Thrombosis associated with L-asparaginase therapy and low fibrinogen levels in adult acute lymphoblastic leukemia

L-asparaginase is a chemotherapeutic agent commonly used in the treatment of both adult and pediatric acute lymphoblastic leukemia (ALL). A major complication is thrombosis, resulting from reduced synthesis of proteins such as antithrombin III. Hypofibrinogenemia, also a side effect, may be a marker of thrombosis and decreased protein synthesis. A retrospective chart review of identically treated patients revealed 9 thrombotic events among 93 patients (10%), 6 (7%) occurring during treatment cycles including L-asparaginase. Twelve (13%) patients had fibrinogen levels <50 mg/dL. Of these, 3 (25%) suffered a thrombotic event. This results in a specificity of 90% and a relative risk of 10 (P = 0.014). Therefore, a fibrinogen <50 mg/dL may serve as a marker for a hypercoagulable state in ALL patients receiving L-asparaginase.     

Safety of levofloxacin as an antibiotic prophylaxis in the induction phase of children newly diagnosed with acute lymphoblastic leukemia: an interim analysis of a randomized,open-label trial in Brazil

BackgroundDespite high cure rates, treatment-related mortality in children with acute lymphoblastic leukemia (ALL) remains significant. About 4% of patients die during remission induction therapy and approximately two-thirds of treatment-related deaths are due to infectious complications.MethodsFrom May 2021 to June 2022, children aged one through 18 years, with a recent diagnosis of ALL, admitted to three pediatric oncology centers in Brazil, were enrolled in this multicenter, open-label, randomized, phase 3 clinical trial. Eligible patients were randomly divided into two groups, based on a 1:1 allocation ratio, to receive, or not, levofloxacin as a prophylactic agent during the induction phase. All patients were treated according to the IC-BFM 2009 chemotherapy protocol. Primary endpoints were carbapenemase-producing Enterobacteriaceae (CPE) colonization, Clostridioides difficile diarrhea, and other adverse events related to the use of levofloxacin. The secondary endpoint was febrile neutropenia during induction. The median follow-up was 289 days.ResultsTwenty patients were included in this trial, 10 in each group (control and levofloxacin). Mild adverse reactions related to levofloxacin were observed in three patients (30%). Three patients had Clostridioides difficile diarrhea, two in the levofloxacin group and one in the control group (p > 0.99). Only one patient presented colonization by CPE. This patient belonged to the levofloxacin group (p > 0.99). Nine patients presented febrile neutropenia, five in the control group and four in the levofloxacin intervention group (p > 0.99), one patient died due to febrile neutropenia.ConclusionThe use of levofloxacin was shown to be safe in the induction phase in children with de novo ALL. The use of this medication did not increase the rate of colonization by CPE nor the rate of diarrhea by C. difficile. All adverse reactions were mild and remitted either spontaneously or after switching medicine administration from oral to intravenous route.     

Glucose metabolism in children with acute lymphoblastic leukemia treated according to two different L-asparaginase schedules

Oral glucose tolerance tests were performed in 47 children with acute lymphoblastic leukemia (ALL), treated according to 2 consecutive protocols. Glucose and insulin values were assessed before and after L-asparaginase (L-asp). 30 children (group A) received L-asp as a single-agent consolidation course, after achieving remission with vincristine (VCR) and prednisone (PDN). Normal insulin and glucose levels were found in all patients before L-asp; 4 children (13%) had a transient impaired glucose tolerance (IGT) after completing L-asp therapy. 17 children (group B) were given L-asp during induction therapy with VCR and PDN, and all achieved complete remission. 5 patients (23%) had IGT, without hypoinsulinemia, before L-asp administration. IGT normalized in 4 patients after L-asp, the other children developed a diabetes mellitus. Only 1 patient, with a normal IGT test before L-asp therapy, showed a transient IGT after L-asp. In patients with ALL, the presence of IGT before treatment may be related to leukemia. The concomitant use of steroids does not influence the incidence of IGT in our series. Our data reveal normal insulinemia in patients with IGT. Thus, the leukemic process itself may play a much more significant role in inducing abnormalities in carbohydrate metabolism.     

Prophylactic therapy with enoxaparin during L-asparaginase treatment in children with acute lymphoblastic leukemia.

Forty-one consecutive children with acute lymphoblastic leukemia (ALL) received prophylaxis therapy with the low molecular weight heparin (LMWH) enoxaparin during L-asparaginase treatment. Enoxaparin was given every 24 h subcutaneously at a median dose of 0.84 mg/kg per day (range, 0.45-1.33 mg/kg per day) starting at the first dose of L-asparaginase until 1 week after the last dose. Molecular analysis for thrombophilic polymorphisms documented prothrombin G20210A mutation in 3/27 (11%), homozygosity for MTHFR C677T mutation in 5/27 (18.5%, and heterozygosity for factor V Leiden mutation in 5/27 (18.5%) children. There were no thrombotic events during 76 courses of L-asparaginase in 41 patients who had received enoxaparin. One patient suffered brain infarct 7 days after enoxaparin was stopped. There were no bleeding episodes. In a historical control group of 50 ALL children who had not received prophylactic enoxaparin during L-asparaginase treatment, two had thromboembolisms (one deep vein thrombosis and one pulmonary embolism). Enoxaparin is safe and seems to be effective in prevention of thromboembolism in ALL patients during L-asparaginase therapy. This study provides pilot data for a future randomized trial of the use of LMWH during ALL therapy for the prevention of asparaginase-associated thrombotic events.     

A circadian rhythm-related MTNR1B genetic variant (rs10830963) modulate body weight change and insulin resistance after 9 months of a high protein/low carbohydrate vs a standard hypocaloric diet

Background & aimsThe risk allele (G) of rs10830963 in the melatonin receptor 1 B (MTNR1B) gene presents an association with biochemical parameters and obesity. We study the effect of this SNP on insulin resistance and weight loss secondary to two hypocaloric diets.Methods270 obese subjects were randomly allocated during 9 months (Diet HP: a high protein/low carbohydrate vs. Diet S: a standard severe hypocaloric diets). Anthropometric parameters, fasting blood glucose, C-reactive protein (CRP), insulin concentration, insulin resistance (HOMA-IR), lipid profile and adipocytokines levels were measured. Genotype of MTNR1B gene polymorphism (rs10830963) was evaluated.ResultsAll adiposity parameters, systolic blood pressure and leptin levels decreased in all subjects after both diets. This improvement of adiposity parameters was higher in non-G allele carriers than G allele carriers. After weight loss with Diet HP, (CC vs. CG + GG at 9 months); total cholesterol (delta: −9.9 ± 2.4 mg/dl vs. −4.8 ± 2.2 mg/dl:p < 0.05), LDL-cholesterol (delta: −8.3 ± 1.9 mg/dl vs. −5.1 ± 2.2 mg/dl: p < 0.05), insulin (delta: −4.7 ± 0.8 UI/L vs. −0.9 ± 1.0 UI/L: p < 0.05), triglycerides (delta: −17.7 ± 3.9 mg/dl vs. −6.1 ± 2.8 mg/dl: p < 0.05) and HOMA IR (delta: −0.8 ± 0.2 units vs. −0.2 ± 0.1 units: p < 0.05) improved only in no G allele carriers. After weight loss with Diet S in non G allele carriers, insulin levels (delta (CC vs. CG + GG): −3.4 ± 0.6 UI/L vs. −1.2 ± 0.4 UI/L: p < 0.05), triglycerides (delta: −29.2 ± 3.4 mg/dl vs. −8.2 ± 3.8 mg/dl: p < 0.05), HOMA-IR (delta (CC vs. CG + GG): −1.1 ± 0.2 units vs. −0.1 ± 0.1 units: p < 0.05), total cholesterol (delta: −15.9 ± 7.4 mg/dl vs. −5.8 ± 2.9 mg/dl:ns) and LDL-cholesterol (delta: −13.7 ± 5.9 mg/dl vs. −6.0 ± 2.9 mg/dl: ns) decreased, too.Conclusionsour study detected a relationship of rs10830963 variant of MTNR1B gene with adiposity changes, cholesterol changes and insulin resistance modification induced by two different hypocaloric during 9 months.     

The role of plasma fibrinogen,D-dimer and fibrinogen degradation products in diagnosis and disease activity in patients with ankylosing spondylitis

Aim of the workTo evaluate the role of coagulation-related markers such as plasma fibrinogen, D-dimer and fibrinogen degradation product (FDP) in ankylosing spondylitis (AS) patients and their relationship with disease activity.Patients and methodsData were collected from 210 AS patients and 204 age and gender matched healthy controls. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was used to divide AS patients into active (≥4) and inactive (score < 4) groups.ResultsThe mean age of the patients was 35.3 ± 16.3 years. They were 156 males and 54 females (M:F 2.9:1) and had a disease duration of 9.4 ± 7.2 years. The mean fibrinogen, D-dimer and FDP were significantly increased in the patients (375.4 ± 125.01 mg/dl, 2874.8 ± 1884.6 ug/l and 18.3 ± 11.3 mg/l) compared to the control (276.7 ± 71.9 mg/dl, 913.3 ± 540.6 ug/l and 3.01 ± 1.2 mg/l respectively; p < 0.001 each). Plasma fibrinogen, D-dimer and FDP increased in active compared to inactive patients (p < 0.001) and were significantly associated with BASDAI (p < 0.001). The optimal cut-off value of plasma fibrinogen, D-dimer and FDP for the diagnosis of AS were >288 mg/dl, >472 ug/l and >1.44 mg/l while to discriminate active from inactive the values were 393 mg/dl, 1228 μg/L and 1.82 mg/L, respectively. Logistic regression analysis showed that D-dimer is an independent predictor for AS disease activity (OR = 2.85, 95%CI: (1.85--4.43), p < 0.001).ConclusionFibrinogen, D-dimer and FDP increased in AS patients and significantly correlated with disease activity. D-dimer may play a role as a novel inflammatory parameter to predict disease activity in AS patients.     

Impact of anti‐oxidant status and apoptosis on the induction phase of chemotherapy in childhood acute lymphoblastic leukemia

Abstract

This study aimed to evaluate oxidative stress and apoptosis in childhood acute lymphoblastic leukemia (ALL) at diagnosis and their impact on outcome at the end of the induction phase. Our study included 50 newly diagnosed children with ALL. Evaluation of oxidative stresses (malondialdehyde and total anti‐oxidant capacity) was made at diagnosis and at the end of the induction phase. Apoptosis level was determined by fluorometric terminal deoxynucleotidyl transferase dUTP nick end labeling system for patients at diagnosis and after 1?week of treatment. Our study showed that there was increased oxidative stress at diagnosis and after treatment with chemotherapy. Apoptosis index was higher after 1?week of treatment with chemotherapy when compared to its level at diagnosis.     

Reduced Leukocyte Adhesiveness in Response to Viral versus Nonviral Infection/Inflammation

Background: Viral infection differs from nonviral infection/inflammation by not producing a significant acute phase response. Since inflammation can cause increased adhesiveness of peripheral white blood cells (WBC), we compared these adhesive properties in individuals with viral infection to those with nonviral infection/inflammation. Patients and Methods: The state of leukocyte adhesiveness/aggregation in the peripheral blood of patients with viral versus nonviral infection/inflammation was examined in 101 consecutive patients with acute febrile disease. Results: A significant difference was found between the two groups; 13.6 ± 7% for viral infection versus 22.8 ± 8.5% for nonviral infection/inflammation (p < 0.0001). There was also a significant difference in the concentration of fibrinogen (361 ± 109 mg/dl vs 554 ± 172 mg/dl, p < 0.0001), and in the CD11b/CD18 cell surface expression (175 ± 66 vs 210 ± 100 in peripheral blood polymorphonuclear leukocytes). Conclusion: The results of this study could explain, at least in part, the differential adhesive behavior of the WBC in the peripheral blood in the two populations. Received: October 10, 1999 · Revision accepted: December 19, 2000     

Incidence of thrombotic complications in adult patients with acute lymphoblastic leukaemia receiving L-asparaginase during induction therapy: a retrospective study. The GIMEMA Group.

The incidence of thrombotic complications chronologically related to L-asparaginase administration is retrospectively analyzed in 238 adult ALL patients treated according to the GIMEMA protocol ALL 0288. The patients (126 males and 112 females, aged 12-68 years, median 29) received E. coli L-asparaginase (L-ase) in the induction phase at a dosage of 6000 U/m2/day x 7 d starting on d 15, as well as vincristine, prednisone, daunorubicin and cyclophosphamide, the last-named by random 1:1. Ten patients (4.2%) developed thrombotic complications 5-15 d (median 11 d) after the start of L-ase treatment. The thrombotic events, which were lethal in 5 patients, involved the cerebral sinus (5 cases), the cerebral arteria (2 cases), the portal vein (1 case), the pulmonary district (1 case), and a deep vein in the lower extremity (1 case). The occurrence of these complications was not related to the general thrombotic risk factors, nor to the main clinical and laboratory data registered at diagnosis and immediately before the start of L-asparaginase treatment. The present study documents for the first time in a sufficiently large series of adult ALL patients that the incidence and the severity of thrombotic events related to L-ase administration are relevant and need further consideration.     

Suppressed neutrophil function in children with acute lymphoblastic leukemia

Infection is a major obstacle in cancer chemotherapy. Neutropenia has been considered to be the most important risk factor for severe infection; however, other factors, such as impaired neutrophil function, may be involved in susceptibility to infection in patients undergoing chemotherapy. In this study, we analyzed neutrophil function in children with acute lymphoblastic leukemia (ALL). Whole blood samples were obtained from 16 children with ALL at diagnosis, after induction chemotherapy, and after consolidation chemotherapy. Oxidative burst and phagocytic activity of neutrophils were analyzed by flow cytometry. Oxidative burst of neutrophils was impaired in ALL patients. The percentage of neutrophils with normal oxidative burst after PMA stimulation was 59.0 ± 13.2 or 70.0 ± 21.0% at diagnosis or after induction chemotherapy, respectively, which was significantly lower compared with 93.8 ± 6.1% in healthy control subjects (P = 0.00004, or 0.002, respectively); however, this value was normal after consolidation chemotherapy. No significant differences were noted in phagocytic activity in children with ALL compared with healthy control subjects. Impaired oxidative burst of neutrophils may be one risk factor for infections in children with ALL, especially in the initial periods of treatment.     

Importance of premeal injection time in insulin therapy: Humalog Mix25 is convenient for improved post-prandial glycemic control in type 2 diabetic patients with Italian dietary habits

Abstract. We investigated the use, in a short period, of Humalog Mix25 (Mix25) in a twice-daily administration regimen compared to a twice-daily injection therapy with Humulin 30/70 (30/70) in diabetic patients with Italian dietary habits. We studied 33 type 2 diabetic patients aged 59.1±8.1 years, BMI 29.8±2.7 kg/m², duration of diabetes and insulin therapy of 14.4±9.8 and 4.2±4.6 years, respectively. After a 4-day leadin period of twice-daily human insulin 30/70 treatment, patients were randomized to one of two treatment sequences: (1) a twice-daily regimen with Mix25 just 5 minutes before the morning and evening meals for 12 days, followed by a twicedaily therapy with human insulin 30/70 given 30 minutes before the morning and evening meals for an additional 12 days; or (2) the alternate sequence. Each patient underwent a mixed meal test: Humulin 30/70 was administered 30 minutes before the meal, while Mix25 was given 5 minutes before. The 2-hour post-prandial glucose concentration after breakfast was significantly lower during treatment with Mix25 than with Humulin 30/70 (157±43.2 vs. 180±43.2 mg/dl, p<0.05). The glycemic excursion after dinner on Mix25 treatment was significantly lower than with Humulin 30/70 (12.2±48.01 vs. 35.5±36.92 mg/dl, p<0.05). AUC_glucose after Mix25 was lower than after Humulin 30/70. Glycemia after test meal was significantly lower with Mix25 than with Humulin 30/70. Insulin and free insulin concentrations after the test meal were significantly higher with Mix25 in comparison to Humulin 30/70. AUC serum insulin and free insulin curves after Mix25 were significantly higher than after Humulin 30/70 (p=0.028 and p=0.005, respectively). Twice-daily injections of Humalog Mix25, compared to human insulin 30/70 in type 2 diabetic patients with Italian dietary habits, provide improved and lasting post-prandial glycemic control, with the great convenience of the injection just before the meal.     

Thrombotic events are not exclusive to the remission induction period in patients with acute lymphoblastic leukemia: a report of two cases of cerebral sinus thrombosis

 It is well established that in acute lymphoblastic leukemia (ALL) patients l-asparaginase (l-Ase) provokes thrombotic events reducing coagulation inhibitors in both adults and children. A tight correlation between thrombotic and hemorrhagic complications and ALL has also been hypothesized because of the high incidence of disseminated intravascular coagulation (DIC) found during the early period of chemotherapeutic treatment apart from l-Ase. All the authors reporting on this subject, however, consider the remission induction phase of treatment the most risky, if not exclusive, for the development of a thrombotic event, in particular if it includes the administration of l-Ase. We report here two cases of ALL patients who experienced a cerebral sinus thrombosis in a later phase of treatment, demonstrating that the thrombotic risk is surely exacerbated by chemotherapy but is not exclusive to the remission induction period. Received: 1 April 1997 / Accepted: 11 June 1997     

ALL R-87 protocol in the treatment of children with acute lymphoblastic leukaemia in early bone marrow relapse

Seventy-three children with acute lymphoblastic leukaemia (ALL) in first bone marrow (BM) relapse, occurring within 30 months from complete remission (CR), were enrolled in an Italian cooperative study (ALL R-87 protocol). This treatment programme consisted of an induction phase with intermediate-dose cytarabine (IDARA-C) plus idarubicin (IDA) and prednisone (PDN), followed by a multidrug consolidation therapy and bone marrow transplant (BMT). 55/73 children achieved CR (75.3%); 15 (20.5%) failed to respond and three (4.2%) died during induction. The response rate was significantly higher for children with a first CR duration 12 months (P = 0.0005) and for those with a white blood cell (WBC) count at relapse <20 × 10⁹/l (P=0.004). The estimated disease-free survival (DFS ± SE) at 82 months was 0.18 ± 0.05 for all responders, and 0.70 ± 0.14 for allotransplanted patients versus 0.05 ± 0.05 for those autografted (P = 0.001). The estimated probabilities of survival ± SE and event-free survival (EFS ± SE) at 83 months were 0.16 ± 0.07 and 0.13 ± 0.04, respectively, for all enrolled children. Univariate analysis showed that age <10 years at initial diagnosis and B-lineage immunophenotype favourably influenced both DFS (P = 0.001) and EFS probabilities (P = 0.0014 and P = 0.012, respectively), whereas a first CR duration 12 months and a WBC count at relapse <20 × 10⁹/l were associated only with a better EFS rate (P = 0.026 and P = 0.004, respectively). Our results show the efficacy of the IDA plus IDARA-C schedule used in the ALL R-87 protocol in high-risk relapsed ALL children. Allogeneic BMT proved effective for patients with an HLA sibling donor. In a multivariate analysis, age 10 years at initial diagnosis (P = 0.016) and WBC count at relapse 20 × 10⁹/l (P = 0.048) were independently associated with a worse disease outcome.     

Impact of lockdown in COVID 19 on glycemic control in patients with type 1 Diabetes Mellitus

Background and aimsCOVID 19 is a novel pandemic affecting globally. Although no reliable data suggests that patients of well controlled Type 1 Diabetes Mellitus (T1DM) being at increased risk of becoming severely ill with SARS-CoV2, but lockdown may impact patients with T1DM requiring regular medications and follow up. Hence this study was planned to see the impact of lockdown on glycemic control in patients with T1DM.MethodsA cross sectional study was done in T1DM patients in whom a structured questionnaire was administered on follow up within 15 days after lockdown. Data regarding hypoglycemic and hyperglycemic episodes, Diabetic ketoacidosis (DKA), insulin dose missed, regular glucose monitoring, dietary compliance, physical activity, hospitalization during the phase of lockdown was taken. Average blood glucose and HbA1C of lockdown phase was compared with the readings of prelockdown phase.ResultsOut of 52 patients, 36.5% had hyperglycemic and 15.3% had hypoglycemic episodes. Insulin dose was missed in 26.9%, glucose monitoring not done routinely in 36.5% and 17.4% were not diet compliant during lockdown. Average blood glucose during lockdown phase was 276.9 ± 64.7 mg/dl as compared to 212.3 ± 57.9 mg/dl during prelockdown phase. Mean HbA1c value of lockdown (10 ± 1.5%) which was much higher that of pre lockdown (8.8 ± 1.3%) and the difference was statistically significant (p < 0.05).ConclusionGlycemic control of T1DM patients has worsened mainly due to non availability of insulin/glucostrips during lockdown period. There is a need for preparedness in future so that complications can be minimised.     

Inhaled Epoprostenol and Milrinone Effect on Right Ventricular Pressure Waveform Monitoring

BackgroundPulmonary hypertension (PH) and right ventricular (RV) dysfunction are major complications in cardiac surgery. This study aimed to evaluate the change in RV pressure waveform in patients receiving a combination of inhaled epoprostenol and inhaled milrinone (iE&iM) before cardiopulmonary bypass (CPB) and to assess the safety of this approach with a matched case-control group.MethodsA prospective single-centre cohort study of adult patients undergoing cardiac surgery administered iE&iM through an ultrasonic mesh nebulizer. RV pressure waveform monitoring was obtained by continuously transducing the RV port of the pulmonary artery (PA) catheter.ResultsThe final analysis included 26 patients receiving iE&iM. There was a significant drop in mean PA pressure (MPAP) (–4.8 ± 8.7, P = 0.010), systolic PA pressure (SPAP) (–8.2 ± 12.8, P = 0.003), RV end-diastolic pressure (RVEDP) (–2.1 ± 2.8, P < 0.001) and RV diastolic pressure gradient (RVDPG) (–1.7 ± 1.4, P < 0.001) after 17 ± 9 minutes of iE&iM administration. Patients also had a significant increase in RV outflow tract (RVOT) gradient (3.7 ± 4.7, P < 0.001), RV maximal rate of pressure rise during early systole (dP/dt max) (68.3 ± 144.7, P = 0.024), and left ventricular (LV) dP/dt max (66.4 ± 90.1, P < 0.001). Change in RVOT gradient was only observed in those with a positive pulmonary vasodilator response to treatment. Treatment with iE&iM did not present adverse effects when compared with a matched case-control group.ConclusionsCoadministration of iE&iM in cardiac surgery patients presenting with PH or signs of RV dysfunction is a safe and effective treatment approach in improving RV function. Appearance of a transient increase in RVOT gradient after iE&iM could be useful to predict response to treatment.     

Safe and effective treatment of diabetes mellitus associated with chronic liver diseases with an alpha-glucosidase inhibitor, acarbose

Glucose intolerance and diabetes mellitus are both prevalent in patients with chronic liver diseases. We examined the efficacy and systemic safety of therapy with an alpha-glucosidase inhibitor, acarbose, in diabetes mellitus associated with chronic liver diseases. Twenty patients with chronic hepatitis or liver cirrhosis and overt diabetes mellitus received acarbose (taken orally) for 8 weeks. The initial dosage of acarbose was 50mg three times daily, taken before meals; this was increased to 100mg three times daily after 2 weeks. The mean fasting plasma glucose level was 173.7±18.6mg/dl (mean±SE) at entry, and was significantly decreased to 132.9±7.5mg/dl (P<0.05) after 8 weeks of acarbose treatment. The improved glycemic control was reflected by a significant decrease in glycosylated hemoglobin (HbA1c) from 7.2±0.3% at entry to 6.3±0.2% (P<0.05) after 8 weeks. Serum levels of both aspartate and alanine aminotransferases fluctuated during acarbose treatment, probably due to the natural course of chronic liver diseases, but the mean values had decreased after 8 weeks of treatment. Plasma ammonia levels increased, from 61.3±10.7μg/dl to 71.1±9.6μg/dl after 8 weeks of acarbose treatment but the increase was not significant. Clinically significant elevation of plasma ammonia concentration was seen in 2 cirrhotic patients (121 and 124μg/dl); this was asymptomatic and gradually returned to the normal range despite continuous acarbose treatment in one patient, and was reversed after the withdrawal of acarbose with the concomitant administration of lactulose in the other patient. No other blood tests results, including albumin, cholinesterase, and prothrombin time, or lipid profile and nutritional status, in terms of rapid turnover proteins, prealbumin, retinol binding protein, and transferrin, were altered throughout the study period. These results indicate that diabetes mellitus associated with chronic liver diseases may be safely and effectively treated with acarbose. However, clinicians must be aware of the possibility of hyperammonemia when they prescribe acarbose for patients with diabetes mellitus and advanced liver cirrhosis.     

Effects of febuxostat on serum urate level in Japanese hyperuricemia patients

Abstract

Objective. We assessed the efficacy and adverse effects of febuxostat in male hyperuricemia patients. Subjects and methods. This was a 12-week, multicenter, open-label, uncontrolled study. The enrolled subjects were 89 hyperuricemic male patients (12 overexcretors, 56 normal excretors, and 21 underexcretors). The endpoint was percent change in serum urate level. Results. The concentration of urate in serum before and 12 weeks after beginning administration of febuxostat in the overexcretors was 9.34 ± 1.48 and 5.59 ± 1.17 mg/dl, respectively, while those were 8.59 ± 1.24 and 5.41 ± 1.35 mg/dl, respectively, in the normal excretors, and 8.29 ± 1.01and 5.11 ± 1.71 mg/dl, respectively, in the underexcretors. After 12 weeks, the rate of change in serum urate after beginning administration of febuxostat was ? 0.384 ± 0.186 in the overexcretors, ? 0.368 ± 0.128 in the normal excretors, and ? 0.365 ± 0.217 in the underexcretors, with no significant differences among them. A common adverse event related to febuxostat was gout flare. Conclusion. Febuxostat effectively reduced the concentration of urate in serum in hyperuricemic patients regardless of the level of uric acid excreted in urine without severe adverse effects.     

Effects of nebivolol therapy on endothelial functions in cardiac syndrome X

Endothelial dysfunction is major pathophysiologic mechanism in cardiac syndrome X (CSX), which causes a decrease in plasma nitrite oxide (NO) levels. It was demonstrated that nebivolol improves endothelial function and increases NO release. Despite this pathophysiologic relation, the effect of nebivolol therapy on endothelial function in patients with CSX is unknown. The aim of this study is to evaluate the effect of nebivolol on patients in CSX. Thirty-eight patients who were diagnosed with CSX were prospectively enrolled in the study. The treatment group consisted of 20 patients and the control group consisted of 18 patients. An oral 5-mg dose of nebivolol was given daily and maintained for 4 weeks in the treatment group. Ultrasonographic parameters (brachial artery flow-mediated dilatation [FMD], brachial artery lumen diameters) and inflammatory markers (high-sensitivity C-reactive protein [hsCRP], von Willebrand factor [vWf], and fibrinogen) were measured at baseline and end of the 4 weeks. Brachial baseline lumen diameter, brachial lumen diameter after reactive hyperemia, and FMD were 4.61 ± 0.49 mm, 4.87 ± 0.53 mm, and 5.6% ± 2.3% at baseline. After the nebivolol therapy, there was a significant increase in both brachial artery baseline lumen diameter and lumen diameter after reactive hyperemia (P < 0.001 and P = 0.002). However, there was no significant change in FMD (5.6% ± 2.2% vs 5.3% ± 2.1%, P not significant). Levels of hsCRP, vWf, and fibrinogen were significantly decreased (hsCRP: 3.4 ± 0.49 mg/dl vs 2.97 ± 0.74 mg/dl, P = 0.001; vWf: 107 ± 62 vs 86 ± 58, P = 0.004; fibrinogen: 341 ± 89 mg/dl vs 299 ± 87 mg/ dl, P = 0.01) in the treatment group. Nebivolol therapy may have a favorable effect on endothelial function in CSX. Further studies are needed to confirm the clinical significance of nebivolol therapy in CSX.     

L-asparaginase induced fatal cortical venous thrombosis in acute lymphoblastic leukemia

L-asparaginase has become an integral part in the treatment of acute lymphoblastic leukemia. The major worry of using L-asparaginase is thromboembolism. The case presented here is a 21-year-old lady who developed fatal cortical venous thrombosis during induction phase of treatment for ALL. Early recognition is very important to treat this potentially catastrophic yet treatable complication.     

Circulatory improvement after hydralazine or isosorbide dinitrate administration in patients with heart failure: Effect on metabolic responses to submaximal exercise

Hydralazine and isosorbide dinitrate can increase the cardiac output during submaximal exercise in patients with heart failure but whether this increase improves oxygen delivery to underperfused exercising muscle is uncertain. To investigate this question, we measured three systemic markers of skeletal muscle oxygen availability—exercise V?O₂, mixed venous lactate concentration and oxygen debt—during submaximal exercise in 15 patients with heart failure both before and after hydralazine (nine patients) or isosorbide dinitrate (eight patients) administration. Hydralazine increased the cardiac output during exercise from 4.9 ± 1.2 liter/min to 6.5 ± 1.8 liter/min (p < 0.01) but had no effect on exercise V?O₂ (control, 531 ± 135 ml/min; hydralazine, 489 ± 102 ml/min), peak lactate concentration (control, 18.3 ± 4.2 mg/dl; hydralazine, 17.9 ± 3.6 mg/dl) or oxygen debt (control, 474 ± 213 ml; hydralazine, 465 ± 170 ml) (all p > 0.10). Isosorbide dinitrate increased the cardiac output during exercise from 4.6 ± 0.9 liter/min to 5.3 ± 0.8 liter/min (p < 0.01) but also did not change exercise V?O₂ (control, 488 ± 62 ml/min; isosorbide, 473 ± 44 ml/min), peak lactate concentration (control, 19.2 ± 6.0 mg/dl; isosorbide, 21.4 ± 8.2 mg/dl) or oxygen debt (control, 522 ± 154 ml; isosorbide, 445 ± 147 ml) (all p > 0.10). We conclude that short-term administration of hydralazine or nitrates to patients with heart failure can substantially improve circulatory function during exercise but that this improvement probably does not enhance skeletal muscle nutritional flow.