Glutathione S-transferase T1-null seems to be associated with graft failure in hematopoietic SCT.

Hematopoietic SCT (HSCT) from HLA-matched donors is sometimes complicated by GVHD or graft rejection, because of mismatched mHA. This study presents data suggesting the involvement of glutathione S-transferase theta-1 (GSTT1), a phase II detoxifying enzyme encoded by GSTT1, in Ab-mediated rejection of HSCT in children with congenital hemoglobinopathies (CHs). Mismatch of GSTT1, which often features a deletion polymorphism variant, can have major consequences in solid organ transplantation outcome. In liver transplantation, it has been shown to lead to de novo hepatitis, whereas in kidney transplantation, chronic allograft rejection has been documented. In this study on 18 children with CH who underwent HSCT, five cases of graft rejection occurred, all in GSTT1-null patients, four of which featured anti-GSTT1 antibodies. The data suggest that when GSTT1-null patients are transplanted with a GSTT1-positive graft, rejection due to an Ab-mediated immune response against GSTT1 displayed on transplanted stem cells may take place. Thus, it seems that detection of anti-GSTT1 antibodies in patients with a GSTT1-null genotype before transplantation may be predictive of graft rejection in the event of a GSTT1-positive donor.

Vancomycin sequestration during cardiopulmonary bypass surgery.

OBJECTIVE: The present study was designed to analyze vancomycin disposition in adult patients undergoing coronary bypass grafting during and following cardiopulmonary bypass (CPB). METHODS: Coronary bypass surgery was performed on 11 adults with a mean age (SD) of 62.9 (9.0) years old, who received a mean (SD) vancomycin prophylactic dose of 12.7 (1.0) mg/kg in a mean period of 41 (0.7) min. Using a two-compartment open model for pharmacokinetic analysis, the following parameters were obtained: alpha half-life, minutes (t(1/2alpha)); beta half-life, hours (t(1/2beta)); apparent volume of distribution, (V(d) l/kg); volume of the central compartment, (V(c) l/kg), constant between the "central to the peripheral" compartment, (k(12)); constant between the "peripheral to the central" compartment, (k(21)); total area under the concentration-time curve, (AUC mg/lxh) and a vancomycin clearance, (Cl(van) ml/min), respectively. RESULTS: The mean (SD) calculated pharmacokinetic parameters were: t(1/2alpha)17.6 (6) min, t(1/2beta) 8.4 (3.8) h, V(d) 0.803 (0.259) l/kg, V(c) 0.270 (0.162) l/kg, k(12) 0.03 (0.015), k(21) 0.012 (0.012), total AUC 10377.2 (3687.6) mg/lxh. The mean (SD) vancomycin clearance by the CPB machine was 9.51 (2.66) l/h, and the mean (SD) total vancomycin sequestrated by CPB was 331.7 (84) mg. A significant difference (6.3%; p = 0.001) was measured between the mean measured AUC during CPB (1088.1 +/- 253.9) and the same calculated parameter (1160.2 +/- 282). Five minutes after starting CPB, a decrease in vancomycin level was detected; this difference was found to be nearly 11% in absolute values. CONCLUSIONS: This confirmatory study demonstrated that the vancomycin blood concentrations obtained during the study allow recommending a safety prophylactic dose of 12mg/kg in adults who undergo open-heart surgery under CPB conditions. Sequestration of vancomycin by the oxygenator or/and tubing system of the CPB machine had occurred and had been measured in this study.

Therapeutic monitoring of busulfan in pediatric bone marrow transplantation.

The aim of this study was to describe busulfan disposition in a pediatric population who underwent bone marrow transplantation (BMT). Busulfan administered dose was 1 mg/kg every 6 h for 4 days. Plasma determinations were performed after the first dosing at 0, 15, 30, 60, 90, 120, 180, 240, 300, and 360 min. A noncompartment analysis model for extravascular absorption was used for the pharmacokinetic analysis. To obtain the area under the concentration-time curve (AUC) within the "therapeutic window" of 1,000-1,200 microM x minutes a busulfan dose adjustment Was performed at the fourth dose. Forty-five busulfan pharmacokinetic analyses were performed in 34 children. Eleven children had their dose adjusted [1.19 +/- 0.14) mg/kg] at the fourth dose and the AUC was monitored at the fifth one. The mean AUC +/- SD after the fifth dose (998.1 +/- 189.2 microM x min) was different (p = .006)from that after the first dose (1 mg/kg) (687.63 +/- 166.43 microM x min). Six children had their first AUC into the "therapeutic window," 17 children had their dose adjusted [1.2 (+/- 0.22) mg/kg], but the "adjusted" AUC was not available. These data suggest that it may be reasonable to recommend a busulfan dose of 1.2 mg/kg to achieve the accepted therapeutic target in children undergoing BMT.

Monitoring of busulfan area under the curve: estimation by a single measurement.

Because the busulfan area under the concentration-time curve (AUC) has been correlated with the outcome of bone marrow transplantation (BMT) and the occurrence of veno-occlusive disease after BMT, a rapid determination of AUC is needed to ensure its suitable dosage. The present work describes a method based on combining aliquots from the 10 blood samples collected for an AUC busulfan determination and performing a single determination of the resulting mixture. In 42 patients undergoing a preparative regimen for bone marrow transplantation this combined sample AUC was compared with the regular determined AUC obtained from 10 consecutive samples drawn at various time intervals after dosing. It is apparent that the AUCs calculated by pharmacokinetic analysis using a noncompartmental model package and those obtained by analyzing the sample mixture are very similar ( r = 0.961). The proposed method allows rapid adjustment of the busulfan dose, reducing the number of uncorrected dosages during therapy.

Nimesulide-induced acute hepatitis.

OBJECTIVE: To report the occurrence of nimesulide-induced acute hepatitis confirmed by biopsy and an in vitro lymphocyte toxicity assay. CASE SUMMARY: A 54-year-old Arabic woman treated with nimesulide for chronic low back pain was admitted to the hospital with acute hepatitis confirmed by biopsy. Her liver function test results returned to normal within one month after nimesulide discontinuation. An in vitro lymphocyte toxicity assay confirmed that the liver injury was due to nimesulide exposure. DISCUSSION: A case of acute hepatitis secondary to nimesulide, confirmed by biopsy and a laboratory in vitro assay, is described. Although the occurrence of clinically significant liver damage due to nonsteroidal antiinflammatory drugs (NSAIDs) is low, the enormous consumption of these drugs has made them an important cause of liver damage. Nimesulide, a relatively new NSAID commonly used in Europe, with a relative selectivity to cyclooxygenase type 2, can cause a wide range of liver injuries, from mild abnormal liver function to severe liver injuries. These effects are usually reversible on discontinuation of the drug, but occasionally can progress to fatal hepatic failure. CONCLUSIONS: Drug-induced acute hepatitis is a well-recognized adverse effect of many drugs, including nimesuilde. Identification of a drug as a cause for this life-threatening disease is important because the discontinuation of it may be life saving. This article confirms the occurrence of nimesulide-induced hepatitis. It also highlights the importance of monitoring liver function test results after initiating therapy with such a drug.

Effect of salicis cortex extract on human platelet aggregation.

The bark of Salix species contains several prodrugs of salicylate, mainly salicin. The aim of this study was to investigate if during pain treatment with Salicis cortex extract platelet aggregation was affected. A total of 51 patients were enrolled in the study. Thirty-five patients suffering from acute exacerbations of chronic low back pain received randomly and double-blind either Salicis cortex extract with 240 mg salicin/day (n = 19) or placebo (n = 16). Further sixteen patients with stable chronic ischemic heart disease were given 100 mg acetylsalicylate per day. Platelet aggregation was studied using an aggregometer. As aggregating agents, arachidonic acid (500 micrograms/ml), adenosine di-phosphate (2 x 10(-5) M) and collagen (0.18 microgram/ml) were used. The mean maximal arachidonic acid induced platelet aggregation was 61%, 78% and 13% in the Salicis cortex extract, placebo and acetylsalicylate groups. Acetylsalicylate had a significant inhibitory effect on platelet aggregation compared to Salicis cortex extract (p = 0.001) and placebo (p = 0.001). There was also a significant difference between the placebo and the willow bark-treated groups in the maximal platelet aggregation induced by arachidonic acid (p = 0.04) and ADP (p = 0.01). No statistical difference was found between the groups when collagen was applied to the human platelets. Daily consumption of Salicis cortex extract with 240 mg salicin per day affects platelet aggregation to a far lesser extent than acetylsalicylate. Further investigation needs to clarify if this finding is of clinical relevance in patients with impaired thrombocyte function.

Accidental busulfan overdose: enhanced drug clearance with hemodialysis in a child with Wiskott-Aldrich syndrome.

A 4.6 kg infant with Wiskott-Aldrich syndrome received an accidental overdose of busulfan during preparation for allogeneic stem cell transplantation. Pharmacokinetic analysis of plasma busulfan levels alerted staff to the dosing error. Hemodialysis was immediately performed and resulted in accelerated clearance of busulfan. There were no acute neurologic and hepatic side-effects of the busulfan overdose, and despite 2 months of cough accompanied by rales, the patient is now free of pulmonary symptoms. Stable partial donor chimerism occurred after transplantation. At present, the patient is thriving and infection-free 12 months after transplantation, although his platelet count remains at the lower limit of normal.

Diffuse alveolar hemorrhage following thrombolytic therapy for acute myocardial infarction.

We describe a 66-year-old patient with hemoptysis, a drop in hematocrit, hypoxemia and new bilateral alveolar infiltrates after receiving streptokinase for acute myocardial infarction. Markedly increased carbon monoxide diffusion capacity suggested a diagnosis of alveolar hemorrhage. Underlying conditions included congestive heart failure. The patient recovered uneventfully within 7 days of conservative treatment. Alveolar hemorrhage is a rare and often unrecognized life-threatening complication of thrombolytic therapy. Particular attention should be paid to the pulmonary status of patients with congestive heart failure scheduled to receive thrombolytic therapy.

Disseminated fat necrosis with asymptomatic pancreatitis: a case report and review of the literature.

A 62-year-old man with multiple nontender skin nodules is presented. Some of these nodules discharged a purulent looking fluid. At presentation, the patient did not have any other complaints. No infectious, neoplastic, or immunologic origin could be found for the nodular rash. Biochemical profile, imaging, and skin biopsy confirmed the diagnosis of disseminated fat necrosis (DFN) accompanying asymptomatic pancreatitis. The process involved the mesenteric, subcutaneous, and intramedullary fat. The skin lesions were surgically treated. Mesenteric and intramedullary fat necrosis were watched closely. A year later, the patient was readmitted with a diagnosis of pancreatitis. Subcutaneous and intramedullary necrosis were completely resolved at this time, and only mesenteric fat necrosis prevailed. The clinical syndrome of DFN, its etiology, pathophysiology, treatment, and prognosis are discussed.

Ascites and pleural effusion secondary to extramedullary hematopoiesis.

Extramedullary hematopoiesis in the pleura and peritoneum is rare. It is usually asymptomatic and generally is diagnosed on post mortem examination. Herein we describe a 33-year-old woman with long-standing myelofibrosis who presented with symptomatic ascites and pleural effusion. After complete evaluation, these were found to have been caused by extramedullary hematopoietic implants to the pleura and peritoneum. The pleural effusion responded to low-dose radiotherapy.

Effective acute desensitization for immediate-type hypersensitivity to human granulocyte-monocyte colony stimulating factor.

BACKGROUND: Granulocyte-monocyte colony stimulating factor (GM-CSF) is the treatment of choice for patients with life threatening neutropenias. Hypersensitivity to GM-CSF may lead to cessation of treatment. Acute desensitization is an alternative mode of managing drug hypersensitivity, especially when other common modes like substitution of offending drug or premedication with antihistamines and/or corticosteroids are not available or fail. CASE REPORT: A 42-year-old woman with a 17-year history of severe chronic mucocutaneous candidal infections became resistant to all common antifungal drugs. As her disorder was associated with defective functions of monocytes and granulocytes, GM-CSF treatment was started yielding a very good clinical effect. After a short period of treatment, however, the patient developed anaphylactic reactions which could not be abolished by preadministration of antihistamines and/or corticosteroids. Replacement of therapy by G-CSF caused identical hypersensitivity phenomena. METHODS: Prick skin tests with 100, 200, or 400 microg/mL of GM-CSF or G-CSF, using also negative and positive controls, were performed on the patient and three healthy control subjects. A positive local reaction was observed only in patient at the prick point of 200 microg/mL GM-CSF or 400 microg/mL G-CSF. Acute desensitization to GM-CSF was initiated adopting a protocol used for parenteral desensitization to penicillin. RESULTS: The patient tolerated the desensitization procedure very well and we could resume the administration of GM-CSF. For the past 30 months the patient has been treated uneventfully by subcutaneous administration of GM-CSF, 500 microg twice weekly, and is free of candidal infections. Skin prick tests were repeated 1 month postdesensitization and resulted in a very weak response to GM-CSF compared with the predesensitization response. CONCLUSIONS: Acute desensitization can be utilized in patients who develop drug hypersensitivity reactions to GM-CSF. As GM-CSF is a very unique agent and in most cases cannot be replaced by another one, acute desensitization may play a very important role in managing failure of GM-CSF treatment due to hypersensitivity reactions.

Pharmacokinetic analysis of amikacin twice and single daily dosage in immunocompromised pediatric patients.

Ten children received amikacin twice daily and 13 were treated using the single daily protocol. All had fever and neutropenia on admission, and received a total daily dose of 20 mg/kg when included in the study. Individual pharmacokinetic parameters were calculated using a one-compartment model for two blood amikacin samples. The mean (+/- SD) of elimination half-life (h), amikacin clearance (l/h/kg), volume of distribution (l/kg), peak concentration (microgram/ml) and trough concentration (microgram/ml) were: 2.51 (0.74) and 2.85 (0.32) h; 0.26 (0.16) and 0.115 (0.02) l/h/kg; 0.74 (0.44) and 0.47 (0.11) l/kg; 19.1 (12.3) and 42.6 (12.6) micrograms/ml; 0.85 (0.74) and 0.18 (0.24) microgram/ml with twice and single daily dosage schedules, respectively. A single daily dose of amikacin had a significantly longer elimination half-life, lower clearance, higher peak concentration and lower trough concentration in comparison to the twice-daily schedule. The use of amikacin 20 mg/kg daily delivered in a single daily dose is recommended for immunocompromised pediatric patients with fever and neutropenia, in spite of the measured pharmacokinetic differences.

Spontaneous pulsatility and pharmacokinetics of growth hormone in liver cirrhotic patients.

BACKGROUND/AIMS: Liver cirrhosis is characterized by high serum growth hormone levels and low serum insulin-like growth factor I and growth hormone-binding protein levels. The present study was designed to characterize the serum profile of growth hormone and growth hormone pharmacokinetics in postnecrotic liver cirrhosis, correlating it with liver function and nutritional states. METHODS: Fifteen patients were grouped by the Child-Pugh score (group 1, score of 5 to 8; group 2, score of 9 to 12). Five healthy subjects served as controls. Nutritional status was assessed by the creatinine-height index. Baseline growth hormone, insulin-like growth factor, and growth hormone binding protein were measured, and growth hormone pharmacokinetics was followed for 48 h after administration of subcutaneous recombinant human growth hormone (0.06 mg/kg). RESULTS: Trough serum growth hormone (microg/l) was higher in both patient groups (5.3+/-3.6) than in controls (1.0+/-0.3; p<0.01). More pulses were recorded in cirrhotic patients, and mean pulse amplitude (microg/l) was higher in cirrhotic patients than in controls (p<0.01). After subcutaneous recombinant human growth hormone injection, maximal growth hormone was higher in cirrhotic patients and the area under the curve over 24 h was greater (626+/-120) than in controls (330+/-54; p<0.01). Single regression analysis showed a weak correlation of both the Child-Pugh score and the creatinine-height index with the pharmacokinetic parameters. CONCLUSIONS: Due to decreased growth hormone clearance, patients with liver cirrhosis have increased trough and peak serum growth hormone levels, as well as lower serum growth hormone binding protein and insulin-like growth factor. Recombinant human growth hormone pharmacokinetics are typical of a high hepatic extraction substance administered to patients with liver disease and portal hypertension, and this may be relevant to the further use of growth hormone therapy.

Group B streptococcal tricuspid valve endocarditis: a case report and review of literature.

Group B streptococcal endocarditis involving the tricuspid valve is an uncommon disease. We describe herein a young healthy woman who developed this disease following an elective abortion. She was treated with penicillin and gentamycin with no response. The patient was operated urgently and recovered. Few reports have described the disease in the last 25 years (our case is the thirteenth). Five of them were IV drug abusers, four patients suffered from debilitating diseases and in five women endocarditis developed following an obstetric procedure. In general the mortality from tricuspid valve endocarditis is low, indeed 2/13 (15%) died. The drug of choice is penicillin with gentamycin.

Pharmacokinetic analysis of vancomycin in steady state in pediatric cancer patients.

Thirty children suffering from different types of malignancies, neutropenic fever, and suspected staphylococcal bacteremia were evaluated for the pharmacokinetics of vancomycin in steady-state conditions and compared with eight children suffering from proven methicillin-resistant staphylococcal infection. All the studied population received intravenous vancomycin at 40 mg/kg daily divided into four daily doses. The individual pharmacokinetic parameters were calculated using a one-compartment model for two blood vancomycin samples. The mean (+/- SD) half-time (t1/2, hours), clearance (L/h/kg), Vss (L/kg), Cmax (microgram/mL), and Cmin (microgram/mL) were 10.5 (7.9) and 14.9 (9.1) hours; 0.11 (0.14) and 0.06 (0.06) L/h/kg; 0.62 (0.33) and 1.3 (0.6) L/kg; 28.3 (11.8) and 22.3 (9.8) micrograms/mL; and 5.7 (6.0) and 7.4 (4.8) micrograms/mL for the malignancy and control groups, respectively. The malignancy group had a significantly shorter t1/2 (P = .005), higher clearance (P = .005), and lower Cmin (P = .03) in comparison with the control group. It is suggested that the prescription of vancomycin at 40 mg/kg daily, divided into four daily doses, is safe and will provide a peak blood level of vancomycin sufficient to cover the broad spectrum of staphylococcal bacteria. The vancomycin dose should be individualized, based on an individual pharmacokinetic profile.