhibit a different reactivity with tyrosyl radicals formed by prostaglandin H synthase. Hydroxyurea quenches preformed tyrosyl radicals in prostaglandin H synthase weakly, whereas 4-hydroxyanisole does not quench tyrosyl radicals in prostaglandin H synthase at all. Eugenol, which quenches preformed prostaglandin H synthase-derived tyrosyl radicals, also quenches the tyrosyl radical in ribonucleotide reductase. The results suggest that the reactivity of protein-linked tyrosyl radicals in ribonucleotide reductase and those formed during prostaglandin H synthase catalysis are very different and have unrelated roles in enzyme catalysis.

Ribonucleotide Reductase Inhibitors Reduce Atherosclerosis in a Double-Injury Rabbit Model

PubMed Central

Gallaugher, Laura D; Henry, Jon C; Kearns, Patrick N; Elford, Howard L; Bergdall, Valerie K; Cardounel, Arturo J

2009-01-01

Atheroproliferative disorders such as atherosclerosis are an important health problem and one of the leading causes of morbidity and mortality in the United States. Minimally invasive therapeutic procedures, including angioplasty with stent deployment, are used frequently for obstructive coronary artery disease. However, restenosis, a proliferative vascular response, is a common sequela to this procedure. The current study investigated the effect of inhibiting ribonucleotide reductase (RR), an enzyme necessary for cellular proliferation, in an attempt to ameliorate the proliferative response. Two RR inhibitors, didox and hydroxyurea, were chosen for their potent antiproliferative properties. Studies were carried out by using a double-injury rabbit model, in which endothelial denudation was followed by the administration of a high-fat diet. At 4 wk after initial endothelial denudation, the developing atherosclerotic lesion was subjected to transluminal balloon dilation to simulate clinical intervention with percutaneous transluminal angioplasty. The degree of restenosis and atheroproliferation was assessed at 8 wk. Histologic evaluation of the lesion demonstrated that treatment with didox and hydroxyurea significantly decreased lesion area and lumen loss. These results suggest that RR inhibition may be an effective new tool for the treatment of atheroproliferative disorders. PMID:20034432

Increased survival in men with metastatic prostate cancer receiving chemo and hormone therapy

Cancer.gov

Men with hormone-sensitive metastatic prostate cancer who received the chemotherapy drug docetaxel given at the start of standard hormone therapy lived longer than patients who received hormone therapy alone, according to early results from a NIH-supporte

Variation in the Use of Therapy following Distal Radius Fractures in the United States

PubMed Central

Waljee, Jennifer F.; Zhong, Lin; Shauver, Melissa

2014-01-01

Background: Distal radius fractures (DRFs) are one of the most common injuries among the elderly, resulting in significant expense and disability. The specific aims of this study are (1) to examine rates of therapy following DRFs and (2) to identify those factors that influence utilization of therapy and time span between DRF treatment and therapy among a national cohort of elderly patients. Methods: We examined national use of physical and occupational therapy among all Medicare beneficiaries who suffered DRFs between January 1, 2007, and October 1, 2007, and assessed the effect of treatment, patient-related, and surgeon-related factors on utilization of therapy. Results: Overall, 20.6% of patients received either physical or occupational therapy following DRF. Use of therapy varied by DRF treatment, and patients who underwent open reduction and internal fixation were more likely to receive therapy compared with patients who received closed reduction. Patients who received open reduction and internal fixation were also referred to therapy earlier compared with patients who received external fixation, percutaneous pinning, and closed reduction. Surgeon specialization is associated with greater use of postoperative therapy. Patient predictors of therapy use include younger age, female sex, higher socioeconomic status, and fewer comorbidity conditions. Conclusion: Use of therapy following DRF varies significantly by both patient- and surgeon-related factors. Identifying patients who benefit from postinjury therapy can allow for better resource utilization following these common injuries. PMID:25289323

Management of Sickle Cell Disease: A Review for Physician Education in Nigeria (Sub-Saharan Africa)

PubMed Central

Adewoyin, Ademola Samson

2015-01-01

Sickle cell disease (SCD) predominates in sub-Saharan Africa, East Mediterranean areas, Middle East, and India. Nigeria, being the most populous black nation in the world, bears its greatest burden in sub-Saharan Africa. The last few decades have witnessed remarkable scientific progress in the understanding of the complex pathophysiology of the disease. Improved clinical insights have heralded development and establishment of disease modifying interventions such as chronic blood transfusions, hydroxyurea therapy, and haemopoietic stem cell transplantation. Coupled with parallel improvements in general supportive, symptomatic, and preventive measures, current evidence reveals remarkable appreciation in quality of life among affected individuals in developed nations. Currently, in Nigeria and other West African states, treatment and control of SCD are largely suboptimal. Improved knowledge regarding SCD phenotypes and its comprehensive care among Nigerian physicians will enhance quality of care for affected persons. This paper therefore provides a review on the aetiopathogenesis, clinical manifestations, and management of SCD in Nigeria, with a focus on its local patterns and peculiarities. Established treatment guidelines as appropriate in the Nigerian setting are proffered, as well as recommendations for improving care of affected persons. PMID:25667774

Phytomedicines and Nutraceuticals: Alternative Therapeutics for Sickle Cell Anemia

PubMed Central

Imaga, Ngozi Awa

2013-01-01

Sickle cell anemia is a genetically inherited disease in which the “SS” individual possesses an abnormal beta globin gene. A single base substitution in the gene encoding the human β-globin subunit results in replacement of β6 glutamic acid by valine, leading to the devastating clinical manifestations of sickle cell disease. This substitution causes drastic reduction in the solubility of sickle cell hemoglobin (HbS) when deoxygenated. Under these conditions, the HbS molecules polymerize to form long crystalline intracellular mass of fibers which are responsible for the deformation of the biconcave disc shaped erythrocyte into a sickle shape. First-line clinical management of sickle cell anemia include, use of hydroxyurea, folic acid, amino acids supplementation, penicillinprophylaxis, and antimalarial prophylaxis to manage the condition and blood transfusions to stabilize the patient's hemoglobin level. These are quite expensive and have attendant risk factors. However, a bright ray of hope involving research into antisickling properties of medicinal plants has been rewarding. This alternative therapy using phytomedicines has proven to not only reduce crisis but also reverse sickling (in vitro). The immense benefits of phytomedicines and nutraceuticals used in the management of sickle cell anemia are discussed in this paper. PMID:23476125

Inflammatory targets of therapy in sickle cell disease

PubMed Central

Owusu-Ansah, Amma; Ihunnah, Chibueze A.; Walker, Aisha L.; Ofori-Acquah, Solomon F.

2015-01-01

Sickle cell disease (SCD) is a monogenic globin disorder characterized by the production of a structurally abnormal hemoglobin (Hb) variant Hb S, which causes severe hemolytic anemia, episodic painful vaso-occlusion and ultimately end-organ damage. The primary disease pathophysiology is intracellular Hb S polymerization and consequent sickling of erythrocytes. It has become evident over several decades that a more complex disease process contributes to the myriad of clinical complications seen in SCD patients with inflammation playing a central role. Drugs targeting specific inflammatory pathways therefore offer an attractive therapeutic strategy to ameliorate many of the clinical events in SCD. In addition they are useful tools to dissecting the molecular and cellular mechanisms that promote individual clinical events, and for developing improved therapeutics to address more challenging clinical dilemmas such as refractoriness to opioids or hyperalgesia. Here, we discuss the prospect of targeting multiple inflammatory pathways implicated in the pathogenesis of SCD with a focus on new therapeutics, striving to link the actions of the anti-inflammatory agents to a defined pathobiology, and specific clinical manifestations of SCD. We also review the anti-inflammatory attributes and the cognate inflammatory targets of hydroxyurea, the only FDA approved drug for SCD. PMID:26226206

Comparison of Downstream Health Care Utilization, Costs, and Long-Term Opioid Use: Physical Therapist Management Versus Opioid Therapy Management After Arthroscopic Hip Surgery.

PubMed

Rhon, Daniel I; Snodgrass, Suzanne J; Cleland, Joshua A; Greenlee, Tina A; Sissel, Charles D; Cook, Chad E

2018-05-01

Physical therapy and opioid prescriptions are common after hip surgery, but are sometimes delayed or not used. The objective of this study was to compare downstream health care utilization and opioid use following hip surgery for different patterns of physical therapy and prescription opioids. The design of this study was an observational cohort. Health care utilization was abstracted from the Military Health System Data Repository for patients who were 18 to 50 years old and were undergoing arthroscopic hip surgery between 2004 and 2013. Patients were grouped into those receiving an isolated treatment (only opioids or only physical therapy) and those receiving both treatments on the basis of timing (opioid first or physical therapy first). Outcomes included overall health care visits and costs, hip-related visits and costs, additional surgeries, and opioid prescriptions. Of 1870 total patients, 82.7% (n = 1546) received physical therapy only, 71.6% (n = 1339) received prescription opioids, and 1073 (56.1%) received both physical therapy and opioids. Because 24 patients received both opioids and physical therapy on the same day, they were eventually removed the final timing-of-care analysis. Adjusted hip-related mean costs were the same in both groups receiving isolated treatments (${\\$}$11,628 vs ${\\$}$11,579), but the group receiving only physical therapy had significantly lower overall total health care mean costs (${\\$}$18,185 vs ${\\$}$23,842) and fewer patients requiring another hip surgery. For patients receiving both treatments, mean hip-related downstream costs were significantly higher in the group receiving opioids first than in the group receiving physical therapy first (${\\$}$18,806 vs ${\\$}$16,955) and resulted in greater opioid use (7.83 vs 4.14 prescriptions), greater total days' supply of opioids (90.17 vs 44.30 days), and a higher percentage of patients with chronic opioid use (69.5% vs 53.2%). Claims data were limited by the accuracy of coding, and observational data limit inferences of causality. Physical therapy first was associated with lower hip-related downstream costs and lower opioid use than opioids first; physical therapy instead of opioids was associated with less total downstream health care utilization. These results need to be validated in prospective controlled trials.

Ondansetron in acute food protein-induced enterocolitis syndrome, a retrospective case-control study.

PubMed

Miceli Sopo, S; Bersani, G; Monaco, S; Cerchiara, G; Lee, E; Campbell, D; Mehr, S

2017-04-01

Therapy for moderate to severe acute food protein-induced enterocolitis syndrome (FPIES) typically consists of intravenous fluids and corticosteroids (traditional therapy). Ondansetron has been suggested as an adjunctive treatment. We aimed to evaluate the efficacy of the parenteral (intravenous or intramuscular) ondansetron vs traditional therapy to resolve the symptoms of acute FPIES. Cases of FPIES who had a positive oral food challenge (OFC) were retrospectively examined at two major hospitals over a two-year period (Rome, Italy; and Sydney, Australia). The efficacy of therapy, based on the percentage of cases who stopped vomiting, was compared in cases who received parenteral ondansetron and in cases who received traditional therapy or no pharmacological therapy. A total of 66 patients were included: 37 had parenteral ondansetron, 14 were treated with traditional therapy, and 15 did not receive any pharmacological therapy. Nineteen percentage of children treated with ondansetron continued vomiting after the administration of the therapy vs 93% of children who received traditional therapy (P < 0.05, relative risk = 0.2). Children who received ondansetron or no therapy were less likely to require an admission overnight compared with those who received traditional therapy (P < 0.05). Parenteral ondansetron is significantly more effective than traditional therapy in resolving acute symptoms of FPIES. The relative risk = 0.2 greatly reduces the bias linked to the lack of randomization. These findings suggest an effective treatment for vomiting in positive FPIES OFCs and allow for more confidence in performing OFCs. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Music Therapy is Associated With Family Perception of More Spiritual Support and Decreased Breathing Problems in Cancer Patients Receiving Hospice Care.

PubMed

Burns, Debra S; Perkins, Susan M; Tong, Yan; Hilliard, Russell E; Cripe, Larry D

2015-08-01

Music therapy is a common discretionary service offered within hospice; however, there are critical gaps in understanding the effects of music therapy on hospice quality indicators, such as family satisfaction with care. The purpose of this study was to examine whether music therapy affected family perception of patients' symptoms and family satisfaction with hospice care. This was a retrospective, cross-sectional analysis of electronic medical records from 10,534 cancer patients cared for between 2006 and 2010 by a large national hospice. Logistic regression was used to estimate the effect of music therapy using propensity scores to adjust for non-random assignment. Overall, those receiving music therapy had higher odds of being female, having longer lengths of stay, and receiving more services other than music therapy, and lower odds of being married/partnered or receiving home care. Family satisfaction data were available for 1495 (14%) and were more likely available if the patient received music therapy (16% vs. 12%, P < 0.01). There were no differences in patient pain, anxiety, or overall satisfaction with care between those receiving music therapy vs. those not. Patients who received music therapy were more likely to report discussions about spirituality (odds ratio [OR] = 1.59, P = 0.01), had marginally less trouble breathing (OR = 0.77, P = 0.06), and were marginally more likely to receive the right amount of spiritual support (OR = 1.59, P = 0.06). Music therapy was associated with perceptions of meaningful spiritual support and less trouble breathing. The results provide preliminary data for a prospective trial to optimize music therapy interventions for integration into clinical practice. Copyright © 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

Response of melanoma to heat and radiation therapy--a review of the literature and experience from The Prince of Wales Hospital, Sydney.

PubMed

Mameghan, H; Knittel, T

1988-11-07

Our review of the literature indicates that radiotherapy and/or heat therapy can provide local control of recurrent or metastatic melanoma in a large proportion of patients. This has undoubted value in the local palliation of symptoms and, in the absence of disseminated disease, can be curative. At The Prince of Wales Hospital, Sydney, we have studied the response of melanoma lesions to heat and radiation therapy and have assessed the reaction in the adjacent normal skin. Thirty-two melanoma lesions that were measurable in 12 patients received radiotherapy and heat therapy in different combinations and dose schedules (15 lesions received radiotherapy alone, six lesions received heat therapy alone, and 11 lesions received combined radiation and heat therapy). The acute normal skin reaction was compared between lesions that received single modality radiation or heat therapy and those that received the combination of heat and radiation therapy. A moderate or severe reaction developed at six of the 21 sites that were treated by a single modality, and at four of the 11 sites that received combined heat and radiation therapy (P = 0.7), and all healed within a few days. Evaluation of the melanoma response to therapy was possible only in 26 of the 32 lesions that were treated because two patients died soon after therapy and the response of their six lesions was not evaluable. A complete response occurred in 14 (54%) of 26 lesions and a partial response occurred in 10 (38%) of 26 lesions. The objective response by treatment modality was 10 of 15 lesions for radiotherapy, six of six lesions for heat therapy and eight of 11 lesions for both therapies combined. We conclude that radiotherapy and heat therapy, separately or combined, produce acceptably-low damage to normal tissue and highly-satisfactory local control of melanoma.

Robot-assisted therapy for long-term upper-limb impairment after stroke.

PubMed

Lo, Albert C; Guarino, Peter D; Richards, Lorie G; Haselkorn, Jodie K; Wittenberg, George F; Federman, Daniel G; Ringer, Robert J; Wagner, Todd H; Krebs, Hermano I; Volpe, Bruce T; Bever, Christopher T; Bravata, Dawn M; Duncan, Pamela W; Corn, Barbara H; Maffucci, Alysia D; Nadeau, Stephen E; Conroy, Susan S; Powell, Janet M; Huang, Grant D; Peduzzi, Peter

2010-05-13

Effective rehabilitative therapies are needed for patients with long-term deficits after stroke. In this multicenter, randomized, controlled trial involving 127 patients with moderate-to-severe upper-limb impairment 6 months or more after a stroke, we randomly assigned 49 patients to receive intensive robot-assisted therapy, 50 to receive intensive comparison therapy, and 28 to receive usual care. Therapy consisted of 36 1-hour sessions over a period of 12 weeks. The primary outcome was a change in motor function, as measured on the Fugl-Meyer Assessment of Sensorimotor Recovery after Stroke, at 12 weeks. Secondary outcomes were scores on the Wolf Motor Function Test and the Stroke Impact Scale. Secondary analyses assessed the treatment effect at 36 weeks. At 12 weeks, the mean Fugl-Meyer score for patients receiving robot-assisted therapy was better than that for patients receiving usual care (difference, 2.17 points; 95% confidence interval [CI], -0.23 to 4.58) and worse than that for patients receiving intensive comparison therapy (difference, -0.14 points; 95% CI, -2.94 to 2.65), but the differences were not significant. The results on the Stroke Impact Scale were significantly better for patients receiving robot-assisted therapy than for those receiving usual care (difference, 7.64 points; 95% CI, 2.03 to 13.24). No other treatment comparisons were significant at 12 weeks. Secondary analyses showed that at 36 weeks, robot-assisted therapy significantly improved the Fugl-Meyer score (difference, 2.88 points; 95% CI, 0.57 to 5.18) and the time on the Wolf Motor Function Test (difference, -8.10 seconds; 95% CI, -13.61 to -2.60) as compared with usual care but not with intensive therapy. No serious adverse events were reported. In patients with long-term upper-limb deficits after stroke, robot-assisted therapy did not significantly improve motor function at 12 weeks, as compared with usual care or intensive therapy. In secondary analyses, robot-assisted therapy improved outcomes over 36 weeks as compared with usual care but not with intensive therapy. (ClinicalTrials.gov number, NCT00372411.) 2010 Massachusetts Medical Society

Evaluation of protein C and protein S levels in patients with diabetes mellitus receiving therapy with statins and ACE inhibitors or angiotensin II receptor blockers.

PubMed

Aktaş, Şerife; Uçak, Sema; Kurt, Fatma; Taşdemir, Mehmet; Kutlu, Orkide; Eker, Pınar

2018-01-01

To evaluate protein C, protein S level in patients with diabetes mellitus receiving statin and ACE inhibitor/ARB therapy. 95 patients were included in the study and divided into four groups depending on the use of statin and ACE inhibitor/ARB therapy. Group 1 comprised of patients receiving statin therapy (n = 15), Group 2 comprised of patients receiving ACE inhibitor/ARB therapy (n = 31), Group 3 comprised of patients receiving statin and ACE inhibitor/ARB therapy (n = 23), and Group 4 comprised of patients who did not receive either statin or ACE inhibitor/ARB therapy (n = 26). These four groups were compared with respect to protein C, protein S, fibrinogen, D-dimer, INR, and aPTT levels. There were statistically significant differences with respect to protein C levels. Group 1 and group 2 had higher protein C levels compared with group 4. (p < .01). Similarly, Group 3 had higher protein C levels compared with group 4. (p < .01). There was no significant difference between the groups with respect to protein S, INR, aPTT, and D-dimer levels. Diabetic patients receiving statin or ACE inhibitor/ARB therapy had higher protein C levels. Use of statin and ACE inhibitor/ARB therapy in diabetic patients decrease hypercoagulability and therefore could reduce the occurrence of cardiovascular events. Copyright © 2017 Elsevier B.V. All rights reserved.

Cytoplasmic localization of Hug1p, a negative regulator of the MEC1 pathway, coincides with the compartmentalization of Rnr2p–Rnr4p

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ainsworth, William B.; Hughes, Bridget Todd; Au, Wei Chun

2013-10-04

Highlights: •Hug1p overexpression sensitizes wild-type cells to DNA damage and hydroxyurea (HU). •Expression of Hug1p in response to HU treatment is delayed relative to Rnr3p. •MEC1 pathway genes are required for cytoplasmic localization of Hug1p. •Hug1p subcellular compartmentalization to the cytoplasm coincides with Rnr2p–Rnr4p. -- Abstract: The evolutionarily conserved MEC1 checkpoint pathway mediates cell cycle arrest and induction of genes including the RNR (Ribonucleotide reductase) genes and HUG1 (Hydroxyurea, ultraviolet, and gamma radiation) in response to DNA damage and replication arrest. Rnr complex activity is in part controlled by cytoplasmic localization of the Rnr2p–Rnr4p subunits and inactivation of negative regulatorsmore » Sml1p and Dif1p upon DNA damage and hydroxyurea (HU) treatment. We previously showed that a deletion of HUG1 rescues lethality of mec1Δ and suppresses dun1Δ strains. In this study, multiple approaches demonstrate the regulatory response of Hug1p to DNA damage and HU treatment and support its role as a negative effector of the MEC1 pathway. Consistent with our hypothesis, wild-type cells are sensitive to DNA damage and HU when HUG1 is overexpressed. A Hug1 polyclonal antiserum reveals that HUG1 encodes a protein in budding yeast and its MEC1-dependent expression is delayed compared to the rapid induction of Rnr3p in response to HU treatment. Cell biology and subcellular fractionation experiments show localization of Hug1p-GFP to the cytoplasm upon HU treatment. The cytoplasmic localization of Hug1p-GFP is dependent on MEC1 pathway genes and coincides with the cytoplasmic localization of Rnr2p–Rnr4p. Taken together, the genetic interactions, gene expression, and localization studies support a novel role for Hug1p as a negative regulator of the MEC1 checkpoint response through its compartmentalization with Rnr2p–Rnr4p.« less

Can pegylated interferon improve the outcome of polycythemia vera patients?

PubMed

Crisà, Elena; Cerrano, Marco; Beggiato, Eloise; Benevolo, Giulia; Lanzarone, Giuseppe; Manzini, Paola Maria; Borchiellini, Alessandra; Riera, Ludovica; Boccadoro, Mario; Ferrero, Dario

2017-01-13

Pegylated interferon (peg-IFN) was proven by phase II trials to be effective in polycythemia vera (PV); however, it is not clear whether it could improve patient outcome compared to hydroxyurea (HU). Here, we present an observational study on 65 PV patients aged 65 years or younger, who received either peg-IFN (30) or HU (35) according to the physician choice. Median follow-up was 75 months. The two cohorts were comparable for patient and disease characteristics. Eighty-seven percent of the patients treated with peg-INF responded, with a CR rate of 70% as compared to 100 and 49% with HU, respectively. Discontinuation rate was similar in the two groups (20% in peg-IFN vs 17% in HU). JAK2 allele burden was monitored in peg-INF arm only, and a reduction was observed in 88% of the patients. No thrombotic events were observed during peg-IFN treatment compared to three on HU. Disease progression to myelofibrosis or acute myeloid leukemia occurred to a patient only in peg-INF, compared to three in HU. Overall, three second malignancies were observed during the study, two in patients who received HU only, and one in a patient largely treated HU who received also peg-IFN for 3 months. Overall survival was significantly better for peg-IFN patients compared to HU, p = 0.027. Our study, albeit limited by small patient and event number and lack of randomization, confirms the efficacy of peg-INF in PV and shows a significant survival advantage for peg-INF-treated patients. Waiting for confirming data from the ongoing phase III trials, our study can support peg-INF as a first-line treatment option for PV, at least for younger patients.

[Cryopresipitate in comprehensive conservative therapy of patients with acute purulent pyelonephritis].

PubMed

Neimark, A I; Samchuk, Yu G; Gatkin, M Ya; Momot, A P

2017-06-01

To investigate the effectiveness of cryoprecipitate in the comprehensive conservative therapy of patients with acute purulent pyelonephritis. We conducted a retrospective analysis of medical records of patients who were diagnosed with acute non-obstructive pyelonephritis from 2007to 2015. During this period, a total of 3912 patients with acute non-obstructive pyelonephritis were treated at the Department of Urology. Patients were assigned to either receive or not receive cryoprecipitate in the comprehensive conservative therapy. The comprehensive conservative therapy of both groups included antibacterial agents, detoxification, anti-inflammatory therapy. In the study group, patients received additional treatment with cryoprecipitate. By that way we estimated the number of patients who avoided surgery in both groups. There were 3912 patients divided into two groups. The first group included 756 patients (19.3%) who received cryoprecipitate in the comprehensive therapy of pyelonephritis. Of them, 735 patients (97.3%) did not require surgical treatment, and only 21 patients (2.7%) underwent surgery. The second group comprised 3156 patients (80.7%) who did not receive cryoprecipitate. Of them, 2974 patients (94.2%) were treated conservatively without surgical intervention and 182 patients (5.8%) received conservative therapy concurrently with surgical treatment. Therefore, including cryoprecipitate in the comprehensive conservative therapy of acute non-obstructive pyelonephritis results in twice smaller percentage of patients (2.7% vs 5.8%) requiring surgery compared to the comprehensive conservative therapy alone.

The use of incentive spirometry in pediatric patients with sickle cell disease to reduce the incidence of acute chest syndrome.

PubMed

Ahmad, Fahd A; Macias, Charles G; Allen, Joseph Y

2011-08-01

To determine if incentive spirometry (IS) in pediatric patients admitted with sickle cell disease for nonrespiratory complaints will decrease acute chest syndrome (ACS). This was an Institutional Review Board-approved before-after 2-year retrospective cohort study evaluating an evidence-based guideline (EBG) initiating mandatory IS in admitted pediatric sickle cell patients from a tertiary children's emergency center. Student t testing and χ² analysis were performed. There were 1551 patient visits. About 258 visits were enrolled in the pre-EBG year, and 230 in the EBG year. Between year characteristics were similar. The EBG year reported higher use of hydroxyurea (P<0.01), analgesics (P=0.02), and chest pain (P=0.03). Sixty-seven patients (25.9%) in the pre-EBG year received transfusions versus 51 (22.5%) in the EBG year (NS). Twenty-five (9.6%) of the pre-EBG patients received blood for ACS versus 14 (6.1%) in the EBG group (absolute risk reduction: 3.5%, 95% confidence interval: -1-8.4%). Subgroup analysis revealed that patients who presented with back pain experienced a significant decrease in the development of ACS in the EBG year (P=0.04, absolute risk reduction: 14%, 95% confidence interval: 1-28%, number needed to treat: 8). Mandatory IS for sickle cell disease patients admitted without respiratory complaints reduces transfusions and ACS, particularly for those presenting with back pain.

A comparative study of symptoms and quality of life among patients with breast cancer receiving target, chemotherapy, or combined therapy.

PubMed

Huang, Sheng-Miauh; Tai, Chen-Jei; Lin, Kuan-Chia; Tai, Cheng-Jeng; Tseng, Ling-Ming; Chien, Li-Yin

2013-01-01

Studies have rarely compared health outcomes for patients with breast cancer at different treatment stages. The purpose of the study was to compare symptoms and quality of life among patients with breast carcinoma receiving target, chemotherapy, or combined therapy. A longitudinal study was carried out with 57 patients receiving chemotherapy, 30 receiving target therapy, and 34 receiving combined therapy. Data were collected before the start of treatment, at 4 weeks, and at 12 weeks following the start of treatment. Symptom severity and interference were assessed by the M. D. Anderson Symptom Inventory. The physical and mental components of quality of life (physical component score [PCS] and mental component score [MCS]) were assessed using SF-36. There were no significant differences in symptom severity and interference for patients in the 3 therapy groups. The PCSs did not differ significantly according to the therapy group but did decrease significantly after each treatment. Patients receiving target therapy had significantly higher MCSs than did patients receiving chemotherapy, but the MCSs did not differ significantly before and after the treatment. Patients with higher symptom severity and interference had worse PCS and MCS. Patients at all treatment groups had worse physical components quality of life after treatment as compared with before treatment. Patients receiving target therapy had better mental components of quality of life. The mental components of quality of life remained stable during treatment. Nurses should assess the patients' symptoms during treatment and provide timely intervention to optimize their quality of life.

Therapy service use among individuals with fragile X syndrome: findings from a US parent survey.

PubMed

Martin, G E; Ausderau, K K; Raspa, M; Bishop, E; Mallya, U; Bailey, D B

2013-09-01

Fragile X syndrome (FXS) is known to be associated with a range of developmental challenges, yet the occurrence and intensity of therapy services along with associated factors have not been determined. In a US national survey, caregivers provided information regarding the therapy services received by their sons (n = 1013) and daughters (n = 283) with FXS (from birth to 63 years; mean = 15.6 years, SD = 10.6). Caregivers reported (1) type, (2) amount, (3) location, and (4) overall satisfaction with services. Associations with other child variables and family income were also examined. Key findings included that 72% of males and 47% of females were currently receiving at least one type of therapy service; the most common services for both males and females were speech-language therapy (ST) and occupational therapy (OT). Overall, males were more likely to receive therapy services as well as a greater number of services than females. Autism status was significantly associated with both males and females receiving ST and males receiving OT and behaviour management therapy. Therapies were provided in a variety of locations, and parents were generally satisfied with the amount and quality of therapy services. Age-related declines were evident in the use of services for both males and females, with very few individuals receiving any therapy services after 20 years of age. This study provides a baseline description of the current state of therapy services for children with FXS, laying a foundation for future research and recommendations for service provision and policy. © 2012 The Authors. Journal of Intellectual Disability Research © 2012 John Wiley & Sons Ltd, MENCAP & IASSID.

Otitis media in Brazilian human immunodeficiency virus infected children undergoing antiretroviral therapy.

PubMed

Miziara, I D; Weber, R; Araújo Filho, B Cunha; Pinheiro Neto, C Diógenes

2007-11-01

To assess changes in the prevalence of otitis media, associated with the use of highly active antiretroviral therapy, in Brazilian human immunodeficiency virus (HIV) infected children. Division of otorhinolaryngology, Hospital das Clínicas, Sao Paulo University Medical School, Brazil. A cohort of 459 HIV-infected children aged below 13 years. The prevalence of otitis media and the serum cluster of differentiation four glycoprotein T lymphocyte count were compared for children receiving highly active antiretroviral therapy (with protease inhibitors) and those receiving standard antiretroviral therapy (without protease inhibitors). Otitis media was present in 33.1 per cent of the children. Children aged from zero years to five years 11 months receiving highly active antiretroviral therapy had a higher prevalence of acute otitis media (p=0.02) and a lower prevalence of chronic otitis media (p=0.02). Children who were receiving highly active antiretroviral therapy had a mean serum cluster of differentiation four glycoprotein T lymphocyte count greater than that of those who were receiving standard antiretroviral therapy (p<0.001). The use of highly active antiretroviral therapy in Brazilian HIV-infected children was associated with a lower prevalence of chronic otitis media.

X-ray-related potentially lethal damage expressed by chromosome condensation and the influence of caffeine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sasaki, H.; Nishimoto, T.

1989-10-01

Caffeine has been reported to induce premature chromosome condensation (PCC) in S-phase cells in the presence of an inhibitor of DNA synthesis. We found that when S-phase cells are treated with caffeine and hydroxyurea after X irradiation, substantially more potentially lethal damage (PLD) is expressed, but the addition of cycloheximide, which inhibits PCC induction in S-phase cells, in the presence of caffeine and hydroxyurea reduces the expression of PLD to the same level as seen with caffeine alone. This can be interpreted to mean that the expression of PLD seen with caffeine in the absence of an inhibitor of DNAmore » synthesis is not associated with chromosome condensation. Evidence that PCC induction in S-phase cells and the influence of caffeine on PLD expression were suppressed by incubation at 40 degrees C of tsBN75 cells with a ts defect in ubiquitin-activating enzyme indicates the involvement of ubiquitin in these two processes. These observations as well as previous findings on ubiquitin suggest to us that caffeine induces changes in DNA-chromatin conformation, which are caused by induction of PCC or ubiquitination of chromosomal protein. Such changes occurring postirradiation would favor expression of PLD.« less

Hydroxyurea-mediated neuroblast ablation establishes birthdates of secondary lineages and addresses neuronal interactions in the developing Drosophila brain

PubMed Central

Lovick, Jennifer K.; Hartenstein, Volker

2015-01-01

The Drosophila brain is comprised of neurons formed by approximately 100 lineages, each of which is derived from a stereotyped, asymmetrically dividing neuroblast. Lineages serve as structural and developmental units of Drosophila brain anatomy and reconstruction of lineage projection patterns represents a suitable map of Drosophila brain circuitry at the level of neuron populations (“macro-circuitry”). Two phases of neuroblast proliferation, the first in the embryo and the second during the larval phase (following a period of mitotic quiescence), produce primary and secondary lineages, respectively. Using temporally controlled pulses of hydroxyurea (HU) to ablate neuroblasts and their corresponding secondary lineages during the larval phase, we analyzed the effect on development of primary and secondary lineages in the late larval and adult brain. Our findings indicate that timing of neuroblast re-activation is highly stereotyped, allowing us to establish “birth dates” for all secondary lineages. Furthermore, our results demonstrate that, whereas the trajectory and projection pattern of primary and secondary lineages is established in a largely independent manner, the final branching pattern of secondary neurons is dependent upon the presence of appropriate neuronal targets. Taken together, our data provide new insights into the degree of neuronal plasticity during Drosophila brain development. PMID:25773365

Molecular structure, vibrational spectra and quantum chemical MP2/DFT studies toward the rational design of hydroxyurea imprinted polymer

NASA Astrophysics Data System (ADS)

Prasad, Bhim Bali; Rai, Garima

2013-03-01

In this study, both experimental and theoretical vibrational spectra of template (hydroxyurea, HU), monomer (N-(4,6-bisacryloyl amino-[1,3,5] triazine-2-yl-)-acryl amide, TAT), and HU-TAT complexes were compared and these were respectively found to be in good agreement. Binding energies of HU, when complexed with different monomers, were computed using second order Moller Plesset theory (MP2) at 6-311++G(d,p) level both in the gas as well as solution phases. HU is an antineoplastic agent extensively being used in the treatment of polycythaemia Vera and thrombocythemia. It is also used to reduce the frequency of painful attacks in sickle cell anemia. It has antiretroviral property in disease like AIDS. All spectral characterizations were made using Density Functional Theory (DFT) at B3LYP employing 6-31+g(2d, 2p) basis set. The theoretical values for 13C and 1H NMR chemical shifts were found to be in accordance with the corresponding experimental values. Of all different monomers studied for the synthesis of molecularly imprinted polymer (MIP) systems, the monomer TAT (2 mol) was typically found to have a best binding score requisite for complexation with HU (1 mol) at the ground state.

Quantification of hydroxyurea in human plasma by HPLC-MS/MS and its application to pharmacokinetics in patients with chronic myeloid leukaemia.

PubMed

Hai, Xin; Guo, Meihua; Gao, Chunlu; Zhou, Jin

2017-04-15

Hydroxyurea (HU) has been used in the treatment of chronic myeloid leukaemia (CML) and other myeloproliferative malignancies. Considering patient's wide variation in clinical response to HU, a new and simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to monitor patients' compliance to treatment and investigate the pharmacokinetics of HU in patients with CML. Stable isotope labeled HU- 13 C 1 , 15 N 2 was used as internal standard. Plasma samples were treated with acetonitrile to precipitate protein. The supernatant was injected directly without derivatization and separated on a hydrophilic interaction liquid chromatography column. HU was quantitatively analyzed with a mobile phase of acetonitrile-1.5mM ammonium formate (90:10, V:V) within 3min. The proposed method provided a linearity range of 1-200μg/mL. The coefficients of variation for intra- and inter-day precision were less than 2.07% and 4.28%, respectively, while the accuracy (bias) was in the range of -3.77 to 2.96%. This method was satisfactorily applied to the determination of HU in two patients with CML. It is suitable for supporting pharmacokinetic studies and clinical therapeutic monitoring. Copyright © 2017 Elsevier B.V. All rights reserved.

Determination of hydroxyurea in human plasma by HPLC-UV using derivatization with xanthydrol.

PubMed

Legrand, Tiphaine; Rakotoson, Marie-Georgine; Galactéros, Frédéric; Bartolucci, Pablo; Hulin, Anne

2017-10-01

A simple and rapid high performance liquid chromatography (HPLC) method using ultraviolet (UV) detection was developed to determine hydroxyurea (HU) concentration in plasma sample after derivatization with xanthydrol. Two hundred microliters samples were spiked with methylurea (MeU) as internal standard and proteins were precipitated by adding methanol. Derivatization of HU and MeU was immediately performed by adding 0.02M xanthydrol and 1.5M HCl in order to obtain xanthyl-derivatives of HU and MeU that can be further separated using HPLC and quantified using UV detection at 240nm. Separation was achieved using a C18 column with a mobile phase composed of 20mM ammonium acetate and acetonitrile in gradient elution mode at a flow rate of 1mL/min. The total analysis time did not exceed 18min. The method was found linear from 5 to 400μM and all validation parameters fulfilled the international requirements. Between- and within-run accuracy error ranged from -4.7% to 3.2% and precision was lower than 12.8%. This simple method requires small volume samples and can be easily implemented in most clinical laboratories to develop pharmacokinetics studies of HU and to promote its therapeutic monitoring. Copyright © 2017 Elsevier B.V. All rights reserved.

Hydroxyurea for hemoglobin E/β-thalassemia: a systematic review and meta-analysis.

PubMed

Algiraigri, Ali H; Kassam, Aliya

2017-12-01

Hemoglobin E-beta thalassemia (Hb E/β-thalassemia) is a distinct, yet common, type of β-thalassemia, in which the patient co-inherits a β-thalassemia allele from one parent, and a structural variant, Hb E, from the other parent. This co-inheritance leads to remarkable clinical heterogeneity, varying degrees of chronic anemia, and a wide spectrum of complications due to ineffective erythropoiesis and iron overload. Hydroxyurea (HU), an oral chemotherapeutic drug, is expected to decrease disease severity. To assess the clinical efficacy and safety of HU in Hb E/β-thalassemia patients. We searched MEDLINE, EMBASE, Cochrane databases, and major preceding conferences for studies that assessed HU in Hb E/β-thalassemias patients. The effect size was estimated as a proportion (responder/sample size). Qualities of eligible studies were assessed using NIH tools. A total of five [one randomized clinical trial (RCT) and four observational] studies involving 106 patients were included. HU was associated with a significant RR of 46% with no statistical heterogeneity. No serious adverse effects were reported. Patients with Hb E/β-thalassemia may benefit from a trial of HU, though large RCTs assessing efficacy should be conducted to confirm the findings of this meta-analysis and to assess long-term toxicity and response sustainability.

A high-yield procedure for isolation of metaphase chromosomes from root tips of Vicia faba L.

PubMed

Doležel, J; Cíhalíková, J; Lucretti, S

1992-08-01

A new method is described for the isolation of large quantities of Vicia faba metaphase chromosomes. Roots were treated with 2.5 mM hydroxyurea for 18 h to accumulate meristem tip cells at the G1/S interface. After release from the block, the cells re-entered the cell cycle with a high degree of synchrony. A treatment with 2.5 μM amiprophos-methyl (APM) was used to accumulate mitotic cells in metaphase. The highest metaphase index (53.9%) was achieved when, 6 h after the release from the hydroxyurea block, the roots were exposed to APM for 4 h. The chromosomes were released from formaldehyde-fixed root tips by chopping with a scalpel in LB01 lysis buffer. Both the quality and the quantity of isolated chromosomes, examined microscopically and by flow cytometry, depended on the extent of the fixation. The best results were achieved after fixation with 6% formaldehyde for 30 min. Under these conditions, 1 · 10(6) chromosomes were routinely obtained from 30 root tips. The chromosomes were morphologically intact and suitable both for high-resolution chromosome studies and for flow-cytometric analysis and sorting. After the addition of hexylene glycol, the chromosome suspensions could be stored at 4° C for six months without any signs of deterioration.

SB202190 affects cell response to hydroxyurea-induced genotoxic stress in root meristems of Vicia faba.

PubMed

Winnicki, Konrad; Maszewski, Janusz

2012-11-01

Genotoxic stress caused by a variety of chemical and physical agents may lead to DNA breaks and genome instability. Response to DNA damage depends on ATM/ATR sensor kinases and their downstream proteins, which arrange cell cycle checkpoints. Activation of ATM (ataxia-telangiectasia-mutated)/ATR (ATM and Rad 3-related) signaling pathway triggers cell cycle arrest (by keeping cyclin-Cdk complexes inactive), combined with gamma-phosphorylation of histone H2A.X and induction of DNA repair processes. However, genotoxic stress activates also mitogen-activated protein kinases (MAPKs) which may control the functions of checkpoint proteins both directly, by post-translational modifications, or indirectly, by regulation of their expression. Our results indicate that in root meristem cells of Vicia faba, MAP kinase signaling pathway takes part in response to hydroxyurea-induced genotoxic stress. It is shown that SB202190, an inhibitor of p38 MAP kinase, triggers PCC (premature chromosome condensation) more rapidly, but only if cell cycle checkpoints are alleviated by caffeine. Since SB202190 and, independently, caffeine reduces HU-mediated histone H4 Lys5 acetylation, it may be that there is a cooperation of MAP kinase signaling pathways and ATM/ATR-dependent checkpoints during response to genotoxic stress. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Adherence to hydroxyurea medication by children with sickle cell disease (SCD) using an electronic device: a feasibility study.

PubMed

Inoue, Susumu; Kodjebacheva, Gergana; Scherrer, Tammy; Rice, Gary; Grigorian, Matthew; Blankenship, Jeremy; Onwuzurike, Nkechi

2016-08-01

Adherence to hydroxyurea (HU) is a significant modifying factor in sickle cell vaso-occlusive pain. We conducted a study using an electronic medication container-monitor-reminder device (GlowCap™) to track adherence and determine whether use of this device affected rates of HU adherence. Subjects were regular attendees to our clinic. They were given a 37-item questionnaire and were asked to use a GlowCap containing HU. When the device cap is opened, it makes a remote "medication taken" record. The device also provides usage reminder in the form of lights and alarm sounds if the cap opening is delayed. Nineteen subjects participated in the survey, and 17 in the intervention phase. Of the 17, 12 had reliable adherence data. Seventeen caregivers of patients and two patients completed the survey. Two most common barriers to adherence identified were lack of reminders and absence of medicine home delivery. The intervention component of this study, which used both the electronic (GlowCap) method and medication possession ratio showed that the median adherence rate for the 12 patients evaluated was 85 %. The GlowCap device accurately kept a record of adherence rates. This device may be an effective tool for increasing HU medication adherence.

Children with Down Syndrome Improved in Motor Functioning and Muscle Tone Following Massage Therapy

ERIC Educational Resources Information Center

Hernandez-Reif, Maria; Field, Tiffany; Largie, Shay; Mora, Dana; Bornstein, Joan; Waldman, Ronnie

2006-01-01

Twenty-one moderate to high functioning young children (mean age, two years) with Down syndrome receiving early intervention (physical therapy, occupational therapy and speech therapy) were randomly assigned to additionally receive two 0.5-hour massage therapy or reading sessions (control group) per week for two months. On the first and last day…

[Timing of Brain Radiation Therapy Impacts Outcomes in Patients with 
Non-small Cell Lung Cancer Who Develop Brain Metastases].

PubMed

Wang, Yang; Fang, Jian; Nie, Jun; Dai, Ling; Hu, Weiheng; Zhang, Jie; Ma, Xiangjuan; Han, Jindi; Chen, Xiaoling; Tian, Guangming; Wu, Di; Han, Sen; Long, Jieran

2016-08-20

Radiotherapy combined with chemotherapy or molecular targeted therapy remains the standard of treatment for brain metastases from non-small cell lung cancer (NSCLC). The aim of this study is to determine if the deferral of brain radiotherapy impacts patient outcomes. Between May 2003 and December 2015, a total of 198 patients with brain metastases from NSCLC who received both brain radiotherapy and systemic therapy (chemotherapy or targeted therapy) were identified. The rate of grade 3-4 adverse reactions related to chemotherapy and radiotherapy had no significant difference between two groups. 127 patients received concurrent brain radiotherapy and systemic therapy, and 71 patients received deferred brain radiotherapy after at least two cycles of chemotherapy or targeted therapy. Disease specific-graded prognostic assessment was similar in early radiotherapy group and deferred radiotherapy group. Median overall survival (OS) was longer in early radiotherapy group compared to deferred radiotherapy group (17.9 months vs 12.6 months; P=0.038). Progression free survival (PFS) was also improved in patients receiving early radiotherapy compared to those receiving deferred radiotherapy (4.0 months vs 3.0 months; P<0.01). Receiving tyrosine kinase inhibitor (TKI) therapy after the diagnosis of brain metastases as any line therapy improved the OS (20.0 months vs 10.7 months; P<0.01), whereas receiving TKI as first line therapy did not (17.9 months vs 15.2 months; P=0.289). Our study suggests that the use of deferred brain radiotherapy may resulted in inferior OS in patients with NSCLC who develop brain metastases. A prospective multi-central randomized study is imminently needed.

Research on the Treatment of Couple Distress

ERIC Educational Resources Information Center

Lebow, Jay L.; Chambers, Anthony L.; Christensen, Andrew; Johnson, Susan M.

2012-01-01

This article reviews the research on couple therapy over the last decade. The research shows that couple therapy positively impacts 70% of couples receiving treatment. The effectiveness rates of couple therapy are comparable to the effectiveness rates of individual therapies and vastly superior to control groups not receiving treatment. The…

Effect of Group Sandtray Therapy with Preadolescents

ERIC Educational Resources Information Center

Flahive, Mon-hsin Wang; Ray, Dee

2007-01-01

The effectiveness of group sandtray therapy, a model of play therapy, was evaluated using a pretest-posttest control group design with 56 preadolescents exhibiting behavioral difficulties. The experimental group (n = 28) received sandtray therapy in small groups for 10 weeks while the wait-list control group (n = 28) received no treatment. Results…

Positron Emission Tomography/Computed Tomography Findings During Therapy Predict Outcome in Patients With Diffuse Large B-Cell Lymphoma Treated With Chemotherapy Alone but Not in Those Who Receive Consolidation Radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dabaja, Bouthaina S., E-mail: bdabaja@mdanderson.org; Hess, Kenneth; Shihadeh, Ferial

2014-06-01

Purpose: To assess the value of mid-therapy positron emission tomography (PET) findings for predicting survival and disease progression in patients with diffuse large B-cell lymphoma, considering type of therapy (chemotherapy with or without radiation therapy). Methods and Materials: We retrospectively evaluated 294 patients with histologically confirmed diffuse large B-cell lymphoma with respect to age, sex, disease stage, International Prognostic Index score, mid-therapy PET findings (positive or negative), and disease status after therapy and at last follow-up. Overall survival (OS) and progression-free survival (PFS) were compared according to mid-therapy PET findings. Results: Of the 294 patients, 163 (55%) were male, 144more » (49%) were age >61 years, 110 (37%) had stage I or II disease, 219 (74%) had International Prognostic Index score ≤2, 216 (73%) received ≥6 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, and 88 (30%) received consolidation radiation therapy. Five-year PFS and OS rates were associated with mid-therapy PET status: PFS was 78% for those with PET-negative (PET−) disease versus 63% for PET-positive (PET+) disease (P=.024), and OS was 82% for PET− versus 62% for PET+ (P<.002). These associations held true for patients who received chemotherapy only (PFS 71% for PET− vs 52% PET+ [P=.012], OS 78% for PET− and 51% for PET+ [P=.0055]) but not for those who received consolidation radiation therapy (PFS 84% PET− vs 81% PET+ [P=.88]; OS 90% PET− vs 81% PET+ [P=.39]). Conclusion: Mid-therapy PET can predict patient outcome, but the use of consolidation radiation therapy may negate the significance of mid-therapy findings.« less

[Non-pharmaceutical therapy of candidates for geriatric rehabilitation: Non-pharmaceutical therapy prescribed by SHI-accredited doctors after application for outpatient geriatric rehabilitative care].

PubMed

Krupp, Sonja; Schnoor, Maike; Lohse, Kristina; Katalinic, Alexander; Willkomm, Martin

2015-06-01

The rejection of an application for ambulant geriatric rehabilitation (AGRV) is usually justified by the argument that non-pharmaceutical therapy prescribed by doctors accredited by social housing institutions (SHI) would suffice. The reality in healthcare during the 6 months following an application is unknown. In this study 203 patients who had made an application for AGRV in the second half of 2010 in Flensburg, Lübeck or Ratzeburg were interviewed by telephone. The survey revealed that 25.7% of the applications for AGRV had been rejected. The majority of these patients received no ambulant non-pharmaceutical therapy (e.g. physical therapy, physiotherapy, occupational therapy, speech therapy or psychological therapy), less than 20% received more than 12 therapy sessions and in most cases exclusively physiotherapy. The 141 successful AGRV applicants received additional ambulant therapies of a similar magnitude. The difference between the intensified interdisciplinary therapy offered in the AGRV and additionally and the offer to rejected applicants is substantial.

Investigation on the ZBG-functionality of phenyl-4-yl-acrylohydroxamic acid derivatives as histone deacetylase inhibitors.

PubMed

Musso, Loana; Cincinelli, Raffaella; Zuco, Valentina; Zunino, Franco; Nurisso, Alessandra; Cuendet, Muriel; Giannini, Giuseppe; Vesci, Loredana; Pisano, Claudio; Dallavalle, Sabrina

2015-10-15

A series of alternative Zn-binding groups were explored in the design of phenyl-4-yl-acrylohydroxamic acid derivatives as histone deacetylase (HDAC) inhibitors. Most of the synthesized compounds were less effective than the parent hydroxamic acid. However, the profile of activity shown by the analog bearing a hydroxyurea head group, makes this derivative promising for further investigation. Copyright © 2015 Elsevier Ltd. All rights reserved.

Current Trends in the Management of Lateral Ankle Sprain in the United States.

PubMed

Feger, Mark A; Glaviano, Neal R; Donovan, Luke; Hart, Joseph M; Saliba, Susan A; Park, Joseph S; Hertel, Jay

2017-03-01

To characterize trends in the acute management (within 30 days) after lateral ankle sprain (LAS) in the United States. Descriptive epidemiology study. Of note, 825 718 ankle sprain patients were identified; 96.2% were patients with LAS. Seven percent had an associated fracture and were excluded from the remaining analysis. Primary and tertiary care settings. We queried a database of national health insurance records for 2007 to 2011 by ICD-9 codes for patients with LAS while excluding medial and syndesmotic sprains and any LAS with an associated foot or ankle fracture. The percentage of patients to receive specific diagnostic imaging, orthopedic devices, or physical therapy treatments within 30 days of the LAS diagnosis and the associated costs. Over two-thirds of patients with LAS without an associated fracture received radiographs, 9% received an ankle brace, 8.1% received a walking boot, 6.5% were splinted, and 4.8% were prescribed crutches. Only 6.8% received physical therapy within 30 days of their LAS diagnosis, 94.1% of which performed therapeutic exercise, 52.3% received manual therapy, and 50.2% received modalities. The annual cost associated with physician visits, diagnostic imaging, orthopedic devices, and physical therapy was 152 million USD, 81.5% was from physician evaluations, 7.9% from physical therapy, 7.2% from diagnostic imaging, and 3.4% from orthopedic devices. Most patients with LAS do not receive supervised rehabilitation. The small proportion of patients with LAS to receive physical therapy get rehabilitation prescribed in accordance with clinical practice guidelines. The majority (>80%) of the LAS financial burden is associated with physician evaluations.

Effect of prior chemotherapy regimens on the efficacy of endocrine therapy within a German cohort of the TEAM trial.

PubMed

Bossart, Michaela; Hadji, Peyman; Klar, Maximilian; Kieback, Dirk G; Hasenburg, Annette

2014-01-01

Prior chemotherapy may affect the efficacy of endocrine therapy. The tamoxifen exemestane adjuvant multinational (TEAM) trial compared 5 years of adjuvant exemestane with the sequence of tamoxifen followed by exemestane in postmenopausal women with hormone-receptor-positive breast cancer. A total of 1,502 patients were enrolled in Germany (739 received tamoxifen followed by exemestan and 610 exemestan alone). A retrospective analysis of the German cohort of TEAM was conducted to determine whether prior chemotherapy affected clinical outcome of endocrine therapy. Overall survival, disease-free survival and distant recurrence were similar between patients who received sequential therapy and those who received exemestane monotherapy, irrespective of prior chemotherapy. Overall survival was not significantly different between patients who had received prior chemotherapy and those who had not (P = 0.2836). Disease-free survival and distant recurrence were significantly better in patients who had not received prior chemotherapy versus those who had (P = 0.0308 and P = 0.0001). In patients receiving sequential therapy, there were no significant differences in overall survival according to prior chemotherapy use (P = 0.1812). However, disease-free survival and distant recurrence were significantly different dependent on prior chemotherapy (P = 0.0143 and P = 0.0053). In conclusion, there was no difference in overall survival between breast cancer patients who did receive prior chemotherapy before endocrine therapy and those who had not. Patients who had not received prior chemotherapy had significantly improved disease-free survival and less distant recurrence versus those who had received chemotherapy.

Treatment of early-stage uterine papillary serous carcinoma at Roswell Park Cancer Institute, 1992-2006.

PubMed

Tchabo, Nana E; McCloskey, Susan; Mashtare, Terry L; Andrews, Christopher; Singh, Anurag K; Mhawech-Fauceglia, Paulette; Odunsi, Kunle; Lele, Shashikant; Jaggernauth, Wainwright

2009-11-01

Optimal management of early-stage uterine papillary serous carcinoma (UPSC) remains controversial. We reviewed our outcomes in this patient population. The Roswell Park Cancer Institute (RPCI) tumor registry identified all patients with Stages I and IIA UPSC treated between January 1992 and June 2006. The Fisher's exact test was used to compare recurrence rates by adjuvant therapy received. Overall survival (OS) estimates were made using the Kaplan-Meier method. Fifty-eight patients with Stage I or IIA UPSC underwent surgery. Thirty-four patients (59%) were surgically staged. Among 21 patients with Stage IA disease, 15 received adjuvant therapy. With a median follow-up of 44.7 months, only one recurrence was observed in a patient who received adjuvant brachytherapy. The 5-year OS was 66%. Among 37 patients with Stages IB-IIA, 30 patients received adjuvant therapy. With a median follow-up of 29 months, there were 7 recurrences. The 5-year OS was 60%. Although there were no significant differences in recurrence by adjuvant therapy received, a significant OS benefit was found in those who received radiation. There was no significant difference in OS distributions of those patients who received Carboplatin/Paclitaxel chemotherapy. Despite the limitations of our retrospective study, we have shown that even comprehensively staged early-stage UPSC patients are still at risk for recurrence despite adjuvant therapy received. Hence, all patients with this histologic diagnosis should be considered at high risk for recurrence and counseled appropriately regarding the risks and benefits of adjuvant therapy.

Impact of partial versus whole breast radiation therapy on fatigue, perceived stress, quality of life and natural killer cell activity in women with breast cancer.

PubMed

Albuquerque, Kevin; Tell, Dina; Lobo, Philip; Millbrandt, Linda; Mathews, Herbert L; Janusek, Linda Witek

2012-06-18

This pilot study used a prospective longitudinal design to compare the effect of adjuvant whole breast radiation therapy (WBRT) versus partial breast radiation therapy (PBRT) on fatigue, perceived stress, quality of life and natural killer cell activity (NKCA) in women receiving radiation after breast cancer surgery. Women (N = 30) with early-stage breast cancer received either PBRT, Mammosite brachytherapy at dose of 34 Gy 10 fractions/5 days, (N = 15) or WBRT, 3-D conformal techniques at dose of 50 Gy +10 Gy Boost/30 fractions, (N = 15). Treatment was determined by the attending oncologist after discussion with the patient and the choice was based on tumor stage and clinical need. Women were assessed prior to initiation of radiation therapy and twice after completion of radiation therapy. At each assessment, blood was obtained for determination of NKCA and the following instruments were administered: Perceived Stress Scale (PSS), Functional Assessment of Cancer Therapy-Fatigue (FACT-F), and Functional Assessment of Cancer Therapy-General (FACT-G). Hierarchical linear modeling (HLM) was used to evaluate group differences in initial outcomes and change in outcomes over time. Fatigue (FACT-F) levels, which were similar prior to radiation therapy, demonstrated a significant difference in trajectory. Women who received PBRT reported progressively lower fatigue; conversely fatigue worsened over time for women who received WBRT. No difference in perceived stress was observed between women who received PBRT or WBRT. Both groups of women reported similar levels of quality of life (FACT-G) prior to initiation of radiation therapy. However, HLM analysis revealed significant group differences in the trajectory of quality of life, such that women receiving PBRT exhibited a linear increase in quality of life over time after completion of radiation therapy; whereas women receiving WBRT showed a decreasing trajectory. NKCA was also similar between therapy groups but additional post hoc analysis revealed that better quality of life significantly predicted higher NKCA regardless of therapy. Compared to WBRT, PBRT results in more rapid recovery from cancer-related fatigue with improved restoration of quality of life after radiation therapy. Additionally, better quality of life predicts higher NKCA against tumor targets, emphasizing the importance of fostering quality of life for women undergoing adjuvant radiation therapy.

Percutaneous coronary intervention and antiplatelet therapy in patients with atrial fibrillation receiving apixaban or warfarin: Insights from the ARISTOTLE trial.

PubMed

Kopin, David; Jones, W Schuyler; Sherwood, Matthew W; Wojdyla, Daniel M; Wallentin, Lars; Lewis, Basil S; Verheugt, Freek W A; Vinereanu, Dragos; Bahit, M Cecilia; Halvorsen, Sigrun; Huber, Kurt; Parkhomenko, Alexander; Granger, Christopher B; Lopes, Renato D; Alexander, John H

2018-03-01

We assessed antiplatelet therapy use and outcomes in patients undergoing percutaneous coronary intervention (PCI) during the ARISTOTLE trial. Patients were categorized based on the occurrence of PCI during follow-up (median 1.8 years); PCI details and outcomes post-PCI are reported. Of the 18,201 trial participants, 316 (1.7%) underwent PCI (152 in apixaban group, 164 in warfarin group). At the time of PCI, 84% (267) were on study drug (either apixaban or warfarin). Of these, 19% did not stop study drug during PCI, 49% stopped and restarted <5 days post-PCI, and 30% stopped and restarted >5 days post-PCI. At 30 days post-PCI, 35% of patients received dual -antiplatelet therapy (DAPT), 23% received aspirin only, and 13% received a P2Y 12 inhibitor only; 29% received no antiplatelet therapy. Triple therapy (DAPT + oral anticoagulant [OAC]) was used in 21% of patients, 23% received OAC only, 15% received OAC plus aspirin, and 9% received OAC plus a P2Y 12 inhibitor; 32% received antiplatelet agents without OAC. Post-PCI, patients assigned to apixaban versus warfarin had numerically similar rates of major bleeding (5.93 vs 6.73 events/100 patient-years; P = .95) and stroke (2.74 vs 1.84 events/100 patient-years; P = .62). PCI occurred infrequently during follow-up. Most patients on study drug at the time of PCI remained on study drug in the peri-PCI period; 19% continued the study drug without interruption. Antiplatelet therapy use post-PCI was variable, although most patients received DAPT. Additional data are needed to guide the use of antithrombotics in patients undergoing PCI. Copyright © 2017 Elsevier Inc. All rights reserved.

Interventions for preventing silent cerebral infarcts in people with sickle cell disease

PubMed Central

Estcourt, Lise J; Fortin, Patricia M; Hopewell, Sally; Trivella, Marialena; Doree, Carolyn; Abboud, Miguel R

2017-01-01

Background Sickle cell disease (SCD) is one of the commonest severe monogenic disorders in the world, due to the inheritance of two abnormal haemoglobin (beta globin) genes. SCD can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Silent cerebral infarcts are the commonest neurological complication in children and probably adults with SCD. Silent cerebral infarcts also affect academic performance, increase cognitive deficits and may lower intelligence quotient. Objectives To assess the effectiveness of interventions to reduce or prevent silent cerebral infarcts in people with SCD. Search methods We searched for relevant trials in the Cochrane Library, MEDLINE (from 1946), Embase (from 1974), the Transfusion Evidence Library (from 1980), and ongoing trial databases; all searches current to 19 September 2016. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register: 06 October 2016. Selection criteria Randomised controlled trials comparing interventions to prevent silent cerebral infarcts in people with SCD. There were no restrictions by outcomes examined, language or publication status. Data collection and analysis We used standard Cochrane methodological procedures. Main results We included five trials (660 children or adolescents) published between 1998 and 2016. Four of the five trials were terminated early. The vast majority of participants had the haemoglobin (Hb)SS form of SCD. One trial focused on preventing silent cerebral infarcts or stroke; three trials were for primary stroke prevention and one trial dealt with secondary stroke prevention. Three trials compared the use of regular long-term red blood cell transfusions to standard care. Two of these trials included children with no previous long-term transfusions: one in children with normal transcranial doppler (TCD) velocities; and one in children with abnormal TCD velocities. The third trial included children and adolescents on long-term transfusion. Two trials compared the drug hydroxyurea and phlebotomy to long-term transfusions and iron chelation therapy: one in primary prevention (children), and one in secondary prevention (children and adolescents). The quality of the evidence was moderate to very low across different outcomes according to GRADE methodology. This was due to trials being at high risk of bias because they were unblinded; indirectness (available evidence was only for children with HbSS); and imprecise outcome estimates. Long-term red blood cell transfusions versus standard care Children with no previous long-term transfusions and higher risk of stroke (abnormal TCD velocities or previous history of silent cerebral infarcts) Long-term red blood cell transfusions may reduce the incidence of silent cerebral infarcts in children with abnormal TCD velocities, risk ratio (RR) 0.11 (95% confidence interval (CI) 0.02 to 0.86) (one trial, 124 participants, low-quality evidence); but make little or no difference to the incidence of silent cerebral infarcts in children with previous silent cerebral infarcts on magnetic resonance imaging and normal or conditional TCDs, RR 0.70 (95% CI 0.23 to 2.13) (one trial, 196 participants, low-quality evidence). No deaths were reported in either trial. Long-term red blood cell transfusions may reduce the incidence of: acute chest syndrome, RR 0.24 (95% CI 0.12 to 0.49) (two trials, 326 participants, low-quality evidence); and painful crisis, RR 0.63 (95% CI 0.42 to 0.95) (two trials, 326 participants, low-quality evidence); and probably reduces the incidence of clinical stroke, RR 0.12 (95% CI 0.03 to 0.49) (two trials, 326 participants, moderate-quality evidence). Long-term red blood cell transfusions may improve quality of life in children with previous silent cerebral infarcts (difference estimate -0.54; 95% confidence interval -0.92 to -0.17; one trial; 166 participants), but may have no effect on cognitive function (least squares means: 1.7, 95% CI -1.1 to 4.4) (one trial, 166 participants, low-quality evidence). Transfusions continued versus transfusions halted: children and adolescents with normalised TCD velocities (79 participants; one trial) Continuing red blood cell transfusions may reduce the incidence of silent cerebral infarcts, RR 0.29 (95% CI 0.09 to 0.97 (low-quality evidence). We are very uncertain whether continuing red blood cell transfusions has any effect on all-cause mortality, Peto odds ratio (OR) 8.00 (95% CI 0.16 to 404.12); or clinical stroke, RR 0.22 (95% CI 0.01 to 4.35) (very low-quality evidence). The trial did not report: comparative numbers for SCD-related adverse events; quality of life; or cognitive function. Hydroxyurea and phlebotomy versus transfusions and chelation Primary prevention, children (121 participants; one trial) We are very uncertain whether switching to hydroxyurea and phlebotomy has any effect on: silent cerebral infarcts (no infarcts); all-cause mortality (no deaths); risk of stroke (no strokes); or SCD-related complications, RR 1.52 (95% CI 0.58 to 4.02) (very low-quality evidence). Secondary prevention, children and adolescents with a history of stroke (133 participants; one trial) We are very uncertain whether switching to hydroxyurea and phlebotomy has any effect on: silent cerebral infarcts, Peto OR 7.28 (95% CI 0.14 to 366.91); all-cause mortality, Peto OR 1.02 (95% CI 0.06 to 16.41); or clinical stroke, RR 14.78 (95% CI 0.86 to 253.66) (very low-quality evidence). Switching to hydroxyurea and phlebotomy may increase the risk of SCD-related complications, RR 3.10 (95% CI 1.42 to 6.75) (low-quality evidence). Neither trial reported on quality of life or cognitive function. Authors’ conclusions We identified no trials for preventing silent cerebral infarcts in adults, or in children who do not have HbSS SCD. Long-term red blood cell transfusions may reduce the incidence of silent cerebral infarcts in children with abnormal TCD velocities, but may have little or no effect on children with normal TCD velocities. In children who are at higher risk of stroke and have not had previous long-term transfusions, long-term red blood cell transfusions probably reduce the risk of stroke, and other SCD-related complications (acute chest syndrome and painful crises). In children and adolescents at high risk of stroke whose TCD velocities have normalised, continuing red blood cell transfusions may reduce the risk of silent cerebral infarcts. No treatment duration threshold has been established for stopping transfusions. Switching to hydroxyurea with phlebotomy may increase the risk of silent cerebral infarcts and SCD-related serious adverse events in secondary stroke prevention. All other evidence in this review is of very low-quality. PMID:28500860

Effects of music therapy on drug avoidance self-efficacy in patients on a detoxification unit: a three-group randomized effectiveness study.

PubMed

Silverman, Michael J

2014-01-01

Self-efficacy is a component of Bandura's social cognitive theory and can lead to abstinence and a reduction of relapse potential for people who have substance abuse disorders. To date, no music therapy researcher has utilized this theoretical model to address abstinence and reduce the likelihood of relapse in people who have addictions. The purpose of this study was to determine the effects of music therapy on drug avoidance self-efficacy in a randomized three-group wait-list control design with patients on a detoxification unit. Participants (N = 131) were cluster randomized to one of three single-session conditions: music therapy, verbal therapy, or wait-list control. Music therapy participants received a group lyric analysis intervention, verbal therapy participants received a group talk therapy session, and wait-list control participants eventually received a group recreational music therapy intervention. Although there was no significant between-group difference in drug avoidance self-efficacy, participants in the music therapy condition tended to have the highest mean drug avoidance self-efficacy scores. Posttest written comments supported the use of both music therapy and verbal therapy sessions. Two music therapy participants specifically noted that their initial skepticism had dissipated after receiving music therapy. Despite a lack of significant differences, the theoretical support of self-efficacy for substance abuse rehabilitation suggests that this may be an area of continued clinical focus and empirical investigation. Clinical anecdotes, limitations of the study, and suggestions for future research are provided.

Impact of Home-Based Family Therapy on Maternal and Child Outcomes in Disadvantaged Adolescent Mothers.

ERIC Educational Resources Information Center

Cherniss, Cary; Herzog, Elaine

1996-01-01

Evaluates the effects of home-based family therapy on 116 high- risk teenage mothers and their children. Subjects received case management, supportive counseling and some received family therapy. Twelve-month follow-up indicated family therapy subjects improved parenting and became less welfare dependent. No significant difference was found at 24…

Nitric oxide-dependent killing of aerobic, anaerobic and persistent Burkholderia pseudomallei

PubMed Central

Jones-Carson, Jessica; Laughlin, James R.; Stewart, Amanda L.; Voskuil, Martin I.; Vázquez-Torres, Andrés

2012-01-01

Burkholderia pseudomallei infections are fastidious to treat with conventional antibiotic therapy, often involving a combination of drugs and long-term regimes. Bacterial genetic determinants contribute to the resistance of B. pseudomallei to many classes of antibiotics. In addition, anaerobiosis and hypoxia in abscesses typical of melioidosis select for persistent populations of B. pseudomallei refractory to a broad spectrum of antibacterials. We tested the susceptibility of B. pseudomallei to the drugs hydroxyurea, spermine NONOate and DETA NONOate that release nitric oxide (NO). Our investigations indicate that B. pseudomallei are killed by NO in a concentration and time-dependent fashion. The cytoxicity of this diatomic radical against B. pseudomallei depends on both the culture medium and growth phase of the bacteria. Rapidly growing, but not stationary phase, B. pseudomallei are readily killed upon exposure to the NO donor spermine NONOate. NO also has excellent antimicrobial activity against anaerobic B. pseudomallei. In addition, persistent bacteria highly resistant to most conventional antibiotics are remarkably susceptible to NO. Sublethal concentrations of NO inhibited the enzymatic activity of [4Fe-4S]-cofactored aconitase of aerobic and anaerobic B. pseudomallei. The strong anti-B. pseudomallei activity of NO described herein merits further studies on the application of NO-based antibiotics for the treatment of melioidosis. PMID:22521523

Nitric oxide-dependent killing of aerobic, anaerobic and persistent Burkholderia pseudomallei.

PubMed

Jones-Carson, Jessica; Laughlin, James R; Stewart, Amanda L; Voskuil, Martin I; Vázquez-Torres, Andrés

2012-06-30

Burkholderia pseudomallei infections are fastidious to treat with conventional antibiotic therapy, often involving a combination of drugs and long-term regimes. Bacterial genetic determinants contribute to the resistance of B. pseudomallei to many classes of antibiotics. In addition, anaerobiosis and hypoxia in abscesses typical of melioidosis select for persistent populations of B. pseudomallei refractory to a broad spectrum of antibacterials. We tested the susceptibility of B. pseudomallei to the drugs hydroxyurea, spermine NONOate and DETA NONOate that release nitric oxide (NO). Our investigations indicate that B. pseudomallei are killed by NO in a concentration and time-dependent fashion. The cytoxicity of this diatomic radical against B. pseudomallei depends on both the culture medium and growth phase of the bacteria. Rapidly growing, but not stationary phase, B. pseudomallei are readily killed upon exposure to the NO donor spermine NONOate. NO also has excellent antimicrobial activity against anaerobic B. pseudomallei. In addition, persistent bacteria highly resistant to most conventional antibiotics are remarkably susceptible to NO. Sublethal concentrations of NO inhibited the enzymatic activity of [4Fe-4S]-cofactored aconitase of aerobic and anaerobic B. pseudomallei. The strong anti-B. pseudomallei activity of NO described herein merits further studies on the application of NO-based antibiotics for the treatment of melioidosis. Copyright © 2012 Elsevier Inc. All rights reserved.

Epidemiology and treatment of relative anemia in children with sickle cell disease in sub-Saharan Africa.

PubMed

Bello-Manga, Halima; DeBaun, Michael R; Kassim, Adetola A

2016-11-01

Sickle cell disease (SCD) is the most common inherited hemoglobinopathy in the world, with the majority of cases in sub-Saharan Africa. Concomitant nutritional deficiencies, infections or exposure to environmental toxins exacerbate chronic anemia in children with SCD. The resulting relative anemia is associated with increased risk of strokes, poor cognitive function and impaired growth. It may also attenuate optimal response to hydroxyurea therapy, the only effective and practical treatment option for SCD in sub-Saharan Africa. This review will focus on the epidemiology, clinical sequelae, and treatment of relative anemia in children with SCD living in low and middle-income countries in sub-Saharan Africa. Areas covered: The causes and treatment of relative anemia in children with SCD in sub-Saharan Africa. The MEDLINE database was searched using medical subject headings (MeSH) and keywords for articles regarding relative anemia in children with SCD in sub-Saharan Africa. Expert commentary: Anemia due to nutritional deficiencies and infectious diseases such as helminthiasis and malaria are prevalent in sub-Saharan Africa. Their co-existence in children with SCD increases morbidity and mortality. Therefore, preventing, diagnosing and treating the underlying cause of this relative anemia will improve SCD-related outcomes in children in sub-Saharan Africa.

How I treat polycythemia vera.

PubMed

Passamonti, Francesco

2012-07-12

Polycythemia vera (PV) is a clonal disorder characterized by unwarranted production of red blood cells. In the majority of cases, PV is driven by oncogenic mutations that constitutively activate the JAK-STAT signal transduction pathway, such as JAK2 V617F, or exon 12 mutations or LNK mutations. Diagnosis of PV is based on the WHO criteria. Diagnosis of post-PV myelofibrosis is established according to the International Working Group for Myeloproliferative Neoplasms Research and Treatment criteria. Different clinical presentations of PV are discussed. Prognostication of PV is tailored to the most frequent complication during follow-up, namely, thrombosis. Age older than 60 years and prior history of thrombosis are the 2 main risk factors for disease stratification. Correlations are emerging between leukocytosis, JAK2(V617F) mutation, BM fibrosis, and different outcomes of PV, which need to be confirmed in prospective studies. In my practice, hydroxyurea is still the "gold standard" when cytoreduction is needed, even though pegylated IFN-alfa-2a and ruxolitinib might be useful in particular settings. Results of phase 1 or 2 studies concerning these latter agents should however be confirmed by the ongoing randomized phase 3 clinical trials. In this paper, I discuss the main problems encountered in daily clinical practice with PV patients regarding diagnosis, prognostication, and therapy.

Repeat surfactant therapy for postsurfactant slump.

PubMed

Katz, L A; Klein, J M

2006-07-01

To evaluate repeat surfactant therapy for the treatment of respiratory failure associated with postsurfactant slump in extremely low birth weight infants (ELBW) by characterizing the population of premature infants who develop postsurfactant slump and measuring their response to a secondary course of surfactant therapy. A retrospective analysis of a cohort of all patients admitted over a 3-year period with birth weights <1000 g (ELBW infants). Information was collected by chart review and the patients were categorized into three distinct groups for analysis. Initial surfactant only, patients who received surfactant replacement therapy only for respiratory distress syndrome (RDS); repeat surfactant, patients who received both initial surfactant replacement for RDS and repeat surfactant therapy for postsurfactant slump (defined as respiratory failure after 6 days of age), and no surfactant, patients in whom no surfactant was ever administered. A respiratory severity score (RSS) was used to measure the severity of lung disease and response to surfactant therapy. Over 3 years, there were 165 ELBW infants who could develop postsurfactant slump and be eligible for repeat surfactant therapy. There were 39 infants who never received any surfactant therapy estimated gestational age (EGA) 27.7 +/- 1.7, birth weight 856 +/- 109 g) either at birth or after 6 days of life. There were 126 patients treated for RDS with initial surfactant replacement therapy (EGA 25.6 +/- 1.9 weeks, birth weight 713 +/- 179 g). Out of these RDS patients, 101 improved with an initial course of surfactant therapy (EGA 26 +/- 1.8, birth weight 751 +/- 143 g), but 25 (20% of the patients with RDS) developed postsurfactant slump and received a repeat course of surfactant therapy (EGA 24.7 +/- 1.2, birth weight 647 +/- 120 g). The repeat surfactant group (postsurfactant slump) was significantly more premature and had significantly lower birth weights compared to both the initial surfactant only group and the no surfactant ever group. Logistic regression analysis revealed that lack of antenatal steroids, earlier gestational age, and the receiving of 2 or more doses of surfactant to treat the initial RDS were significantly associated with receiving repeat surfactant therapy for postsurfactant slump. Of the 25 patients treated with a repeat course of surfactant therapy more than 70% of patients (n = 18) had an improvement in their lung disease with a 15% reduction in their RSS. This improvement was significant at all time points evaluated (12, 24, and 48 h). We found that a repeat course of surfactant therapy, after day of life 6, led to a significant improvement in hypoxemic respiratory failure in premature infants with postsurfactant slump. Infants who received repeat surfactant therapy were born at a significantly earlier gestational age, had significantly smaller birth weight and had significantly worse lung disease. They were significantly less likely to have received antenatal steroids and were significantly more likely to have received multiple doses of surfactant to treat their initial RDS. A repeat course of surfactant therapy for patients with postsurfactant slump appeared beneficial in the short-term. These initial findings would support performing randomized control trials of repeat surfactant therapy for postsurfactant slump.

Stage III Melanoma in the Axilla: Patterns of Regional Recurrence After Surgery With and Without Adjuvant Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pinkham, Mark B., E-mail: mark.pinkham@health.qld.gov.au; University of Queensland, Brisbane; Foote, Matthew C.

Purpose: To describe the anatomic distribution of regionally recurrent disease in patients with stage III melanoma in the axilla after curative-intent surgery with and without adjuvant radiation therapy. Methods and Materials: A single-institution, retrospective analysis of a prospective database of 277 patients undergoing curative-intent treatment for stage III melanoma in the axilla between 1992 and 2012 was completed. For patients who received radiation therapy and those who did not, patterns of regional recurrence were analyzed, and univariate analyses were performed to assess for potential factors associated with location of recurrence. Results: There were 121 patients who received adjuvant radiation therapymore » because their clinicopathologic features conferred a greater risk of regional recurrence. There were 156 patients who received no radiation therapy. The overall axillary control rate was 87%. There were 37 patients with regional recurrence; 17 patients had received adjuvant radiation therapy (14%), and 20 patients (13%) had not. The likelihood of in-field nodal recurrence was significantly less in the adjuvant radiation therapy group (P=.01) and significantly greater in sites adjacent to the axilla (P=.02). Patients with high-risk clinicopathologic features who did not receive adjuvant radiation therapy also tended to experience in-field failure rather than adjacent-field failure. Conclusions: Patients who received adjuvant radiation therapy were more likely to experience recurrence in the adjacent-field regions rather than in the in-field regions. This may not simply reflect higher-risk pathology. Using this data, it may be possible to improve outcomes by reducing the number of adjacent-field recurrences after adjuvant radiation therapy.« less

Patients With Brain Tumors: Who Receives Postacute Occupational Therapy Services?

PubMed

Chan, Vincy; Xiong, Chen; Colantonio, Angela

2015-01-01

Data on the utilization of occupational therapy among patients with brain tumors have been limited to those with malignant tumors and small samples of patients outside North America in specialized palliative care settings. We built on this research by examining the characteristics of patients with brain tumors who received postacute occupational therapy services in Ontario, Canada, using health care administrative data. Between fiscal years 2004-2005 and 2008-2009, 3,199 patients with brain tumors received occupational therapy services in the home care setting after hospital discharge; 12.4% had benign brain tumors, 78.2% had malignant brain tumors, and 9.4% had unspecified brain tumors. However, patients with benign brain tumors were older (mean age=63.3 yr), and a higher percentage were female (65.2%). More than 90% of patients received in-home occupational therapy services. Additional research is needed to examine the significance of these differences and to identify factors that influence access to occupational therapy services in the home care setting. Copyright © 2015 by the American Occupational Therapy Association, Inc.

Real-time dose adjustment using point-of-care platelet reactivity testing in a double-blind study of prasugrel in children with sickle cell anaemia.

PubMed

Jakubowski, Joseph A; Hoppe, Carolyn C; Zhou, Chunmei; Smith, Brendan E; Brown, Patricia B; Heath, Lori E; Inusa, Baba; Rees, David C; Small, David S; Gupta, Neehar; Yao, Suqin; Heeney, Matthew; Kanter, Julie

2017-02-28

Patients with sickle cell anaemia (SCA) have vaso-occlusive crises resulting from occlusive hypoxic-ischaemic injury. Prasugrel inhibits platelet activation and aggregation involved in SCA pathophysiology. Determining Effects of Platelet Inhibition on Vaso-Occlusive Events (DOVE) was a phase 3, double-blind, randomised, placebo-controlled trial assessing prasugrel efficacy. DOVE sought to bring patients' P2Y12 reaction unit (PRU) value within a targeted range via prasugrel dose adjustments using encrypted VerifyNow P2Y12 ® (VN-P2Y12) point-of-care testing and an interactive voice-response system (IVRS). After PRU determination, randomised patients received 0.08 mg/kg/day prasugrel or placebo. Encrypted PRUs and IVRS provided double-blind dose adjustments to achieve a defined PRU target range of 136-231; placebo patients had mock titrations. Of 341 randomised patients, 166 placebo and 160 prasugrel patients reached the fully titrated dose (FTD). Most prasugrel patients (n=104, 65 %) remained on the initial 0.08 mg/kg dose; doses escalations occurred in 23 % of patients (n=36). Mean PRUs for the pharmacodynamic population at baseline were similar in the prasugrel (273 ± 44.9) and placebo groups (273 ± 51.7), with significant reductions in PRU (p<0.001) for prasugrel patients at the FTD and at 9 months. Concomitant use of hydroxyurea did not affect platelet reactivity at any time. The majority of prasugrel patients (n=135, 84.4 %) at the FTD were within the target range of 136-231 PRUs. Mean VN-P2Y12 percentage inhibition at baseline was similar in the prasugrel (2.8  ± 5.4 %) and placebo groups (2.0 ± 4.7 %); prasugrel patients had significant increases in inhibition (p<0.001) at FTD and at 9 months. Patients with higher PRU values at baseline required higher prasugrel doses to bring PRU within the prespecified range. DOVE is the first study to successfully employ double-blind, real-time, encrypted, point-of-care platelet testing and IVRS to dose-adjust antiplatelet therapy to a targeted range of platelet inhibition.

Outcomes of cancer therapy administered to treatment-naïve lung cancer patients in the intensive care unit

PubMed Central

Chen, Yen-Fu; Lin, Jou-Wei; Ho, Chao-Chi; Yang, Ching-Yao; Chang, Chia-Hao; Huang, Tao-Min; Chen, Chung-Yu; Chen, Kuan-Yu; Shih, Jin-Yuan; Yu, Chong-Jen

2017-01-01

Objectives: Therapy outcomes for newly diagnosed, critically ill lung cancer patients have seldom been evaluated. This study evaluated therapy outcomes for treatment-naïve lung cancer patients in the intensive care unit (ICU). Materials and Methods: Patients were excluded if they had previously received lung cancer treatment, such as systemic chemotherapy, targeted therapy, radiotherapy, or surgical lung resection before ICU admission. The therapeutic strategies for the treatment-naïve patients were determined while they were in the ICU. The patients' demographic data, clinical outcomes, and treatment-related toxicities were analyzed. Results: Newly diagnosed lung cancer patients (n = 72) who did not receive any anticancer treatment before ICU admission were included. Most patients had locally advanced disease, and 61 (84.7%) required intensive care due to cancer-related events. In the ICU, 24 (33.3%) patients received chemotherapy, 24 (33.3%) received epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy and 24 (33.3%) received best supportive care (BSC). Patients receiving chemotherapy or EGFR-TKIs in the ICU demonstrated better ICU (p = 0.011) and in-hospital (p = 0.034) survival than those receiving BSC only. Among patients requiring mechanical ventilation, those receiving chemotherapy had higher weaning rates than those receiving EGFR-TKIs or BSC (p = 0.002). In multivariate analysis, receipt of chemotherapy (hazard ratio [HR], 0.443; p = 0.083) and mechanical ventilation (HR, 0.270; p = 0.022) were significantly associated with longer ICU survival after adjusting for clinical factors. Conclusions: Anticancer therapy in the ICU might provide better short-term ICU survival for treatment-naïve, critically ill lung cancer patients. PMID:28819399

Outcomes of cancer therapy administered to treatment-naïve lung cancer patients in the intensive care unit.

PubMed

Chen, Yen-Fu; Lin, Jou-Wei; Ho, Chao-Chi; Yang, Ching-Yao; Chang, Chia-Hao; Huang, Tao-Min; Chen, Chung-Yu; Chen, Kuan-Yu; Shih, Jin-Yuan; Yu, Chong-Jen

2017-01-01

Objectives: Therapy outcomes for newly diagnosed, critically ill lung cancer patients have seldom been evaluated. This study evaluated therapy outcomes for treatment-naïve lung cancer patients in the intensive care unit (ICU). Materials and Methods: Patients were excluded if they had previously received lung cancer treatment, such as systemic chemotherapy, targeted therapy, radiotherapy, or surgical lung resection before ICU admission. The therapeutic strategies for the treatment-naïve patients were determined while they were in the ICU. The patients' demographic data, clinical outcomes, and treatment-related toxicities were analyzed. Results: Newly diagnosed lung cancer patients (n = 72) who did not receive any anticancer treatment before ICU admission were included. Most patients had locally advanced disease, and 61 (84.7%) required intensive care due to cancer-related events. In the ICU, 24 (33.3%) patients received chemotherapy, 24 (33.3%) received epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy and 24 (33.3%) received best supportive care (BSC). Patients receiving chemotherapy or EGFR-TKIs in the ICU demonstrated better ICU (p = 0.011) and in-hospital (p = 0.034) survival than those receiving BSC only. Among patients requiring mechanical ventilation, those receiving chemotherapy had higher weaning rates than those receiving EGFR-TKIs or BSC (p = 0.002). In multivariate analysis, receipt of chemotherapy (hazard ratio [HR], 0.443; p = 0.083) and mechanical ventilation (HR, 0.270; p = 0.022) were significantly associated with longer ICU survival after adjusting for clinical factors. Conclusions: Anticancer therapy in the ICU might provide better short-term ICU survival for treatment-naïve, critically ill lung cancer patients.

A Strategy Using Photodynamic Therapy and Clofibric Acid to Treat Peritoneal Dissemination of Ovarian Cancer.

PubMed

Yokoyama, Yoshihito; Shigeto, Tatsuhiko; Miura, Rie; Kobayashi, Asami; Mizunuma, Makito; Yamauchi, Aisa; Futagami, Masayuki; Mizunuma, Hideki

2016-01-01

The current study examined the effectiveness of concurrent therapy using photodynamic therapy (PDT) and clofibric acid (CA) to treat peritoneal carcinomatosis resulting from ovarian cancer. Nude rats were used to create a model of peritoneal carcinomatosis resulting from ovarian cancer and the effectiveness of PDT with 5-aminolevulinic acid methyl ester hydrochloride (methyl-ALA-PDT) was determined. The survival time of rats receiving that therapy was compared to the survival time of a control group. Rats with peritoneal carcinomatosis resulting from ovarian cancer were divided into 3 groups: a group that received debulking surgery (DS) alone, a group that received DS+methyl-ALA-PDT, and a group that received DS+methyl-ALA-PDT+CA. The survival time of the 3 groups was compared. Protoporphyrin, a metabolite of methyl-ALA, produces a photochemical action when activated by light. The level of protoporphyrin (the concentration) that reached organs in the abdomen was measured with HPLC. Rats receiving methyl- ALA-PDT had a significantly longer survival time compared to the controls. Rats with peritoneal carcinomatosis that received DS+methyl-ALA-PDT+CA had a significantly longer survival time compared to the rats that received DS alone. Some of the rats that received concurrent therapy survived for a prolonged period. Protoporphyrin was highly concentrated in peritoneal metastases, but only small amounts reached major organs in the abdomen. PDT was not found to result in necrosis in the intestines. The results indicated that concurrent therapy consisting of PDT with methyl-ALA and CA is effective at treating peritoneal carcinomatosis resulting from ovarian cancer without damaging organs.

Randomized trial comparing two methods of re-irradiation after salvage surgery in head and neck squamous cell carcinoma: Once daily split-course radiotherapy with concomitant chemotherapy or twice daily radiotherapy with cetuximab.

PubMed

Tao, Yungan; Faivre, Laura; Laprie, Anne; Boisselier, Pierre; Ferron, Christophe; Jung, Guy Michel; Racadot, Séverine; Gery, Bernard; Even, Caroline; Breuskin, Ingrid; Bourhis, Jean; Janot, François

2018-05-18

A previous randomized trial in recurrent Head and Neck squamous-cell carcinoma (HNSCC) has shown re-irradiation combined with chemotherapy after salvage surgery significantly improved disease-free survival (DFS). The objective of this randomized trial was to compare two methods of re-irradiation in terms of toxicity and survival. Patients with recurrence/second primary in previously irradiated area were randomly allocated to receive either 60 Gy over 11 weeks with concomitant 5FU - hydroxyurea (VP-arm), or 60 Gy (1.2 Gy twice daily) over 5 weeks with cetuximab (HFR-arm). Primary endpoint was treatment interruption >15 days (acute toxicity). Twenty-six patients were included in VP-arm and 27 in HFR-arm. One patient in VP-arm experienced >15 days interruption due to toxicity, and none in HFR-arm. In both arms, all patients received at least 60 Gy. In VP-arm, 8/26 patients had chemotherapy delay and/or dose reduction. In HFR-arm, 4/27 patients had <6 cycles cetuximab. There was no significant difference in overall survival (Median OS: 37.4 months vs 21.9 months, p = 0.12). Toxicities and DFS were not different between 2 arms. Twice daily schedule of re-irradiation of 60 Gy/5 weeks with cetuximab was tolerable and no significant difference in treatment delays occurred between two arms. Copyright © 2018 Elsevier B.V. All rights reserved.

The Saccharomyces cerevisiae MUM2 gene interacts with the DNA replication machinery and is required for meiotic levels of double strand breaks.

PubMed Central

Davis, L; Barbera, M; McDonnell, A; McIntyre, K; Sternglanz, R; Jin , Q; Loidl, J; Engebrecht, J

2001-01-01

The Saccharomyces cerevisiae MUM2 gene is essential for meiotic, but not mitotic, DNA replication and thus sporulation. Genetic interactions between MUM2 and a component of the origin recognition complex and polymerase alpha-primase suggest that MUM2 influences the function of the DNA replication machinery. Early meiotic gene expression is induced to a much greater extent in mum2 cells than in meiotic cells treated with the DNA synthesis inhibitor hydroxyurea. This result indicates that the mum2 meiotic arrest is downstream of the arrest induced by hydroxyurea and suggests that DNA synthesis is initiated in the mutant. Genetic analyses indicate that the recombination that occurs in mum2 mutants is dependent on the normal recombination machinery and on synaptonemal complex components and therefore is not a consequence of lesions created by incompletely replicated DNA. Both meiotic ectopic and allelic recombination are similarly reduced in the mum2 mutant, and the levels are consistent with the levels of meiosis-specific DSBs that are generated. Cytological analyses of mum2 mutants show that chromosome pairing and synapsis occur, although at reduced levels compared to wild type. Given the near-wild-type levels of meiotic gene expression, pairing, and synapsis, we suggest that the reduction in DNA replication is directly responsible for the reduced level of DSBs and meiotic recombination. PMID:11238403

Differential effects of hydroxyurea and INC424 on mutant allele burden and myeloproliferative phenotype in a JAK2-V617F polycythemia vera mouse model.

PubMed

Kubovcakova, Lucia; Lundberg, Pontus; Grisouard, Jean; Hao-Shen, Hui; Romanet, Vincent; Andraos, Rita; Murakami, Masato; Dirnhofer, Stephan; Wagner, Kay-Uwe; Radimerski, Thomas; Skoda, Radek C

2013-02-14

To establish a preclinical animal model for testing drugs with potential effects on myeloproliferative neoplasms (MPNs), we first performed a detailed phenotypic characterization of Cre-inducible transgenic JAK2-V617F mice. Deleting the conditional mouse Jak2-knockout alleles increased erythropoiesis and accentuated the polycythemia vera phenotype, but did not alter platelet or granulocyte levels. In a transplantation assay, JAK2-V617F(+) BM cells had an advantage over wild-type competitor cells. Using this competitive repopulation assay, we compared the effects of INC424 (ruxolitinib), a dual Jak1/Jak2 inhibitor, and hydroxyurea (HU). HU led to weight loss, but did not reduce spleen weight. The hematologic parameters were lowered and a slight decrease of the mutant allele burden was noted. INC424 had little effect on body weight, but strongly decreased spleen size and rapidly normalized RBC and neutrophil parameters. No significant decrease in the mutant allele burden was observed. INC424 reduced the phospho-Stat5 levels, whereas HU strongly increased phospho-Stat5, most likely because of the elevated erythropoietin levels in response to the HU-induced anemia. This compensatory increase in JAK/STAT signaling may counteract the beneficial effects of cytoreduction at higher doses of HU and represents an adverse effect that should be avoided.

Regulation of DNA repair in serum-stimulated xeroderma pigmentosum cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gupta, P.K.; Sirover, M.A.

1984-10-01

The regulation of DNA repair during serum stimulation of quiescent cells was examined in normal human cells, in fibroblasts from three xeroderma pigmentosum complementation groups (A, C, and D), in xeroderma pigmentosum variant cells, and in ataxia telangiectasia cells. The regulation of nucleotide excision repair was examined by exposing cells to ultraviolet irradiation at discrete intervals after cell stimulation. Similarly, base excision repair was quantitated after exposure to methylmethane sulfonate. WI-38 normal human diploid fibroblasts, xeroderma pigmentosum variant cells, as well as ataxia telangiectasia cells enhanced their capacity for both nucleotide excision repair and for base excision repair prior tomore » their enhancement of DNA synthesis. Further, in each cell strain, the base excision repair enzyme uracil DNA glycosylase was increased prior to the induction of DNA polymerase using the identical cells to quantitate each activity. In contrast, each of the three xeroderma complementation groups that were examined failed to increase their capacity for nucleotide excision repair above basal levels at any interval examined. This result was observed using either unscheduled DNA synthesis in the presence of 10 mM hydroxyurea or using repair replication in the absence of hydroxyurea to quantitate DNA repair. However, each of the three complementation groups normally regulated the enhancement of base excision repair after methylmethane sulfonate exposure and each induced the uracil DNA glycosylase prior to DNA synthesis. 62 references, 3 figures, 2 tables.« less

Hydroxyurea for nontransfusion-dependent β-thalassemia: A systematic review and meta-analysis.

PubMed

Algiraigri, Ali H; Wright, Nicola A M; Paolucci, Elizabeth Oddone; Kassam, Aliya

2017-09-01

Nontransfusion-dependent β-thalassemia (NTDβT) syndromes consist of β-thalassemia intermedia and moderate hemoglobin E/β thalassemias. They are characterized by varying degrees of chronic anemia and a wide spectrum of complications due to ineffective erythropoiesis and iron overload from chronic transfusions. Hydroxyurea (HU), an oral chemotherapeutic drug, is anticipated to decrease disease severity. We performed a meta-analysis to evaluate the clinical efficacy and safety of HU in NTDβT patients of any age. MEDLINE, EMBASE, Cochrane databases, and major conference proceedings for studies that assessed HU in NTDβT patients were searched. Qualities of eligible studies were assessed by National Institutes of Health tools. Seventeen studies, collectively involving 709 patients, fulfilled the eligibility criteria. HU was associated with a significant decrease in transfusion need in severe NTDβT with complete and overall (≥50%) response rates of 42% and 79%, respectively. For mild NTDβT, HU was effective in raising hemoglobin by 1g/L in 64% of patients. HU appears to be effective, well tolerated, and associated with mild and transient adverse events. NTDβT patients may benefit from a trial of HU, although large randomized clinical trials assessing its efficacy should be conducted to confirm the findings of this meta-analysis and to assess its long-term toxicity and response sustainability. Copyright © 2017 King Faisal Specialist Hospital & Research Centre. Published by Elsevier B.V. All rights reserved.

Anagrelide reduces thrombotic risk in essential thrombocythaemia vs. hydroxyurea plus aspirin.

PubMed

Dombi, Péter; Illés, Árpád; Demeter, Judit; Homor, Lajos; Simon, Zsofia; Karadi, Eva; Udvardy, Miklos; Egyed, Miklos

2017-02-01

To evaluate the reduction in thrombotic events (TE) in patients with essential thrombocythaemia (ET) treated with anagrelide versus hydroxyurea + aspirin (HU + ASA). A questionnaire was developed using 2008 WHO diagnostic criteria, and thrombotic risk factors were stratified according to Landolfi criteria. Through questionnaire completion, clinicians at Hungarian haematological centres entered data into the Hungarian MPN Registry on patients with myeloproliferative neoplasms. Based on ET registry data, TEs in anagrelide-treated patients (n = 139) were compared with HU + ASA-treated patients (n = 141). Patients were followed up for (median) 6 yr. TEs were reported in significantly fewer anagrelide-treated patients versus HU + ASA (15.1% versus 49.6%; P < 0.001). Numbers of major arterial and major venous events were similar between the groups, although there were over fivefold more minor arterial and minor venous events in the HU + ASA group (P < 0.001). While median age at diagnosis was older and length of follow-up shorter in the HU + ASA group (P < 0.05), this did not influence TE incidence; medication and TE before diagnosis only influenced TE incidence. Anagrelide significantly decreased the number of patients experiencing minor arterial and minor venous TEs versus HU + ASA over 6 yr. Risk of TE after diagnosis was significantly increased if the patient had TE before diagnosis. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Evaluation of the RBC Pig-a and PIGRET assays using single doses of hydroxyurea and melphalan in rats.

PubMed

Adachi, Hideki; Uematsu, Yasuaki; Yamada, Toru

2016-11-15

To evaluate the suitability of the rat Pig-a assay on reticulocytes (PIGRET assay) as a short-term test, red blood cell (RBC) Pig-a and PIGRET assays after single doses with hydroxyurea (HU) and melphalan (L-PAM) were conducted and the results of both assays were compared. HU was administered once orally to male SD rats at 250, 500 and 1000mg/kg, and both assays were conducted using peripheral blood withdrawn from the jugular vein at 1, 2 and 4 weeks after dosing. L-PAM was administered at 1.25, 2.5 and 5mg/kg in the same manner. L-PAM produced significant dose-dependent increases in mutant frequencies in the PIGRET assay after single oral doses, but did not produce dose-dependent increases in mutant frequencies in the RBC Pig-a assay. These results suggest that the PIGRET assay is more sensitive for the evaluation of the mutagenic potential of L-PAM than the RBC Pig-a assay. In contrast, HU, a clastogenic but not DNA-reactive compound, gave negative results in both assays. The results with these 2 chemicals indicate that the single-dose PIGRET assay in rats has the potential to properly detect DNA-reactive compounds that directly cause DNA damage in a short-term assay. Copyright © 2016 Elsevier B.V. All rights reserved.

Adenoid cystic carcinoma of the lacrimal gland.

PubMed

Sanders, Jason C; Mendenhall, William M; Werning, John W

2016-01-01

This is a retrospective analysis of the 50-year University of Florida experience treating adenoid cystic carcinoma of the lacrimal gland with radiation therapy. Between 1965 and 2015, 8 patients with adenoid cystic carcinoma of the lacrimal gland received radiation therapy with curative intent. Four patients received postoperative radiation therapy and 4 received definitive radiation therapy alone. The median follow-up was 3.3 years (range, 0.3 to 11.2 years). All 4 patients who received postoperative radiation therapy received 74.4 Gy. The 4 patients who received radiation therapy alone received a median dose of 72.3 Gy (range, 70.0 to 74.4 Gy). The overall survival rates at 5 and 10 years were 25% and 13%, respectively. The cause-specific survival rates at 5 and 10 years were 29% and 14%, respectively. The local control and freedom from metastases rates at 5 and 10 years were both 43%. Local recurrences occurred in 50% of patients, and distant metastatic disease occurred in 38% of patients. No patients experienced acute complications of treatment that warranted a treatment break. Two patients experienced bone exposure as late complications of treatment. The results of this study illustrate the propensity for adenoid cystic carcinoma of the lacrimal gland to recur both locally and with distant metastases despite aggressive local treatment measures. This study also demonstrates the relatively poor outcomes for individuals with this type of tumor. Copyright © 2016 Elsevier Inc. All rights reserved.

A novel component from citrus, ginger, and mushroom family exhibits antitumor activity on human meningioma cells through suppressing the Wnt/β-catenin signaling pathway.

PubMed

Das, Arabinda; Miller, Rickey; Lee, Philip; Holden, Chrysanthe Alyssa; Lindhorst, Scott M; Jaboin, Jerry; Vandergrift, William A; Banik, Naren L; Giglio, Pierre; Varma, Abhay K; Raizer, Jeffery J; Patel, Sunil J

2015-09-01

Recurrent meningiomas constitute an uncommon but significant problem after standard (surgery and radiation) therapy failure. Current chemotherapies (hydroxyurea, RU-486, and interferon-α) are only of marginal benefit. There is an urgent need for more effective treatments for meningioma patients who have failed surgery and radiation therapy. Limonin, Tangeritin, Zerumbone, 6-Gingerol, Ganoderic Acid A, and Ganoderic Acid DM are some of the plant derivatives that have anti-tumorgenic properties and cause cell death in meningioma cells in vitro. Due to its ease of administration, long-term tolerability, and low incidence of long-term side effects, we explored its potential as a therapeutic agent against meningiomas by examining their efficacy in vitro against meningioma cells. Treatment effects were assessed using MTT assay, Western blot analysis, caspases assay, and DNA fragmentation assay. Results indicated that treatments of IOMM-Lee and CH157MN meningioma cells with Limonin, Tangeritin, Zerumbone, 6-Gingerol, Ganoderic Acid A, and Ganoderic Acid DM induced apoptosis with enhanced phosphorylation of glycogen synthase kinase 3 β (GSK3β) via inhibition of the Wnt5/β-catenin pathway. These drugs did not induce apoptosis in normal human neurons. Other events in apoptosis included downregulation of tetraspanin protein (TSPAN12), survival proteins (Bcl-XL and Mcl-1), and overexpression apoptotic factors (Bax and caspase-3). These results provide preliminary strong evidence that medicinal plants containing Limonin, Tangeritin, 6-Gingerol, Zerumbone, Ganoderic Acid A, and Ganoderic Acid DM can be applied to high-grade meningiomas as a therapeutic agent, and suggests that further in vivo studies are necessary to explore its potential as a therapeutic agent against malignant meningiomas.

Philadelphia chromosome-negative classical myeloproliferative neoplasms: revised management recommendations from European LeukemiaNet.

PubMed

Barbui, Tiziano; Tefferi, Ayalew; Vannucchi, Alessandro M; Passamonti, Francesco; Silver, Richard T; Hoffman, Ronald; Verstovsek, Srdan; Mesa, Ruben; Kiladjian, Jean-Jacques; Hehlmann, Rȕdiger; Reiter, Andreas; Cervantes, Francisco; Harrison, Claire; Mc Mullin, Mary Frances; Hasselbalch, Hans Carl; Koschmieder, Steffen; Marchetti, Monia; Bacigalupo, Andrea; Finazzi, Guido; Kroeger, Nicolaus; Griesshammer, Martin; Birgegard, Gunnar; Barosi, Giovanni

2018-05-01

This document updates the recommendations on the management of Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-neg MPNs) published in 2011 by the European LeukemiaNet (ELN) consortium. Recommendations were produced by multiple-step formalized procedures of group discussion. A critical appraisal of evidence by using Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methodology was performed in the areas where at least one randomized clinical trial was published. Seven randomized controlled trials provided the evidence base; earlier phase trials also informed recommendation development. Key differences from the 2011 diagnostic recommendations included: lower threshold values for hemoglobin and hematocrit and bone marrow examination for diagnosis of polycythemia vera (PV), according to the revised WHO criteria; the search for complementary clonal markers, such as ASXL1, EZH2, IDH1/IDH2, and SRSF2 for the diagnosis of myelofibrosis (MF) in patients who test negative for JAK2V617, CALR or MPL driver mutations. Regarding key differences of therapy recommendations, both recombinant interferon alpha and the JAK1/JAK2 inhibitor ruxolitinib are recommended as second-line therapies for PV patients who are intolerant or have inadequate response to hydroxyurea. Ruxolitinib is recommended as first-line approach for MF-associated splenomegaly in patients with intermediate-2 or high-risk disease; in case of intermediate-1 disease, ruxolitinib is recommended in highly symptomatic splenomegaly. Allogeneic stem cell transplantation is recommended for transplant-eligible MF patients with high or intermediate-2 risk score. Allogeneic stem cell transplantation is also recommended for transplant-eligible MF patients with intermediate-1 risk score who present with either refractory, transfusion-dependent anemia, blasts in peripheral blood > 2%, adverse cytogenetics, or high-risk mutations. In these situations, the transplant procedure should be performed in a controlled setting.

Antiretroviral drugs and acute pancreatitis in HIV/AIDS patients: is there any association? A literature review

PubMed Central

Oliveira, Natalia Mejias; Ferreira, Felipe Augusto Yamauti; Yonamine, Raquel Yumi; Chehter, Ethel Zimberg

2014-01-01

ABSTRACT In HIV-seropositive individuals, the incidence of acute pancreatitis may achieve 40% per year, higher than the 2% found in the general population. Since 1996, when combined antiretroviral therapy, known as HAART (highly active antiretroviral therapy), was introduced, a broad spectrum of harmful factors to the pancreas, such as opportunistic infections and drugs used for chemoprophylaxis, dropped considerably. Nucleotide analogues and metabolic abnormalities, hepatic steatosis and lactic acidosis have emerged as new conditions that can affect the pancreas. To evaluate the role of antiretroviral drugs to treat HIV/AIDS in a scenario of high incidence of acute pancreatitis in this population, a systematic review was performed, including original articles, case reports and case series studies, whose targets were HIV-seropositive patients that developed acute pancreatitis after exposure to any antiretroviral drugs. This association was confirmed after exclusion of other possible etiologies and/or a recurrent episode of acute pancreatitis after re-exposure to the suspected drug. Zidovudine, efavirenz, and protease inhibitors are thought to lead to acute pancreatitis secondary to hyperlipidemia. Nucleotide reverse transcriptase inhibitors, despite being powerful inhibitors of viral replication, induce a wide spectrum of side effects, including myelotoxicity and acute pancreatitis. Didanosine, zalcitabine and stavudine have been reported as causes of acute and chronic pancreatitis. They pose a high risk with cumulative doses. Didanosine with hydroxyurea, alcohol or pentamidine are additional risk factors, leading to lethal pancreatitis, which is not a frequent event. In addition, other drugs used for prophylaxis of AIDS-related opportunistic diseases, such as sulfamethoxazole-trimethoprim and pentamidine, can produce necrotizing pancreatitis. Despite comorbidities that can lead to pancreatic involvement in the HIV/AIDS population, antiretroviral drug-induced pancreatitis should always be considered in the diagnosis of patients with abdominal pain and elevated pancreatic enzymes. PMID:24728257

The Texas Experience with DepoProvera: 1980-1990.

ERIC Educational Resources Information Center

Emory, L. E.; And Others

1992-01-01

Compared sex offenders who received DepoProvera to group who had same clinical and legal problems but who refused pharmacotherapy. Both groups received group therapy, individual therapy, and sometimes family therapy. Results indicated that possible factors signifying increased likelihood of reoffense were high initial plasma testosterone,…

The impact of patient-perceived restricted access to anti-TNF therapy for rheumatoid arthritis: a qualitative study

PubMed Central

Sanderson, Tessa; Calnan, Michael; Morris, Marianne; Richards, Pam; Hewlett, Sarah

2010-01-01

Objective To explore rheumatoid arthritis patients’ experience of access to anti-TNF therapy in the UK, and of switching therapies after an initial failure. Methods Patients were asked about their experience of accessing, receiving and discontinuing anti-TNF therapy in face-to-face informal interviews, within the context of the larger study about treatment outcomes. 17 individuals with a diagnosis of rheumatoid arthritis and experience of receiving anti-TNF therapy were interviewed in one hospital trust in England. Results Different emotions (Theme 1) surrounded the process of accessing anti-TNF therapy: hope, desperation, apprehension, anxiety, and frustration. Experience of receiving anti-TNF therapy (Theme 2) included not only positive transformation, but also fear of failure and discontinuation. The subsequent value that patients placed on anti-TNF therapy (Theme 3) included having a right to receive therapy and being lucky. These three themes were underpinned by the core category of ‘willing to try anything’. Those switching therapies reported increased caution over the possibility of recurring side effects, but some suggestion of benefit. There was a perception that access to anti-TNF therapy was restricted by cost, rather than being recommended for those in clinical need. Conclusions Anti-TNF therapies may have a sudden and dramatic impact on RA patients’ lives that contrasts with other available medications. However, the stress of the patient’s journey through the need to “qualify” for anti-TNF therapy, and the fear of failing or discontinuation of therapy should not be underestimated by clinicians. PMID:19127529

Delays in accessing electroconvulsive therapy: a comparison between two urban and two rural populations in Australia.

PubMed

Johnston, Natalie E

2015-10-01

A comparison of the timing, rates and characteristics of electroconvulsive therapy use between urban and rural populations. The medical records of patients who received an acute course of electroconvulsive therapy at two rural and two urban psychiatric hospitals in New South Wales (NSW), Australia, in 2010 were reviewed retrospectively. Main outcome measures were the time from symptom onset, diagnosis and admission to commencing electroconvulsive therapy. Rates of use of electroconvulsive therapy were also compared between rural and urban hospitals using NSW statewide data. There was a significant delay in the time it took for rural patients to receive electroconvulsive therapy compared with urban patients when measured both from the time of symptom onset and from when they received a diagnosis. There were corresponding delays in the time taken for rural patients to be admitted to hospital compared with urban patients. There was no difference in the time it took to commence electroconvulsive therapy once a patient was admitted to hospital. NSW statewide urban-rural comparisons showed rates of electroconvulsive therapy treatment were significantly higher in urban hospitals. Patients in rural areas receive electroconvulsive therapy later in their acute illness due to delays in being admitted to hospital. The rate of use of electroconvulsive therapy also differs geographically. © The Royal Australian and New Zealand College of Psychiatrists 2015.

Effects of Music Therapy on Drug Therapy of Adult Psychiatric Outpatients: A Pilot Randomized Controlled Study

PubMed Central

Degli Stefani, Mario; Biasutti, Michele

2016-01-01

Objective: Framed in the patients’ engagement perspective, the current study aims to determine the effects of group music therapy in addition to drug care in comparison with drug care in addition to other non-expressive group activities in the treatment of psychiatric outpatients. Method: Participants (n = 27) with ICD-10 diagnoses of F20 (schizophrenia), F25 (schizoaffective disorders), F31 (bipolar affective disorder), F32 (depressive episode), and F60 (specific personality disorders) were randomized to receive group music therapy plus standard care (48 weekly sessions of 2 h) or standard care only. The clinical measures included dosages of neuroleptics, benzodiazepines, mood stabilizers, and antidepressants. Results: The participants who received group music therapy demonstrated greater improvement in drug dosage with respect to neuroleptics than those who did not receive group music therapy. Antidepressants had an increment for both groups that was significant only for the control group. Benzodiazepines and mood stabilizers did not show any significant change in either group. Conclusion: Group music therapy combined with standard drug care was effective for controlling neuroleptic drug dosages in adult psychiatric outpatients who received group music therapy. We discussed the likely applications of group music therapy in psychiatry and the possible contribution of music therapy in improving the psychopathological condition of adult outpatients. In addition, the implications for the patient-centered perspective were also discussed. PMID:27774073

Monocarboxylate transporters MCT1 and MCT4 are independent prognostic biomarkers for the survival of patients with clear cell renal cell carcinoma and those receiving therapy targeting angiogenesis.

PubMed

Cao, Yan-Wei; Liu, Yong; Dong, Zhen; Guo, Lei; Kang, En-Hao; Wang, Yong-Hua; Zhang, Wei; Niu, Hai-Tao

2018-04-12

Prognostic biomarkers for patients with clear cell renal cell carcinoma (ccRCC), particularly those receiving therapy targeting angiogenesis, are not well established. In this study, we examined the correlations of monocarboxylate transporter 1 (MCT1) and MCT4, 2 critical transporters for glycolytic metabolism, with various clinicopathological parameters as well as survival of patients with ccRCC and those treated with vascular endothelial growth factor receptor (VEGFR) inhibitors. A cohort of 150 ccRCC patients were recruited into this study. All patients underwent radical or partial nephrectomy as the first-line treatment, and 38 received targeted therapy (sorafenib or sunitinib) after the surgery. Expression levels of MCT1, MCT4, and CD34 were examined by immunohistochemistry. Correlations between MCT1 or MCT4 expression and different clinicopathological parameters or patient survival were analyzed among all as well as patients receiving targeted therapy. MCT1 or MCT4 expression did not significantly correlate with sex, age, tumor diameter, microvascular density, tumor staging, pathological Furmann grade, or MSKCC (P>0.05). High expression of either MCT1 or MCT4 significantly correlated with reduced overall survival (OS) and progression-free survival (PFS) among the total cohort of ccRCC patients. For patients receiving targeted therapy, high expression of either MCT1 or MCT4 significantly correlated with reduced PFS, but not OS. Both conditions were independent prognostic biomarkers for reduced PFS among all patients or those receiving targeted therapy. MCT1 and MCT4 are prognostic biomarkers for patients with ccRCC or those receiving targeted therapy. High expression of these 2 proteins predicts reduced PFS in these patients. Copyright © 2018 Elsevier Inc. All rights reserved.

Patient Satisfaction with Treatments for Moderate-to-Severe Plaque Psoriasis in Clinical Practice

PubMed Central

Takeshita, J.; Krueger, G.G.; Robertson, A.D.; Troxel, A.B.; Shin, D.B.; Van Voorhees, A.S.; Gelfand, J.M.

2014-01-01

Background Treatment satisfaction among moderate-to-severe psoriasis patients has not been studied and compared across treatments using a validated instrument. Objectives To assess patient-reported satisfaction with systemic and phototherapy treatments for moderate-to-severe psoriasis in clinical practice and to correlate satisfaction with disease severity and quality of life measures. Methods Cross-sectional study of 1182 patients with moderate-to-severe psoriasis in the Dermatology Clinical Effectiveness Research Network in the United States. Patients receiving either topical therapies only; monotherapy with oral systemic therapies, biologics, or narrowband ultraviolet B phototherapy; or combination therapy with biologics and methotrexate completed the Treatment Satisfaction Questionnaire for Medication version II. Results Median unadjusted Overall Satisfaction scores were highest for patients receiving biologic monotherapies, biologic-methotrexate combinations, or phototherapy (83.3); scores were lowest for those receiving topical therapies only or acitretin (66.7). In fully adjusted models, compared to patients receiving methotrexate monotherapy, those receiving adalimumab, etanercept, ustekinumab, phototherapy, or adalimumab with methotrexate had significantly higher median Overall Satisfaction scores by 7.2 to 8.3 points, while those receiving topical therapies only had significantly lower Overall Satisfaction by 8.9 points. Adjusted Convenience scores were the lowest for patients receiving topical therapies only or infliximab. Modest but significant correlations were found between Overall Satisfaction and Psoriasis Area and Severity Index (ρ = −0.36, p < 0.001) and Dermatology Life Quality Index (−0.47, p < 0.001). Conclusions Discernable differences were found in treatment satisfaction among therapies, particularly regarding treatment effectiveness and convenience. Further application of treatment satisfaction measures may inform treatment decisions and guideline development. PMID:24266717

Impact of initial local therapy on survival in men later receiving chemotherapy for prostate cancer: a population-based, propensity-weighted multivariable analysis.

PubMed

Zabell, Joseph R; Adejoro, Oluwakayode; Jarosek, Stephanie L; Elliott, Sean P; Konety, Badrinath R

2016-10-01

Prostate cancer remains a common disease that is frequently treated with multimodal therapy. The goal of this study was to assess the impact of treatment of the primary tumor on survival in men who go onto receive chemotherapy for prostate cancer. Using surveillance, epidemiology and end results (SEER)-Medicare data from 1992 to 2009, we identified a cohort of 1614 men who received chemotherapy for prostate cancer. Primary outcomes were prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM). We compared survival among men who had previously undergone radical prostatectomy (RP), radiation therapy (RT), or neither of these therapies. Propensity score adjusted Cox proportional hazard models and weighted Kaplan-Meier curves were used to assess survival. Compared to men who received no local treatment, PCSM was lower for men who received RP ± RT (HR 0.65, p < 0.01) and for those who received RT only (HR 0.79, p < 0.05). Patients receiving neither RP nor RT demonstrated higher PCSM and ACM than those receiving treatment in a weighted time-to-event analysis. Men who received RP + RT had longer mean time from diagnosis to initiation of chemotherapy (100.7 ± 47.7 months) than men with no local treatment (48.8 ± 35.0 months, p < 0.05). In patients who go on to receive chemotherapy, treatment of the primary tumor for prostate cancer appears to confer a survival advantage over those who do not receive primary treatment. These data suggest continued importance for local treatment of prostate cancer, even in patients at high risk of failing local therapy.

Dactinomycin

MedlinePlus

... in combination with other medications, surgery, and/or radiation therapy to treat Wilms' tumor (a type of ... you have previously received or are currently receiving radiation therapy.tell your doctor if you are pregnant, ...

Intensive diabetes therapy and ocular surgery in type 1 diabetes.

PubMed

Aiello, Lloyd Paul; Sun, Wanjie; Das, Arup; Gangaputra, Sapna; Kiss, Szilard; Klein, Ronald; Cleary, Patricia A; Lachin, John M; Nathan, David M

2015-04-30

The Diabetes Control and Complications Trial (DCCT) showed a beneficial effect of 6.5 years of intensive glycemic control on retinopathy in patients with type 1 diabetes. Between 1983 and 1989, a total of 1441 patients with type 1 diabetes in the DCCT were randomly assigned to receive either intensive diabetes therapy or conventional therapy aimed at preventing hyperglycemic symptoms. They were treated and followed until 1993. Subsequently, 1375 of these patients were followed in the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study. The self-reported history of ocular surgical procedures was obtained annually. We evaluated the effect of intensive therapy as compared with conventional therapy on the incidence and cost of ocular surgery during these two studies. Over a median follow-up of 23 years, 130 ocular operations were performed in 63 of 711 patients assigned to intensive therapy (8.9%) and 189 ocular operations in 98 of 730 patients assigned to conventional therapy (13.4%) (P<0.001). After adjustment for DCCT baseline factors, intensive therapy was associated with a reduction in the risk of any diabetes-related ocular surgery by 48% (95% confidence interval [CI], 29 to 63; P<0.001) and a reduction in the risk of all such ocular procedures by 37% (95% CI, 12 to 55; P=0.01). Forty-two patients who received intensive therapy and 61 who received conventional therapy underwent cataract extraction (adjusted risk reduction with intensive therapy, 48%; 95% CI, 23 to 65; P=0.002); 29 patients who received intensive therapy and 50 who received conventional therapy underwent vitrectomy, retinal-detachment surgery, or both (adjusted risk reduction, 45%; 95% CI, 12 to 66; P=0.01). The costs of surgery were 32% lower in the intensive-therapy group. The beneficial effects of intensive therapy were fully attenuated after adjustment for mean glycated hemoglobin levels over the entire follow-up. Intensive therapy in patients with type 1 diabetes was associated with a substantial reduction in the long-term risk of ocular surgery. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; DCCT/EDIC ClinicalTrials.gov numbers, NCT00360893 and NCT00360815.).

Endocrine therapy use among elderly hormone receptor-positive breast cancer patients enrolled in Medicare Part D

PubMed Central

Riley, Gerald F.; Warren, Joan L.; Harlan, Linda C.; Blackwell, Steven A.

2011-01-01

Background Clinical guidelines recommend that women with hormone-receptor positive breast cancer receive endocrine therapy (selective estrogen receptor modulators [SERMs] or aromatase inhibitors [AIs]) for five years following diagnosis. Objective To examine utilization and adherence to therapy for SERMs and AIs in Medicare Part D prescription drug plans. Data Linked Surveillance, Epidemiology, and End Results (SEER)-Medicare data. Study design We identified 15,542 elderly women diagnosed with hormone-receptor positive breast cancer in years 2003-2005 (the latest SEER data at the time of the study) and enrolled in a Part D plan in 2006 or 2007 (the initial years of Part D). This permitted us to compare utilization and adherence to therapy at various points within the recommended five-year timeframe for endocrine therapy. SERM and AI use was measured from claim records. Non-adherence to therapy was defined as a medication possession ratio of less than 80 percent. Principal findings Between May 2006 and December 2007, 22 percent of beneficiaries received SERM, 52 percent AI, and 26 percent received neither. The percent receiving any endocrine therapy decreased with time from diagnosis. Among SERM and AI users, 20-30 percent were non-adherent to therapy; out-of-pocket costs were higher for AI than SERM and were strongly associated with non-adherence. For AI users without a low income subsidy, adherence to therapy deteriorated after reaching the Part D coverage gap. Conclusions Many elderly breast cancer patients were not receiving therapy for the recommended five years following diagnosis. Choosing a Part D plan that minimizes out-of-pocket costs is critical to ensuring beneficiary access to essential medications. PMID:22340780

Blood-brain barrier permeability assessed by perfusion computed tomography predicts hemorrhagic transformation in acute reperfusion therapy.

PubMed

Kim, Taewon; Koo, Jaseong; Kim, Seong-Hoon; Song, In-Uk; Chung, Sung-Woo; Lee, Kwang-Soo

2018-06-16

Hemorrhagic transformation (HT) is one of the most feared complications of acute recanalization therapies. The aim of this study was to evaluate whether blood-brain barrier permeability (BBBP) imaging can predict HT in the setting of acute recanalization therapy and to determine the sensitivity and specificity of BBBP for the prediction of HT according to the type of reperfusion therapy. We assessed a total of 46 patients who received recanalization therapy (intravenous (IV) recombinant tissue plasminogen activator (tPA), mechanical thrombectomy with a stent retriever or both) for acute ischemic stroke within the internal carotid artery or middle cerebral artery. BBBP above the threshold was significantly associated with HT after adjustment for confounding factors in all patients (OR 45.4, 95% CI 2.9~711.2, p = 0.007), patients who received IV tPA (OR 20.1, 95% CI 1.2-336.7, p = 0.037), and patients who received endovascular therapy (OR 47.2, 95% CI 1.9-1252.5, p = 0.022). The sensitivity and specificity of the initial BBBP measurement as a predictor of HT in the overall 46 patients were 80 and 71%, respectively. These values were 75 and 64% in only IV tPA group, 100 and 80% in only endovascular group, 77 and 67% in IV tPA with or without endovascular therapy group, and 86 and 76% in endovascular therapy with or without bridging IV tPA therapy group. Increased pretreatment BBBP values were significantly associated with HT after acute recanalization therapy. This correlation with HT was stronger in patients receiving endovascular mechanical thrombectomy than in patients receiving IV rtPA.

Antiretroviral therapy during pregnancy and the risk of an adverse outcome.

PubMed

Tuomala, Ruth E; Shapiro, David E; Mofenson, Lynne M; Bryson, Yvonne; Culnane, Mary; Hughes, Michael D; O'Sullivan, M J; Scott, Gwendolyn; Stek, Alice M; Wara, Diane; Bulterys, Marc

2002-06-13

Some studies suggest that combination antiretroviral therapy in pregnant women with human immunodeficiency virus type 1 (HIV-1) infection increases the risk of premature birth and other adverse outcomes of pregnancy. We studied pregnant women with HIV-1 infection who were enrolled in seven clinical studies and delivered their infants from 1990 through 1998. The cohort comprised 2123 women who received antiretroviral therapy during pregnancy (monotherapy in 1590, combination therapy without protease inhibitors in 396, and combination therapy with protease inhibitors in 137) and 1143 women who did not receive antiretroviral therapy. After standardization for the CD4+ cell count and use or nonuse of tobacco, alcohol, and illicit drugs, the rate of premature delivery (<37 weeks of gestation) was similar among the women who received antiretroviral therapy and those who did not (16 percent and 17 percent, respectively); the rate of low birth weight (<2500 g) was 16 percent among the infants born to both groups; and the rate of very low birth weight (<1500 g) was 2 percent for the group that received antiretroviral therapy and 1 percent for the group that did not. The rates of low Apgar scores (<7) and stillbirth were also similar or the same in the two groups. After adjustment for multiple risk factors, combination antiretroviral therapy was not associated with an increased risk of premature delivery as compared with monotherapy (odds ratio, 1.08; 95 percent confidence interval, 0.71 to 1.62) or delivery of an infant with low birth weight (odds ratio, 1.03; 95 percent confidence interval, 0.64 to 1.63). Seven of the women who received combination therapy with protease inhibitors (5 percent) had infants with very low birth weight, as compared with nine women who received combination therapy without protease inhibitors (2 percent) (adjusted odds ratio, 3.56; 95 percent confidence interval, 1.04 to 12.19). As compared with no antiretroviral therapy or monotherapy, combination therapy for HIV-1 infection in pregnant women is not associated with increased rates of premature delivery or with low birth weight, low Apgar scores, or stillbirth in their infants. The association between combination therapy with protease inhibitors and an increased risk of very low birth weight requires confirmation.

Half-body irradiation in the treatment of multiple myeloma: a report of nine cases.

PubMed

Plesnicar, A; Jereb, B; Zaletel-Kragelj, L

1996-01-01

We report the results of treatment of 9 patients with advanced multiple myeloma (MM) using half-body irradiation. Six nonresponders to chemotherapy received it as consolidation therapy after the plateau phase of MM had been observed, and 4 patients received it as salvage therapy of refractory or relapsing MM. One of the patients received it twice, first as consolidation and later during the course of her disease also as salvage therapy. Objective response was obtained in 1 of 6 patients who received half-body irradiation as consolidation therapy and in 3 of 4 patients who received it as salvage therapy. Responders to half-body irradiation generally achieved a longer relapse-free interval. Treatment with half-body irradiation was especially effective in combination with human leukocyte interferon as salvage therapy in 2 of the patients with refractory MM, leading to a relapse-free interval of more than 27 months in one of them. Symptomatic relief was observed in 5 of 6 patients. All had transient post-irradiation pancytopenia, with pneumonitis, nausea and vomiting observed in those who had the upper half of the body irradiated first. It is thus our opinion that halfbody irradiation should not be used as consolidation therapy in nonresponders to chemotherapy, because it causes undue toxicity to heavily pretreated patients. Its role in the treatment of refractory or relapsing MM in combination with human leukocyte interferon should be fully evaluated.

Concomitant Use of Immunomodulators Affects the Durability of Infliximab Therapy in Children With Crohn's Disease.

PubMed

Grossi, Victoria; Lerer, Trudy; Griffiths, Anne; LeLeiko, Neal; Cabrera, Jose; Otley, Anthony; Rick, James; Mack, David; Bousvaros, Athos; Rosh, Joel; Grossman, Andrew; Saeed, Shehzaad; Kay, Marsha; Boyle, Brendan; Oliva-Hemker, Maria; Keljo, David; Pfefferkorn, Marian; Faubion, William; Kappelman, Michael D; Sudel, Boris; Markowitz, James; Hyams, Jeffrey S

2015-10-01

It is important to determine the effects of immunomodulators on the ability of children to remain on infliximab therapy for Crohn's disease (durability of therapy), given the potential benefits and risks of concomitant therapy-especially with thiopurines in male patients. We investigated how immunomodulatory treatment affects the durability of infliximab therapy. We collected data from the Pediatric Inflammatory Bowel Disease Collaborative Research Group Registry, from January 2002 through August 2014, on 502 children with Crohn's disease who participated in a prospective multicenter study. Data were collected from patients who received at least a 3-dose induction regimen of infliximab, and their concomitant use of immunomodulators: no thiopurine or methotrexate treatment, treatment for 6 months or less during infliximab therapy, or treatment for more than 6 months during infliximab therapy. The probabilities (± standard error) that children remained on infliximab therapy for 1 year, 3 years, and 5 years after the treatment began were 0.84 ± 0.02, 0.69 ± 0.03, and 0.60 ± 0.03, respectively. Age, sex, and disease extent or location did not affect the durability of infliximab therapy. Greater length of concomitant use of immunomodulators was associated with increased time of infliximab therapy. The probability that patients with more than 6 months of immunomodulator use remained on infliximab therapy for 5 years was 0.70 ± 0.04, compared with 0.48 ± 0.08 for patients who did not receive immunomodulators and 0.55 ± 0.06 for patients who received immunomodulators for 6 months or less (P < .001). In boys who received immunomodulators for 6 months or more after starting infliximab, the overall durability of infliximab therapy was greater among patients receiving methotrexate than thiopurine (P < .01); the probabilities that they remained on infliximab therapy for 5 years were 0.97 ± 0.03 vs 0.58 ± 0.08, respectively. In children with Crohn's disease, concomitant treatment with an immunomodulator for more than 6 months after starting infliximab therapy increases the chances that patients will remain on infliximab. In boys, methotrexate appears to increase the durability of infliximab therapy compared with thiopurine. Copyright © 2015. Published by Elsevier Inc.

Payer incentives and physical rehabilitation therapy for nonelderly institutional long-term care residents: evidence from Michigan and Ontario.

PubMed

Wodchis, Walter P; Fries, Brant E; Pollack, Harold

2004-02-01

To examine the effect of payment incentives on the provision of rehabilitation therapy to non elderly nursing home residents. Retrospective cross-sectional study. Nursing homes in Michigan or complex continuing care facilities in Ontario, Canada, in 1998 or 1999. Non elderly nursing home residents (N=5189) admitted to nursing homes. Not applicable. The effect of payment on access to physical therapy (PT) and occupational therapy (OT) and total weekly time for each therapy type. A Medicare policy change from cost-based to a patient-specific case-mix payment method was associated with greater likelihood of receiving OT but reduced weekly minutes of PT and OT provided to residents. Medicare cost-based and private insurance were associated with greater likelihood of receiving OT and PT and more therapy time for both types of therapy compared with private-pay residents. Global budget payment was associated with greater access to PT but fewer weekly minutes of OT and PT. Little information exists to describe the characteristics and treatment of non elderly nursing home residents. This study found that many of these residents received rehabilitation and that residents whose care was paid for by more generous payers, such as Medicare, received more therapy than those paid for by less generous payers.

Helping Older Adults Sustain Their Physical Therapy Gains: A Theory-Based Intervention to Promote Adherence to Home Exercise Following Rehabilitation.

PubMed

Gallagher, Kristel M

2016-01-01

The benefits of exercise gained by older adults during physical therapy are often not maintained once the program is over. This lack of sustained benefits is thought to be partially the result of poor adherence to the prescribed home exercise program to be continued once therapy is completed. Most of what is known about older adults' adherence to physical therapy and home exercise comes from research seeking to identify and understand predictors of adherence, rather than trying to enhance adherence explicitly. The purpose of this study was to test a theoretically grounded approach to promoting adherence to home exercise programs in older adults. Sixty older adults (M age = 69.3 (6.87) years) in a program of physical therapy received 1 of 2 print messages and magnets promoting adherence to home exercise. The content of the messages was informed by the goal-specific tenets of socioemotional selectivity theory-one message described the emotional and meaningful benefits of home exercise, such as time with loved ones and independence, and one message described facts and information about physiological benefits, such as balance and strength. Adherence to home exercise was measured 2 weeks after participants were discharged from physical therapy by calculating the percentage of the prescribed exercises participants reported completing at home. An analysis of covariance indicated that there was no statistically significant difference in adherence rates between participants receiving either message. However, a 2×2 analysis of covariance did reveal a significant interaction between the type of message participants received and the time at which they received that message. Post hoc analyses separately examined the rates of adherence in participants who received the intervention message with time remaining in their therapy program and participants who received the intervention message on the day of discharge. In the subset of participants who received their intervention message with time remaining in their therapy program, those who received the emotion and meaning message were somewhat more adherent to their home exercise program than those who received the facts and information message (63.6% vs 50.8%; P = .07). Those who received the emotion and meaning message also performed on average more exercises outside of their home exercise program (2.4 vs 1.3; P = .06). Despite lacking a statistically significant difference between message groups, the results of this study suggest that highlighting the emotional and meaningful benefits of home exercise versus providing facts and information about the physiological benefits may encourage older adults to be adherent to their home exercise programs. This may especially be the case if they receive the information while still in therapy. As this was the first study to empirically test an intervention targeting adherence to post-physical therapy home exercise in older adults, future research is needed to better understand what motivates older adults to be adherent.

Prevention and management of hepatitis B virus reactivation in patients with hematological malignancies treated with anticancer therapy

PubMed Central

Law, Man Fai; Ho, Rita; Cheung, Carmen K M; Tam, Lydia H P; Ma, Karen; So, Kent C Y; Ip, Bonaventure; So, Jacqueline; Lai, Jennifer; Ng, Joyce; Tam, Tommy H C

2016-01-01

Hepatitis due to hepatitis B virus (HBV) reactivation can be severe and potentially fatal, but is preventable. HBV reactivation is most commonly reported in patients receiving cancer chemotherapy, especially rituximab-containing therapy for hematological malignancies and those receiving stem cell transplantation. All patients with hematological malignancies receiving anticancer therapy should be screened for active or resolved HBV infection by blood tests for hepatitis B surface antigen (HBsAg) and antibody to hepatitis B core antigen (anti-HBc). Patients found to be positive for HBsAg should be given prophylactic antiviral therapy to prevent HBV reactivation. For patients with resolved HBV infection, no standard strategy has yet been established to prevent HBV reactivation. There are usually two options. One is pre-emptive therapy guided by serial HBV DNA monitoring, whereby antiviral therapy is given as soon as HBV DNA becomes detectable. However, there is little evidence regarding the optimal interval and period of monitoring. An alternative approach is prophylactic antiviral therapy, especially for patients receiving high-risk therapy such as rituximab, newer generation of anti-CD20 monoclonal antibody, obinutuzumab or hematopoietic stem cell transplantation. This strategy may effectively prevent HBV reactivation and avoid the inconvenience of repeated HBV DNA monitoring. Entecavir or tenofovir are preferred over lamivudine as prophylactic therapy. Although there is no well-defined guideline on the optimal duration of prophylactic therapy, there is growing evidence to recommend continuing prophylactic antiviral therapy for at least 12 mo after cessation of chemotherapy, and even longer for those who receive rituximab or who had high serum HBV DNA levels before the start of immunosuppressive therapy. Many novel agents have recently become available for the treatment of hematological malignancies, and these agents may be associated with HBV reactivation. Although there is currently limited evidence to guide the optimal preventive measures, we recommend antiviral prophylaxis in HBsAg-positive patients receiving novel treatments, especially the Bruton tyrosine kinase inhibitors and the phosphatidylinositol 3-kinase inhibitors, which are B-cell receptor signaling modulators and reduce proliferation of malignant B-cells. Further studies are needed to clarify the risk of HBV reactivation with these agents and the best prophylactic strategy in the era of targeted therapy for hematological malignancies. PMID:27605883

Review of electroconvulsive therapy practice from a tertiary Child and Adolescent Psychiatry Centre.

PubMed

Jacob, Preeti; Gogi, Prabhu Kiran Vishwanath; Srinath, Shoba; Thirthalli, Jagadisha; Girimaji, Satish; Seshadri, Shekhar; Sagar, John Vijay

2014-12-01

The use of electroconvulsive therapy (ECT) in children and adolescents is a controversial issue. This study was done to examine the pattern and practice as well as the outcome of electroconvulsive therapy administered to children and adolescents admitted to a tertiary care centre. A 10 year retrospective chart review of all children and adolescents (up to 16 years of age) admitted in the Child and Adolescent Psychiatry Centre, National Institute of Mental Health and Neurosciences (NIMHANS) who had received at least 1 session of ECT was done. Information regarding diagnosis, reasons for prescribing electroconvulsive therapy, details regarding the procedure and outcome variables was collected from the records. Clinical Global Impressions (CGI) scale rating of the severity of illness and improvement seen were done by 2 trained psychiatrists independently. 22 children and adolescents received electroconvulsive therapy over 10 years. There were an equal number of boys and girls. All received modified ECT. Most patients who received electroconvulsive therapy were severely ill. Catatonic symptoms 54.5% (12) were the most common reason for prescribing electroconvulsive therapy. It was efficacious in 77.3% (17) of the patients. Electroconvulsive therapy was relatively safe, and most experienced no acute side effects. 68.2% (15) who were on follow up and did not experience any long term side effects due to the electroconvulsive therapy. Electroconvulsive therapy has a place in the acute management of severe childhood psychiatric disorders. Further long term prospective studies are required. Copyright © 2014 Elsevier B.V. All rights reserved.

Cognitive Behavioral Therapy for Psychosis (CBT-p) Delivered in a Community Mental Health Setting: A Case Comparison of Clients Receiving CBT Informed Strategies by Case Managers Prior to Therapy.

PubMed

Sivec, Harry J; Montesano, Vicki L; Skubby, David; Knepp, Kristen A; Munetz, Mark R

2017-02-01

This exploratory case comparison examines the influence of case management activities on engagement and progress in psychotherapy for clients with schizophrenia. Six clients were recruited to participate in ten sessions of Cognitive Behavioral Therapy for psychosis (CBT-p). Three clients who had received Cognitive Behavioral techniques for psychosis (CBt-p, a low-intensity case management intervention) prior to receiving therapy were selected from referrals. A comparison group of three clients who had received standard case management services was selected from referrals. Cases within and across groups were compared on outcome measures and observations from case review were offered to inform future research. Delivering CBT-p services on a continuum from low- to high-intensity is discussed.

Music Therapy for Symptom Management After Autologous Stem Cell Transplantation: Results From a Randomized Study.

PubMed

Bates, Debbie; Bolwell, Brian; Majhail, Navneet S; Rybicki, Lisa; Yurch, Melissa; Abounader, Donna; Kohuth, Joseph; Jarancik, Shannon; Koniarczyk, Heather; McLellan, Linda; Dabney, Jane; Lawrence, Christine; Gallagher, Lisa; Kalaycio, Matt; Sobecks, Ronald; Dean, Robert; Hill, Brian; Pohlman, Brad; Hamilton, Betty K; Gerds, Aaron T; Jagadeesh, Deepa; Liu, Hien D

2017-09-01

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is frequently performed in patients with hematologic malignancies. ASCT can result in significant nausea, pain, and discomfort. Supportive care has improved, and pharmacologic therapies are frequently used, but with limitations. Music has been demonstrated to improve nausea and pain in patients undergoing chemotherapy, but little data are available regarding the effects of music therapy in the transplantation setting. In a prospective study, patients with lymphoma or multiple myeloma undergoing ASCT were randomized to receive either interactive music therapy with a board-certified music therapist or no music therapy. The music therapy arm received 2 music therapy sessions on days +1 and +5. Primary outcomes were perception of pain and nausea measured on a visual analog scale. Secondary outcomes were narcotic pain medication use from day -1 to day +5 and impact of ASCT on patient mood as assessed by Profile of Mood States (POMS) on day +5. Eighty-two patients were enrolled, with 37 in the music therapy arm and 45 in the no music therapy arm. Patients who received MT had slightly increased nausea by day +7 compared with the no music therapy patients. The music therapy and no music therapy patients had similar pain scores; however, the patients who received music therapy used significantly less narcotic pain medication (median, 24 mg versus 73 mg; P = .038). Music therapy may be a viable nonpharmacologic method of pain management for patients undergoing ASCT; the music therapy patients required significantly fewer morphine equivalent doses compared with the no music therapy patients. Additional research is needed to better understand the effects of music therapy on patient-perceived symptoms, such as pain and nausea. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Combined Aspirin and Anticoagulant Therapy in Patients with Atrial Fibrillation

PubMed Central

So, Charlotte H.; Eckman, Mark H.

2016-01-01

Background The combined use of aspirin and oral anticoagulant therapy in patients with atrial fibrillation (AF) and stable coronary artery disease (CAD) has been questioned due to an increased risk of major bleeding with little to no benefit in preventing ischemic events. Objective (1) To better understand patterns and indications for combined antiplatelet and anticoagulant therapy and identify patients who might reasonably be treated with oral anticoagulant (OAC) therapy alone. (2) To perform an updated literature review regarding the use of combined antiplatelet and OAC therapy in patients with AF and stable CAD. Design and Participants Retrospective review. Patients within the University of Cincinnati Health System with a diagnosis of non-valvular AF, excluding those with acute coronary syndrome or revascularization within the last 12 months. Main Measures Numbers and indications for combined antiplatelet and anticoagulant therapy and sequence of events leading to the initiation of each. Key Results Of 948 patients receiving OAC, 430 (45%) were receiving concomitant OAC and aspirin. Among patients receiving combined antiplatelet and anticoagulant therapy, 49% and 42% of patients respectively, had CAD or DM. In a more detailed analysis including chart review of 219 patients receiving combined OAC and aspirin, 27% had a diagnosis of CAD and 14% had a diagnosis of DM prior to the development of AF. These patients were initially treated with aspirin. Warfarin was added when they subsequently developed AF but aspirin wasn’t discontinued. A surprisingly large proportion of patients (22.8%) had no obvious indication for dual therapy. Conclusions Prior myocardial infarction, CAD, vascular disease and DM (among others) increase the likelihood of receiving combined antiplatelet and anticoagulant therapy among patients with AF. A literature review suggests this may lead to increased major bleeding with little benefit in decreasing either AF-related stroke or cardiovascular events. PMID:27665101

[Outcome of patients with relapsed/refractory adult T-cell leukemia-lymphoma after salvage therapy].

PubMed

Taniguchi, Hiroaki; Imaizumi, Yoshitaka; Makiyama, Junya; Itonaga, Hidehiro; Ando, Koji; Sawayama, Yasushi; Imanishi, Daisuke; Taguchi, Jun; Tsushima, Hideki; Hata, Tomoko; Hasegawa, Hiroo; Hayashi, Tomayoshi; Niino, Daisuke; Ohshima, Koichi; Tsukasaki, Kunihiro; Miyazaki, Yasushi

2013-12-01

We retrospectively analyzed 81 relapsed or refractory adult T-cell leukemia-lymphoma (ATL) patients who received salvage therapy in our institution between 2000 and 2010. These patients had received chemotherapy, radiation, or hematopoietic stem cell transplantation (HSCT) as an initial treatment, and were then given chemotherapy, radiation, HSCT, or donor lymphocyte infusion (DLI) as salvage therapy. Median survival time was 3.9 months. Of 5 long-term survivors, who survived more than 2 years after the first salvage therapy, 4 patients received HSCT or DLI, and the other was given mogamulizumab as the salvage therapy. For patients with relapsed or refractory ATL, HSCT/DLI is a promising treatment for achieving long-term survival. Mogamulizumab may be the good choice for those who are ineligible for HSCT.

Retrospective Audit: Does Prior Assessment by Oral and Maxillofacial Surgeons Reduce the Risk of Osteonecrosis of The Jaw in Patients Receiving Bone-Targeted Therapies for Metastatic Cancers to the Skeleton?--Part II.

PubMed

Turner, Bruce; Ali, Sacha; Pati, Jhumur; Nargund, Vinod; Ali, Enamul; Cheng, Leo; Wells, Paula

2016-01-01

Men who receive bone-targeted therapy for metastatic prostate cancer are at increased risk of osteonecrosis of the jaw (ONJ). Development of ONJ has been associated with the administration of bone-targeted therapies in association with other risk factors. ONJ can be distressing for a patient because it can cause pain, risk of jaw fracture, body image disturbance, difficultly eating, and difficulty maintaining good oral hygiene. The aim of this article is to report results of an audit of prior assessment by oral and maxillofacial surgeons (OMFS) before initiation of bone-targeted therapies and whether it may reduce the risk of ONJ in patients receiving bone-targeted therapies for advanced cancers.

E-cigarette use in patients receiving home oxygen therapy.

PubMed

Lacasse, Yves; Légaré, Martin; Maltais, François

2015-01-01

Current smokers who are prescribed home oxygen may not benefit from the therapy. In addition to being an obvious fire hazard, there is some evidence that the physiological mechanisms by which home oxygen is believed to operate are inhibited by smoking. Although their effectiveness is yet to be demonstrated, electronic cigarettes (e-cigarettes) are often regarded as an aid to smoking cessation. However, several burn accidents in e-cigarette smokers receiving home oxygen therapy have also been reported, leading Health Canada to release a warning of fire risk to oxygen therapy patients from e-cigarettes. It is the authors' position that patients receiving oxygen should definitely not use e-cigarettes. The authors provide suggestions for addressing the delicate issue of home oxygen therapy in current cigarette and⁄or e-cigarette smokers.

Androgen deprivation in veterans with prostate cancer: implications for skeletal health.

PubMed

Wilcox, Andrew; Carnes, Molly L; Moon, Timothy D; Tobias, Renee; Baade, Heather; Stamos, Emily; Elliott, Mary E

2006-12-01

Common risk factors for osteoporosis in older men include smoking, heavy use of alcohol, propensity to falls, and use of bone-toxic medications such as prednisone. There is also increasing appreciation of the skeletal risk faced by men receiving androgen deprivation therapy (ADT) for prostate cancer. Measures to prevent bone loss in such patients are available. To test the following hypotheses in a population of veterans receiving ADT for prostate cancer: (1) fracture risk factors in addition to androgen deprivation would be found in most patients, (2) bone mass measurements would be assessed in a minority of patients, and (3) a minority of the subjects would receive bisphosphonate therapy or have contraindications for such treatment. We conducted a retrospective chart review of male veterans receiving ADT from 1993 through 2001, at the Veterans Affairs Medical Center, Madison, WI. One hundred and seventy-four subjects met study criteria, with a mean age of 76 years and median duration of 21 months of ADT. Eighty-one percent had risk factors in addition to ADT. Only 13% underwent bone density measurement by dual energy X-ray absorptiometry (DXA) and, of those measured, more than half had osteoporosis. Only 19% of the men received both calcium and vitamin D supplements. Antiresorptive therapy was provided to 11% of men, although more than two-thirds had no contraindications to therapy. A total of 24 men sustained a fracture after starting ADT. For men who did undergo bone density measurement, 77% received antiresorptive therapy. Of those who exhibited osteoporosis by DXA scan, 85% received antiresorptive therapy. Male veterans receiving ADT for prostate cancer received inadequate evaluation and treatment for osteoporosis. Based on our data, a simple and practical strategy to prompt further evaluation and improved care may be to undertake bone density measurements in men prior to or soon after commencing ADT.

The natural history and treatment outcome of blast phase BCR-ABL− myeloproliferative neoplasms

PubMed Central

Tam, Constantine S.; Nussenzveig, Roberto M.; Popat, Uday; Bueso-Ramos, Carlos E.; Thomas, Deborah A.; Cortes, Jorge A.; Champlin, Richard E.; Ciurea, Stefan E.; Manshouri, Taghi; Pierce, Sherry M.; Kantarjian, Hagop M.

2008-01-01

We analyzed the outcomes of 74 patients diagnosed with BCR-ABL− myeloproliferative neoplasms in blast phase receiving induction chemotherapy (55%), low-intensity therapy (16%), stem cell transplantation (SCT; 3%), or supportive care (26%). Median survival from the date of blastic transformation was 5 months. Patients receiving supportive therapy had a median survival of 6 weeks. Complete remission with or without blood recovery was achieved in 46% of patients receiving induction chemotherapy, but remissions were not durable with a median progression-free survival of only 5 months. Eight patients received SCT either as first therapy or after responding to antileukemia therapy. These patients had a markedly superior survival, with 73% alive at a median follow-up of 31 months. JAK2V617F kinetics were assessed in 16 patients: 0 of 4 negative patients became positive at transformation, and among 12 positive patients, 1 had an increase in JAK2V617F% at transformation, 7 had a substantial decrease, and 4 had stable levels. Myeloproliferative neoplasm blast phase is associated with a dismal prognosis. Responses to chemotherapy can be achieved but are not durable. Long-term survivors had all received SCT either as first therapy or in first remission. PMID:18566326

Outcome after intensive reinduction therapy and allogeneic stem cell transplant in paediatric relapsed acute myeloid leukaemia.

PubMed

Karlsson, Lene; Forestier, Erik; Hasle, Henrik; Jahnukainen, Kirsi; Jónsson, Ólafur G; Lausen, Birgitte; Norén Nyström, Ulrika; Palle, Josefine; Tierens, Anne; Zeller, Bernward; Abrahamsson, Jonas

2017-08-01

Given that 30-40% of children with acute myeloid leukaemia (AML) relapse after primary therapy it is important to define prognostic factors and identify optimal therapy. From 1993 to 2012, 543 children from the Nordic countries were treated according to two consecutive protocols: 208 children relapsed. The influence of disease characteristics, first line treatment, relapse therapy and duration of first remission on outcome was analysed. Second complete remission (CR2) was achieved in 146 (70%) patients. Estimated 5-year overall survival (OS 5y ) was 39 ± 4% for the whole group and 43 ± 4% for the 190 patients given re-induction therapy, of whom 76% received regimens that included fludarabine, cytarabine (FLA) ± anthracyclines, 18% received Nordic Society for Paediatric Haematology and Oncology (NOPHO) upfront blocks and 5% received other regimens. Late relapse ≥1 year from diagnosis, no allogeneic stem cell transplantation (SCT) in first remission and core binding factor AML were independent favourable prognostic factors for survival. For the 128 children (124 in CR2) that received SCT as consolidation therapy after relapse, OS 5y was 61 ± 5%. Four of 19 children (21%) survived without receiving SCT as part of relapse therapy. Our data show that intensive re-induction followed by SCT can give cure rates of 40% in children with relapsed AML. © 2017 John Wiley & Sons Ltd.

[Effectiveness of transcranial magnetic therapy in the complex treatment of alcohol abstinent syndrome].

PubMed

Staroverov, A T; Zhukov, O B; Raĭgorodskiĭ, Iu M

2008-01-01

Fifty-four abstinent alcohol-dependent patients have been studied. Twenty-nine patients (a main group) received, along with basic therapy, a physiotherapeutic treatment (transcranial dynamic magnetic therapy) and 25 patients (a control group) received only basic therapy. The comparison of the efficacy of treatment in patients of the main and control groups revealed the benefits of transcranial dynamic magnetic therapy in CNS function, performance on memory and attention tests, state of autonomic nervous system and psychoemotional state of patients (the reduction of anxiety and depression).

Safety and immunogenicity of yellow fever 17D vaccine in adults receiving systemic corticosteroid therapy: an observational cohort study.

PubMed

Kernéis, Solen; Launay, Odile; Ancelle, Thierry; Iordache, Laura; Naneix-Laroche, Véronique; Méchaï, Frédéric; Fehr, Thierry; Leroy, Jean-Philippe; Issartel, Bertrand; Dunand, Jean; van der Vliet, Diane; Wyplosz, Benjamin; Consigny, Paul-Henri; Hanslik, Thomas

2013-09-01

To assess the safety and immunogenicity of live attenuated yellow fever (YF) 17D vaccine in adults receiving systemic corticosteroid therapy. All adult travelers on systemic corticosteroid therapy who had received the YF17D vaccine in 24 French vaccination centers were prospectively enrolled and matched with healthy controls (1:2) on age and history of YF17D immunization. Safety was assessed in a self-administered standardized questionnaire within 10 days after immunization. YF-specific neutralizing antibody titers were measured 6 months after vaccination in patients receiving corticosteroids. Between July 2008 and February 2011, 102 vaccine recipients completed the safety study (34 receiving corticosteroids and 68 controls). The median age was 54.9 years (interquartile range [IQR] 45.1-60.3 years) and 45 participants had a history of previous YF17D immunization. The median time receiving corticosteroid therapy was 10 months (IQR 1-67 months) and the prednisone or equivalent dosage was 7 mg/day (IQR 5-20). Main indications were autoimmune diseases (n = 14), rheumatoid arthritis (n = 9), and upper respiratory tract infections (n = 8). No serious adverse event was reported; however, patients receiving corticosteroids reported more frequent moderate/severe local reactions than controls (12% and 2%, respectively; relative risk 8.0, 95% confidence interval 1.4-45.9). All subjects receiving corticosteroids who were tested (n = 20) had neutralizing antibody titers >10 after vaccination. After YF17D immunization, moderate/severe local reactions may be more frequent in patients receiving systemic corticosteroid therapy. Immunogenicity seems satisfactory. Large-scale studies are needed to confirm these results. Copyright © 2013 by the American College of Rheumatology.

Musculoskeletal safety outcomes of patients receiving daptomycin with HMG-CoA reductase inhibitors.

PubMed

Bland, Christopher M; Bookstaver, P Brandon; Lu, Z Kevin; Dunn, Brianne L; Rumley, Kathey Fulton

2014-10-01

Daptomycin, a cyclic lipopeptide antibiotic, and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are commonly administered in the inpatient setting and are associated with creatine phosphokinase (CPK) elevations, myalgias, and muscle weakness. Safety data for coadministration of daptomycin with statins are limited. To determine the safety of coadministration of daptomycin with statin therapy, a multicenter, retrospective, observational study was performed at 13 institutions in the Southeastern United States. Forty-nine adult patients receiving statins concurrently with daptomycin were compared with 171 patients receiving daptomycin without statin therapy. Detailed information, including treatment indication and duration, infecting pathogen, baseline and subsequent CPK levels, and presence of myalgias or muscle complaints, was collected. Myalgias were noted in 3/49 (6.1%) patients receiving combination therapy compared with 5/171 (2.9%) of patients receiving daptomycin alone (P = 0.38). CPK elevations of >1,000 U/liter occurred in 5/49 (10.2%) patients receiving combination therapy compared to 9/171 (5.3%) patients receiving daptomycin alone (P = 0.32). Two of five patients experiencing CPK elevations of >1,000 U/liter in the combination group had symptoms of myopathy. Three patients (6.1%) discontinued therapy due to CPK elevations with concurrent myalgias in the combination group versus 6 patients (3.5%) in the daptomycin-alone group (P = 0.42). CPK levels and myalgias reversed upon discontinuation of daptomycin therapy. Overall musculoskeletal toxicity was numerically higher in the combination group but this result was not statistically significant. Further prospective study is warranted in a larger population. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Evaluation of Therapy Management and Patient Compliance in Postmenopausal Patients with Hormone Receptor-positive Breast Cancer Receiving Letrozole Treatment: The EvaluateTM Study

PubMed Central

Fasching, P. A.; Fehm, T.; Kellner, S.; de Waal, J.; Rezai, M.; Baier, B.; Baake, G.; Kolberg, H.-C.; Guggenberger, M.; Warm, M.; Harbeck, N.; Würstlein, R.; Deuker, J.-U.; Dall, P.; Richter, B.; Wachsmann, G.; Brucker, C.; Siebers, J. W.; Fersis, N.; Kuhn, T.; Wolf, C.; Vollert, H.-W.; Breitbach, G.-P.; Janni, W.; Landthaler, R.; Kohls, A.; Rezek, D.; Noesslet, T.; Fischer, G.; Henschen, S.; Praetz, T.; Heyl, V.; Kühn, T.; Krauß, T.; Thomssen, C.; Kümmel, S.; Hohn, A.; Tesch, H.; Mundhenke, C.; Hein, A.; Rauh, C.; Bayer, C. M.; Jacob, A.; Schmidt, K.; Belleville, E.; Hadji, P.; Wallwiener, D.; Grischke, E.-M.; Beckmann, M. W.; Brucker, S. Y.

2014-01-01

Introduction: The EvaluateTM study (Evaluation of therapy management and patient compliance in postmenopausal hormone receptor-positive breast cancer patients receiving letrozole treatment) is a prospective, non-interventional study for the assessment of therapy management and compliance in the routine care of postmenopausal women with invasive hormone receptor-positive breast cancer receiving letrozole. The parameters for inclusion in the study are presented and discussed here. Material and Methods: Between January 2008 and December 2009 a total of 5045 patients in 310 study centers were recruited to the EvaluateTM study. Inclusion criteria were hormone receptor-positive breast cancer and adjuvant treatment or metastasis. 373 patients were excluded from the analysis for various reasons. Results: A total of 4420 patients receiving adjuvant treatment and 252 patients with metastasis receiving palliative treatment were included in the study. For 4181 patients receiving adjuvant treatment, treatment with the aromatase inhibitor letrozole commenced immediately after surgery (upfront). Two hundred patients had initially received tamoxifen and started aromatase inhibitor treatment with letrozole at 1–5 years after diagnosis (switch), und 39 patients only commenced letrozole treatment 5–10 years after diagnosis (extended endocrine therapy). Patient and tumor characteristics were within expected ranges, as were comorbidities and concurrent medication. Conclusion: The data from the EvaluateTM study will offer a good overview of therapy management in the routine care of postmenopausal women with hormone receptor-positive breast cancer. Planned analyses will look at therapy compliance and patient satisfaction with how information is conveyed and the contents of the conveyed information. PMID:25568468

Can patient navigation improve receipt of recommended breast cancer care? Evidence from the National Patient Navigation Research Program.

PubMed

Ko, Naomi Y; Darnell, Julie S; Calhoun, Elizabeth; Freund, Karen M; Wells, Kristin J; Shapiro, Charles L; Dudley, Donald J; Patierno, Steven R; Fiscella, Kevin; Raich, Peter; Battaglia, Tracy A

2014-09-01

Poor and underserved women face barriers in receiving timely and appropriate breast cancer care. Patient navigators help individuals overcome these barriers, but little is known about whether patient navigation improves quality of care. The purpose of this study is to examine whether navigated women with breast cancer are more likely to receive recommended standard breast cancer care. Women with breast cancer who participated in the national Patient Navigation Research Program were examined to determine whether the care they received included the following: initiation of antiestrogen therapy in patients with hormone receptor-positive breast cancer; initiation of postlumpectomy radiation therapy; and initiation of chemotherapy in women younger than age 70 years with triple-negative tumors more than 1 cm. This is a secondary analysis of a multicenter quasi-experimental study funded by the National Cancer Institute to evaluate patient navigation. Multiple logistic regression was performed to compare differences in receipt of care between navigated and non-navigated participants. Among participants eligible for antiestrogen therapy, navigated participants (n = 380) had a statistically significant higher likelihood of receiving antiestrogen therapy compared with non-navigated controls (n = 381; odds ratio [OR], 1.73; P = .004) in a multivariable analysis. Among the participants eligible for radiation therapy after lumpectomy, navigated participants (n = 255) were no more likely to receive radiation (OR, 1.42; P = .22) than control participants (n = 297). We demonstrate that navigated participants were more likely than non-navigated participants to receive antiestrogen therapy. Future studies are required to determine the full impact patient navigation may have on ensuring that vulnerable populations receive quality care. © 2014 by American Society of Clinical Oncology.

Can Patient Navigation Improve Receipt of Recommended Breast Cancer Care? Evidence From the National Patient Navigation Research Program

PubMed Central

Ko, Naomi Y.; Darnell, Julie S.; Calhoun, Elizabeth; Freund, Karen M.; Wells, Kristin J.; Shapiro, Charles L.; Dudley, Donald J.; Patierno, Steven R.; Fiscella, Kevin; Raich, Peter; Battaglia, Tracy A.

2014-01-01

Purpose Poor and underserved women face barriers in receiving timely and appropriate breast cancer care. Patient navigators help individuals overcome these barriers, but little is known about whether patient navigation improves quality of care. The purpose of this study is to examine whether navigated women with breast cancer are more likely to receive recommended standard breast cancer care. Patients and Methods Women with breast cancer who participated in the national Patient Navigation Research Program were examined to determine whether the care they received included the following: initiation of antiestrogen therapy in patients with hormone receptor–positive breast cancer; initiation of postlumpectomy radiation therapy; and initiation of chemotherapy in women younger than age 70 years with triple-negative tumors more than 1 cm. This is a secondary analysis of a multicenter quasi-experimental study funded by the National Cancer Institute to evaluate patient navigation. Multiple logistic regression was performed to compare differences in receipt of care between navigated and non-navigated participants. Results Among participants eligible for antiestrogen therapy, navigated participants (n = 380) had a statistically significant higher likelihood of receiving antiestrogen therapy compared with non-navigated controls (n = 381; odds ratio [OR], 1.73; P = .004) in a multivariable analysis. Among the participants eligible for radiation therapy after lumpectomy, navigated participants (n = 255) were no more likely to receive radiation (OR, 1.42; P = .22) than control participants (n = 297). Conclusion We demonstrate that navigated participants were more likely than non-navigated participants to receive antiestrogen therapy. Future studies are required to determine the full impact patient navigation may have on ensuring that vulnerable populations receive quality care. PMID:25071111

Randomized prospective trial of ganciclovir maintenance therapy for cytomegalovirus retinitis.

PubMed

Jacobson, M A; O'Donnell, J J; Brodie, H R; Wofsy, C; Mills, J

1988-07-01

We report the first randomized prospective comparative study of long-term maintenance ganciclovir (9-[2-hydroxy-1-(hydroxymethyl)ethoxymethyl]guanine, BW759U, DHPG) therapy for cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome (AIDS). Eleven retinitis patients who received a 10-day course of ganciclovir induction therapy and then were randomized to receive either immediate daily ganciclovir maintenance therapy or deferred maintenance (eight deferred maintenance, three immediate maintenance) were evaluated for drug efficacy. Median time to retinitis progression was 42 days for the immediate maintenance group compared with 16 days for the deferred maintenance group, (P = 0.07). After crossing over to maintenance therapy, patients in the deferred group had a median time to retinitis progression of 58 days compared to 16 days while not on maintenance therapy (P = 0.13). Only 9% of cultures obtained while patients received maintenance therapy were positive for cytomegalovirus, vs 40% of those obtained off maintenance (P less than 0.001). We can state then that maintenance therapy with ganciclovir delays, but does not halt, progression of cytomegalovirus retinitis and suppresses, but does not eradicate, cytomegalovirus shedding in patients with AIDS.

Comparing the effects of manual therapy versus electrophysical agents in the management of knee osteoarthritis.

PubMed

Ali, Syed Shahzad; Ahmed, Syed Imran; Khan, Muhammad; Soomro, Rabail Rani

2014-07-01

To evaluate the effectiveness of Manual Therapy in comparison to Electrophysical agents in Knee Osteoarthritis. Total 50 patients with knee osteoarthritis were recruited from OPD of orthopedics civil hospital and Institute Of Physical Medicine & Rehabilitation, Dow University of Health Sciences Karachi. All those patients who fulfilled inclusion criteria were selected on voluntary basis. Selected patients were equally divided and randomly assigned into two groups with age and gender matching. The Manual therapy group received program of Maitland joint mobilization whereas Electrophysical Agent group received a program of TENS and cold pack. Both group received a program of exercise therapy as well. Patients received 3 treatment sessions per week for 4 successive weeks. Clinical assessment was performed using WOMAC index at baseline and on 12th treatment session. Both study groups showed clinically and statistically considerable improvements in WOMAC index. However, Related 2 sample t-test showed better clinical results in Manual Therapy group (p = 0.000) than Electrophysical Agents group (p = 0.008). The mean improvement in total WOMAC index was relatively higher in Manual Therapy group (22.36 ± 13.91) than Electrophysical Agent group (9.72 ± 6.10). This study concluded that manual therapy is clinically more effective in decreasing pain, stiffness and improving physical function in knee osteoarthritis.

Radiation Therapy

MedlinePlus

... cancer patients receive it. The radiation may be external, from special machines, or internal, from radioactive substances that a doctor places inside your body. The type of radiation therapy you receive depends on many factors, including The type of cancer The size of ...

The effect of the duration of intravenous zolendronate medication on the success of non-surgical endodontic therapy: a retrospective study.

PubMed

Dereci, Ömür; Orhan, Ekim Onur; Irmak, Özgür; Ay, Sinan

2016-02-01

Aim of this study is to compare the clinical and radiographic success of non-surgical endodontic therapy in patients receiving intravenous zolendronate less than 1 year and more than 1 year. The clinical and radiographic follow-up data of 24 patients who were receiving IV zolendronate with 37 teeth were retrieved from the archives to evaluate clinical and radiographic healing at the end of 12 months after non-surgical endodontic therapy. The clinical and radiographic scores of teeth treated with non-surgical endodontic therapy were analyzed. The amount of non-healed and incomplete healed teeth in patients receiving zolendronate more than 1 year were more than the amount of teeth of non-healed and incomplete healed in patients receiving bisphosphonates less than 1 year (p <0.05). There was a strong relationship between the duration of the bisphosphonate medication and endodontic success.

Hydroxyurea enhances SMN2 gene expression through nitric oxide release.

PubMed

Xu, Cheng; Chen, Xin; Grzeschik, Susanna M; Ganta, Madhuri; Wang, Ching H

2011-02-01

Small molecules that increase full-length survivor motor neuron (SMN) gene transcript are promising therapeutic candidates for spinal muscular atrophy (SMA). Hydroxyurea (HU) has recently been shown to increase full-length SMN transcript in cultured lymphocytes from patients with SMA. We investigate the mechanism by which HU enhances full-length SMN2 gene expression in SMA lymphocytes. Nitric oxide (NO) is a major intracellular metabolite of HU. We test whether NO donors can themselves enhance full-length SMN2 expression. Eighteen cell lines (five type I, five type II, six type III SMA, and two non-SMA controls) were treated with or without NO donors for 48 h. SMA cells treated with HU and three NO donors: two long-acting donors, Deta-NONOate and S-nitrosoglutathione, and one short-acting donor, 3-ethyl-3-(ethylaminoethyl)-1-hydroxy-2-oxo-1-triazene, resulted in significant increase in full-length SMN2 mRNA. These effects were abolished by co-treatment with an NO scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide. One short-acting NO donor, S-nitroso-N-acetyl-DL-penicillamine, failed to show significant effect on full-length SMN2 expression, possibly due to high degree of cytotoxicity. These results were observed using both densitometry and quantitative PCR methods. We conclude that HU enhances SMN2 expression through the release of NO. NO donors may themselves be considered as new therapeutic candidates for SMA.

TiO(2) doping by hydroxyurea at the nucleation stage: towards a new photocatalyst in the visible spectral range.

PubMed

Azouani, R; Tieng, S; Chhor, K; Bocquet, J-F; Eloy, P; Gaigneaux, E M; Klementiev, K; Kanaev, A V

2010-10-07

We report an original method of preparation of OCN-doped TiO(2) for photocatalysis in the visible spectral range. The preparation is achieved by a sol-gel route using titanium tetraisopropoxide precursor. Special attention was paid to fluid micromixing, which enables homogeneous reaction conditions in the reactor bulk and monodispersity of the produced clusters/nanoparticles. The dopant hydroxyurea (HyU, CH(4)N(2)O(2)) is injected into the reactive fluid at the nucleation stage, which lasts tens of milliseconds. The doping results in a strong yellow coloration of the nanocolloids due to the absorption band in the spectral range 380-550 nm and accelerates the aggregation kinetics of both nuclei at the induction stage and sub-nuclei units (clusters) at the nucleation stage. FTIR, Raman and UV-visible absorption analyses show the formation of a stable HyU-TiO(2) complex. EXAFS spectra indicate no appreciable changes of the first-shell Ti atom environment. The doping agent takes available surface sites of TiO(2) clusters/nanoparticles attaining ∼10% molar loading. The reaction kinetics then accelerates due to a longer collisional lifetime between nanoparticles induced by the formation of a weak [double bond, length as m-dash]OTi bond. The OCN-group bonding to titanium atoms produces a weakening of the C[double bond, length as m-dash]O double bond and a strengthening of the C-N and N-O bonds.

Caffeine-Induced Premature Chromosome Condensation Results in the Apoptosis-Like Programmed Cell Death in Root Meristems of Vicia faba

PubMed Central

Rybaczek, Dorota; Musiałek, Marcelina Weronika; Balcerczyk, Aneta

2015-01-01

We have demonstrated that the activation of apoptosis-like programmed cell death (AL-PCD) was a secondary result of caffeine (CF) induced premature chromosome condensation (PCC) in hydroxyurea-synchronized Vicia faba root meristem cells. Initiation of the apoptotic-like cell degradation pathway seemed to be the result of DNA damage generated by treatment with hydroxyurea (HU) [double-stranded breaks (DSBs) mostly] and co-treatment with HU/CF [single-stranded breaks (SSBs) mainly]. A single chromosome comet assay was successfully used to study different types of DNA damage (neutral variant–DSBs versus alkaline–DSBs or SSBs). The immunocytochemical detection of H2AXS139Ph and PARP-2 were used as markers for DSBs and SSBs, respectively. Acridine orange and ethidium bromide (AO/EB) were applied for quantitative immunofluorescence measurements of dead, dying and living cells. Apoptotic-type DNA fragmentation and positive TUNEL reaction finally proved that CF triggers AL-PCD in stressed V. faba root meristem cells. In addition, the results obtained under transmission electron microscopy (TEM) further revealed apoptotic-like features at the ultrastructural level of PCC-type cells: (i) extensive vacuolization; (ii) abnormal chromatin condensation, its marginalization and concomitant degradation; (iii) formation of autophagy-like vesicles (iv) protoplast shrinkage (v) fragmentation of cell nuclei and (vi) extensive degeneration of the cells. The results obtained have been discussed with respect to the vacuolar/autolytic type of plant-specific AL-PCD. PMID:26545248

The effect of a whole-body vibration therapy on the sitting balance of subacute stroke patients: a randomized controlled trial.

PubMed

Lee, Jong Hwa; Kim, Sang Beom; Lee, Kyeong Woo; Lee, Sook Joung; Park, Hyuntae; Kim, Dong Won

2017-09-01

The use of a whole-body vibration (WBV) therapy has recently been applied and investigated as a rehabilitation method for subacute stroke patients. To evaluate the effects of a WBV therapy on recovery of balance in subacute stroke patients who were unable to gain sitting balance. The conventional rehabilitation group (CG) received conventional physical therapy, including sitting balance training by a physical therapist, for 30 min a one session, for twice a day for five days a week for two weeks. The whole-body vibration group (VG) received one session of conventional physical therapy, and received WBV therapy instead of conventional physical therapy for 30 min a day for five days a week for two weeks. There were 15 patients in the CG and 15 patients in the VG who completed the two-week therapy. After the two-week therapy, both groups showed functional improvement. Patients in the VG improved functional ambulation categories, Berg balance scale, trunk impairment scale scores. But, no statistically significant correlations between the therapeutic methods and outcomes were observed in either group. Our results suggest that WBV therapy led to improvement of the recovery in balance recovery for subacute stroke patients. Because the WBV therapy was as effective as conventional physical therapy, we can consider a WBV therapy as a clinical method to improve the sitting balance of subacute stoke patients.

Use of Combination Thermal Therapy and Radiation in Breast-Conserving Treatment of Extensive Intraductal Breast Cancer

DTIC Science & Technology

1997-07-01

Review Board of the DFCI is provided in Appendix A . The investigator will keep the following information on each patient: 1. Past medical ...treatments, you will receive radiation therapy to your breast. Your radiation oncologist will decide what radiation dose you receive . On the basis of... Activities 6/87 Controversies in radiation therapy in

Improvement in platelet count after 3rd-line and 4th-line eradication therapy for Helicobacter pylori in patients with immune thrombocytopenia.

PubMed

Jomen, Wataru; Sato, Takashi; Maesawa, Chihaya

2017-01-01

Case 1: A 78-year-old woman was diagnosed with H. pylori positive gastritis at a previous hospital in April 2012 and received 3rd-line H. pylori eradication therapy, which ended in failure. She was referred to our department due to oral hemorrhage, petechiae involving all four extremities, and thrombocytopenia in January 2016. She was hospitalized with a diagnosis of ITP and received inpatient treatment. While receiving outpatient prednisolone (PSL) treatment, we administered 4th-line eradication therapy in March. Her platelet levels have since returned to normal, and PSL treatment has been discontinued. She is currently followed without treatment. Case 2: A 65-year-old woman was diagnosed with ITP at a previous hospital in June 2013 and received 2nd-line eradication therapy, which ended in failure. Thereafter, PSL treatment was continued but she was later referred to our department in March 2016. Since 3rd-line eradication therapy was successful, her platelet count normalized and PSL treatment has been discontinued. She is currently followed without treatment. Based on our observations in these two cases, third-line H. pylori eradication therapy is potentially effective in ITP patients.

Trends and variations in the use of adjuvant therapy for patients with head and neck cancer.

PubMed

Chen, Michelle M; Roman, Sanziana A; Yarbrough, Wendell G; Burtness, Barbara A; Sosa, Julie A; Judson, Benjamin L

2014-11-01

The National Comprehensive Cancer Network guidelines recommend that patients with surgically resected head and neck cancers that have adverse pathologic features should receive adjuvant therapy in the form of radiotherapy (RT) or chemoradiation (CRT). To the authors' knowledge, the current study is the first analysis of temporal trends and use patterns of adjuvant therapy for these patients. Patients with head and neck cancer and adverse pathologic features were identified in the National Cancer Data Base (1998-2011). Data were analyzed using chi-square, Student t, and log-rank tests; multivariate logistic regression; and Cox multivariate regression. A total of 73,088 patients were identified: 41.5% had received adjuvant RT, 33.5% had received adjuvant CRT, and 25.0% did not receive any adjuvant therapy. From 1998 to 2011, the increase in the use of adjuvant CRT was greatest for patients with oral cavity (6-fold) and laryngeal (5-fold) cancers. Multivariate analysis demonstrated that Medicare/Medicaid insurance (odds ratio [OR], 1.05; 95% confidence interval [95% CI], 1.01-1.11), distance ≥34 miles from the cancer center (OR, 1.66; 95% CI, 1.59-1.74), and academic (OR, 1.26; 95% CI, 1.20-1.31) and high-volume (OR, 1.10; 95% CI, 1.05-1.15) centers were independently associated with patients not receiving adjuvant therapy. Receipt of adjuvant therapy was found to be independently associated with improved overall survival (hazard ratio, 0.84; 95% CI, 0.81-0.86). Approximately 25% of patients are not receiving National Comprehensive Cancer Network guideline-directed adjuvant therapy. Patient-level and hospital-level factors are associated with variations in the receipt of adjuvant therapy. Further evaluation of these differences in practice patterns is needed to standardize practice and potentially improve the quality of care. Cancer 2014;120:3353-3360. © 2014 American Cancer Society. © 2014 American Cancer Society.

Treatment patterns from 647 patients with Gaucher disease: An analysis from the Gaucher Outcome Survey.

PubMed

Deegan, P; Fernandez-Sasso, D; Giraldo, P; Lau, H; Panahloo, Z; Zimran, A

2018-02-01

The Gaucher Outcome Survey (GOS) is an international disease-specific registry established in 2010 for patients with a confirmed diagnosis of Gaucher disease (GD), regardless of GD type or treatment status. For insight into how GD management varies among countries, we analyzed treatment patterns in GOS. As of October 30, 2015, data on GD-specific treatment (enzyme replacement therapy, substrate reduction therapy, or chemical chaperone therapy) received at any time were available for 647 patients. At analysis, velaglucerase alfa (316/573, 55.1%) and imiglucerase (184/573, 32.1%) were the treatments most widely used. Of the 647 treated patients, 446 (68.9%) had been treated for >5years and 368 (56.9%) had received only one GD-specific drug therapy. There were 377 patients who received velaglucerase alfa. Velaglucerase alfa was most widely used at 60U/kg every other week (134/492 dose entries, 27.2%), but there were differences in dosing between the three highest-enrolling countries (defined as >100 GOS patients enrolled in each), with most patients in Israel receiving <20U/kg, most patients in the United Kingdom receiving 20 to <40U/kg, and most in the United States receiving 60U/kg. This analysis provides a foundation upon which to examine real-life outcomes data from different treatment regimens globally. Copyright © 2016 Shire Human Genetic Therapies, Inc. Published by Elsevier Inc. All rights reserved.

Effect of Early Statin Treatment in Patients with Cardiogenic Shock Complicating Acute Myocardial Infarction

PubMed Central

Sim, Doo Sun; Cho, Kyung Hoon; Ahn, Youngkeun; Kim, Young Jo; Chae, Shung Chull; Hong, Taek Jong; Seong, In Whan; Chae, Jei Keon; Kim, Chong Jin; Cho, Myeong Chan; Rha, Seung-Woon; Bae, Jang Ho; Seung, Ki Bae; Park, Seung Jung

2013-01-01

Background and Objectives The benefit of early statin treatment following acute myocardial infarction (MI) complicated with cardiogenic shock (CS) has not been well studied. We sought to assess the effect of early statin therapy in patients with CS complicating acute MI. Subjects and Methods We studied 553 statin-naive patients with acute MI and CS (Killip class IV) who underwent revascularization therapy between November 2005 and January 2008 at 51 hospitals in the Korea Acute Myocardial Infarction Registry. Patients were divided into 2 groups: those who received statins during hospitalization (n=280) and those who did not (n=273). The influence of statin treatment on a 12-month clinical outcome was examined using a matched-pairs analysis (n=200 in each group) based on the propensity for receiving statin therapy during hospitalization. Results Before adjustment, patients receiving statin, compared to those not receiving statin, had a more favorable clinical profile, were less likely to suffer procedural complications, and more likely to receive adequate medical therapy. Patients receiving statin had lower unadjusted in-hospital mortality and composite rate of mortality, MI, and repeat revascularization at 12 months, which remained significantly lower after adjustment for patient risk, procedural characteristics, and treatment propensity. Conclusion In CS patients with acute MI undergoing revascularization therapy, early statin treatment initiated during hospitalization was associated with lower rates of in-hospital death and 12-month adverse cardiac events. PMID:23508129

Evaluation of Quality of Life Following Placement of Self-Expanding Plastic Stents as a Bridge to Surgery in Patients Receiving Neoadjuvant Therapy for Esophageal Cancer

PubMed Central

Cannon, Robert M.; Brown, Russell E.; Ellis, Susan F.; Williams, Sharon; Scoggins, C.R.; Abbas, Abbas E.

2014-01-01

Purpose. To determine whether self-expanding plastic stent (SEPS) placement significantly improves quality of life and maintains optimal nutrition while allowing full-dose neoadjuvant therapy (NAT) in patients with esophageal cancer. Patients and Methods. A prospective, dual-institution, single-arm, phase II (http://ClinicalTrials.gov: NCT00727376) evaluation of esophageal cancer patients undergoing NAT prior to resection. All patients had a self-expanding polymer stent placed prior to NAT. The European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-OG25, Functional Assessment of Cancer Therapy–Anorexia, and Functional Assessment of Cancer Therapy–General surveys were administered prior to stenting, within 1 week post-stent placement, and at the completion of neoadjuvant therapy. Results. Fifty-two patients were enrolled; 3 (5.8%) had stent migrations requiring replacement. There were no instances of esophageal erosion or perforation. All patients received some form of neoadjuvant therapy. Thirty-six (69%) received chemoradiation; 34 (93%) of these patients received the planned dose of chemotherapy, and 27 (75%) received the full planned dose of radiotherapy. There were 16 (31%) patients receiving chemotherapy alone; 12 (74%) of patients in the chemotherapy-alone group completed the planned dose of therapy. Conclusion. Placement of SEPS appears to provide significant improvement in quality of life related to dysphagia and eating restriction in patients with esophageal cancer undergoing neoadjuvant therapy. Consideration of SEPS instead of percutaneous feeding tube should be initiated as a first line in dysphagia palliation and NAT nutritional support. PMID:24567281

Massage therapy and exercise therapy in patients with multiple sclerosis: a randomized controlled pilot study.

PubMed

Negahban, Hossein; Rezaie, Solmaz; Goharpey, Shahin

2013-12-01

The primary aim was to investigate the comparative effects of massage therapy and exercise therapy on patients with multiple sclerosis. The secondary aim was to investigate whether combination of both massage and exercise has an additive effect. Randomized controlled pilot trial with repeated measurements and blinded assessments. Local Multiple Sclerosis Society. A total of 48 patients with multiple sclerosis were randomly assigned to four equal subgroups labelled as massage therapy, exercise therapy, combined massage-exercise therapy and control group. The treatment group received 15 sessions of supervised intervention for five weeks. The massage therapy group received a standard Swedish massage. The exercise therapy group was given a combined set of strength, stretch, endurance and balance exercises. Patients in the massage-exercise therapy received a combined set of massage and exercise treatments. Patients in the control group were asked to continue their standard medical care. Pain, fatigue, spasticity, balance, gait and quality of life were assessed before and after intervention. Massage therapy resulted in significantly larger improvement in pain reduction (mean change 2.75 points, P = 0.001), dynamic balance (mean change, 3.69 seconds, P = 0.009) and walking speed (mean change, 7.84 seconds, P = 0.007) than exercise therapy. Patients involved in the combined massage-exercise therapy showed significantly larger improvement in pain reduction than those in the exercise therapy (mean change, 1.67 points, P = 0.001). Massage therapy could be more effective than exercise therapy. Moreover, the combination of massage and exercise therapy may be a little more effective than exercise therapy alone.

Ticagrelor for Neuroendovascular Procedures: A Case Series.

PubMed

Davis, Kyle; Morrison, Christopher

2018-02-01

The development of thromboembolism is one of the most common complications of neuroendovascular procedures. Although several small studies have deemed clopidogrel safe and effective in the prevention of intracranial stent thrombosis, ticagrelor has yet to be assessed in this setting. The objective of this study was to retrospectively evaluate the safety and efficacy of ticagrelor in patients undergoing neuroendovascular procedures. A retrospective review of patients receiving ticagrelor following neuroendovascular aneurysm repair. A total of 5 patients undergoing neuroendovascular aneurysm repair received ticagrelor for a median of 5 days while hospitalized. Three patients were treated with stent-assisted coiling, while 2 received pipeline embolization devices. All patients received additional low-dose aspirin therapy. One patient received ticagrelor after experiencing a thrombotic event on clopidogrel, while a second patient was treated with ticagrelor after developing a dermatologic reaction to clopidogrel. Three (60%) patients were successfully treated and discharged on ticagrelor therapy. Two patients experienced cerebrovascular accidents following aneurysm repair while receiving ticagrelor, one of which was potentially due to medication omission. One (20%) patient receiving ticagrelor experienced a small retroperitoneal hematoma; however, ticagrelor therapy was continued without further complication. Therapy with ticagrelor may be a safe and effective treatment option for patients undergoing neuroendovascular aneurysm repair. However, future studies are warranted to substantiate these findings.

The effect of stimulation therapy and donepezil on cognitive function in Alzheimer's disease. A community based RCT with a two-by-two factorial design.

PubMed

Andersen, Fred; Viitanen, Matti; Halvorsen, Dag S; Straume, Bjørn; Wilsgaard, Tom; Engstad, Torgeir A

2012-07-19

Progressive neurodegeneration in Alzheimer's disease (AD) induces cognitive deterioration, and there is controversy regarding the optimal treatment strategy in early AD. Stimulation therapy, including physical exercise and cholinesterase inhibitors are both reported to postpone cognitive deterioration in separate studies. We aimed to study the effect of stimulation therapy and the additional effect of donepezil on cognitive function in early AD. A two-by-two factorial trial comprising stimulation therapy for one year compared to standard care to which a randomized double-blinded placebo controlled trial with donepezil was added. Nine rural municipalities in Northern Norway. 187 participants 65 years and older with a recent diagnosis of mild or moderate AD were included in the study of which 146 completed a one-year follow-up. In five municipalities the participants received stimulation therapy whereas participants in four received standard care. All participants were randomised double-blindly to donepezil or placebo and tested with three different cognitive tests four times during the one-year study period. Changes in MMSE sum score.Secondary outcome: Changes in ADAS-Cog and Clock Drawing Test. MMSE scores remained unchanged amongst AD participants receiving stimulation therapy and those receiving standard care. The results were consistent for ADAS-Cog and Clock Drawing Test. No time trend differences were found during one-year follow-up between groups receiving stimulation therapy versus standard care or between donepezil versus placebo. In rural AD patients non-pharmacological and pharmacological therapy did not improve outcome compared with standard care but all groups retained cognitive function during one year follow-up. Other studies are needed to confirm these results. ClinicalTrials.gov (Identifier: NCT00443014). EudraCT database (no 2004-002613-37).

Optimal In-Hospital and Discharge Medical Therapy in Acute Coronary Syndromes in Kerala: Results from the Kerala ACS Registry

PubMed Central

Huffman, Mark D; Prabhakaran, Dorairaj; Abraham, AK; Krishnan, Mangalath Narayanan; Nambiar, C. Asokan; Mohanan, Padinhare Purayil

2013-01-01

Background In-hospital and post-discharge treatment rates for acute coronary syndrome (ACS) remain low in India. However, little is known about the prevalence and predictors of the package of optimal ACS medical care in India. Our objective was to define the prevalence, predictors, and impact of optimal in-hospital and discharge medical therapy in the Kerala ACS Registry of 25,718 admissions. Methods and Results We defined optimal in-hospital ACS medical therapy as receiving the following five medications: aspirin, clopidogrel, heparin, beta-blocker, and statin. We defined optimal discharge ACS medical therapy as receiving all of the above therapies except heparin. Comparisons by optimal vs. non-optimal ACS care were made via Student’s t test for continuous variables and chi-square test for categorical variables. We created random effects logistic regression models to evaluate the association between GRACE risk score variables and optimal in-hospital or discharge medical therapy. Optimal in-hospital and discharge medical care was delivered in 40% and 46% of admissions, respectively. Wide variability in both in-hospital and discharge medical care was present with few hospitals reaching consistently high (>90%) levels. Patients receiving optimal in-hospital medical therapy had an adjusted OR (95%CI)=0.93 (0.71, 1.22) for in-hospital death and an adjusted OR (95%CI)=0.79 (0.63, 0.99) for MACE. Patients who received optimal in-hospital medical care were far more likely to receive optimal discharge care (adjusted OR [95%CI]=10.48 [9.37, 11.72]). Conclusions Strategies to improve in-hospital and discharge medical therapy are needed to improve local process-of-care measures and improve ACS outcomes in Kerala. PMID:23800985

External Beam Radiotherapy for Prostate Cancer Patients on Anticoagulation Therapy: How Significant is the Bleeding Toxicity?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Choe, Kevin S.; Jani, Ashesh B.; Liauw, Stanley L., E-mail: sliauw@radonc.uchicago.ed

Purpose: To characterize the bleeding toxicity associated with external beam radiotherapy for prostate cancer patients receiving anticoagulation (AC) therapy. Methods and Materials: The study cohort consisted of 568 patients with adenocarcinoma of the prostate who were treated with definitive external beam radiotherapy. Of these men, 79 were receiving AC therapy with either warfarin or clopidogrel. All patients were treated with three-dimensional conformal radiotherapy or intensity-modulated radiotherapy. Bleeding complications were recorded during treatment and subsequent follow-up visits. Results: With a median follow-up of 48 months, the 4-year actuarial risk of Grade 3 or worse bleeding toxicity was 15.5% for those receivingmore » AC therapy compared with 3.6% among those not receiving AC (p < .0001). On multivariate analysis, AC therapy was the only significant factor associated with Grade 3 or worse bleeding (p < .0001). For patients taking AC therapy, the crude rate of bleeding was 39.2%. Multivariate analysis within the AC group demonstrated that a higher radiotherapy dose (p = .0408), intensity-modulated radiotherapy (p = 0.0136), and previous transurethral resection of the prostate (p = .0001) were associated with Grade 2 or worse bleeding toxicity. Androgen deprivation therapy was protective against bleeding, with borderline significance (p = 0.0599). Dose-volume histogram analysis revealed that Grade 3 or worse bleeding was minimized if the percentage of the rectum receiving >=70 Gy was <10% or the rectum receiving >=50 Gy was <50%. Conclusion: Patients taking AC therapy have a substantial risk of bleeding toxicity from external beam radiotherapy. In this setting, dose escalation or intensity-modulated radiotherapy should be used judiciously. With adherence to strict dose-volume histogram criteria and minimizing hotspots, the risk of severe bleeding might be reduced.« less

Development of a vancomycin dosing approach for critically ill patients receiving hybrid hemodialysis using Monte Carlo simulation.

PubMed

Lewis, Susan J; Mueller, Bruce A

2018-01-01

Prolonged intermittent renal replacement therapy is an increasingly popular treatment for acute kidney injury in critically ill patients that runs at different flow rates and durations than conventional hemodialysis or continuous renal replacement therapies. Pharmacokinetic studies conducted in patients receiving prolonged intermittent renal replacement therapy are scarce; consequently, clinicians are challenged to dose antibiotics effectively. The purpose of this study was to develop vancomycin dosing recommendations for patients receiving prolonged intermittent renal replacement therapy. Monte Carlo simulations were performed in thousands of virtual patients derived from previously published demographic, pharmacokinetic, and dialytic information derived from critically ill patients receiving vancomycin and other forms of renal replacement therapy. We conducted "in silico" vancomycin pharmacokinetic/pharmacodynamics analyses in these patients receiving prolonged intermittent renal replacement therapy to determine what vancomycin dose would achieve vancomycin 24-h area under the curve (AUC 24h ) of 400-700 mg·h/L, a target associated with positive clinical outcomes. Nine different vancomycin dosing regimens were tested using four different, commonly used prolonged intermittent renal replacement therapy modalities. A dosing nomogram based on serum concentration data achieved after the third dose was developed to individualize vancomycin therapy. An initial vancomycin dose of 15 or 20 mg/kg immediately followed by 15 mg/kg after subsequent prolonged intermittent renal replacement therapy treatments achieved AUC 24h of ≥400 mg·h/L for ≥90% of patients regardless of prolonged intermittent renal replacement therapy duration, modality, or time of vancomycin dose relative to prolonged intermittent renal replacement therapy. Many patients experienced AUC 24h of ≥700 mg·h/L, but once the dosing nomogram was applied to serum concentrations obtained after the third vancomycin dose, 67%-88% of patients achieved AUC 24h of 400-700 mg·h/L. An initial loading dose of 15-20 mg/kg followed by a maintenance regimen of 15 mg/kg after every prolonged intermittent renal replacement therapy session coupled with serum concentration monitoring should be used to individualize vancomycin dosing. These predictions need clinical verification.

Diminished origin licensing capacity specifically sensitises tumour cells to replication stress

PubMed Central

Zimmerman, Kristin M.; Jones, Rebecca M.; Petermann, Eva; Jeggo, Penelope A.

2013-01-01

Previous studies have shown that dormant licensed replication origins can be exploited to enhance recovery from replication stress. Since tumour cells express high levels of origin licensing proteins, we examined whether depletion of such factors might specifically sensitise tumour versus non-tumour cells. Consistent with previous findings, we observed that three tumour-derived cell lines overexpress ORC1, a licensing component, compared to four non-tumour cell lines and that a greater level of ORC1 was required to maintain viability in the tumour cells. We determined siRNA-mediated knockdown conditions for each line that maximally reduced ORC1 but did not impact upon viability, which we considered would optimally deplete dormant origins. ORC1 depletion hypersensitised the tumour-derived cells to hydroxyurea (HU) and H202 but did not affect the sensitivity of the non-tumour lines. Similar results were observed following depletion of ORC6 or CDC6. Further, co-depletion of p53 and ORC1 modestly impaired viability of 1BR3hTERT non-tumour fibroblasts and more dramatically caused hypersensitivity to HU. Finally, overexpression of the c-Myc oncogene combined with ORC1 depletion in non-tumour BJhTERT cells diminished viability. Collectively, these findings suggest that tumour cells may have a reliance on origin licensing capacity, suggesting that licensing factors could represent a target for drug-based cancer therapy. PMID:23364533

Brazilian Guidelines for transcranial doppler in children and adolescents with sickle cell disease

PubMed Central

Lobo, Clarisse Lopes de Castro; Cançado, Rodolfo Delfini; Leite, Ana Claudia Celestino Bezerra; dos Anjos, Ana Claudia Mendonça; Pinto, Ana Cristina Silva; Matta, Andre Palma da Cunha; Silva, Célia Maria; Silva, Gisele Sampaio; Friedrisch, João Ricardo; Braga, Josefina Aparecida Pellegrini; Lange, Marcos Christiano; Figueiredo, Maria Stella; Rugani, Marília Álvares; Veloso, Orlando; Moura, Patrícia Gomes; Cortez, Paulo Ivo; Adams, Robert; Gualandro, Sandra Fátima Menosi; de Castilho, Shirley Lopes; Thomé, Ursula; Zetola, Viviane Flumignan

2011-01-01

Background Sickle cell disease is the most common monogenic hereditary disease in Brazil. Although strokes are one of the main causes of morbidity and mortality in these patients, the use of transcranial Doppler to identify children at risk is not universally used. Objective To develop Brazilian guidelines for the use of transcranial Doppler in sickle cell disease children and adolescents, so that related health policies can be expanded, and thus contribute to reduce morbidity and mortality. Methods The guidelines were formulated in a consensus meeting of experts in transcranial Doppler and sickle cell disease. The issues discussed were previously formulated and scientific articles in databases (MEDLINE, SciELO and Cochrane) were carefully analyzed. The consensus for each question was obtained by a vote of experts on the specific theme. Results Recommendations were made, including indications for the use of transcranial Doppler according to the sickle cell disease genotype and patients age; the necessary conditions to perform the exam and its periodicity depending on exam results; the criteria for the indication of blood transfusions and iron chelation therapy; the indication of hydroxyurea; and the therapeutic approach in cases of conditional transcranial Doppler. Conclusion The Brazilian guidelines on the use of transcranial doppler in sickle cell disease patients may reduce the risk of strokes, and thus reduce the morbidity and mortality and improve the quality of life of sickle cell disease patients. PMID:23284243

[Sickle cell anemia: experience in a center].

PubMed

Gómez-Chiari, M; Tusell Puigbert, J; Ortega Aramburu, J

2003-02-01

Sickle cell anemia is a structural hemoglobinopathy in which morphological and physical changes in erythrocytes cause vaso-occlusive episodes in various organs and tissues. The disease is common among blacks and the African population. As a result of the growing migratory flow, this is an emerging disease in Spain. To present the casuistics of a pediatric hospital: clinical onset, the most frequent features and complications, and treatment. We performed a retrospective study of 22 patients aged less than 18 years old diagnosed with sickle cell anemia between January 1985 and December 2001. Epidemiologic data, symptoms, complications, blood test results, treatment, and response were recorded. The mean age of the patients was 39 months. In 54 %, diagnosis was established before the age of 2 years. No differences were found in sex. The countries of origin were Gambia in 32 %, Morocco in 23 %, and Senegal in 18 % as well as other African and Central America countries; 53 % of the children were born in Spain. The most common complaint was vaso-occlusive pain localized in the abdomen (45 %). The most frequent complications were infections and 13.7 % suffered stroke. Twenty-eight percent of the patients diagnosed before the age of 2 years presented complications. Eleven patients received hydroxyurea for recurrent vaso-occlusive crises with favorable results; one patient underwent splenectomy and another received an allogenic bone marrow transplant from an HLA-identical brother with excellent results. This study reproduces the data described in the literature from countries with a high prevalence of the disease. Morbidity could be minimized by early diagnosis and preventive treatment and good healthcare. Given the increasing incidence of the disease, screening of black and African neonates and genetic counseling are recommended together with guidelines for prompt and appropriate treatment in primary health centers and emergency departments.

The dynamics of histone H2A ubiquitination in HeLa cells exposed to rapamycin, ethanol, hydroxyurea, ER stress, heat shock and DNA damage.

PubMed

Nakata, Shiori; Watanabe, Tadashi; Nakagawa, Koji; Takeda, Hiroshi; Ito, Akihiro; Fujimuro, Masahiro

2016-03-25

Polyubiquitination plays key roles in proteasome-dependent and independent cellular events, whereas monoubiquitination is involved in gene expression, DNA repair, protein-protein interaction, and protein trafficking. We previously developed an FK2 antibody, which specifically recognizes poly-Ub moieties but not free Ub. To elucidate the role of Ub conjugation in response to cellular stress, we used FK2 to investigate whether chemical stress (rapamycin, ethanol, or hydroxyurea), ER stress (thapsigargin or tunicamycin), heat shock or DNA damage (H2O2 or methyl methanesulfonate) affect the formation of Ub conjugates including histone H2A (hH2A) ubiquitination. First, we found that all forms of stress tested increased poly-ubiquitinated proteins in HeLa cells. Furthermore, rapamycin and hydroxyurea treatment, and ER stress increased ubiquitination of hH2A, while methyl methanesulfonate (MMS) treatment induced deubiquitination of hH2A. The ethanol and H2O2 treatments, and heat shock transiently induced hH2A de-ubiquitination, although deubiquitinated hH2A were ubiquitinated again by subsequent cultivation. We also revealed that FK2 reacts with not only polyubiquitinated proteins but also mono-ubiquitinated hH2A. With the exception of MMS, all forms of stress tested increased the acetylation of K5-hH2A, K9-hH3 and K8-hH4 in addition to ubiquitination. K118 and K119 of hH2A were ubiquitinated in cells under normal conditions, and K119 was the major ubiquitination site. The MMS-treatment and heat shock induced the deubiquitination of both K118 and K119-histone H2A. Interestingly, MMS treatment did not affect cell HeLa cell viability expressing double-mutant hH2A (KK118,119AA-hH2A), while heat shock slightly but significantly decreased viability of double-mutant hH2A expressing cells, indicating that ubiquitination of both sites associates with recovery from heat shock but not MMS treatment. Thus, we characterized FK2 reactivity and demonstrated that various stresses alter the ubiquitination status, particularly ubiquitinated hH2A and with histone acetylation, and highlight the physiological importance of hH2A ubiquitination after exposure to stress stimuli. Copyright © 2016 Elsevier Inc. All rights reserved.

Impact of Prior Platinum-Based Therapy on Patients Receiving Salvage Systemic Treatment for Advanced Urothelial Carcinoma.

PubMed

Sonpavde, G; Pond, G R; Di Lorenzo, G; Buonerba, C; Rozzi, A; Lanzetta, G; Necchi, A; Giannatempo, P; Raggi, D; Matsumoto, K; Choueiri, T K; Mullane, S; Niegisch, G; Albers, P; Lee, J L; Kitamura, H; Kume, H; Bellmunt, J

2016-12-01

Trials of salvage therapy for advanced urothelial carcinoma have required prior platinum-based therapy. This practice requires scrutiny because non-platinum-based first-line therapy may be offered to cisplatin-ineligible patients. Data of patients receiving salvage systemic chemotherapy were collected. Data on prior first-line platinum exposure were required in addition to treatment-free interval, hemoglobin, Eastern Cooperative Oncology Group performance status, albumin, and liver metastasis status. Cox proportional hazard regression was used to evaluate their association with overall survival (OS) after accounting for salvage single-agent or combination chemotherapy. Data were obtained from 455 patients previously exposed to platinum-based therapy and 37 not exposed to platinum. In the group exposed to prior platinum therapy, salvage therapy consisted of a single-agent taxane (n = 184) or a taxane-containing combination chemotherapy (n = 271). In the group not exposed to prior platinum therapy, salvage therapy consisted of taxane or vinflunine (n = 20), 5-fluorouracil (n = 1), taxane-containing combination chemotherapy (n = 12), carboplatin-based combinations (n = 2), and cisplatin-based combinations (n = 2). The median OS for the prior platinum therapy group was 7.8 months (95% confidence interval, 7.0, 8.1), and for the group that had not received prior platinum therapy was 9.0 months (95% confidence interval, 6.0, 11.0; P = .50). In the multivariable analysis, prior platinum therapy versus no prior platinum exposure did not confer an independent impact on OS (hazard ratio, 1.10; 95% confidence interval, 0.75, 1.64; P = .62). Prior platinum- versus non-platinum-based chemotherapy did not have a prognostic impact on OS after accounting for major prognostic factors in patients receiving salvage systemic chemotherapy for advanced urothelial carcinoma. Lack of prior platinum therapy should not disqualify patients from inclusion onto trials of salvage therapy. Copyright © 2016 Elsevier Inc. All rights reserved.

Gene therapy for immune disorders: good news tempered by bad news.

PubMed

Puck, Jennifer M; Malech, Harry L

2006-04-01

After a dozen years of human gene therapy trials characterized by minimal gene correction and disappointing clinical impact, the field of gene therapy received some good news in 2000. Infants with X-linked severe combined immunodeficiency who received retroviral gene addition to cells from their bone marrow developed impressive immune reconstitution. During the following 2 years, additional patients were treated and the news was even better-babies receiving gene therapy had sustained T-cell production and in several cases developed better cell function than most patients treated with standard bone marrow transplants. Unfortunately, bad news followed. Three of the patients experienced leukemic T-cell expansions, found to be associated with retroviral insertions into genomic DNA. Where does the field stand today?

Photodynamic therapy in treatment of severe oral lichen planus.

PubMed

Rabinovich, O F; Rabinovich, I M; Guseva, A V

2016-01-01

The aim of the study was to elaborate the rationale for the application of photodynamic therapy in complex treatment of patient with severe oral lichen planus. Complex clinical and laboratory examination and treatment was performed in 54 patients divided on 3 groups. Diagnosis of oral lichen planus was based on clinical, histological and immunohistochemical features. Group 1 received standard treatment, in the second group photodynamic therapy was conducted in addition to conventional treatment, patients in the third group received only photodynamic therapy. The study results proved photodynamic therapy to be useful tool in complex treatment of severe oral lichen planus.

Differences in skeletal muscle loss caused by cytotoxic chemotherapy and molecular targeted therapy in patients with advanced non‐small cell lung cancer

PubMed Central

Tsuruoka, Hazime; Morikawa, Kei; Furuya, Naoki; Inoue, Takeo; Miyazawa, Teruomi; Mineshita, Masamichi

2017-01-01

Background Recent studies have revealed a reduction in the skeletal muscle area in patients with advanced non‐small cell lung cancer (NSCLC) after chemotherapy. EGFR and ALK tyrosine kinase inhibitor (TKI)‐based therapies are less cytotoxic than chemotherapy, but differences in skeletal muscle mass between patients receiving EGFR and ALK TKI therapies and patients receiving cytotoxic chemotherapy have not yet been reported. Methods Data of pathologically proven NSCLC patients were reviewed, and chest computed tomography and/or positron emission tomography‐computed tomography images obtained from January 2012 to December 2014 were selected. Patients were divided into two groups: cytotoxic chemotherapy (CG) and molecular targeted (MG). Muscle mass was measured with a single cross‐sectional area of the muscle at the third lumber vertebra (L3MA). To estimate skeletal muscle changes during chemotherapy, we defined the following L3 skeletal muscle index (L3SMI) ratio: post L3SMI/pre L3SMI. Differences in the SMI ratio between the groups were evaluated using the Wilcoxon signed‐rank test. Results Sixty‐five patients were included in this study: 44 patients received cytotoxic chemotherapy and 21 received molecular targeted therapy (EGFR and ALK TKI). The loss of L3MA in the CG was higher than in the MG (P = 0.03). In the CG, the L3SMI ratio defined to evaluate skeletal muscle mass changes was significantly lower than in the MG (P = 0.0188). Conclusion Our results suggest that skeletal muscle loss during first‐line therapy was significantly different between patients receiving cytotoxic chemotherapy and those receiving TKIs. Specifically, skeletal muscle loss was lower in patients receiving TKIs than in patients receiving cytotoxic chemotherapy. PMID:29067769

Randomized Selection Design Trial Evaluating CD8+-Enriched Versus Unselected Tumor-Infiltrating Lymphocytes for Adoptive Cell Therapy for Patients With Melanoma

PubMed Central

Dudley, Mark E.; Gross, Colin A.; Somerville, Robert P.T.; Hong, Young; Schaub, Nicholas P.; Rosati, Shannon F.; White, Donald E.; Nathan, Debbie; Restifo, Nicholas P.; Steinberg, Seth M.; Wunderlich, John R.; Kammula, Udai S.; Sherry, Richard M.; Yang, James C.; Phan, Giao Q.; Hughes, Marybeth S.; Laurencot, Carolyn M.; Rosenberg, Steven A.

2013-01-01

Purpose Adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TILs) and high-dose interleukin-2 (IL-2) administered to lymphodepleted patients with melanoma can cause durable tumor regressions. The optimal TIL product for ACT is unknown. Patients and Methods Patients with metastatic melanoma were prospectively assigned to receive unselected young TILs versus CD8+-enriched TILs. All patients received lymphodepleting chemotherapy and high-dose IL-2 therapy and were assessed for response, toxicity, survival, and immunologic end points. Results Thirty-four patients received unselected young TILs with a median of 8.0% CD4+ lymphocytes, and 35 patients received CD8+-enriched TILs with a median of 0.3% CD4+ lymphocytes. One month after TIL infusion, patients who received CD8+-enriched TILs had significantly fewer CD4+ peripheral blood lymphocytes (P = .01). Twelve patients responded to therapy with unselected young TILs (according to Response Evaluation Criteria in Solid Tumors [RECIST]), and seven patients responded to CD8+-enriched TILs (35% v 20%; not significant). Retrospective studies showed a significant association between response to treatment and interferon gamma secretion by the infused TILs in response to autologous tumor (P = .04), and in the subgroup of patients who received TILs from subcutaneous tumors, eight of 15 patients receiving unselected young TILs responded but none of eight patients receiving CD8+-enriched TILs responded. Conclusion A randomized selection design trial was feasible for improving individualized TIL therapy. Since the evidence indicates that CD8+-enriched TILs are not more potent therapeutically and they are more laborious to prepare, future studies should focus on unselected young TILs. PMID:23650429

Antiemetic Therapy With or Without Olanzapine in Preventing Chemotherapy-Induced Nausea and Vomiting in Patients With Cancer Receiving Highly Emetogenic Chemotherapy | Division of Cancer Prevention

Cancer.gov

This randomized phase III trial studies antiemetic therapy with olanzapine to see how well they work compared to antiemetic therapy alone in preventing chemotherapy-induced nausea and vomiting in patients with cancer receiving highly emetogenic (causes vomiting) chemotherapy. Antiemetic drugs, such as palonosetron hydrochloride, ondansetron, and granisetron hydrochloride, may

Changes in endogenous microflora among febrile granulocytopenic patients receiving empiric antibiotic therapy: implications for fungal superinfection.

PubMed Central

Bow, E J; Louie, T J

1987-01-01

The ecologic effect of empiric systemic antibiotic therapy on the endogenous microflora was evaluated in 83 febrile granulocytopenic patients with cancer who were randomly allocated to receive moxalactam plus ticarcillin (45 patients) or tobramycin plus ticarcillin (38 patients) for suspected infection. Serial surveillance cultures of the nasal passages, oropharynx and feces performed twice a week showed that patients who received the former regimen had higher elimination rates and significantly lower acquisition rates (p = 0.027) for aerobic gram-negative bacilli than did patients who received the latter regimen. However, therapy with moxalactam plus ticarcillin also resulted in significantly higher acquisition rates for yeasts (p = 0.004). This was associated with a significantly higher fungal superinfection rate among these patients than among those who received tobramycin plus ticarcillin (40% v. 16%) (p less than 0.05). Moxalactam plus ticarcillin therapy created a greater microbial ecologic vacuum by the elimination of intestinal anaerobes, which, in turn, permitted fungal colonization and an increased risk of superinfection. Our results support the recommendation that an antipseudomonal penicillin plus an aminoglycoside be selected as empiric therapy for suspected infection in febrile granulocytopenic patients with cancer. Such a regimen would spare the anaerobic intestinal microflora, thereby reducing the risk of fungal colonization and infection. PMID:3304600

Losartan/hydrochlorothiazide combination is safe and effective for morning hypertension in Very-Elderly patients.

PubMed

Uchiwa, Hiroki; Kai, Hisashi; Iwamoto, Yoshiko; Anegawa, Takahiro; Kajimoto, Hidemi; Fukuda, Kenji; Imaizumi, Tsutomu; Fukumoto, Yoshihiro

2018-01-01

Morning hypertension is an independent risk for cerebrovascular and cardiovascular events. Although the prevalence of morning hypertension increases with age, treatment of morning hypertension has not been established, particularly in Very-Elderly patients. We compared the safety and efficacy of a losartan/hydrochlorothiazide (HCTZ) combination in controlling morning hypertension between Very-Elderly (≥75 years) and Young/Elderly patients (<75 years). This study was a subanalysis of the Morning Hypertension and Angiotensin Receptor Blocker/Hydrochlorothiazide Combination Therapy study, in which patients with morning hypertension (≥135/85 mmHg) received a 50-mg losartan/12.5-mg HCTZ combination tablet (combination therapy) or 100-mg losartan (high-dose therapy) for 3 months. High adherence rates and few adverse effects were observed in Very-Elderly patients receiving combination (n = 32) and high-dose (n = 34) therapies and in Young/Elderly patients receiving combination (n = 69) and high-dose (n = 66) therapies. Baseline morning systolic BP (SBP) was similar in both age groups receiving either therapy. Morning SBP was reduced by 20.2 and 18.1 mmHg with combination therapy and by 7.1 and 9.1 mmHg with high-dose therapy in the Very-Elderly and Young/Elderly patients, respectively. Morning BP target (<135/85 mmHg) was achieved in 40.6% and 55.1% by combination therapy and in 14.7% and 24.2% by high-dose therapy in the Very-Elderly and Young/Elderly patients, respectively. Neither therapy changed renal function and serum potassium in Very-Elderly patients. In conclusion, the losartan/HCTZ combination was safe and effective in controlling morning hypertension in Very-Elderly as well as Young/Elderly patients. In addition, combination therapy was also superior to high-dose therapy for lowering morning SBP in Very-Elderly patients.

Neurologic music therapy in upper-limb rehabilitation in children with severe bilateral cerebral palsy: a randomized controlled trial.

PubMed

Marrades-Caballero, Eugenio; Santonja-Medina, Clara S; Sanz-Mengibar, Jose M; Santonja-Medina, Fernando

2018-02-26

After receiving neurologic music therapy, functional improvements in children with severe bilateral cerebral palsy have not been found in the literature. Musical training with instruments allows interrelationships between movement, emotions and cognition for task-based learning, in order to improve motor control. To understand whether neurologic music therapy has an impact on the functionality of children with severe cerebral palsy. A randomized controlled assessor-blind trial was carried out. Children were recruited and treated in their own community center. Eighteen children with severe bilateral cerebral palsy between 4 and 16 years old were studied. The intervention group (n=18) received music therapy for 16 weeks, in addition to its usual physiotherapy input. Two music therapists implemented a neurologic music therapy program of therapeutic instrumental music performance. The control group (n=9) received its usual therapeutic input, similar to the intervention group, but not neurologic music therapy. Overall and specific "Chailey levels of Ability" were quantified, as well as the Locomotor Stages. Significant improvements in the overall and specific "arm and hand position" as well as "activities" from the Chailey Levels of Ability and the Locomotor Stages were observed (p<.05) in the group which received the music therapy (corregir si se acepta en la editing proofs). All these improvements persisted after 4 months. The control group showed no improvements after a four-month follow-up. Optimized intervention of neurologic music therapy can improve the functionality of children with severe bilateral cerebral palsy. Music therapy is a useful tool in rehabilitation and its positive effects remain four months after completing the treatment.

A combination of a ribonucleotide reductase inhibitor and histone deacetylase inhibitors downregulates EGFR and triggers BIM-dependent apoptosis in head and neck cancer

PubMed Central

Habtemichael, Negusse; Bier, Carolin; Unruhe, Britta; Weisheit, Simona; Spange, Stephanie; Nonnenmacher, Frank; Fetz, Verena; Ginter, Torsten; Reichardt, Sigrid; Liebmann, Claus; Schneider, Günter; Krämer, Oliver H.

2012-01-01

Head and neck squamous cell carcinomas (HNSCCs) are the sixth most common malignant neoplasm and more than 50% of patients succumb to this disease. HNSCCs are characterized by therapy resistance, which relies on the overexpression of anti-apoptotic proteins and on the aberrant regulation of the epidermal growth factor receptor (EGFR). As inherent and acquired resistance to therapy counteracts improvement of long-term survival, novel multi-targeting strategies triggering cancer cell death are urgently required. We investigated how induction of replicational stress by the ribonucleotide reductase inhibitor hydroxyurea (HU) combined with histone deacetylase inhibitors (HDACi) exerts anti-tumor activity. We treated HNSCC cell lines and freshly isolated tumor cells with HDACi, such as the clinically approved anti-epileptic drug valproic acid (VPA), in combination with HU. Our data demonstrate that at clinically achievable levels VPA/HU combinations efficiently block proliferation as well as clonogenic survival, and trigger apoptosis of HNSCC cells. In the presence of VPA/HU, such tumor cells increase expression of the pro-apoptotic BCL-2 family protein BIM, independent of wild-type p53 signaling and in the absence of increased expression of the p53 targets PUMA and BAX. The pro-apoptotic activity of BIM in HNSCCs was found critical for tumor cell death; ectopic overexpression of BIM induced HNSCC apoptosis and RNAi-mediated depletion of BIM protected HNSCC cells from VPA/HU. Also, significantly elevated BIM levels (p<0.01) were detectable in the apoptotic tumor centers versus proliferating tumor margins in HNSCC patients (n=31), underlining BIM's clinical relevance. Importantly, VPA/HU treatment additionally reduces expression and cell surface localization of EGFR. Accordingly, in a xenograft mouse model, VPA/HU efficiently blocked tumor growth (P<0.001) correlating with BIM induction and EGFR downregulation. We provide a molecular rationale for the potent anti-cancer activities of this drug combination. Our data suggest its exploitation as a potential strategy for the treatment of HNSCC and other tumor entities characterized by therapy resistance linked to dysregulated EGFR activation. PMID:22289787

Opportunities for improvement in anti-thrombotic therapy and other strategies for the management of acute coronary syndromes: Insights from EPICOR, an international study of current practice patterns.

PubMed

Bueno, Héctor; Sinnaeve, Peter; Annemans, Lieven; Danchin, Nicolas; Licour, Muriel; Medina, Jesús; Pocock, Stuart; Sánchez-Covisa, Joaquín; Storey, Robert F; Jukema, J Wouter; Zeymer, Uwe; Van de Werf, Frans

2016-02-01

To describe international patterns and opportunities for improvement of pre- and in-hospital care of patients hospitalized for acute coronary syndromes (ACS), with special focus on anti-thrombotic therapy. EPICOR (long-tErm follow-uP of anti-thrombotic management patterns In acute CORonary syndrome patients), an international, cohort study, which enrolled 10,568 consecutive ACS survivors from 555 hospitals in 20 countries across Europe and Latin America (September 2010 to March 2011), prospectively registered detailed information on pre- and in-hospital management. Globally, 4738 (44.8%) were attended before hospitalization, 4241 (40.1%) had an ECG, 2119 (20%) received anti-platelet therapy and 101 STEMI patients (2%) fibrinolysis. In-hospital, 7944 patients (75.2%) received dual anti-platelet therapy, most often with clopidogrel (69.7%), and less with prasugrel (5.4%); 1705 (16.1%) had triple anti-platelet therapy, and 849 (8%) single anti-platelet therapy. STEMI patients more often received pre-hospital anti-thrombotics, and prasugrel, GP IIb/IIIa inhibitors and UFH in-hospital (all p < 0.001). More NSTE-ACS patients received clopidogrel, single anti-platelet therapy, and fondaparinux (all p < 0.001). As many as 33% of ACS patients were medically managed. A significant decreasing gradient was found between Northern, Southern and Eastern Europe and Latin America in use of more potent patterns of anti-platelet therapy, reperfusion therapy and invasive strategy. This large international study shows room for improvement in use of anti-thrombotic drugs and other strategies for optimal management of ACS, including pre-hospital ECG and anti-thrombotic therapy. Regional practice differences not based on evidence or conditioned by economic constraints should be reduced. © The European Society of Cardiology 2015.

Age, Comorbidity, and Breast Cancer Severity: Impact on Receipt of Definitive Local Therapy and Rate of Recurrence among Older Women with Early Stage Breast Cancer

PubMed Central

Field, Terry S; Bosco, Jaclyn LF; Prout, Marianne N; Gold, Heather T; Cutrona, Sarah; Pawloski, Pamala A; Yood, Marianne Ulcickas; Quinn, Virginia P; Thwin, Soe Soe; Silliman, Rebecca A

2011-01-01

Background The definitive local therapy options for early stage breast cancer are 1) mastectomy and 2) breast conserving surgery followed by radiation therapy. Older women and those with comorbidities frequently receive breast conserving surgery alone. The interaction of age and comorbidity with breast cancer severity and their impact on receipt of definitive therapy have not been well studied Study Design In a cohort of 1837 women age≥65 years receiving treatment for early stage breast cancer in 6 integrated healthcare delivery systems in 1990–1994 and followed for 10 years, we examined predictors of receiving non-definitive local therapy and assessed the impact on breast cancer recurrence within levels of severity, defined as level of risk for recurrence. Results Age and comorbidity were associated with receipt of non-definitive therapy. Compared to those at low risk, women at the highest risk were less likely to receive non-definitive therapy (odds ratio (OR) 0.32, 95% confidence interval (CI) 0.22, 0.47) while women at moderate risk were about half as likely (OR 0.54, CI 0.35, 0.84). Non-definitive local therapy was associated with higher rates of recurrence among women at moderate (HR 5.1, CI 1.9, 13.5) and low risk (HR 3.2, CI 1.1, 8.9). The association among women at high risk was weak (HR 1.3, CI 0.75, 2.1). Conclusions Among these older women with early stage breast cancer, decisions about therapy partially balanced breast cancer severity against age and comorbidity. However, even among women at low risk, omitting definitive local therapy was associated with increased recurrence. PMID:22014658

Plan-sponsor savings and member experience with point-of-service prescription step therapy.

PubMed

Motheral, Brenda R; Henderson, Rochelle; Cox, Emily R

2004-07-01

To examine the effect of prescription step-therapy programs in terms of plan-sponsor savings and member experience at the point of service. Plan-sponsor savings were measured using a quasi-experimental, case-control design. Member experience with step therapy was measured using a self-administered mailed survey. A 20,000-member plan implemented 3 step therapy programs in September 2002: proton pump inhibitors, selective serotonin reuptake inhibitors, and nonsteroidal anti-inflammatory drugs. Pharmacy claims from September 1, 2001, through June 30, 2003, were examined to compare changes in per-member-per-month (PMPM) net cost between the intervention group and a random sample of members from commercial plans without the step therapy programs. A mailed, self-administered survey was sent to members with a step edit from September 1, 2002 to December 31, 2002. The employer experienced a decrease of 0.83 dollars in net cost after implementing step therapy, while the comparison group had an upward trend of 0.10 dollars PMPM for these therapy classes. Member-reported outcomes indicated that approximately 30% of patients received a generic, 23% were granted a medical exception for the brand, 17% received no medication, and 16% paid the full retail price for the brand. If the pharmacist vs the patient contacted the physician, members were 8 times more likely to receive a medication covered by the health plan (OR, 8.10; 95% CI, 2.94-22.33 vs OR, 8.23; 95% CI, 3.11-21.93). Compared with those who received first-line therapy, those who paid out of pocket for the brand medication vs those who did not receive any medication were less likely to be satisfied with their pharmacy benefit (OR, 0.25; 95% CI, 0.08-0.80 vs OR, 0.12; 95% CI, 0.04-0.41). Step therapy produces significant drug savings. However, there appear to be opportunities to further members' and providers' understanding of these programs.

Physical Therapy for Chronic Low Back Pain in North Carolina: Overuse, Underuse, or Misuse?

PubMed Central

Carey, Timothy S.; Holmes, George M.

2011-01-01

Background There are limited population-based studies of determinants of physical therapy use for chronic low back pain (LBP) and of the types of treatments received by individuals who see a physical therapist. Objective The purposes of this study were: (1) to identify determinants of physical therapy use for chronic LBP, (2) to describe physical therapy treatments for chronic LBP, and (3) to compare use of treatments with current best evidence on care for this condition. Design This study was a cross-sectional, population-based telephone survey of North Carolinians. Methods Five hundred eighty-eight individuals with chronic LBP who had sought care in the previous year were surveyed on their health and health care use. Bivariate and multivariable analyses were conducted to identify predisposing, enabling, and need characteristics associated with physical therapy use. Descriptive analyses were conducted to determine the use of physical treatments for individuals who saw a physical therapist. Use of treatments was compared with evidence from systematic reviews. Results Of our sample, 29.7% had seen a physical therapist in the previous year, with a mean of 15.6 visits. In multivariable analyses, receiving workers' compensation, seeing physician specialists, and higher Medical Outcomes Study 12-Item Short-Form Health Survey questionnaire (SF-12) physical component scores were positively associated with physical therapy use. Having no health insurance was negatively associated with physical therapy use. Exercise was the most frequent treatment received (75% of sample), and traction was the least frequent treatment received (7%). Some effective treatments were underutilized, whereas some ineffective treatments were overutilized. Limitations Only one state was examined, and findings were based on patient report. Conclusions Fewer than one third of individuals with chronic LBP saw a physical therapist. Health-related and non–health-related factors were associated with physical therapy use. Individuals who saw a physical therapist did not always receive evidence-based treatments. There are potential opportunities for improving access to and quality of physical therapy for chronic LBP. PMID:21330449

The Associations Between Physical Therapy and Long-Term Outcomes for Individuals with Lumbar Spinal Stenosis in the SPORT study

PubMed Central

Fritz, Julie M.; Lurie, Jon D.; Zhao, Wenyan; Whitman, Julie M.; Delitto, Anthony; Brennan, Gerard P.; Weinstein, James N.

2013-01-01

Background/Context A period of non-surgical management is advocated prior to surgical treatment for most patients with lumbar spinal stenosis. Currently, little evidence is available to define optimal non-surgical management. Physical therapy is often used, however its use and effectiveness relative to other non-surgical strategies has not been adequately explored. Purpose Describe the utilization of physical therapy and other non-surgical interventions by patients with lumbar spinal stenosis and examine the relationship between physical therapy and long-term prognosis. Study Design Secondary analysis of the Spine Patient Outcomes Research Trial (SPORT) combining data from randomized and observational studies. Setting 13 spine clinics in 11 states in the United States. Patient Sample Patients with lumbar spinal stenosis receiving non-surgical management including those who did or did not receive physical therapy within 6 weeks of enrollment. Outcome Measures Primary outcome measures included cross-over to surgery, the bodily pain and physical function scales changes from the Survey Short Form 36 (SF-36), and the modified Oswestry Disability Index. Secondary outcome measures were patient satisfaction and the Sciatica Bothersomeness Index. Methods Baseline characteristics and rates of cross-over to surgery were compared between patients who did or did not receive physical therapy. Baseline factors predictive of receiving physical therapy were examined with logistic regression. Mixed effects models were used to compare outcomes between groups at 3 and 6 months, and 1 year after enrollment adjusted for baseline severity and patient characteristics. Results Physical therapy was used in the first 6 weeks by 90 of 244 patients (37%) and was predicted by the absence of radiating pain and being single instead of married. Physical therapy was associated with a reduced likelihood of cross-over to surgery after 1 year (21% vs 33%, p=0.045), and greater reductions on the SF-36 physical functioning scale after 6 months (mean difference =6.0, 95% CI: 0.2, 11.7) and 1 year (mean difference =6.5, 95% CI: 0.6, 12.4). There were no differences in bodily pain or Oswestry scores across time. Conclusion Many patients with lumbar spinal stenosis pursuing conservative management receive physical therapy. Using physical therapy was associated with reduced likelihood of patients receiving surgery within 1 year. Results for other outcomes were mixed with no differences in several measures. Further research is needed to examine the effectiveness of physical therapy relative to other non-surgical management strategies for patients with lumbar spinal stenosis. PMID:24373681

Methods for Teratogenic Screening of Air Force Chemicals

DTIC Science & Technology

1978-01-01

7 2 4 3 2.3 7 8 2 1 7 2.6 8 5 1 1 4 2.5 20 0 10 22 8 1 1 7 2.8 26 6 5 2 4 2.4 3 Gross Abnormalities Number of Fetuses with Abnormality Anophthalmia ...meningoencephalocoele), anophthalmia , cleft palate, cleft lip, misplaced ears, clubbed hind limbs, fused vertebrae, fused ribs, split centra and scoliosis.* In...experimentation with hydroxyurea in Fisher 344 rats, at 250 mg/kg on day nine of pregnancy, our results showed anophthalmia , brain abnormalities

Alteration of adenyl dinucleotide metabolism by environmental stress.

PubMed Central

Baker, J C; Jacobson, M K

1986-01-01

Exposure of cultured mammalian cells to a variety of conditions that induce the synthesis of stress proteins, including hyperthermia, ethanol, cadmium, and arsenite resulted in an increased cellular content of adenyl dinucleotides including diadenosine tetraphosphate (Ap4A). Exposure to other agents that cause metabolic perturbations not known to induce the synthesis of stress proteins, such as cyclohexamide, cytosine arabinoside, hydroxyurea, and ultraviolet irradiation did not alter the content of these nucleotides. It is proposed that these unique nucleotides may mediate adaptive responses of mammalian cells to environmental stress. PMID:3458199

In real life, one-quarter of patients with hormone receptor-positive metastatic breast cancer receive chemotherapy as initial palliative therapy: a study of the Southeast Netherlands Breast Cancer Consortium.

PubMed

Lobbezoo, D J A; van Kampen, R J W; Voogd, A C; Dercksen, M W; van den Berkmortel, F; Smilde, T J; van de Wouw, A J; Peters, F P J; van Riel, J M G H; Peters, N A J B; de Boer, M; Peer, P G M; Tjan-Heijnen, V C G

2016-02-01

The objective of this study was to present initial systemic treatment choices and the outcome of hormone receptor-positive (HR+) metastatic breast cancer. All the 815 consecutive patients diagnosed with metastatic breast cancer in 2007-2009 in eight participating hospitals were identified. From the 611 patients with HR+ disease, a total of 520 patients with HER2-negative (HER2-) breast cancer were included. Initial palliative systemic treatment was registered. Progression-free survival (PFS) and overall survival (OS) per initial palliative systemic therapy were obtained using the Kaplan-Meier method and compared using the log-rank test. From the total of 520 patients with HR+/HER2- metastatic breast cancer, 482 patients (93%) received any palliative systemic therapy. Patients that received initial chemotherapy (n = 116) were significantly younger, had less comorbidity, had received more prior adjuvant systemic therapy and were less likely to have bone metastasis only compared with patients that received initial endocrine therapy (n = 366). Median PFS of initial palliative chemotherapy was 5.3 months [95% confidence interval (CI) 4.2-6.2] and of initial endocrine therapy 13.3 months (95% CI 11.3-15.5), with a median OS of 16.1 and 36.9 months, respectively. Initial chemotherapy was also associated with worse outcome in terms of PFS and OS after adjustment for prognostic factors. A high percentage of patients with HR+ disease received initial palliative chemotherapy, which was associated with worse outcome, even after adjustment of relevant prognostic factors. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Immunoadsorption (IAS) as a rescue therapy in SLE: considerations on safety and efficacy.

PubMed

Stummvoll, Georg H; Aringer, Martin; Jansen, Martin; Smolen, Josef S; Derfler, Kurt; Graninger, Winfried B

2004-11-30

In SLE, extracorporeal procedures aiming at reduction of immunoglobulin (Ig) and immune complexes (IC) are used as a rescue therapy. Plasma exchange (PE) has not been proven overall effective in SLE, and long-term treatment in particular has been associated with severe bacterial and viral infections. Immunoadsorption (IAS), in contrast, selectively removes Ig and IC and may thus be safer. We therefore investigated the rate of infections in SLE patients who were undergoing long-term IAS. 16 SLE patients were treated with > or = 10 courses of IAS, and nine patients with highly active disease received pulse cyclophosphamide (IVCP) therapy in parallel. We retrospectively analysed the records of all these patients for the occurrence of infections. Patients receiving IAS therapy plus IVCP were compared with 25 patients with similarly active disease treated with standard IVCP therapy within the same observation period. Patients receiving IAS without additional IVCP were compared with patients with similarly moderate disease activity receiving neither IAS nor IVCP. No potentially life-threatening viral infection occurred in IAS-treated patients and episodes of herpes zoster were equally distributed. No severe infection was observed during IAS without concomittant cyclophosphamide. As expected, more patients with highly active disease receiving IVCP experienced infections than those with less active disease (16 of 34 [47%] vs. 2 of 22 [9%], p < 0.04). On comparing the two groups with highly active disease, infections were similar (IAS+IVCP: 3 of 9 patients [33%], IVCP only: 5 of 25 [20%]), but one patient receiving IAS+IVCP died of septicaemia. Disease activity significantly decreased in both groups treated with IAS. IAS has an acceptable safety profile with regard to severe infections and appears safe with regard to severe viral disease. Highly active disease and IVCP therapy increase the risk of severe infections in SLE.

Infections during induction therapy for children with acute lymphoblastic leukemia. the role of sulfamethoxazole-trimethoprim (SMX-TMP) prophylaxis.

PubMed

Rungoe, Christine; Malchau, Emma Louise; Larsen, Line Nordahl; Schroeder, Henrik

2010-08-01

Bacteremias are frequent during induction therapy for acute lymphoblastic leukemia (ALL) in children. Antibacterial prophylaxis therapy may thus be warranted. The purpose of this study was to analyze the rate of infections during induction therapy in two cohorts of children with ALL where one cohort received prophylactic sulfamethoxazole-trimethoprim (SMX-TMP). All infections were registered through a retrospective non-randomized review of medical records of 171 consecutive children newly diagnosed with ALL below 15 years of age at diagnosis. A total of 85 children treated from 1992 to 2000 did not receive SMX-TMP, whereas 86 children treated from 2000 to 2008 received SMX-TMP 20 mg/kg in one daily oral dose during induction therapy. A total of 26% of all children had no febrile episodes during induction. Infections were more frequent in children below 5 years of age. Significantly fewer children receiving SMX-TMP developed fever (17% vs. 34%, P = 0.02) and bacteremia (20% vs. 45%, P = 0.0003). Especially children with non-high risk criteria had fewer infections when receiving prophylaxis. When adjusting for age, type of catheter, and SMX-TMP prophylaxis on the risk of bacteremia by a multiple Cox regression analysis, we found that age and prophylaxis, but not the type of catheter, were associated with a significantly reduced risk of bacteremia. Children with ALL receiving SMX-TMP prophylaxis during induction therapy experienced fewer febrile episodes, fewer days with fever demanding intravenous antibiotic treatment, and fewer episodes of bacteremia. Both SMX-TMP prophylaxis and age played significant independent roles for the occurrence of bacteremia. (c) 2010 Wiley-Liss, Inc.

Mediators and treatment matching in behavior therapy, cognitive therapy and cognitive behavior therapy for chronic insomnia.

PubMed

Harvey, Allison G; Dong, Lu; Bélanger, Lynda; Morin, Charles M

2017-10-01

To examine the mediators and the potential of treatment matching to improve outcome for cognitive behavior therapy (CBT) for insomnia. Participants were 188 adults (117 women; Mage = 47.4 years, SD = 12.6) meeting the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; text rev.; DSM-IV-TR; American Psychiatric Association [APA], 2000) diagnostic criteria for chronic insomnia (Mduration: 14.5 years, SD: 12.8). Participants were randomized to behavior therapy (BT; n = 63), cognitive therapy (CT; n = 65), or CBT (n = 60). The outcome measure was the Insomnia Severity Index (ISI). Hypothesized BT mediators were sleep-incompatible behaviors, bedtime variability (BTv), risetime variability (RTv) and time in bed (TIB). Hypothesized CT mediators were worry, unhelpful beliefs, and monitoring for sleep-related threat. The behavioral processes mediated outcome for BT but not CT. The cognitive processes mediated outcome in both BT and CT. The subgroup scoring high on both behavioral and cognitive processes had a marginally significant better outcome if they received CBT relative to BT or CT. The subgroup scoring relatively high on behavioral but low on cognitive processes and received BT or CBT did not differ from those who received CT. The subgroup scoring relatively high on cognitive but low on behavioral processes and received CT or CBT did not differ from those who received BT. The behavioral mediators were specific to BT relative to CT. The cognitive mediators were significant for both BT and CT outcomes. Patients exhibiting high levels of both behavioral and cognitive processes achieve better outcome if they receive CBT relative to BT or CT alone. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Interdisciplinary Cognitive-Behavioral Therapy as Part of Lumbar Spinal Fusion Surgery Rehabilitation: Experience of Patients With Chronic Low Back Pain.

PubMed

Lindgreen, Pil; Rolving, Nanna; Nielsen, Claus Vinther; Lomborg, Kirsten

2016-01-01

Patients receiving lumbar spinal fusion surgery often have persisting postoperative pain negatively affecting their daily life. These patients may be helped by interdisciplinary cognitive-behavioral therapy which is recognized as an effective intervention for improving beneficial pain coping behavior, thereby facilitating the rehabilitation process of patients with chronic pain. The purpose of this study was to describe the lived experience of patients recovering from lumbar spinal fusion surgery and to explore potential similarities and disparities in pain coping behavior between receivers and nonreceivers of interdisciplinary cognitive-behavioral group therapy. We conducted semistructured interviews with 10 patients; 5 receiving cognitive-behavioral therapy in connection with their lumbar spinal fusion surgery and 5 receiving usual care. We conducted a phenomenological analysis to reach our first aim and then conducted a comparative content analysis to reach our second aim. Patients' postoperative experience was characterized by the need to adapt to the limitations imposed by back discomfort (coexisting with the back), need for recognition and support from others regarding their pain, a relatively long rehabilitation period during which they "awaited the result of surgery", and ambivalence toward analgesics. The patients in both groups had similar negative perception of analgesics and tended to abstain from them to avoid addiction. Coping behavior apparently differed among receivers and nonreceivers of interdisciplinary cognitive-behavioral group therapy. Receivers prevented or minimized pain by resting before pain onset, whereas nonreceivers awaited pain onset before resting. The postoperative experience entailed ambivalence, causing uncertainty, worry and insecurity. This ambivalence was relieved when others recognized the patient's pain and offered support. Cognitive-behavioral therapy as part of rehabilitation may have encouraged beneficial pain coping behavior by altering patients' pain perception and coping behavior, thereby reducing adverse effects of pain.

Neuromuscular stimulation therapy after incomplete spinal cord injury promotes recovery of interlimb coordination during locomotion

NASA Astrophysics Data System (ADS)

Jung, R.; Belanger, A.; Kanchiku, T.; Fairchild, M.; Abbas, J. J.

2009-10-01

The mechanisms underlying the effects of neuromuscular electrical stimulation (NMES) induced repetitive limb movement therapy after incomplete spinal cord injury (iSCI) are unknown. This study establishes the capability of using therapeutic NMES in rodents with iSCI and evaluates its ability to promote recovery of interlimb control during locomotion. Ten adult female Long Evans rats received thoracic spinal contusion injuries (T9; 156 ± 9.52 Kdyne). 7 days post-recovery, 6/10 animals received NMES therapy for 15 min/day for 5 days, via electrodes implanted bilaterally into hip flexors and extensors. Six intact animals served as controls. Motor function was evaluated using the BBB locomotor scale for the first 6 days and on 14th day post-injury. 3D kinematic analysis of treadmill walking was performed on day 14 post-injury. Rodents receiving NMES therapy exhibited improved interlimb coordination in control of the hip joint, which was the specific NMES target. Symmetry indices improved significantly in the therapy group. Additionally, injured rodents receiving therapy more consistently displayed a high percentage of 1:1 coordinated steps, and more consistently achieved proper hindlimb touchdown timing. These results suggest that NMES techniques could provide an effective therapeutic tool for neuromotor treatment following iSCI.

Recurrent hemorrhage from corpus luteum during anticoagulant therapy.

PubMed Central

Wong, K. P.; Gillett, P. G.

1977-01-01

A 43-year old woman had recurrent massive intraperitoneal hemorrhage from rupture of a hemorrhagic corpus luteum in two successive menstrual cycles while receiving anticoagulant therapy. Left oophorectomy was performed on the first occasion and right salpingo-oophorectomy with left salpingectomy on the second. While the precise incidence cannot be determined, rupture from a hemorrhagic corpus luteum appears to be a rare but potentially catastrophic complication of anticoagulant therapy. Hence possible ovarian hemorrhage should be considered in women of reproductive age receiving heparin or sodium warfarin therapy. PMID:844024

[Magnetic therapy for complex treatment of chronic periodontal disease].

PubMed

P'yanzina, A V

The aim of the study was to elaborate the methodology of magnetic therapy for complex treatment of chronic periodontal disease (CPD). The study included 60 patients aged 35 to 65 years with moderate CPD divided in 2 groups. Patients in group 1 (controls) received impulse carbonate irrigation for 12 min №10, group 2 additionally received magnetic therapy for 5 min №10 in maxillary and mandibular areas. periodontal and rheological indices proved magnetic therapy to be useful tool for eradication of inflammation, periodontal tissue functional recovery and stabilization.

Assessing Adverse Events of Postprostatectomy Radiation Therapy for Prostate Cancer: Evaluation of Outcomes in the Regione Emilia-Romagna, Italy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Showalter, Timothy N., E-mail: tns3b@virginia.edu; Hegarty, Sarah E.; Division of Biostatistics, Department of Pharmacology and Experimental Therapeutics, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania

Purpose: Although the likelihood of radiation-related adverse events influences treatment decisions regarding radiation therapy after prostatectomy for eligible patients, the data available to inform decisions are limited. This study was designed to evaluate the genitourinary, gastrointestinal, and sexual adverse events associated with postprostatectomy radiation therapy and to assess the influence of radiation timing on the risk of adverse events. Methods: The Regione Emilia-Romagna Italian Longitudinal Health Care Utilization Database was queried to identify a cohort of men who received radical prostatectomy for prostate cancer during 2003 to 2009, including patients who received postprostatectomy radiation therapy. Patients with prior radiation therapymore » were excluded. Outcome measures were genitourinary, gastrointestinal, and sexual adverse events after prostatectomy. Rates of adverse events were compared between the cohorts who did and did not receive postoperative radiation therapy. Multivariable Cox proportional hazards models were developed for each class of adverse events, including models with radiation therapy as a time-varying covariate. Results: A total of 9876 men were included in the analyses: 2176 (22%) who received radiation therapy and 7700 (78%) treated with prostatectomy alone. In multivariable Cox proportional hazards models, the additional exposure to radiation therapy after prostatectomy was associated with increased rates of gastrointestinal (rate ratio [RR] 1.81; 95% confidence interval [CI] 1.44-2.27; P<.001) and urinary nonincontinence events (RR 1.83; 95% CI 1.83-2.80; P<.001) but not urinary incontinence events or erectile dysfunction. The addition of the time from prostatectomy to radiation therapy interaction term was not significant for any of the adverse event outcomes (P>.1 for all outcomes). Conclusion: Radiation therapy after prostatectomy is associated with an increase in gastrointestinal and genitourinary adverse events. However, the timing of radiation therapy did not influence the risk of radiation therapy–associated adverse events in this cohort, which contradicts the commonly held clinical tenet that delaying radiation therapy reduces the risk of adverse events.« less

Dysphagia management: an analysis of patient outcomes using VitalStim therapy compared to traditional swallow therapy.

PubMed

Kiger, Mary; Brown, Catherine S; Watkins, Lynn

2006-10-01

This study compares the outcomes using VitalStim therapy to outcomes using traditional swallowing therapy for deglutition disorders. Twenty-two patients had an initial and a followup videofluoroscopic swallowing study or fiberoptic endoscopic evaluation of swallowing and were divided into an experimental group that received VitalStim treatments and a control group that received traditional swallowing therapy. Outcomes were analyzed for changes in oral and pharyngeal phase dysphagia severity, dietary consistency restrictions, and progression from nonoral to oral intake. Results of chi(2) analysis showed no statistically significant difference in outcomes between the experimental and control groups.

Adjunct Systemic Corticosteroid Therapy in Children With Community-Acquired Pneumonia in the Outpatient Setting.

PubMed

Ambroggio, Lilliam; Test, Matthew; Metlay, Joshua P; Graf, Thomas R; Blosky, Mary Ann; Macaluso, Maurizio; Shah, Samir S

2015-03-01

The role of adjunct systemic corticosteroid therapy in children with community-acquired pneumonia (CAP) is not known. The objective was to determine the association between adjunct systemic corticosteroid therapy and treatment failure in children who received antibiotics for treatment of CAP in the outpatient setting. The study included a retrospective cohort study of children, aged 1-18 years, with a diagnosis of CAP who were managed at an outpatient practice affiliated with Geisinger Health System from January 1, 2008 to January 31, 2010. The primary exposure was the receipt of adjunct corticosteroid therapy. The primary outcome was treatment failure defined as a respiratory-associated follow-up within 14 days of diagnosis in which the participant received a change in antibiotic therapy. The probability of receiving adjunct systemic corticosteroid therapy was calculated using a matched propensity score. A multivariable conditional logistic regression model was used to estimate the association between adjunct corticosteroids and treatment failure. Of 2244 children with CAP, 293 (13%) received adjunct corticosteroids, 517 (23%) had underlying asthma, and 624 (28%) presented with wheezing. Most patients received macrolide monotherapy for their CAP diagnosis (n = 1329; 59%). Overall, treatment failure was not associated with adjunct corticosteroid treatment (odds ratio [OR], 1.72; 95% confidence interval [CI], 0.93 and 3.19), but the association was statistically significant among patients with no history of asthma (OR, 2.38; 95% CI, 1.03 and 5.52), with no statistical association among patients with a history of asthma. Adjunct corticosteroid therapy was associated with treatment failure among children diagnosed with CAP who did not have underlying asthma. © The Author 2014. Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

The Efficacy and Safety of Long-term Pirfenidone Therapy in Patients with Idiopathic Pulmonary Fibrosis.

PubMed

Ogawa, Kazumasa; Miyamoto, Atsushi; Hanada, Shigeo; Takahashi, Yui; Murase, Kyoko; Mochizuki, Sayaka; Uruga, Hironori; Takaya, Hisashi; Morokawa, Nasa; Kishi, Kazuma

2018-05-18

Objective Pirfenidone (PFD) is often used for years, but the efficacy and safety of long-term PFD therapy in patients with idiopathic pulmonary fibrosis (IPF) are not fully understood. Methods and Patients We retrospectively evaluated 46 patients with IPF who received PFD between February 2009 and August 2014. The efficacy and safety of PFD therapy were compared between 2 groups: long-term therapy patients who received PFD for over 1 year (group L, n=30, 65%) and short-term therapy patients who could not receive PFD for more than 1 year due to worsening of their condition or side effects (group S, n=16, 35%). Results The median age of the 46 patients was 70.5 years, and the median baseline % predicted forced vital capacity (%FVC) was 70.0%. The changes in the FVC in group L were -120 mL and -170 mL at 12 and 24 months after receiving PFD, respectively. The respective median survival times after PFD therapy in groups L and S were 1,612 days and 285 days (p<0.001). The patients in group L experienced a longer time free of acute exacerbation of IPF than those in group S (947 days vs. 145 days, p=0.001). A multivariate analysis revealed that %FVC <60% was a predictor of the inability to receive PFD for over 1 year (odds ratio 0.240, 95% confidence interval 0.060-0.958; p=0.043). With regard to grade 3-5 adverse events, only one patient exhibited grade 3 hyponatremia. Conclusions Long-term PFD therapy is effective, with few severe adverse events.

Hospital variation and the impact of postoperative complications on the use of perioperative chemo(radio)therapy in resectable gastric cancer. Results from the Dutch Upper GI Cancer Audit.

PubMed

Schouwenburg, M G; Busweiler, L A D; Beck, N; Henneman, D; Amodio, S; van Berge Henegouwen, M I; Cats, A; van Hillegersberg, R; van Sandick, J W; Wijnhoven, B P L; Wouters, M W J; Nieuwenhuijzen, G A P

2018-04-01

Dutch national guidelines on the diagnosis and treatment of gastric cancer recommend the use of perioperative chemotherapy in patients with resectable gastric cancer. However, adjuvant chemotherapy is often not administered. The aim of this study was to evaluate hospital variation on the probability to receive adjuvant chemotherapy and to identify associated factors with special attention to postoperative complications. All patients who received neoadjuvant chemotherapy and underwent an elective surgical resection for stage IB-IVa (M0) gastric adenocarcinoma between 2011 and 2015 were identified from a national database (Dutch Upper GI Cancer Audit). A multivariable linear mixed model was used to evaluate case-mix adjusted hospital variation and to identify factors associated with adjuvant therapy. Of all surgically treated gastric cancer patients who received neoadjuvant chemotherapy (n = 882), 68% received adjuvant chemo(radio)therapy. After adjusting for case-mix and random variation, a large hospital variation in the administration rates for adjuvant was observed (OR range 0.31-7.1). In multivariable analysis, weight loss, a poor health status and failure of neoadjuvant chemotherapy completion were strongly associated with an increased likelihood of adjuvant therapy omission. Patients with severe postoperative complications had a threefold increased likelihood of adjuvant therapy omission (OR 3.07 95% CI 2.04-4.65). Despite national guidelines, considerable hospital variation was observed in the probability of receiving adjuvant chemo(radio)therapy. Postoperative complications were strongly associated with adjuvant chemo(radio)therapy omission, underlining the need to further reduce perioperative morbidity in gastric cancer surgery. Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

[One-shot therapy and transcatheter arterial embolization (TAE) therapy of unresectable hepatocellular carcinoma].

PubMed

Tanikawa, K; Hirai, K; Kawazoe, Y; Yamashita, K; Kumagai, M; Abe, M

1985-10-01

407 cases of unresectable hepatocellular carcinoma (HCC) occurring from 1970 to March 1985, including 107 cases receiving conservative therapy, 176 cases receiving one-shot therapy and 124 cases receiving transcatheter arterial embolization (TAE) therapy, were studied and the efficacy of chemotherapy was compared with that of TAE therapy. The results were as follows; One-year survival rate was 2.8% with a median survival time of 1.3 months in conservative therapy. In the 176 cases of one-shot therapy, one-year survival rate was 21.0%, two-year 6.8% and three-year 2.3% and the median survival time was 4.8% months. In 120 cases of one-shot therapy which were compatible with criteria for one-shot injection of anticancer drugs via the hepatic artery for HCC, one-year survival rate was 30%. However the rate was 1.8% in 56 cases which were not compatible with the criteria. In 37 cases in which Mitomycin C (MMC) and Adriamycin (ADR) were administered alternately, one-year survival rate was 41.7%, two-year 16.1% and three-year 4.3%. The highest survival rate was obtained by TAE therapy. One-year survival rate was 66.9%, two-year 33.8% and three-year 28.9%. Decrease of AFP after therapy was noted in 42.4% of cases given one-shot therapy and in 95.2% of cases given TEA therapy. The results suggest that alternate administration of anticancer agents produces good chemotherapeutic effects and that the best life-prolongation is obtained by TAE therapy.

Cost effectiveness of ciprofloxacin plus metronidazole versus imipenem-cilastatin in the treatment of intra-abdominal infections.

PubMed

Walters, D J; Solomkin, J S; Paladino, J A

1999-11-01

To compare the cost effectiveness of sequential intravenous (i.v.) to oral ciprofloxacin plus metronidazole (CIP/MTZ i.v./PO) with that of i.v. ciprofloxacin plus i.v. metronidazole (CIP/MTZ i.v.) and i.v. imipenem-cilastatin (IMI i.v.) in patients with intra-abdominal infections. Patients enrolled in a double-blind randomised clinical trial were eligible for inclusion into this cost-effectiveness analysis. Decision analysis was used to characterise the economic outcomes between groups and provide a structure upon which to base the sensitivity analyses. 1996 cost values were used throughout. The economic perspective of the analysis was that of a hospital provider. Among 446 economically evaluable patients, 176 could be switched from i.v. to oral administration. The 51 patients randomised to CIP/MTZ i.v./PO who received active oral therapy had a success rate of 98%, mean duration of therapy of 9.1 days and mean cost of $US7678. There were 125 patients randomized to either CIP/MTZ i.v. or IMI i.v. who received oral placebo while continuing on active i.v. antibacterials; their success rate was 94%, mean duration of therapy was 10.1 days and mean cost was $US8774 (p = 0.029 vs CIP/MTZ i.v./PO). Of the 270 patients who were unable to receive oral administration, 97 received IMI i.v. and had a success rate of 75%, mean duration of therapy of 13.8 days and a mean cost of $US12,418, and 173 received CIP/MTZ i.v. and had a success rate of 77%, mean duration of therapy of 13.4 days and mean cost of $US12,219 (p = 0.26 vs IMI i.v.). In patients able to receive oral therapy, sequential i.v. to oral treatment with ciprofloxacin plus metronidazole was cost effective compared with full i.v. courses of ciprofloxacin plus metronidazole or imipenem-cilastatin. In patients unable to receive oral therapy, no difference in mean cost was found between i.v. imipenem-cilastatin or i.v. ciprofloxacin plus i.v. metronidazole.

Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG).

PubMed

Wang, Winfred C; Ware, Russell E; Miller, Scott T; Iyer, Rathi V; Casella, James F; Minniti, Caterina P; Rana, Sohail; Thornburg, Courtney D; Rogers, Zora R; Kalpatthi, Ram V; Barredo, Julio C; Brown, R Clark; Sarnaik, Sharada A; Howard, Thomas H; Wynn, Lynn W; Kutlar, Abdullah; Armstrong, F Daniel; Files, Beatrice A; Goldsmith, Jonathan C; Waclawiw, Myron A; Huang, Xiangke; Thompson, Bruce W

2011-05-14

Sickle-cell anaemia is associated with substantial morbidity from acute complications and organ dysfunction beginning in the first year of life. Hydroxycarbamide substantially reduces episodes of pain and acute chest syndrome, admissions to hospital, and transfusions in adults with sickle-cell anaemia. We assessed the effect of hydroxycarbamide therapy on organ dysfunction and clinical complications, and examined laboratory findings and toxic effects. This randomised trial was undertaken in 13 centres in the USA between October, 2003, and September, 2009. Eligible participants had haemoglobin SS (HbSS) or haemoglobin Sβ(0)thalassaemia, were aged 9-18 months at randomisation, and were not selected for clinical severity. Participants received liquid hydroxycarbamide, 20 mg/kg per day, or placebo for 2 years. Randomisation assignments were generated by the medical coordinating centre by a pre-decided schedule. Identical appearing and tasting formulations were used for hydroxycarbamide and placebo. Patients, caregivers, and coordinating centre staff were masked to treatment allocation. Primary study endpoints were splenic function (qualitative uptake on (99)Tc spleen scan) and renal function (glomerular filtration rate by (99m)Tc-DTPA clearance). Additional assessments included blood counts, fetal haemoglobin concentration, chemistry profiles, spleen function biomarkers, urine osmolality, neurodevelopment, transcranial Doppler ultrasonography, growth, and mutagenicity. Study visits occurred every 2-4 weeks. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00006400. 96 patients received hydroxycarbamide and 97 placebo, of whom 83 patients in the hydroxycarbamide group and 84 in the placebo group completed the study. Significant differences were not seen between groups for the primary endpoints (19 of 70 patients with decreased spleen function at exit in the hydroxycarbamide group vs 28 of 74 patients in the placebo group, p=0·21; and a difference in the mean increase in DTPA glomerular filtration rate in the hydroxycarbamide group versus the placebo group of 2 mL/min per 1·73 m(2), p=0·84). Hydroxycarbamide significantly decreased pain (177 events in 62 patients vs 375 events in 75 patients in the placebo group, p=0·002) and dactylitis (24 events in 14 patients vs 123 events in 42 patients in the placebo group, p<0·0001), with some evidence for decreased acute chest syndrome, hospitalisation rates, and transfusion. Hydroxyurea increased haemoglobin and fetal haemoglobin, and decreased white blood-cell count. Toxicity was limited to mild-to-moderate neutropenia. On the basis of the safety and efficacy data from this trial, hydroxycarbamide can now be considered for all very young children with sickle-cell anaemia. The US National Heart, Lung, and Blood Institute; and the National Institute of Child Health and Human Development. Copyright © 2011 Elsevier Ltd. All rights reserved.

Adjuvant neutron therapy in complex treatment of patients with locally advanced breast cancer

NASA Astrophysics Data System (ADS)

Lisin, V. A.; Velikaya, V. V.; Startseva, Zh. A.; Popova, N. O.; Goldberg, V. E.

2017-09-01

The study included 128 patients with stage T2-4N0-3M0 locally advanced breast cancer. All patients were divided into two groups. Group I (study group) consisted of 68 patients, who received neutron therapy, and group II (control group) comprised 60 patients, who received electron beam therapy. Neutron therapy was well tolerated by the patients and 1-2 grade radiation skin reactions were the most common. Neutron therapy was shown to be effective in multimodality treatment of the patients with locally advanced breast cancer. The 8-year recurrence-free survival rate in the patients with locally advanced breast cancer was 94.5 ± 4.1% after neutron therapy and 81.4 ± 5.9% after electron beam therapy (p = 0.05).

The impact of cognitive behavioral group training on event-free survival in patients with myocardial infarction: the ENRICHD experience.

PubMed

Saab, Patrice G; Bang, Heejung; Williams, Redford B; Powell, Lynda H; Schneiderman, Neil; Thoresen, Carl; Burg, Matthew; Keefe, Francis

2009-07-01

Although the Enhancing Recovery in Coronary Heart Disease (ENRICHD) treatment was designed to include individual therapy and cognitive behavioral group training for patients with depression and/or low perceived social support, only 31% of treated participants received group training. Secondary analyses classified intervention participants into two subgroups, (1) individual therapy only or (2) group training (i.e., coping skills training) plus individual therapy, to determine whether medical outcomes differed in participants who received the combination of group training and individual therapy compared to participants who received individual therapy only or usual care. Secondary analyses of 1243 usual care, 781 individual therapy only, and 356 group plus individual therapy myocardial infarction (MI) patients were performed. Depression was diagnosed using modified Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria; low perceived social support was determined by the ENRICHD Social Support Instrument. Psychosocial treatment followed MI, and for participants with severe or unremitting depression, was supplemented with a selective serotonin reuptake inhibitor. Cox proportional hazards regression was used to estimate intervention effects on time to first occurrence of the composite end point of death plus nonfatal MI. To control for confounding of group participation with survival (because individual sessions preceded group), we used risk set sampling to match minimal survival time of those receiving or not receiving group training. Analyses correcting for differential survival among comparison groups showed that group plus individual therapy was associated with a 33% reduction (hazard ratio=0.67; 95% confidence interval, 0.49-0.92, P=.01) in medical outcome compared to usual care. No significant effect on event-free survival was associated with individual therapy alone. The group training benefit was reduced to 23% (hazard ratio=0.77; 95% confidence interval: 0.56-1.07, P=.11) in the multivariate-adjusted model. Findings suggest that adding group training to individual therapy may be associated with reduction in the composite end point. A randomized controlled trial is warranted to definitively resolve this issue.

Is It All about the Higher Dose? Why Psychoanalytic Therapy Is an Effective Treatment for Major Depression.

PubMed

Zimmermann, Johannes; Löffler-Stastka, Henriette; Huber, Dorothea; Klug, Günther; Alhabbo, Sarah; Bock, Astrid; Benecke, Cord

2015-01-01

Empirical evidence for the effectiveness of long-term psychodynamic psychotherapy (LTPP) in patients with mood disorders is growing. However, it is unclear whether the effectiveness of LTPP is due to distinctive features of psychodynamic/psychoanalytic techniques or to a higher number of sessions. We tested these rival hypotheses in a quasi-experimental study comparing psychoanalytic therapy (i.e., high-dose LTPP) with psychodynamic therapy (i.e., low-dose LTPP) and cognitive-behavioural therapy (CBT) for depression. Analyses were based on a subsample of 77 subjects, with 27 receiving psychoanalytic therapy, 26 receiving psychodynamic therapy and 24 receiving CBT. Depressive symptoms, interpersonal problems and introject affiliation were assessed prior to treatment, after treatment and at the 1-, 2- and 3-year follow-ups. Psychoanalytic techniques were assessed from three audiotaped middle sessions per treatment using the Psychotherapy Process Q-Set. Subjects receiving psychoanalytic therapy reported having fewer interpersonal problems, treated themselves in a more affiliative way directly after treatment and tended to improve in depressive symptoms and interpersonal problems during follow-up as compared with patients receiving psychodynamic therapy and/or CBT. Multilevel mediation analyses suggested that post-treatment differences in interpersonal problems and introject affiliation were mediated by the higher number of sessions, and follow-up differences in depressive symptoms were mediated by the more pronounced application of psychoanalytic techniques. We also found some evidence for indirect treatment effects via psychoanalytic techniques on changes in introject affiliation during follow-up. These results provide support for the prediction that both a high dose and the application of psychoanalytic techniques facilitate therapeutic change in patients with major depression. Psychoanalytic therapy is an effective treatment for major depression, especially in the long run. The differential effectiveness of psychoanalytic therapy cannot be fully explained by its higher dose. Distinctive features of psychoanalytic technique (e.g., focusing on patients' dreams, fantasies, sexual experiences or childhood memories) may play an important role in establishing sustained therapeutic change. Copyright © 2014 John Wiley & Sons, Ltd.

Adding chemo after radiation treatment improves survival for adults with a type of brain tumor

Cancer.gov

Adults with low-grade gliomas, a form of brain tumor, who received chemotherapy following completion of radiation therapy lived longer than patients who received radiation therapy alone, according to long-term follow-up results from a NIH-supported random

Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial.

PubMed

Weaver, Frances M; Follett, Kenneth; Stern, Matthew; Hur, Kwan; Harris, Crystal; Marks, William J; Rothlind, Johannes; Sagher, Oren; Reda, Domenic; Moy, Claudia S; Pahwa, Rajesh; Burchiel, Kim; Hogarth, Penelope; Lai, Eugene C; Duda, John E; Holloway, Kathryn; Samii, Ali; Horn, Stacy; Bronstein, Jeff; Stoner, Gatana; Heemskerk, Jill; Huang, Grant D

2009-01-07

Deep brain stimulation is an accepted treatment for advanced Parkinson disease (PD), although there are few randomized trials comparing treatments, and most studies exclude older patients. To compare 6-month outcomes for patients with PD who received deep brain stimulation or best medical therapy. Randomized controlled trial of patients who received either deep brain stimulation or best medical therapy, stratified by study site and patient age (< 70 years vs > or = 70 years) at 7 Veterans Affairs and 6 university hospitals between May 2002 and October 2005. A total of 255 patients with PD (Hoehn and Yahr stage > or = 2 while not taking medications) were enrolled; 25% were aged 70 years or older. The final 6-month follow-up visit occurred in May 2006. Bilateral deep brain stimulation of the subthalamic nucleus (n = 60) or globus pallidus (n = 61). Patients receiving best medical therapy (n = 134) were actively managed by movement disorder neurologists. The primary outcome was time spent in the "on" state (good motor control with unimpeded motor function) without troubling dyskinesia, using motor diaries. Other outcomes included motor function, quality of life, neurocognitive function, and adverse events. Patients who received deep brain stimulation gained a mean of 4.6 h/d of on time without troubling dyskinesia compared with 0 h/d for patients who received best medical therapy (between group mean difference, 4.5 h/d [95% CI, 3.7-5.4 h/d]; P < .001). Motor function improved significantly (P < .001) with deep brain stimulation vs best medical therapy, such that 71% of deep brain stimulation patients and 32% of best medical therapy patients experienced clinically meaningful motor function improvements (> or = 5 points). Compared with the best medical therapy group, the deep brain stimulation group experienced significant improvements in the summary measure of quality of life and on 7 of 8 PD quality-of-life scores (P < .001). Neurocognitive testing revealed small decrements in some areas of information processing for patients receiving deep brain stimulation vs best medical therapy. At least 1 serious adverse event occurred in 49 deep brain stimulation patients and 15 best medical therapy patients (P < .001), including 39 adverse events related to the surgical procedure and 1 death secondary to cerebral hemorrhage. In this randomized controlled trial of patients with advanced PD, deep brain stimulation was more effective than best medical therapy in improving on time without troubling dyskinesias, motor function, and quality of life at 6 months, but was associated with an increased risk of serious adverse events. clinicaltrials.gov Identifier: NCT00056563.

A retrospective study of treatment persistence and adherence to α-blocker plus antimuscarinic combination therapies, in men with LUTS/BPH in the Netherlands.

PubMed

Drake, Marcus J; Bowditch, Sally; Arbe, Emilio; Hakimi, Zalmai; Guelfucci, Florent; Amri, Ikbel; Nazir, Jameel

2017-05-22

To assess treatment persistence and adherence in men ≥45 years of age with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH), using prescription records from the Netherlands IMS Lifelink™ LRx database. In this retrospective, observational cohort study, we identified men who received combination therapy with an α-blocker plus an antimuscarinic (e.g. solifenacin or tolterodine) between 1 November 2013 and 31 October 2014. Treatment could be received as a fixed-dose combination (FDC) tablet or as two drugs administered together (concomitant therapy), if both combination drugs were prescribed within 30 days. The primary objective was to assess treatment persistence, defined as the time from initiation of combination therapy until first discontinuation of the FDC or at least one of the drugs given concomitantly (i.e. ≥30 days without prescription renewal). Subgroup and sensitivity analyses were conducted to assess persistence by antimuscarinic agent, and with different gap lengths used to define discontinuation (45, 60 and 90 days), respectively. A total of 1891 men received an α-blocker plus an antimuscarinic (FDC, N = 665; concomitant therapy, N = 1226). Median time to discontinuation was significantly longer with FDC versus concomitant therapy (414 vs. 112 days; adjusted hazard ratio [HR] 2.04, 95% confidence interval 1.77, 2.35; p < 0.0001). Persistence at 12 months (51.3% vs. 29.9%) was also significantly greater with FDC compared with concomitant therapy. Assessment of antimuscarinic subgroups showed that median time to discontinuation was longest with solifenacin combinations (214 days) compared with other antimuscarinic combinations (range, 47-164 days; adjusted HR range, 1.27-1.77, p = 0.037). No observable impact on treatment persistence was found by adjusting the gaps used to define discontinuation. This study of real-world evidence of men with LUTS/BPH treated with α-blocker plus antimuscarinic combination therapy in the Netherlands showed that treatment persistence was significantly greater in those who received a FDC tablet compared with combination therapy given concomitantly. The study also shows that treatment persistence was extended in men who received combination therapy containing solifenacin compared with other antimuscarinics. Overall, these findings may be useful for prescribers, as improved persistence on-treatment may translate into improved outcomes for men with LUTS/BPH. Further study is warranted to establish the key drivers of persistence in men receiving combination therapy for LUTS/BPH.

Visual Outcomes in Pediatric Optic Pathway Glioma After Conformal Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Awdeh, Richard M.; Kiehna, Erin N.; Drewry, Richard D.

Purpose: To assess visual outcome prospectively after conformal radiation therapy (CRT) in children with optic pathway glioma. Methods and Materials: We used CRT to treat optic pathway glioma in 20 children (median age 9.3 years) between July 1997 and January 2002. We assessed changes in visual acuity using the logarithm of the minimal angle of resolution after CRT (54 Gy) with a median follow-up of 24 months. We included in the study children who underwent chemotherapy (8 patients) or resection (9 patients) before CRT. Results: Surgery played a major role in determining baseline (pre-CRT) visual acuity (better eye: P=.0431; worsemore » eye: P=.0032). The visual acuity in the worse eye was diminished at baseline (borderline significant) with administration of chemotherapy before CRT (P=.0726) and progression of disease prior to receiving CRT (P=.0220). In the worse eye, improvement in visual acuity was observed in patients who did not receive chemotherapy before CRT (P=.0289). Conclusions: Children with optic pathway glioma initially treated with chemotherapy prior to receiving radiation therapy have decreased visual acuity compared with those who receive primary radiation therapy. Limited surgery before radiation therapy may have a role in preserving visual acuity.« less

A post-hoc analysis of music therapy services for residents in nursing homes receiving hospice care.

PubMed

Hilliard, Russell E

2004-01-01

This study analyzed the use of music therapy for residents in nursing homes receiving hospice care. An ex-post facto design was utilized to evaluate participants' length of life on the hospice program, time of death in relation to last visit by the social worker and music therapist, the number of sessions and total number of minutes spent in direct care by the social worker and music therapist, and care plan needs treated by the nurse, social worker, and music therapist. A total of 80 participants' medical records were randomly selected for this study. All participants were in nursing homes, 40 of whom had been referred to music therapy. Results showed no significant differences on the time of death in relation to last visit by hospice professional, but there were significant differences in the length of life for those receiving music therapy. Females in this study lived significantly longer than males. Participants received significantly more music therapy sessions than social work sessions, and music therapists spent significantly more time in direct care with participants than did social workers. Care plan needs were analyzed graphically and indicate that music therapists meet important needs of participants.

The effects of psychotherapy on behavior problems of sexually abused deaf children.

PubMed

Sullivan, P M; Scanlan, J M; Brookhouser, P E; Schulte, L E; Knutson, J F

1992-01-01

This study assessed the effectiveness of a broad based psychotherapeutic intervention with a sample of 72 children sexually abused at a residential school for the deaf. An untreated comparison group emerged when about half of their parents refused the offer for psychotherapy provided by the school. Treated and untreated children were randomly assigned to two assessment groups: those who participated in a pretreatment assessment and those who did not. Houseparents at the residential school used the Child Behavior Checklist (CBC) to rate the pretreatment assessment children before treatment and all 72 children one year after the implementation of psychotherapy. Children receiving therapy had significantly fewer behavior problems than children not receiving therapy. There was a differential response to therapy on the basis of sex. Boys receiving therapy had significantly lower scores on the following CBC scales than the no treatment group: Total, Internal, External, Somatic, Uncommunicative, Immature, Hostile, Delinquent, Aggressive, and Hyperactive. There were no differences on the Schizoid and Obsessive scales. Girls receiving therapy had significantly lower scores than the no treatment group on the following CBC scales: Total, External, Depressed, Aggressive, and Cruel. There were no differences on the Internal, Anxious, Schizoid, Immature, Somatic, and Delinquent scales.

Efficacy of palonosetron and 1-day dexamethasone in moderately emetogenic chemotherapy compared with fosaprepitant, granisetron, and dexamethasone: a prospective randomized crossover study.

PubMed

Kitayama, Hiromitsu; Tsuji, Yasushi; Sugiyama, Junko; Doi, Ayako; Kondo, Tomohiro; Hirayama, Michiaki

2015-12-01

Although palonosetron (PALO) and NK1 receptor antagonist both reduce chemotherapy-induced nausea and vomiting, no comparison trial in moderately emetogenic chemotherapy (MEC) had been reported. The purpose of this study was to find out which drug combinations are preferable for patients receiving MEC. Chemotherapy-naive patients receiving MEC were randomized to two groups; group A first received PALO therapy [PALO plus 1-day dexamethasone (DEX)], and group B first received fosaprepitant (FAPR) therapy [FAPR, granisetron (GRAN), and DEX]. Patients were re-allocated to the other therapy, respectively, for the second cycle of chemotherapy. We administered intravenous PALO (0.75 mg) and DEX (9.9 mg) to the PALO therapy group, and FAPR (150 mg), DEX (4.95 mg), and GRAN (3 mg) to the FAPR therapy group, on Day 1. Complete response (CR) was the primary endpoint; complete control (CC), total control (CT), and the therapy chosen by the patients for their third and following cycles of antiemetic therapy were the secondary endpoints. We evaluated CR, CC, and TC in the acute phase, in the delayed phase, and over the whole period. A total of 35 patients and 70 cycles of therapy was evaluable for analysis. No significant difference was found at all evaluation points. Overall CR rates for PALO and FAPR therapy were 74 vs 69 % (P = 0.567), CC rates 66 vs 69 % (P = 0.521), and TC rates 46 vs 60 % (P = 0.235), respectively. Patients also showed no clear preference for their third and following cycles of chemotherapy, choosing both regimens almost equally often (PALO 10 vs FAPR 13). PALO and 1-day DEX is almost equivalent to FAPR, GRAN, and DEX for MEC.

Prediction model of critical weight loss in cancer patients during particle therapy.

PubMed

Zhang, Zhihong; Zhu, Yu; Zhang, Lijuan; Wang, Ziying; Wan, Hongwei

2018-01-01

The objective of this study is to investigate the predictors of critical weight loss in cancer patients receiving particle therapy, and build a prediction model based on its predictive factors. Patients receiving particle therapy were enroled between June 2015 and June 2016. Body weight was measured at the start and end of particle therapy. Association between critical weight loss (defined as >5%) during particle therapy and patients' demographic, clinical characteristic, pre-therapeutic nutrition risk screening (NRS 2002) and BMI were evaluated by logistic regression and decision tree analysis. Finally, 375 cancer patients receiving particle therapy were included. Mean weight loss was 0.55 kg, and 11.5% of patients experienced critical weight loss during particle therapy. The main predictors of critical weight loss during particle therapy were head and neck tumour location, total radiation dose ≥70 Gy on the primary tumour, and without post-surgery, as indicated by both logistic regression and decision tree analysis. Prediction model that includes tumour locations, total radiation dose and post-surgery had a good predictive ability, with the area under receiver operating characteristic curve 0.79 (95% CI: 0.71-0.88) and 0.78 (95% CI: 0.69-0.86) for decision tree and logistic regression model, respectively. Cancer patients with head and neck tumour location, total radiation dose ≥70 Gy and without post-surgery were at higher risk of critical weight loss during particle therapy, and early intensive nutrition counselling or intervention should be target at this population. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Performance of a Nomogram Predicting Disease-Specific Survival After an R0 Resection for Gastric Cancer in Patients Receiving Postoperative Chemoradiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dikken, Johan L.; Department of Surgery, Leiden University Medical Center, Leiden; Coit, Daniel G.

Purpose: The internationally validated Memorial Sloan-Kettering Cancer Center (MSKCC) gastric carcinoma nomogram was based on patients who underwent curative (R0) gastrectomy, without any other therapy. The purpose of the current study was to assess the performance of this gastric cancer nomogram in patients who received chemoradiation therapy after an R0 resection for gastric cancer. Methods and Materials: In a combined dataset of 76 patients from the Netherlands Cancer Institute (NKI), and 63 patients from MSKCC, who received postoperative chemoradiation therapy (CRT) after an R0 gastrectomy, the nomogram was validated by means of the concordance index (CI) and a calibration plot. Results:more » The concordance index for the nomogram was 0.64, which was lower than the CI of the nomogram for patients who received no adjuvant therapy (0.80). In the calibration plot, observed survival was approximately 20% higher than the nomogram-predicted survival for patients receiving postoperative CRT. Conclusions: The MSKCC gastric carcinoma nomogram significantly underpredicted survival for patients in the current study, suggesting an impact of postoperative CRT on survival in patients who underwent an R0 resection for gastric cancer, which has been demonstrated by randomized controlled trials. This analysis stresses the need for updating nomograms with the incorporation of multimodal strategies.« less

Analysis of Factors Associated With Radiation-Induced Bronchiolitis Obliterans Organizing Pneumonia Syndrome After Breast-Conserving Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Katayama, Norihisa; Sato, Shuhei; Katsui, Kuniaki

Purpose: To evaluate factors associated with radiation-induced bronchiolitis obliterans organizing pneumonia (BOOP) syndrome after breast-conserving therapy. Methods and Materials: A total of 702 women with breast cancer who received radiotherapy after breast-conserving surgery at seven institutions between July 1995 and December 2006 were analyzed. In all patients, the whole breast was irradiated with two tangential photon beams. The criteria used for the diagnosis of radiation-induced BOOP syndrome were as follows: (1) radiotherapy to the breast within 12 months, (2) general and/or respiratory symptoms lasting for {>=}2 weeks, (3) radiographs showing lung infiltration outside the radiation port, and (4) no evidencemore » of a specific cause. Results: Radiation-induced BOOP syndrome was seen in 16 patients (2.3%). Eleven patients (68.8%) were administered steroids. The duration of steroid administration ranged from 1 week to 3.7 years (median, 1.1 years). Multivariate analysis revealed that age ({>=}50 years; odds ratio [OR] 8.88; 95% confidence interval [CI] 1.16-67.76; p = 0.04) and concurrent endocrine therapy (OR 3.05; 95% CI 1.09-8.54; p = 0.03) were significantly associated with BOOP syndrome. Of the 161 patients whose age was {>=}50 years and who received concurrent endocrine therapy, 10 (6.2%) developed BOOP syndrome. Conclusions: Age ({>=}50 years) and concurrent endocrine therapy can promote the development of radiation-induced BOOP syndrome after breast-conserving therapy. Physicians should carefully follow patients who received breast-conserving therapy, especially those who are older than 50 years and received concurrent endocrine therapy during radiotherapy.« less

Retrospective analysis of antiretroviral therapy uptake and retention of male clients receiving methadone maintenance therapy in two provinces in Vietnam: potential synergy of the two therapies.

PubMed

Pham, Linh Thi Thuy; Kitamura, Akiko; Do, Hoa Mai; Lai, Kim Anh; Le, Nhan Tuan; Nguyen, Van Thi Thuy; Kato, Masaya

2017-02-17

Vietnam has a concentrated HIV epidemic with injection drug use being the dominant mode of HIV transmission. Vietnam has rapidly expanded antiretroviral therapy (ART) and methadone maintenance therapy (MMT). This study aims to analyze ART uptake and retention among male clients receiving MMT in Vietnam in the early phase of the MMT program. The male clients (age ≥18) who were newly enrolled in care or started ART at two HIV clinics in Hanoi (2009 to 2011) and three HIV clinics in Can Tho (2010 to 2012) were included for the analysis. The CD4 lymphocyte count at HIV care enrollment and ART initiation and retention on ART were retrospectively analyzed. The values of those receiving MMT were compared with the values of two groups: those in whom injection drug use (IDU) status was documented, but were not receiving MMT, and all male clients not receiving MMT. To analyze retention, survival analysis with log rank test and Cox proportional hazard model was used. During the study period, 663 adult men were newly enrolled in HIV care (237 had IDU status documented) and 456 initiated ART (167 had IDU status documented). Among those who initiated ART, 28 were receiving MMT. At care enrolment, those receiving MMT had a median CD4 count of 230 (IQR 57-308) cells/mm 3 , while men self-reporting IDU and not receiving MMT and all men not receiving MMT had a median CD4 count of 158 (IQR 50-370) cells/mm 3 and 143 (IQR 35-366) cells/mm 3 , respectively. At ART initiation, men receiving MMT had significantly higher CD4 count with median at 203 (IQR 64-290) cells/mm 3 than men self-reporting IDU and not receiving MMT (80, IQR 40-220, cells/mm 3 , p = 0.038) and all men not receiving MMT (76, IQR 20-199, cells/mm 3 , p = 0.009). Those receiving MMT had a significantly higher retention rate than those self-reporting IDU but not receiving MMT (hazard ratio = 0.18, p = 0.019) and men not receiving MMT (hazard ratio = 0.20, p = 0.041). Our analysis suggests that men receiving MMT in Vietnam are achieving relatively early uptake and high retention rates on ART. The findings support potential benefits of integrating MMT and ART services in Vietnam.

Switch maintenance therapy with docetaxel and bevacizumab after induction therapy with cisplatin, pemetrexed, and bevacizumab in advanced non-squamous non-small cell lung cancer: a phase II study.

PubMed

Nishimoto, Koji; Karayama, Masato; Inui, Naoki; Yasui, Hideki; Hozumi, Hironao; Suzuki, Yuzo; Furuhashi, Kazuki; Fujisawa, Tomoyuki; Enomoto, Noriyuki; Nakamura, Yutaro; Inami, Nao; Matsuura, Shun; Kaida, Yusuke; Matsui, Takashi; Asada, Kazuhiro; Matsuda, Hiroyuki; Fujii, Masato; Toyoshima, Mikio; Imokawa, Shiro; Suda, Takafumi

2018-06-16

Switch maintenance therapy, using alternative agents that were not administered during induction chemotherapy, is a treatment option for advanced non-squamous non-small cell lung cancer (NSCLC). Bevacizumab is known to increase the efficacy of other chemotherapeutic agents; however, switch maintenance therapy with docetaxel and bevacizumab has not been adequately studied. The goal of this study was to evaluate the efficacy and safety of switch maintenance therapy with docetaxel and bevacizumab following induction therapy with cisplatin, pemetrexed, and bevacizumab. Chemotherapy-naïve non-squamous NSCLC patients received induction therapy of four cycles of cisplatin (75 mg/m 2 ), pemetrexed (500 mg/m 2 ), and bevacizumab (15 mg/kg). Patients who achieved disease control after induction therapy then received maintenance therapy with docetaxel (50 mg/m 2 ) and bevacizumab (15 mg/kg) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival from enrollment. This study enrolled 49 NSCLC patients, among which 38 (77.6%) completed the four cycles of induction therapy and received maintenance therapy. The median progression-free survival from enrollment was 7.8 months (95% confidence interval: 4.7-11.0 months). The most common toxicities of grade 3 or higher were neutropenia (68.4%), leukopenia (50.0%), febrile neutropenia (31.8%), and hypertension. Switch maintenance therapy with docetaxel and bevacizumab following induction therapy with cisplatin, pemetrexed, and bevacizumab demonstrated modest efficacy and frequent hematologic toxicity in non-squamous NSCLC patients.

Influence of Music Therapy on Coping Skills and Anger Management in Forensic Psychiatric Patients: An Exploratory Study.

PubMed

Hakvoort, Laurien; Bogaerts, Stefan; Thaut, Michael H; Spreen, Marinus

2015-07-01

The effect of music therapy on anger management and coping skills is an innovative subject in the field of forensic psychiatry. This study explores the following research question: Can music therapy treatment contribute to positive changes in coping skills, anger management, and dysfunctional behavior of forensic psychiatric patients? To investigate this question, first a literature review is offered on music therapy and anger management in forensic psychiatry. Then, an explorative study is presented. In the study, a pre- and post-test design was used with a random assignment of patients to either treatment or control condition. Fourteen participants' complete datasets were collected. All participants received "treatment as usual." Nine of the participants received a standardized, music therapy anger management program; the five controls received, unplanned, an aggression management program. Results suggested that anger management skills improved for all participants. The improvement of positive coping skills and diminishing of avoidance as a coping skill were measured to show greater changes in music therapy participants. When controlling for the exact number of treatment hours, the outcomes suggested that music therapy might accelerate the process of behavioral changes. © The Author(s) 2013.

Dyslipidemia in HIV Infected Children Receiving Highly Active Antiretroviral Therapy.

PubMed

Mandal, Anirban; Mukherjee, Aparna; Lakshmy, R; Kabra, Sushil K; Lodha, Rakesh

2016-03-01

To assess the prevalence of dyslipidemia and lipodystrophy in Indian children receiving non-nucleoside reverse transcriptase inhibitor (NNRTI) based highly active antiretroviral therapy (HAART) and to determine the associated risk factors for the same. The present cross-sectional study was conducted at a Pediatric Clinic of a tertiary care teaching center in India, from May 2011 through December 2012. HIV infected children aged 5-15 y were enrolled if they did not have any severe disease or hospital admission within last 3 mo or receive any medications known to affect the lipid profile. Eighty-one children were on highly active antiretroviral therapy (HAART) for at least 6 mo and 16 were receiving no antiretroviral therapy (ART). Participants' sociodemographic, nutritional, clinical, and laboratory data were recorded in addition to anthropometry and evidence of lipodystrophy. Fasting lipid profile, apolipoprotein A1 and B levels were done for all the children. Among the children on highly active antiretroviral therapy (HAART), 38.3 % had dyslipidemia and 80.2 % had lipodystrophy, while 25 % antiretroviral therapy (ART) naïve HIV infected children had dyslipidemia. No clinically significant risk factors could be identified that increased the risk of dyslipidemia or lipodystrophy in children on highly active antiretroviral therapy (HAART). There is a high prevalence of dyslipidemia and lipodystrophy in Indian children with HIV infection with an imminent need to establish facilities for testing and treatment of these children for metabolic abnormalities.

Mirror therapy enhances upper extremity motor recovery in stroke patients.

PubMed

Mirela Cristina, Luca; Matei, Daniela; Ignat, Bogdan; Popescu, Cristian Dinu

2015-12-01

The purpose of this study was to evaluate the effects of mirror therapy program in addition with physical therapy methods on upper limb recovery in patients with subacute ischemic stroke. 15 subjects followed a comprehensive rehabilitative treatment, 8 subjects received only control therapy (CT) and 7 subjects received mirror therapy (MT) for 30 min every day, five times a week, for 6 weeks in addition to the conventional therapy. Brunnstrom stages, Fugl-Meyer Assessment (upper extremity), the Ashworth Scale, and Bhakta Test (finger flexion scale) were used to assess changes in upper limb motor recovery and motor function after intervention. After 6 weeks of treatment, patients in both groups showed significant improvements in the variables measured. Patients who received MT showed greater improvements compared to the CT group. The MT treatment results included: improvement of motor functions, manual skills and activities of daily living. The best results were obtained when the treatment was started soon after the stroke. MT is an easy and low-cost method to improve motor recovery of the upper limb.

Therapy service use in children and adolescents with cerebral palsy: An Australian perspective.

PubMed

Meehan, Elaine; Harvey, Adrienne; Reid, Susan M; Reddihough, Dinah S; Williams, Katrina; Crompton, Kylie E; Omar, Suhaila; Scheinberg, Adam

2016-03-01

The aim of this study was to describe the patterns of therapy service use for a sample of children and adolescents with cerebral palsy over a 1 year period and to identify factors associated with frequency of therapy and parental satisfaction with therapy frequency. Parents of 83 children completed a survey on their child's use of occupational therapy, physiotherapy and speech and language pathology services over the previous year. Participants were randomly selected from a sample stratified by age and Gross Motor Function Classification System (GMFCS) level. During the year prior to survey completion, 83% of children had received occupational therapy, 88% had received physiotherapy and 60% had received speech and language pathology services. Frequency of therapy was higher for younger children (P < 0.01), those classified at GMFCS levels IV-V (P < 0.05) and those attending schools specifically for children with disabilities. Current structures for therapy service delivery for children with cerebral palsy are systems-based, and age-based funding systems and the organisation of services around the education system are preventing the delivery of needs-based therapy. Paediatricians that care for children and young people with cerebral palsy need to pay particular attention to those that may miss out on therapy due to age or school type, and support these families in accessing appropriate therapy. © 2015 The Authors. Journal of Paediatrics and Child Health © 2015 Paediatrics and Child Health Division (Royal Australasian College of Physicians).

Topiramate increases the risk of valproic acid-induced encephalopathy.

PubMed

Noh, Young; Kim, Dong Wook; Chu, Kon; Lee, Soon-Tae; Jung, Keun-Hwa; Moon, Hye-Jin; Lee, Sang Kun

2013-01-01

Metabolic encephalopathy is a rare but serious complication of valproic acid (VPA) therapy that usually presents with impaired consciousness or increased seizure frequency. Although it has been suggested that topiramate (TPM) increases the risk of VPA-induced encephalopathy, the additional risk in patients receiving TPM therapy has not been evaluated. We reviewed all adult patients who took VPA between January 2005 and February 2009 at the Seoul National University Hospital and identified patients with VPA-induced encephalopathy based on clinical and electroencephalography (EEG) data. Information on sex, age, serum ammonia level, serum VPA level, liver function test, and EEG was collected from patient registry and medical data. We enrolled 8,372 patients who received VPA therapy and 1,236 patients who received VPA/TPM combination therapy. We identified 11 patients with VPA-induced encephalopathy (0.13%), 7 of whom received a combination therapy of VPA and TPM. The odds ratio of VPA-induced encephalopathy with TPM over that without TPM was 10.16. There were no significant differences in sex distribution, number of antiepileptic agents, ammonia level, VPA serum level, underlying diseases, dosage of VPA, duration of VPA treatment, treatment of encephalopathy, and outcomes between the two groups. Our study showed that the prevalence of VPA-induced encephalopathy is approximately 0.1% among patients treated with VPA and that the risk of this condition, although still low, can increase by approximately 10 times in the presence of TPM therapy. Based on these results, we suggest that TPM should be carefully used in patients receiving VPA treatment. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

Clinical outcomes in children with herpes simplex encephalitis receiving steroid therapy.

PubMed

Maraş Genç, Hülya; Uyur Yalçın, Emek; Sayan, Murat; Bayhan, Asuman; Öncel, Selim; Arısoy, Emin Sami; Kara, Bülent

2016-07-01

Herpes simplex virus encephalitis (HSE) is a significant cause of morbidity and mortality. Neurologic sequelae are common even after early initiation of acyclovir treatment. The host immune response during HSE can also lead to brain damage. There are an increasing number of reports favoring steroid use in HSE. We aimed to compare the prognosis of children with HSE with and without steroid therapy. We retrospectively screened our hospital archive from 2009 to 2014 for patients diagnosed with HSE with a positive result for herpes simplex virus polymerase chain reaction in cerebrospinal fluid. Patients ≥1 month and ≤18 years at diagnosis were included in the study. Clinical outcomes in terms of cognitive function, motor function, electroencephalographic findings, seizure frequency, and radiologic findings were compared in patients who received adjuvant steroid therapy with those who did not. Six patients (1 boy, 5 girls; aged 4 months to 10 years) were included. Overall symptom duration before hospital admission was ≤5days. Patients received acyclovir treatment for 21-28days. Three received steroid therapy early during the disease and three patients did not. No adverse effects related to steroids were observed. Follow-up duration was 6 months to 5 years. All patients had radiologic sequelae of encephalitis. Cognition, motor function, and seizure control were better in patients who received steroid therapy. Adjuvant steroid therapy seems to be effective in decreasing morbidity in children with HSE but the radiologic sequelae were the same in both groups. Copyright © 2016 Elsevier B.V. All rights reserved.

Vitiligo-like lesions occurring in patients receiving anti-programmed cell death-1 therapies are clinically and biologically distinct from vitiligo.

PubMed

Larsabal, Maiana; Marti, Aurélie; Jacquemin, Clément; Rambert, Jérôme; Thiolat, Denis; Dousset, Léa; Taieb, Alain; Dutriaux, Caroline; Prey, Sorilla; Boniface, Katia; Seneschal, Julien

2017-05-01

The use of anti-programmed cell death (PD)-1 therapies in metastatic tumors is associated with cutaneous side effects including vitiligo-like lesions. We sought to characterize clinically and biologically vitiligo-like lesions occurring in patients receiving anti-PD-1 therapies by studying a case series of 8 patients with metastatic tumors and 30 control subjects with vitiligo. Eight patients receiving anti-PD-1 therapies with features of vitiligo-like lesions seen in our department were recruited. Clinical features and photographs were analyzed. For some patients, skin and blood samples were obtained. Results were compared with the vitiligo group. All patients developed lesions localized on photoexposed areas with a specific depigmentation pattern consisting of multiple flecked lesions without Koebner phenomenon. In contrast to vitiligo, patients receiving anti-PD-1 therapies who developed vitiligo-like lesions did not report any personal or family histories of vitiligo, thyroiditis, or other autoimmune disorders. Analysis of blood and skin samples revealed increased C-X-C motif ligand 10 levels in serum of patients developing vitiligo-like lesions, associated with skin infiltration of CD8 T-cells expressing C-X-C motif receptor 3 and producing elevated levels of interferon-γ and tumor necrosis factor-alfa. This cross-sectional study concerned a single center. Clinical and biological patterns of vitiligo-like lesions occurring in patients receiving anti-PD-1 therapies differ from vitiligo, suggesting a different mechanism. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Associations of ATM Polymorphisms With Survival in Advanced Esophageal Squamous Cell Carcinoma Patients Receiving Radiation Therapy.

PubMed

Du, Zhongli; Zhang, Wencheng; Zhou, Yuling; Yu, Dianke; Chen, Xiabin; Chang, Jiang; Qiao, Yan; Zhang, Meng; Huang, Ying; Wu, Chen; Xiao, Zefen; Tan, Wen; Lin, Dongxin

2015-09-01

To investigate whether single nucleotide polymorphisms (SNPs) in the ataxia telangiectasia mutated (ATM) gene are associated with survival in patients with esophageal squamous cell carcinoma (ESCC) receiving radiation therapy or chemoradiation therapy or surgery only. Four tagSNPs of ATM were genotyped in 412 individuals with clinical stage III or IV ESCC receiving radiation therapy or chemoradiation therapy, and in 388 individuals with stage I, II, or III ESCC treated with surgery only. Overall survival time of ESCC among different genotypes was estimated by Kaplan-Meier plot, and the significance was examined by log-rank test. The hazard ratios (HRs) and 95% confidence intervals (CIs) for death from ESCC among different genotypes were computed by a Cox proportional regression model. We found 2 SNPs, rs664143 and rs664677, associated with survival time of ESCC patients receiving radiation therapy. Individuals with the rs664143A allele had poorer median survival time compared with the rs664143G allele (14.0 vs 20.0 months), with the HR for death being 1.45 (95% CI 1.12-1.89). Individuals with the rs664677C allele also had worse median survival time than those with the rs664677T allele (14.0 vs 23.5 months), with the HR of 1.57 (95% CI 1.18-2.08). Stratified analysis showed that these associations were present in both stage III and IV cancer and different radiation therapy techniques. Significant associations were also found between the SNPs and locosregional progression or progression-free survival. No association between these SNPs and survival time was detected in ESCC patients treated with surgery only. These results suggest that the ATM polymorphisms might serve as independent biomarkers for predicting prognosis in ESCC patients receiving radiation therapy. Copyright © 2015 Elsevier Inc. All rights reserved.

Magnetic resonance imaging/angiography and transcranial Doppler velocities in sickle cell anemia: results from the SWiTCH trial

PubMed Central

Helton, Kathleen J.; Adams, Robert J.; Kesler, Karen L.; Lockhart, Alex; Aygun, Banu; Driscoll, Catherine; Heeney, Matthew M.; Jackson, Sherron M.; Krishnamurti, Lakshmanan; Miller, Scott T.; Sarnaik, Sharada A.; Schultz, William H.

2014-01-01

The Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) trial compared standard (transfusions/chelation) to alternative (hydroxyurea/phlebotomy) treatment to prevent recurrent stroke and manage iron overload in children chronically transfused over 7 years before enrollment. Standardized brain magnetic resonance imaging/magnetic resonance angiography (MRA) and transcranial Doppler (TCD) exams were performed at entry and exit, with a central blinded review. A novel MRA vasculopathy grading scale demonstrated frequent severe baseline left/right vessel stenosis (53%/41% ≥Grade 4); 31% had no vessel stenosis on either side. Baseline parenchymal injury was prevalent (85%/79% subcortical, 53%/37% cortical, 50%/35% subcortical and cortical). Most children had low or uninterpretable baseline middle cerebral artery TCD velocities, which were associated with worse stenoses (incidence risk ratio [IRR] = 5.1, P ≤ .0001 and IRR = 4.1, P < .0001) than normal velocities; only 2% to 12% had any conditional/abnormal velocity. Patients with adjudicated stroke (7) and transient ischemic attacks (19 in 11 standard/8 alternative arm subjects) had substantial parenchymal injury/vessel stenosis. At exit, 1 child (alternative arm) had a new silent infarct, and another had worse stenosis. SWiTCH neuroimaging data document severe parenchymal and vascular abnormalities in children with SCA and stroke and support concerns about chronic transfusions lacking effectiveness for preventing progressive cerebrovascular injury. The novel SWiTCH vasculopathy grading scale warrants validation testing and consideration for use in future clinical trials. This trial was registered at www.clinicaltrials.gov as #NCT00122980. PMID:24914136

The leukemia-associated Rho guanine nucleotide exchange factor LARG is required for efficient replication stress signaling

PubMed Central

Beveridge, Ryan D; Staples, Christopher J; Patil, Abhijit A; Myers, Katie N; Maslen, Sarah; Skehel, J Mark; Boulton, Simon J; Collis, Spencer J

2014-01-01

We previously identified and characterized TELO2 as a human protein that facilitates efficient DNA damage response (DDR) signaling. A subsequent yeast 2-hybrid screen identified LARG; Leukemia-Associated Rho Guanine Nucleotide Exchange Factor (also known as Arhgef12), as a potential novel TELO2 interactor. LARG was previously shown to interact with Pericentrin (PCNT), which, like TELO2, is required for efficient replication stress signaling. Here we confirm interactions between LARG, TELO2 and PCNT and show that a sub-set of LARG co-localizes with PCNT at the centrosome. LARG-deficient cells exhibit replication stress signaling defects as evidenced by; supernumerary centrosomes, reduced replication stress-induced γH2AX and RPA nuclear foci formation, and reduced activation of the replication stress signaling effector kinase Chk1 in response to hydroxyurea. As such, LARG-deficient cells are sensitive to replication stress-inducing agents such as hydroxyurea and mitomycin C. Conversely we also show that depletion of TELO2 and the replication stress signaling kinase ATR leads to RhoA signaling defects. These data therefore reveal a level of crosstalk between the RhoA and DDR signaling pathways. Given that mutations in both ATR and PCNT can give rise to the related primordial dwarfism disorders of Seckel Syndrome and Microcephalic osteodysplastic primordial dwarfism type II (MOPDII) respectively, which both exhibit defects in ATR-dependent checkpoint signaling, these data also raise the possibility that mutations in LARG or disruption to RhoA signaling may be contributory factors to the etiology of a sub-set of primordial dwarfism disorders. PMID:25485589

Hydroxyurea and Growth in Young Children With Sickle Cell Disease

PubMed Central

Houston, Patricia E.; Wang, Winfred C.; Iyer, Rathi V.; Goldsmith, Jonathan; Casella, James F.; Reed, Caroline K.; Rogers, Zora R.; Waclawiw, Myron A.; Thompson, Bruce

2014-01-01

BACKGROUND: Growth impairment is a known complication of sickle cell disease. Effects of hydroxyurea (HU) on growth in very young children are not known. METHODS: Height, weight, BMI, and head circumference (HC) were compared with World Health Organization (WHO) standards in BABY HUG, a multicenter, randomized, double-blinded, placebo-controlled 2-year clinical trial of HU in 193 children 9 to 18 months of age. Anthropometric data were closely monitored and converted to z scores by using WHO standardized algorithms for descriptive analyses. The treatment and placebo groups were compared longitudinally by using a mixed model analysis. RESULTS: At entry, the z scores of BABY HUG children were higher than WHO norms. After 2 years of HU or placebo treatment, there were no significant differences between the groups, except for the mean HC z scores at study exit (HU: +0.8 versus placebo: +1.0, P = .05). Baseline z scores were the best predictors of z scores at study exit. The absolute neutrophil count, absolute reticulocyte count, and total white blood cell count had significant negative correlations with growth measures. CONCLUSIONS: Both groups had normal or near normal anthropometric measures during the study. The HC z scores at study entry and exit were slightly greater than WHO norms. Higher baseline white blood cell count, absolute reticulocyte count, and absolute neutrophil count were associated with poorer growth. The significance of the slightly lower HC in the treatment group at study exit is not clear. Trends toward normalization of weight and height and effects on HC will be monitored in ongoing BABY HUG follow-up studies. PMID:25157002

New Late Gene, dar, Involved in DNA Replication of Bacteriophage T4 I. Isolation, Characterization, and Genetic Location.

PubMed

Wu, J R; Yeh, Y C

1975-05-01

Suppressors of gene 59-defective mutants were isolated by screening spontaneous, temperature-sensitive (ts) revertants of the amber mutant, amC5, in gene 59. Six ts revertants were isolated. No gene 59-defective ts recombinant was obtained by crossing each ts revertant with the wild type, T4D. However, suppressors of gene 59-defective mutants were obtained from two of these ts revertants. These suppressor mutants are referred to as dar (DNA arrested restoration). dar mutants specifically restored the abnormalities, both in DNA synthesis and burst size, caused by gene 59-defective mutants to normal levels. It is unlikely that dar mutants are nonsense suppressors since theý failed to suppress amber mutations in 11 other genes investigated. The genetic expression of dar is controlled by gene 55; therefore, dar is a late gene. The genetic location of dar has been mapped between genes 24 and 25, a region contiguous to late genes. dar appears to be another nonessential gene of T4 since burst sizes of dar were almost identical to those of the wild type. Mutations in dar did not affect genetic recombination and repair of UV-damaged DNA, but caused a sensitivity to hydroxyurea in progeny formation. The effect of the dar mutation on host DNA degradation cannot account for its hydroxyurea sensitivity. dar mutant alleles were recessive to the wild-type allele as judged by restoration of arrested DNA synthesis. The possible mechanisms for the suppression of defects in gene 59 are discussed.

Cell cycle progression in irradiated endothelial cells cultured from bovine aorta

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rubin, D.B.; Drab, E.A.; Ward, W.F.

1988-11-01

Logarithmically growing endothelial cells from bovine aortas were exposed to single doses of 0-10 Gy of 60Co gamma rays, and cell cycle phase distribution and progression were examined by flow cytometry and autoradiography. In some experiments, cells were synchronized in the cell cycle with hydroxyurea (1 mM). Cell number in sham-irradiated control cultures doubled in approximately 24 h. Estimated cycle stage times for control cells were 14.4 h for G1 phase, 7.2 h for S phase, and 2.4 h for G2 + M phase. Irradiated cells demonstrated a reduced distribution at the G1/S phase border at 4 h, and anmore » increased distribution in G2 + M phase at 24 h postirradiation. Autoradiographs of irradiated cells after continuous (3H)thymidine labeling indicated a block in G1 phase or at the G1/S-phase border. The duration of the block was dose dependent (2-3 min/cGy). Progression of the endothelial cells through S phase after removal of the hydroxyurea block also was retarded by irradiation, as demonstrated by increased distribution in early S phase and decreased distribution in late S phase. These results indicate that progression of asynchronous cultured bovine aortic endothelial cells through the DNA synthetic cycle is susceptible to radiation inhibition at specific sites in the cycle, resulting in redistribution and partial synchronization of the population. Thus aortic endothelial cells, diploid cells from a normal tissue, resemble many immortal cell types that have been examined in this regard in vitro.« less

Developmental Injury to the Cerebellar Cortex Following Hydroxyurea Treatment in Early Postnatal Life: An Immunohistochemical and Electron Microscopic Study.

PubMed

Martí, Joaquín; Molina, Vanesa; Santa-Cruz, M C; Hervás, José P

2017-02-01

Postnatal development of the cerebellar cortex was studied in rats administered with a single dose (2 mg/g) of the cytotoxic agent hydroxyurea (HU) on postnatal day (P) 9 and collected at appropriate times ranging from 6 h to 45 days. Quantification of several parameters such as the density of pyknotic, mitotic, BrdU-positive, and vimentin-stained cells revealed that HU compromises the survival of the external granular layer (EGL) cells. Moreover, vimentin immunocytochemistry revealed overexpression and thicker immunoreactive glial processes in HU-treated rats. On the other hand, we also show that HU leads to the activation of apoptotic cellular events, resulting in a substantial number of dying EGL cells, as revealed by TUNEL staining and at the electron microscope level. Additionally, we quantified several features of the cerebellar cortex of rats exposed to HU in early postnatal life and collected in adulthood. Data analysis indicated that the analyzed parameters were less pronounced in rats administered with this agent. Moreover, we observed several alterations in the cerebellar cortex cytoarchitecture of rats injected with HU. Anomalies included ectopic placement of Purkinje cells and abnormities in the dendritic arbor of these macroneurons. Ectopic granule cells were also found in the molecular layer. These findings provide a clue for investigating the mechanisms of HU-induced toxicity during the development of the central nervous system. Our results also suggest that it is essential to avoid underestimating the adverse effects of this hydroxylated analog of urea when administered during early postnatal life.

Effect of Spirulina maxima and its protein extract on micronuclei induction by hydroxyurea in pregnant mice and their fetuses.

PubMed

Álvarez-González, Isela; Vázquez-Sánchez, Jorge; Chamorro-Cevallos, Germán; Madrigal-Bujaidar, Eduardo

2013-11-01

The purpose of the present report was to determine the inhibitory effect of Spirulina maxima (Sm) and its protein extract (PE), mainly consisting of C-phycocyanin, on the increase in micronuclei and bone marrow cytotoxicity induced by hydroxyurea (HU) in pregnant mice and their fetuses. The two tested antimutagenic agents were administered daily from day 10 to day 18 of pregnancy, and HU (300 mg/kg) was administered once on day 16 of the assay. The experimental design also included mice that were administered only Sm or PE (1000 and 400 mg/kg, respectively), two control groups that were administered with vehicles (water and 0.5% Tween 80), and one additional group that was treated solely with HU. Blood samples from the pregnant mice and their fetuses were examined at day 19 of pregnancy. Significant increases in the number of micronucleated polychromatic erythrocytes and in the total number of micronucleated erythrocytes were observed in all HU-treated animals. In contrast, similarly low numbers of micronuclei were observed in the two control groups and in the groups treated with Sm and PE alone. The administration of Sm (100, 500, and 1000 mg/kg) and PE (100, 200, and 400 mg/kg) to HU-treated animals conferred moderate genotoxic protection (∼30%) and some protection against the cytotoxicity induced by HU in mice. The obtained results provide new information regarding the capacity of the tested agents to confer protection to adult mice and transplacentally, as well as on a specific subclass of micronuclei.

Intrathecal Baclofen Therapy: Benefits and Complications

ERIC Educational Resources Information Center

Zdolsek, Helena Aniansson; Olesch, Christine; Antolovich, Giuliana; Reddihough, Dinah

2011-01-01

Background: Spasticity and dystonia in children with cerebral palsy has been treated with intrathecal baclofen therapy (ITB) at the Royal Children's Hospital, Melbourne, Australia (RCH) since 1999. Methods: The records of children having received or still receiving ITB during the period September 1999 until August 2005 were studied to evaluate…

CENTRAL SEROUS CHORIORETINOPATHY IN POSTMENOPAUSAL WOMEN RECEIVING EXOGENOUS TESTOSTERONE.

PubMed

Conway, Mandi D; Noble, Jason A; Peyman, Gholam A

2017-01-01

Central serous chorioretinopathy (CSR) is a serous detachment of the neurosensory retina commonly associated with male sex, Type-A personality and corticosteroid use. Exogenous administration of androgens and development of CSR in men has been reported. Only one case of CSR in a postmenopausal woman receiving exogenous androgen therapy has been reported. The authors describe three cases of chronic CSR in postmenopausal women receiving exogenous testosterone therapy. Diagnosis was based on characteristic clinical, fluorescein angiographic, and optical coherence tomography findings. The three women were being treated with exogenous testosterone and progesterone therapy for symptoms of menopause and libido loss. Average age at presentation was 54.7 years (53-56 years), average duration of exogenous androgen use was 61 months (36-87 months), with average 19.7-month follow-up. Resolution of symptoms seemed correlated with cessation of androgen use despite treatment with oscillatory photodynamic therapy and intravitreal pharmacotherapy with antivascular endothelial growth factor agents. Exogenous testosterone is increasingly prescribed for menopausal symptoms and libido loss. Treatment with oscillatory photodynamic therapy, supplemental bevacizumab intravitreal pharmacotherapy, and cessation of exogenous androgen therapy was successful in three cases of chronic, therapy-resistant CSR. Ophthalmologists should inquire about androgen usage in patients who present with CSR, especially in the setting of therapy resistance.

The efficacy of a commercial shampoo and whirlpooling in the treatment of canine pruritus - a double-blinded, randomized, placebo-controlled study.

PubMed

Löflath, A; von Voigts-Rhetz, A; Jaeger, K; Schmid, M; Kuechenhoff, H; Mueller, R S

2007-12-01

Twenty-two dogs with a history of at least 4 weeks pruritus were studied to determine the effect of whirlpool use on the efficacy of topical therapy with an antipruritic shampoo (Allermyl, Virbac; Bad Oldesloe, Germany). Dogs in group 1 received initially topical therapy with conventional shampooing (2 mL shampoo per kilogram bodyweight) once weekly for 4 weeks. Dogs in group 2 received the same therapy using a whirlpool (Sanwhirl, Peter Aschauer GmbH; Gräfelfing, Germany). The treatments were crossed between the groups resulting in each dog in groups 1 and 2 receiving both therapies. Group 3 was the control group and was treated once weekly in the whirlpool without any shampoo during the 8 weeks of study. Prior to each therapy, dogs were evaluated by a clinician not aware of the type of treatment using a clinical scoring system (Canine Atopic Dermatitis Extent and Severity Index - CADESI). Owners evaluated the pruritus daily on a visual analogue scale. There was a significant difference in pruritus scores but not CADESI scores after therapy between the control treatment and the conventional shampoo therapy or shampoo treatment in the whirlpool. These results provide evidence for the short-term benefit of shampoo therapy for canine pruritus.

Correction of anemia in a transfusion-dependent patient with primary myelofibrosis receiving iron chelation therapy with deferasirox (Exjade®, ICL670)

PubMed Central

Di Tucci, Anna Angela; Murru, Roberta; Alberti, Daniele; Rabault, Bertrand; Deplano, Simona; Angelucci, Emanuele

2007-01-01

Transfusional iron overload in patients with chronic anemias can result in multiple organ failure. Experience in the management of iron overload in patients with myelodysplastic syndromes is limited, as many do not receive chelation therapy due to short-life expectancy and the difficulties associated with the administration of the current reference standard chelator, deferoxamine. There have, however, been some reports of reduced transfusion requirement associated with chelation therapy in patients with myelodysplastic syndromes and myelofibrosis. Here, we discuss a patient with primary myelofibrosis and related transfusion-dependent anemia who received chelation therapy with the once-daily oral iron chelator, deferasirox. In addition to the reduced iron levels, the patient demonstrated an unexpected reduction in blood transfusion requirement, ultimately resulting in long-lasting transfusion-free survival. PMID:17391307

Phase I study of magnesium pidolate in combination with hydroxycarbamide for children with sickle cell anaemia.

PubMed

Hankins, Jane S; Wynn, Lynn W; Brugnara, Carlo; Hillery, Cheryl A; Li, Chin-Shang; Wang, Winfred C

2008-01-01

In sickle cell anaemia, red cell dehydration increases intracellular HbS concentration and promotes sickling. Higher erythrocyte magnesium reduces water loss through negative regulation of membrane transporters. Hydroxycarbamide (also known as hydroxyurea) reduces sickling partly by increasing intracellular HbF. Combining drugs with distinct mechanisms could offer additive effects. A phase I trial combining oral magnesium pidolate and hydroxycarbamide was performed to estimate the maximum tolerated dose (MTD) and toxicity of magnesium. Cohorts of three children with HbSS, who were on a stable dose of hydroxycarbamide (median 28.5 mg/kg/d), received magnesium pidolate for 6 months beginning at 83 mg/kg/d. The dose was escalated by 50% for subsequent cohorts. Laboratory evaluations were performed at 0, 3, 6 and 9 months. Sixteen children (aged 4-12 years) participated. All four dose-limiting toxicities (grade III diarrhoea and abdominal pain) occurred within the first month of starting magnesium. Additionally, diarrhoea grades I (n = 1) and II (n = 3), and abdominal pain grade II (n = 3) occurred. Hydroxycarbamide dose reduction or interruption was not required. The MTD for magnesium pidolate used in combination with hydroxycarbamide was 125 mg/kg/d. KCl co-transporter activity declined after 3 months of magnesium pidolate (P = 0.02). A phase II study is needed to investigate the efficacy of this drug combination.

Group therapy use and its impact on the outcomes of inpatient rehabilitation following traumatic brain injury: Data from TBI-PBE project

PubMed Central

Hammond, Flora M.; Barrett, Ryan; Dijkers, Marcel P.; Zanca, Jeanne M.; Horn, Susan D.; Smout, Randall J.; Guerrier, Tami; Hauser, Elizabeth; Dunning, Megan R.

2015-01-01

Objective To describe the amount and content of group therapies provided during inpatient rehabilitation for traumatic brain injury (TBI), and assess the relationships of group therapy with patient, injury, and treatment factors as well as outcomes. Design Prospective observational cohort. Setting Inpatient rehabilitation. Participants 2,130 consecutive admissions for initial TBI rehabilitation at 10 inpatient rehabilitation facilities (9 in US and 1 Canada) from October 2008 to September 2011. Interventions n/a Main Outcome Measure(s) proportion of sessions that were group therapy (two or more patients were treated simultaneously by one or more clinicians); proportion of patients receiving group therapy; type of activity performed and amount of time spent in group therapy, by discipline; rehabilitation length of stay (RLOS); discharge location; FIM Cognitive and Motor scores at discharge. Results 79% of patients received at least 1 session of group therapy, with group therapy accounting for 13.7% of all therapy sessions and 15.8% of therapy hours. On average, patients spent 2.9 hours per week in group therapy. The greatest proportion of treatment time in group format was in Therapeutic Recreation (25.6%), followed by Speech Therapy (16.2%), Occupational Therapy (10.4%), Psychology (8.1%), and Physical Therapy (7.9%). Group therapy time and type of treatment activities varied among admission FIM cognitive subgroups and treatment sites. Several factors appear to be predictive of receiving group therapy, with treatment site being a major influence. However, group therapy as a whole offered little explanation of differences in the outcomes studied. Conclusion(s) Group therapy is commonly used in TBI rehabilitation, to varying degrees among disciplines, sites, and cognitive impairment subgroups. Various therapeutic activities take place in group therapy, indicating its perceived value in addressing many domains of functioning. Variation in outcomes is not explained well by overall percent of therapy time delivered in groups. PMID:26212404

Group Therapy Use and Its Impact on the Outcomes of Inpatient Rehabilitation After Traumatic Brain Injury: Data From Traumatic Brain Injury-Practice Based Evidence Project.

PubMed

Hammond, Flora M; Barrett, Ryan; Dijkers, Marcel P; Zanca, Jeanne M; Horn, Susan D; Smout, Randall J; Guerrier, Tami; Hauser, Elizabeth; Dunning, Megan R

2015-08-01

To describe the amount and content of group therapies provided during inpatient rehabilitation for traumatic brain injury (TBI), and to assess the relations of group therapy with patient, injury, and treatment factors and outcomes. Prospective observational cohort. Inpatient rehabilitation. Consecutive admissions (N=2130) for initial TBI rehabilitation at 10 inpatient rehabilitation facilities (9 in the United States, 1 in Canada) from October 2008 to September 2011. Not applicable. Proportion of sessions that were group therapy (≥2 patients were treated simultaneously by ≥1 clinician); proportion of patients receiving group therapy; type of activity performed and amount of time spent in group therapy, by discipline; rehabilitation length of stay; discharge location; and FIM cognitive and motor scores at discharge. Of the patients, 79% received at least 1 session of group therapy, with group therapy accounting for 13.7% of all therapy sessions and 15.8% of therapy hours. On average, patients spent 2.9h/wk in group therapy. The greatest proportion of treatment time in group format was in therapeutic recreation (25.6%), followed by speech therapy (16.2%), occupational therapy (10.4%), psychology (8.1%), and physical therapy (7.9%). Group therapy time and type of treatment activities varied among admission FIM cognitive subgroups and treatment sites. Several factors appear to be predictive of receiving group therapy, with the treatment site being a major influence. However, group therapy as a whole offered little explanation of differences in the outcomes studied. Group therapy is commonly used in TBI rehabilitation, to varying degrees among disciplines, sites, and cognitive impairment subgroups. Various therapeutic activities take place in group therapy, indicating its perceived value in addressing many domains of functioning. Variation in outcomes is not explained well by overall percentage of therapy time delivered in groups. Copyright © 2015 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Assertion training therapy in psychiatric milieus.

PubMed

Aschen, S R

1997-02-01

The current investigation involved an attempt to develop a clinical procedure to decrease anxiety and increase responsiveness (assertion) of psychiatric inpatients of both sexes in mixed diagnostic categories and to evaluate the effectiveness of the procedure. Using a Solomon Four-Group Design, patients, matched on age, sex, and diagnosis, were assigned to one of the following conditions: (1) pretest, treatment, posttest; (2) pretest, no treatment, posttest; (3) treatment, posttest; or (4) no treatment, posttest. The Gambrill-Richey Assertive Inventory was used to assess patient Degree of Discomfort and Response Probability with and without assertion training therapy. Results indicated that (1) patients receiving assertion training therapy were less anxious and more responsive after treatment than before, (2) patients receiving assertion training therapy were less anxious and more responsive than were matched control subjects, (3) control subjects who received no assertion training therapy and who were pretested showed moderate significant gains on the posttest measure, (4) patients reported a greater reduction of anxiety than they did an increase in responsiveness, and (5) pretesting did not significantly influence posttest scores.

Fluid Therapy Management in Hospitalized Patients: Results From a Cross-sectional Study.

PubMed

Brugnolli, Anna; Canzan, Federica; Bevilacqua, Anita; Marognolli, Oliva; Verlato, Giuseppe; Vincenzi, Silvia; Ambrosi, Elisa

2017-02-01

Intravenous (IV) fluid therapy is widely used in hospitalized patients. It has been internationally studied in surgical patients, but little attention to date has been dedicated to medical patients within the Italian context. The aims of the present study were to describe the prevalence of fluid therapy and associated factors among Italian patients admitted to medical and surgical units, describe the methods used to manage fluid therapy, and analyze the monitoring of patients by clinical staff. In this cross-sectional study of 7 hospitals in northern Italy, data on individual and monitoring variables were collected, and their associations with in-hospital fluid therapy were analyzed by using logistic regression analysis. Patients aged ≥18 years who were admitted to medical and surgical units were included. Patients who received at least 500 mL of continuous fluids were included in the fluid therapy group. In total, 785 (median age, 72 years; women, 52%) patients were included in the study, and 293 (37.3%) received fluid therapy. Maintenance was the most frequent reason for prescribing IV fluid therapy (59%). The mean (SD) volume delivered was 1177 (624) mL/d, and the highest volume was infused for replacement therapy (1660 [931] mL/d). The mean volume infused was 19.55 (13) mL/kg/d. The most commonly used fluid solutions were 0.9% sodium chloride (65.7%) and balanced crystalloid without glucose (32.9%). The proportion of patients assessed for urine output (52.6% vs 36.8%; P < 0.001), serum electrolyte concentrations (74.4% vs 65.0%; P = 0.005), and renal function (70.0% vs 58.7%; P = 0.002) was significantly higher in patients who did receive fluid therapy versus those who did not. In contrast, the use of weight and fluid assessments was not significantly different between the 2 groups (P = 0.216 and 0.256, respectively). Patients admitted for gastrointestinal disorders (odds ratio [OR], 3.5 [95% CI, 1.8-7.05) and for fluid/electrolyte imbalances (OR, 3.35 [95% CI, 1.06-10.52) were more likely to receive fluids. However, the likelihood of receiving fluids was lower for patients admitted to a surgical unit (OR, 0.36 [95% CI, 0.22-0.59]) and with cardiovascular diseases (OR, 0.37 [95% CI, 0.17-0.79). Only one third of the study patients received fluid therapy. Crystalloid fluids, are the fluids of choice for maintaining plasma volume. During fluid therapy, measurement of the serum electrolyte concentrations, renal function, and urine output was largely used while weight and fluid balance were rarely assessed. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

Nutrition Therapy in Critically Ill Patients Following Cardiac Surgery: Defining and Improving Practice.

PubMed

Rahman, Adam; Agarwala, Ravi; Martin, Claudio; Nagpal, Dave; Teitelbaum, Michael; Heyland, Daren K

2017-09-01

Malnutrition is a predictor of poor outcome following cardiac surgery. We define nutrition therapy after cardiac surgery to identify opportunities for improvement. International prospective studies in 2007-2009, 2011, and 2013 were combined. Sites provided institutional and patient characteristics from intensive care unit (ICU) admission to ICU discharge for a maximum of 12 days. Patients had valvular, coronary artery bypass graft (CABG) surgery, or combined procedures and were mechanically ventilated and staying in the ICU for ≥3 days. There were 787 patients from 144 ICUs. In total, 120 patients (15.2%) had valvular surgery, 145 patients (18.4%) had CABG, and 522 patients (66.3%) underwent a combined procedure. Overall, 60.1% of patients received artificial nutrition support. For these patients, 78% received enteral nutrition (EN) alone, 17% received a combination of EN and parenteral nutrition (PN), and 5% received PN alone. The remaining 314 patients (40%) received no nutrition. The mean (SD) time from ICU admission to EN initiation was 2.3 (1.8) days. The adequacy of calories was 32.4% ± 31.9% from EN and PN and 25.5% ± 27.9% for patients receiving only EN. In EN patients, 57% received promotility agents and 20% received small bowel feeding. There was no significant relationship between increased energy or protein provision and 60-day mortality. Postoperative cardiac surgery patients who stay in the ICU for 3 or more days are at high risk for inadequate nutrition therapy. Further studies are required to determine if targeted nutrition therapy may alter clinical outcomes.

Differences in skeletal muscle loss caused by cytotoxic chemotherapy and molecular targeted therapy in patients with advanced non-small cell lung cancer.

PubMed

Kakinuma, Kazutaka; Tsuruoka, Hazime; Morikawa, Kei; Furuya, Naoki; Inoue, Takeo; Miyazawa, Teruomi; Mineshita, Masamichi

2018-01-01

Recent studies have revealed a reduction in the skeletal muscle area in patients with advanced non-small cell lung cancer (NSCLC) after chemotherapy. EGFR and ALK tyrosine kinase inhibitor (TKI)-based therapies are less cytotoxic than chemotherapy, but differences in skeletal muscle mass between patients receiving EGFR and ALK TKI therapies and patients receiving cytotoxic chemotherapy have not yet been reported. Data of pathologically proven NSCLC patients were reviewed, and chest computed tomography and/or positron emission tomography-computed tomography images obtained from January 2012 to December 2014 were selected. Patients were divided into two groups: cytotoxic chemotherapy (CG) and molecular targeted (MG). Muscle mass was measured with a single cross-sectional area of the muscle at the third lumber vertebra (L3MA). To estimate skeletal muscle changes during chemotherapy, we defined the following L3 skeletal muscle index (L3SMI) ratio: post L3SMI/pre L3SMI. Differences in the SMI ratio between the groups were evaluated using the Wilcoxon signed-rank test. Sixty-five patients were included in this study: 44 patients received cytotoxic chemotherapy and 21 received molecular targeted therapy (EGFR and ALK TKI). The loss of L3MA in the CG was higher than in the MG (P = 0.03). In the CG, the L3SMI ratio defined to evaluate skeletal muscle mass changes was significantly lower than in the MG (P = 0.0188). Our results suggest that skeletal muscle loss during first-line therapy was significantly different between patients receiving cytotoxic chemotherapy and those receiving TKIs. Specifically, skeletal muscle loss was lower in patients receiving TKIs than in patients receiving cytotoxic chemotherapy. © 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

Periosteal Electrical Dry Needling as an Adjunct to Exercise and Manual Therapy for Knee Osteoarthritis: A Multi-Center Randomized Clinical Trial.

PubMed

Dunning, James; Butts, Raymond; Young, Ian; Mourad, Firas; Galante, Victoria; Bliton, Paul; Tanner, Michelle; Fernández-de-Las-Peñas, César

2018-05-28

To compare the effects of adding electrical dry needling into a manual therapy and exercise program on pain, stiffness, function, and disability in individuals with painful knee osteoarthritis (OA). Two hundred and forty-two participants (n=242) with painful knee OA were randomized to receive 6 weeks of electrical dry needling, manual therapy and exercise (n=121) or manual therapy and exercise (n=121). The primary outcome was related-disability as assessed by the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index at 3 months. Individuals receiving the combination of electrical dry needling, manual therapy and exercise experienced significantly greater improvements in related-disability (WOMAC: F=35.504; P<0.001) than those receiving manual therapy and exercise alone at 6 weeks and 3 months. Patients receiving electrical dry needling were 1.7 times more likely to have completely stopped taking medication for their pain at 3 months than individuals receiving manual therapy and exercise (OR: 1.6; 95%CI: 1.24-2.01; P=0.001). Based on the cutoff score of +5 on the Global Rating of Change (GROC), significantly (X =14.887; P<0.001) more patients (n=91, 75%) within the dry needling group achieved a successful outcome compared to the manual therapy and exercise group (n=22, 18%) at 3 months. Effect sizes were large (SMD>0.82) for all outcome measures in favor of the electrical dry needling group at 3 months. The inclusion of electrical dry needling into a manual therapy and exercise program was more effective for improving pain, function and related-disability than the application of manual therapy and exercise alone in individuals with painful knee OA. Therapy, Level 1b. Prospectively registered February 10, 2015 on http://www.clinicaltrials.gov (NCT02373631)This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/.

Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis.

PubMed

Sandborn, William J; Su, Chinyu; Sands, Bruce E; D'Haens, Geert R; Vermeire, Séverine; Schreiber, Stefan; Danese, Silvio; Feagan, Brian G; Reinisch, Walter; Niezychowski, Wojciech; Friedman, Gary; Lawendy, Nervin; Yu, Dahong; Woodworth, Deborah; Mukherjee, Arnab; Zhang, Haiying; Healey, Paul; Panés, Julian

2017-05-04

Tofacitinib, an oral, small-molecule Janus kinase inhibitor, was shown to have potential efficacy as induction therapy for ulcerative colitis in a phase 2 trial. We further evaluated the efficacy of tofacitinib as induction and maintenance therapy. We conducted three phase 3, randomized, double-blind, placebo-controlled trials of tofacitinib therapy in adults with ulcerative colitis. In the OCTAVE Induction 1 and 2 trials, 598 and 541 patients, respectively, who had moderately to severely active ulcerative colitis despite previous conventional therapy or therapy with a tumor necrosis factor antagonist were randomly assigned to receive induction therapy with tofacitinib (10 mg twice daily) or placebo for 8 weeks. The primary end point was remission at 8 weeks. In the OCTAVE Sustain trial, 593 patients who had a clinical response to induction therapy were randomly assigned to receive maintenance therapy with tofacitinib (either 5 mg or 10 mg twice daily) or placebo for 52 weeks. The primary end point was remission at 52 weeks. In the OCTAVE Induction 1 trial, remission at 8 weeks occurred in 18.5% of the patients in the tofacitinib group versus 8.2% in the placebo group (P=0.007); in the OCTAVE Induction 2 trial, remission occurred in 16.6% versus 3.6% (P<0.001). In the OCTAVE Sustain trial, remission at 52 weeks occurred in 34.3% of the patients in the 5-mg tofacitinib group and 40.6% in the 10-mg tofacitinib group versus 11.1% in the placebo group (P<0.001 for both comparisons with placebo). In the OCTAVE Induction 1 and 2 trials, the rates of overall infection and serious infection were higher with tofacitinib than with placebo. In the OCTAVE Sustain trial, the rate of serious infection was similar across the three treatment groups, and the rates of overall infection and herpes zoster infection were higher with tofacitinib than with placebo. Across all three trials, adjudicated nonmelanoma skin cancer occurred in five patients who received tofacitinib and in one who received placebo, and adjudicated cardiovascular events occurred in five who received tofacitinib and in none who received placebo; as compared with placebo, tofacitinib was associated with increased lipid levels. In patients with moderately to severely active ulcerative colitis, tofacitinib was more effective as induction and maintenance therapy than placebo. (Funded by Pfizer; OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain ClinicalTrials.gov numbers, NCT01465763 , NCT01458951 , and NCT01458574 , respectively.).

Population pharmacokinetics and pharmacodynamics of hydroxyurea in sickle cell anemia patients, a basis for optimizing the dosing regimen

PubMed Central

2011-01-01

Background Hydroxyurea (HU) is the first approved pharmacological treatment of sickle cell anemia (SCA). The objectives of this study were to develop population pharmacokinetic(PK)-pharmacodynamic(PD) models for HU in order to characterize the exposure-efficacy relationships and their variability, compare two dosing regimens by simulations and develop some recommendations for monitoring the treatment. Methods The models were built using population modelling software NONMEM VII based on data from two clinical studies of SCA adult patients receiving 500-2000 mg of HU once daily. Fetal hemoglobin percentage (HbF%) and mean corpuscular volume (MCV) were used as biomarkers for response. A sequential modelling approach was applied. Models were evaluated using simulation-based techniques. Comparisons of two dosing regimens were performed by simulating 10000 patients in each arm during 12 months. Results The PK profiles were described by a bicompartmental model. The median (and interindividual coefficient of variation (CV)) of clearance was 11.6 L/h (30%), the central volume was 45.3 L (35%). PK steady-state was reached in about 35 days. For a given dosing regimen, HU exposure varied approximately fivefold among patients. The dynamics of HbF% and MCV were described by turnover models with inhibition of elimination of response. In the studied range of drug exposures, the effect of HU on HbF% was at its maximum (median Imax was 0.57, CV was 27%); the effect on MCV was close to its maximum, with median value of 0.14 and CV of 49%. Simulations showed that 95% of the steady-state levels of HbF% and MCV need 26 months and 3 months to be reached, respectively. The CV of the steady-state value of HbF% was about 7 times larger than that of MCV. Simulations with two different dosing regimens showed that continuous dosing led to a stronger HbF% increase in some patients. Conclusions The high variability of response to HU was related in part to pharmacokinetics and to pharmacodynamics. The steady-state value of MCV at month 3 is not predictive of the HbF% value at month 26. Hence, HbF% level may be a better biomarker for monitoring HU treatment. Continuous dosing might be more advantageous in terms of HbF% for patients who have a strong response to HU. Trial Registration The clinical studies whose data are analysed and reported in this work were not required to be registered in France at their time. Both studies were approved by local ethics committees (of Mondor Hospital and of Kremlin-Bicetre Hospital) and written informed consent was obtained from each patient. PMID:21619673

Procedural Pain Heart Rate Responses in Massaged Preterm Infants

PubMed Central

Diego, Miguel A.; Field, Tiffany; Hernandez-Reif, Maria

2009-01-01

Heart rate (HR) responses to the removal of a monitoring lead were assessed in 56 preterm infants who received moderate pressure, light pressure or no massage therapy. The infants who received moderate pressure massage therapy exhibited lower increases in HR suggesting an attenuated pain response. The heart rate of infants who received moderate pressure massage also returned to baseline faster than the heart rate of the other two groups, suggesting a faster recovery rate. PMID:19185352

Comparison of the efficacy and cost effectiveness of pre-emptive therapy as directed by CMV antigenemia and prophylaxis with ganciclovir in lung transplant recipients.

PubMed

Kelly, J; Hurley, D; Raghu, G

2000-04-01

CMV disease remains a major complication of lung transplantation and attempts to prevent it have met with marginal success. In a previous study we documented that universal prophylaxis did not prevent CMV disease but merely delayed it, and was very costly. We compared the efficacy and cost of pre-emptive therapy with ganciclovir, guided by CMV antigenemia, to that of historic controls that received universal prophylaxis with ganciclovir. CMV antigenemia assay was done routinely and pre-emptive therapy was initiated if greater than 25 CMV positive cells per 100,000 polymorphonuclear cells were found. Nineteen patients were enrolled; 6 of of whom received 12 courses of pre-emptive therapy. The incidence of CMV disease was 26% compared to 38% for the historical controls (p = 0.51). None of the patients that received pre-emptive therapy developed CMV disease following that therapy. Antigenemia failed to predict disease in 5 patients that developed it, and thus it is unknown if pre-emptive therapy could have prevented it. There was no mortality in either the study patients or historic controls directly related to CMV. The net savings with pre-emptive therapy was $2569 per patient. We conclude that pre-emptive therapy with ganciclovir is as safe and effective as universal prophylaxis in preventing CMV disease in lung transplant recipients, and is less expensive. The appropriate surveillance technique and timing remain to be determine to optimize the efficacy of pre-emptive therapy.

Effect of live music therapy for patients undergoing magnetic resonance imaging.

PubMed

Walworth, Darcy D

2010-01-01

The purpose of the current study was to identify the effects of live music therapy interventions compared with preferred recorded music for patients undergoing MRI scans. To date, there has not been a published study involving the use of live music therapy during MRI scans. The current study investigated the differences between teenage through adult patients receiving live music therapy intervention during outpatient MRI scans versus the standard protocol of care listening to recorded music (N = 88). Subjects ranged in age from 15 to 93 years old. Results indicated subjects who received the live music therapy protocol reported significantly better perception of the MRI procedure (p < 0.05). Additionally, subjects receiving the live music therapy protocol had fewer scans repeated due to movement. Of the repeated images, 26% occurred in the live music group and 73% occurred in the recorded music group. Subjects receiving live music therapy also requested less breaks from the scan. Two percent of the live music subjects requested a break and 17.6% of the control patients requested breaks. When comparing the same type of scan between groups, subjects receiving the live music protocol required less time to complete the scans. For lumbar scans without contrast (N = 14, n = 7, n = 7), live music subjects spent an average of 4.63 less min per scan for a total of 32 less min for 7 subjects. For brain scans (N = 8, n = 4, n = 4), live music subjects spent an average of 5.8 less min per scan for a total of 23 less min for 4 subjects. Results of the current study supports the use of live music therapy intervention for teenage and adult patients undergoing MRI scans to reduce patient anxiety and improve patient perception of the scan experience. Additionally, live music therapy has the potential to shorten the length of time required for patients to complete MRI scans due to decreased patient movements and fewer breaks requested during the scans. The cost savings impact of reduced procedure time can positively impact the facility productivity by allowing more scans to be scheduled daily.

Beneficial Effect of the Nitric Oxide Donor Compound 3-(1,3-Dioxoisoindolin-2-yl)Benzyl Nitrate on Dysregulated Phosphodiesterase 5, NADPH Oxidase, and Nitrosative Stress in the Sickle Cell Mouse Penis: Implication for Priapism Treatment.

PubMed

Silva, Fábio H; Karakus, Serkan; Musicki, Biljana; Matsui, Hotaka; Bivalacqua, Trinity J; Dos Santos, Jean L; Costa, Fernando F; Burnett, Arthur L

2016-11-01

Patients with sickle cell disease (SCD) display priapism, and dysregulated nitric oxide (NO) pathway may contribute to this condition. However, current therapies offered for the prevention of priapism in SCD are few. The 3-(1,3-dioxoisoindolin-2-yl)benzyl nitrate (compound 4C) was synthesized through molecular hybridization of hydroxyurea and thalidomide, which displays an NO-donor property. This study aimed to evaluate the effects of compound 4C on functional and molecular alterations of erectile function in murine models that display low NO bioavailability, SCD transgenic mice, and endothelial NO synthase and neuronal NO synthase double gene-deficient (dNOS -/ ) mice, focusing on the dysregulated NO-cGMP- phosphodiesterase type 5 (PDE5) pathway and oxidative stress in erectile tissue. Wild-type, SCD, and dNOS -/- mice were treated with compound 4C (100 μmol/kg/d, 3 weeks). Intracavernosal pressure in anesthetized mice was evaluated. Corpus cavernosum tissue was dissected free and mounted in organ baths. SCD and dNOS -/- mice displayed a priapism phenotype, which was reversed by compound 4C treatment. Increased corpus cavernosum relaxant responses to acetylcholine and electrical-field stimulation were reduced by 4C in SCD mice. Likewise, increased sodium nitroprusside-induced relaxant responses were reduced by 4C in cavernosal tissue from SCD and dNOS -/- mice. Compound 4C reversed PDE5 protein expression and reduced protein expressions of reactive oxygen species markers, NADPH oxidase subunit gp91 phox , and 3-nitrotyrosine in penises from SCD and dNOS -/- mice. In conclusion, 3-week therapy with the NO donor 4C reversed the priapism in murine models that display lower NO bioavailability. NO donor compounds may constitute an additional strategy to prevent priapism in SCD. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Socioeconomic factors affect the selection of proton radiation therapy for children.

PubMed

Shen, Colette J; Hu, Chen; Ladra, Matthew M; Narang, Amol K; Pollack, Craig E; Terezakis, Stephanie A

2017-10-15

Proton radiotherapy remains a limited resource despite its clear potential for reducing radiation doses to normal tissues and late effects in children in comparison with photon therapy. This study examined the impact of race and socioeconomic factors on the use of proton therapy in children with solid malignancies. This study evaluated 12,101 children (age ≤ 21 years) in the National Cancer Data Base who had been diagnosed with a solid malignancy between 2004 and 2013 and had received photon- or proton-based radiotherapy. Logistic regression analysis was used to evaluate patient, tumor, and socioeconomic variables affecting treatment with proton radiotherapy versus photon radiotherapy. Eight percent of the patients in the entire cohort received proton radiotherapy, and this proportion increased between 2004 (1.7%) and 2013 (17.5%). Proton therapy was more frequently used in younger patients (age ≤ 10 years; odds ratio [OR], 1.9; 95% confidence interval [CI], 1.6-2.2) and in patients with bone/joint primaries and ependymoma, medulloblastoma, and rhabdomyosarcoma histologies (P < .05). Patients with metastatic disease were less likely to receive proton therapy (OR, 0.4; 95% CI, 0.3-0.6). Patients with private/managed care were more likely than patients with Medicaid or no insurance to receive proton therapy (P < .0001). A higher median household income and educational attainment were also associated with increased proton use (P < .001). Patients treated with proton therapy versus photon therapy were more likely to travel more than 200 miles (13% vs 5%; P < .0001). Socioeconomic factors affect the use of proton radiotherapy in children. Whether this disparity is related to differences in the referral patterns, the knowledge of treatment modalities, or the ability to travel for therapy needs to be further clarified. Improving access to proton therapy in underserved pediatric populations is essential. Cancer 2017;123:4048-56. © 2017 American Cancer Society. © 2017 American Cancer Society.

Study of Default Options in Advance Directives

ClinicalTrials.gov

2015-06-29

COPD; Severe or Very Severe Airflow Obstruction and/or Receiving or Eligible to Receive Long-term Oxygen Therapy; Idiopathic Pulmonary Fibrosis; Other Interstitial Lung Disease Without Curative Therapy; Congestive Heart Failure; NYHA Class IV or NYHA Class III Plus 1 Hospitalization in the Past Year; Malignancy; Any Stage 3B or 4 Solid Tumor

Cerebral Palsy Symptoms in Children Decreased Following Massage Therapy

ERIC Educational Resources Information Center

Hernandez-Reif, Maria; Field, Tiffany; Largie, Shay; Diego, Miguel; Manigat, Natasha; Seoanes, Jacqueline; Bornstein, Joan

2005-01-01

Twenty young children (mean age = 32 months) with cerebral palsy (CP) recruited from early intervention programs received 30 minutes of massage or reading twice weekly for 12 weeks. The children receiving massage therapy showed fewer physical symptoms including reduced spasticity, less rigid muscle tone overall and in the arms, and improved fine…

The Experiences of School Nurses Caring for Students Receiving Continuous Subcutaneous Insulin Infusion Therapy

ERIC Educational Resources Information Center

Darby, Wendy

2006-01-01

Diabetes mellitus is the most common metabolic disorder in childhood. Today, children with diabetes are receiving new technologically advanced treatment options, such as continuous subcutaneous insulin infusion (CSII) therapy. School nurses are the primary health caregivers of children with diabetes during school hours. Therefore, it is important…

Intense pulsed light, near infrared pulsed light, and fractional laser combination therapy for skin rejuvenation in Asian subjects: a prospective multi-center study in China.

PubMed

Tao, Li; Wu, Jiaqiang; Qian, Hui; Lu, Zhong; Li, Yuanhong; Wang, Weizhen; Zhao, Xiaozhong; Tu, Ping; Yin, Rui; Xiang, Leihong

2015-09-01

Ablative skin rejuvenation therapies have limitations for Asian people, including post-inflammatory hyperpigmentation and long down time. Non-ablative lasers are safer but have limited efficacy. This study is to investigate the safety and efficacy of a combination therapy consisting of intense pulsed light (IPL), near infrared (NIR) light, and fractional erbium YAG (Er:YAG) laser for skin rejuvenation in Asian people. This study recruited 113 subjects from six sites in China. Subjects were randomly assigned to a full-face group, who received combination therapy, and split-face groups, in which one half of the face received combination therapy and the other half received IPL monotherapy. Each subject received five treatment sessions during a period of 90 days. Subjects were followed up at 1 and 3 months post last treatment. Three months after last treatment, the full-face group (n = 57) had a global improvement rate of 29 % and 29 % for wrinkles, 32 % for skin texture, 33 % for pigment spots, 28 % for pore size, respectively. For patients in the split-face groups (n = 54), monotherapy side had a global improvement rate of 23 % and 20 % for wrinkles, 27 % for skin texture, 25 % for pigment spots, 25 % for pore size, respectively. Both combination therapy and monotherapy resulted in significant improvements at the follow-up visits compared to baseline (P < 0.001). Combination therapy showed significantly greater improvements compared to monotherapy at two follow-up visits (P < 0.05). Combination therapy is a safe and more effective strategy than IPL monotherapy for skin rejuvenation in Asian people.