Maintenance of efficacy and safety of rabeprazole in children with endoscopically proven GERD.

OBJECTIVE: The aim of the present study was to evaluate 24-week maintenance of efficacy and safety of rabeprazole in children with endoscopically proven gastroesophageal reflux disease (GERD). METHODS: Children ages 1 to 11 years who achieved endoscopic/histologic healing (defined as grade 0 of the Hetzel-Dent Classification scale and/or grade 0 of the Histological Features of Reflux Esophagitis scale) in a 12-week treatment phase were continued on the same dose for an additional 24 weeks during the maintenance phase. The dose was determined by weight: children weighing 6 to 14.9 kg (low-weight cohort) received 5 or 10 mg and children weighing ≥ 15 kg (high-weight cohort) received 10 or 20 mg. RESULTS: Healing was maintained in 90% of children (100% [low-weight cohort]; 89% [10 mg, high-weight cohort]; 85% [20 mg, high-weight cohort]). The Total GERD Symptom and Severity score continued to improve slightly in all of the children across all dose groups (P = 0.026) during the maintenance phase, except the 10-mg dose group (low-weight cohort), which experienced a slight worsening of 3.6 points. Overall, 71% children felt better on the GERD Symptom Relief score (P < 0.001); 95% of investigators and 92% of parent/caregivers rated "Good to Excellent" on the Global Treatment Satisfaction scale and Clinical Global Impressions Improvement scale, respectively. Overall incidence of treatment-emergent adverse events was 63%; upper respiratory tract infections (13%) and vomiting (11%) were the most commonly reported (>10%). CONCLUSIONS: Rabeprazole was effective in maintaining endoscopic/histologic healing during a 24-week maintenance period in children with endoscopically proven GERD. The clinical effect and safety profile were largely similar across dose groups.

Pharmacokinetics and tolerability of rabeprazole in children 1 to 11 years old with gastroesophageal reflux disease.

BACKGROUND: The pharmacokinetics of rabeprazole after a single oral dose and once-daily administration for 5 consecutive days was characterized in children 1 to 11 years old with gastroesophageal reflux disease (GERD). PATIENTS AND METHODS: The initial 8 patients received rabeprazole sodium (hereafter referred to as rabeprazole) 0.14 mg/kg (part 1); the next 20 patients were randomized to receive 0.5 or 1 mg/kg (part 2) to target concentrations in plasma expected to be safe and effective. Pharmacokinetic parameters of rabeprazole and the thioether metabolite were calculated using noncompartmental methods. Subjective evaluations of GERD severity, rabeprazole short-term effectiveness, palatability, and safety were also characterized. RESULTS: Rabeprazole concentrations increased in a dose-dependent manner. Little or no accumulation was observed after repeated administration. The results suggest that formation of the thioether is an important metabolic pathway in young patients, which is consistent with adults. Plasma area under the concentration-time curve values of rabeprazole and the metabolite were poorly correlated with individual age and body weight. Furthermore, oral rabeprazole clearance values (not adjusted for weight) were similar to historical adult data. However, weight-adjusted values were higher for the pediatric patients, and approximately 2 to 3 times the milligram per kilogram dose of rabeprazole in these children was necessary to achieve comparable concentrations in adults. Subjective evaluations demonstrated an improvement of GERD symptoms in most patients after rabeprazole treatment. CONCLUSIONS: Palatability of the formulation was reported to be good or excellent. Rabeprazole was well tolerated, with no notable differences in safety among the dose groups.

Lack of correlation of 24- vs. 48-h itraconazole minimum inhibitory concentrations with microbiological and survival outcomes in a guinea pig model of disseminated candidiasis.

A 'trailing' effect has been commonly observed when azole antifungals are tested against Candida spp. Previous experience with fluconazole indicates that 24-h minimum inhibitory concentration (MIC) values are more compatible endpoints when compared with clinical outcomes. We evaluated the trailing effect of Candida isolates tested with itraconazole in a guinea pig model of systemic candidiasis. Survival and organ burden were only significantly affected by using a higher dose of itraconazole, irrespective of the MIC differences at 24 and 48 h. A fluconazole-resistant strain with susceptible dose-dependent MICs to itraconazole was successfully treated with high-dose itraconazole. Our data suggests that survival and microbiological response depend more on drug dosing than on the trailing phenotype of the isolates.

Efficacy of epoetin alfa administered every 2 weeks to maintain hemoglobin and quality of life in anemic HIV-infected patients.

Anemia, a common hematological abnormality in HIV, contributes to decreased quality of life (QOL). This study assessed once-every-2-week epoetin alfa on maintaining QOL and hemoglobin (Hb) in anemic HIV-infected patients in a 24-week, open-label, multicenter study. HIV-infected patients (Hb < or =12 g/dl) received epoetin alfa 40,000 units subcutaneously once weekly, until reaching Hb > or =13 g/dl. Patients then entered a maintenance phase (MP), in which epoetin alfa was administered every other week or at longer intervals. The trial objectives were to determine if QOL, as measured by the Medical Outcomes Study-HIV (MOS-HIV) general health perceptions (GHP) domain and Hb, was maintained. Safety was also assessed. A total of 292 patients were enrolled (72% on HAART). Mean baseline laboratory values were Hb = 10.8 g/dl, CD4(+) count = 280 cells/microl, and HIV RNA = 51,867 copies/ml. In all, 81% of patients reached Hb > or =13 g/dl and 92% reached Hb > or =12 g/dl. QOL was maintained from the beginning (GHP = 44.2 points) to the end of MP (GHP = 43.4 points) with every other week or longer dosing. Mean Hb at the beginning of MP was 13.4 +/- 0.5 g/dl and was 12.8 +/- 1.4 g/dl at study end. Epoetin alfa was well tolerated; adverse events were consistent with those reported in previous studies of epoetin alfa in HIV-infected patients. Although the clinical approach tested in this study is not consistent with current prescribing recommendations, the results confirm the efficacy of prolonged dosing intervals (every 2-4 weeks) in maintaining optimal Hb levels and QOL in anemic HIV-infected patients.

Intravenous and oral itraconazole versus intravenous and oral fluconazole for long-term antifungal prophylaxis in allogeneic hematopoietic stem-cell transplant recipients. A multicenter, randomized trial.

BACKGROUND: Allogeneic hematopoietic stem-cell transplant recipients often receive fluconazole or an amphotericin B preparation for antifungal prophylaxis. Because of concerns about fungal resistance with fluconazole and toxicity with amphotericin B, alternative prophylactic regimens have become necessary. OBJECTIVE: To compare the efficacy and safety of intravenous and oral itraconazole with the efficacy and safety of intravenous and oral fluconazole for long-term prophylaxis of fungal infections. DESIGN: Open-label, multicenter, randomized trial. SETTING: Five transplantation centers in the United States. PATIENTS: 140 patients undergoing allogeneic hematopoietic stem-cell transplantation. INTERVENTION: Itraconazole (200 mg intravenously every 12 hours for 2 days followed by 200 mg intravenously every 24 hours or a 200-mg oral solution every 12 hours) or fluconazole (400 mg intravenously or orally every 24 hours) from day 1 until day 100 after transplantation. MEASUREMENTS: Proven invasive or superficial fungal infection, drug-related side effects, mortality from fungal infection, and overall mortality. RESULTS: Proven invasive fungal infections occurred in 6 of 71 itraconazole recipients (9%) and in 17 of 67 fluconazole recipients (25%) during the first 180 days after transplantation (difference, -16 percentage points [95% CI, -29.2 to -4.7 percentage points]; P = 0.01). Superficial fungal infections occurred in 3 of 71 itraconazole recipients (4%) and in 2 of 67 fluconazole recipients (3%). In a multivariable analysis using factors known to affect the risk for invasive fungal infection after hematopoietic stem-cell transplantation, prophylaxis with itraconazole was still associated with fewer invasive fungal infections (odds ratio, 0.300 [CI, 0.111 to 0.814]; P = 0.02) caused by either yeasts or molds. More fungal pathogens were found to be resistant to fluconazole than to itraconazole. Except for more frequent gastrointestinal side effects (nausea, vomiting, diarrhea, or abdominal pain) in patients given itraconazole (24% vs. 9%; difference, 15 percentage points [CI, 2.9 to 27.0 percentage points]; P = 0.02), both itraconazole and fluconazole were well tolerated. The overall mortality rate was similar in each group (32 of 71 patients in the itraconazole group [45%] vs. 28 of 67 patients in the fluconazole group [42%]; difference, 3 percentage points [CI, -13.2 to 19.8 percentage points]; P > 0.2), but fewer deaths were related to fungal infection in patients given itraconazole (6 of 71 [9%]) than in patients given fluconazole (12 of 67 [18%]) (difference, 9 percentage points [CI, -20.6 to 1.8 percentage points]; P = 0.13). CONCLUSION: Itraconazole is more effective than fluconazole for long-term prophylaxis of invasive fungal infections after allogeneic hematopoietic stem-cell transplantation. Except for gastrointestinal side effects, itraconazole is well tolerated.

Once-weekly epoetin alfa improves quality of life and increases hemoglobin in anemic HIV+ patients.

This prospective, open-label, multicenter trial evaluated the effects of once-weekly (qw) epoetin alfa on quality of life (QOL) and hemoglobin (Hb) levels in anemic human immunodeficiency virus (HIV)-infected adult receiving antiretroviral therapy. A total of 650 patients with Hb < or = 11 g/dl received epoetin alfa 40,000 U qw subcutaneously, with dose escalation to 60,000 qw if Hb increase was <1 g/dl after 4 weeks. The linear Analog Scale Assessment (LASA) overall QOL score, LASA energy score, and LASA activity score each significantly improved from baseline to final measurement (p < 0.0001 for each parameter). Improvements in the Medical Outcomes Study (MOS)-HIV physical and mental health summary scores were also significant (p < 0.0001), and coincided with Hb increases. Mean Hb increased from baseline to final measurement by 2.5 g/dl (95% CI: 2.3, 2.6 g/dl; p < 0.0001). Objective hematological response rate, defined as a > or = 1 g/dl Hb increase from baseline to week 8, was 86%. Hemoglobin increased significantly in all subgroups of race, zidovudine use, CD4+ cell count, and viral load. Once-weekly epoetin alfa was well tolerated. Once-weekly epoetin alfa is effective in improving QOL and Hb measures.

Erythropoietin is neuroprotective in models of HIV sensory neuropathy.

HIV-associated sensory neuropathy (HIV-SN) is the most common neurological complication of HIV infection. Presently, there are no effective therapies for this painful neuropathy. The pathology of HIV-SN is characterized by 'dying back' sensory axonal degeneration and a more modest loss of dorsal root ganglion (DRG) sensory neurons. It has been hypothesized that HIV-SN results from neurotoxicity by secreted viral proteins, such as the HIV envelope glycoprotein gp120. Furthermore, neurotoxicity by dideoxynucleoside (DDX) agents, results in the observed higher incidence of HIV-SN in HIV-infected patients taking these antiretroviral drugs. In this study we show that administration of picomolar amounts of the hormone erythropoietin (EPO) prevents sensory axonal degeneration and in vitro DRG neuronal death by both gp120 and ddC (a neurotoxic DDX drug). Our results suggest that EPO may be useful in the treatment of HIV-SN.

Erythropoietic response to anemia in chronic hepatitis C patients receiving combination pegylated interferon/ribavirin.

OBJECTIVES: In hepatitis C virus (HCV)-infected patients receiving pegylated interferon (PEG-IFN)/ribavirin (RBV) combination therapy, anemia is a well-known side effect. The purpose of this study was to describe the time course and extent of hemoglobin (Hb) changes and the erythropoietic response to PEG-IFN/RBV-induced anemia. METHODS: In this multicenter, observational, 8-wk study, laboratory parameters were measured weekly for 8 wk or until early withdrawal. Primary endpoints included changes in Hb and serum erythropoietin (sEPO) from baseline to week 8; other measures were changes in reticulocytes and RBV dose. The predictive value of baseline factors for maximum Hb decline was assessed. RESULTS: In the 97 evaluable patients, mean Hb decreased from 14.4 +/- 1.4 g/dl (baseline) to 11.9 +/- 1.3 g/dl (week 8). Twenty-one percent of patients withdrew before week 8. The estimated erythropoietic response was lower than that seen in two historic control populations of iron deficiency anemia patients. Mean RBV dose decreased from 986 +/- 190 mg/day (baseline) to 913 +/- 228 mg/day (week 8). Fifty-seven out of 77 (74%) patients who completed the study maintained their initial prescribed RBV dose. Patients maintained on the initial dose of RBV who had a higher baseline Hb and viral load showed a trend toward larger Hb declines. Platelets and white blood cells (WBCs) also declined during the study. CONCLUSIONS: HCV-infected patients receiving PEG-IFN/RBV therapy have reductions in Hb, platelets, and WBCs, possibly due to bone marrow suppression. They also have diminished endogenous sEPO production for their degree of anemia.

Pharmacokinetics of intravenous itraconazole in stable hemodialysis patients.

The pharmacokinetics of intravenous itraconazole (ITC) was studied in dialysis patients. Dialysis had no effect on the half-life and clearance of ITC or OH-ITC. However, dialysis allowed the clearance of hydroxypropyl-beta-cyclodextrin (HP-beta-CD). The area under the concentration-time curve from time zero to infinity (AUC(0- infinity)) for HP-beta-CD administered before dialysis was lower than the AUC(0- infinity) when it was administered after dialysis (P < 0.01). Administration of ITC intravenously just prior to hemodialysis appears to produce adequate systemic exposures of ITC and OH-ITC while allowing dialysis clearance of HP-beta-CD. Studies of multiple administrations are warranted.

A novel endogenous erythropoietin mediated pathway prevents axonal degeneration.

Clinically relevant peripheral neuropathies (such as diabetic and human immunodeficiency virus sensory neuropathies) are characterized by distal axonal degeneration, rather than neuronal death. Here, we describe a novel, endogenous pathway that prevents axonal degeneration. We show that in response to axonal injury, periaxonal Schwann cells release erythropoietin (EPO), which via EPO receptor binding on neurons, prevents axonal degeneration. We demonstrate that the relevant axonal injury signal that stimulates EPO production from surrounding glial cells is nitric oxide. In addition, we show that this endogenous pathway can be therapeutically exploited by administering exogenous EPO. In an animal model of distal axonopathy, systemic EPO administration prevents axonal degeneration, and this is associated with a reduction in limb weakness and neuropathic pain behavior. Our in vivo and in vitro data suggest that EPO prevents axonal degeneration and therefore may be therapeutically useful in a wide variety of human neurological diseases characterized by axonopathy.

Intravenous itraconazole for prophylaxis of systemic fungal infections in patients with acute myelogenous leukemia and high-risk myelodysplastic syndrome undergoing induction chemotherapy.

BACKGROUND: Systemic fungal infections remain the leading cause of mortality in patients with newly diagnosed acute myelogenous leukemia (AML) and high-risk myelodysplastic syndrome (MDS). The objective of the current study was to determine whether intravenous itraconazole (i.v. ITRA) reduced the incidence of probable/proven fungal infections in this group of patients, and compare the results with those of a historic control group treated with fluconazole plus itraconazole capsules (F+I). METHODS: Patients with AML and high-risk MDS who underwent induction chemotherapy received 200 mg of i.v. itraconazole over 60 minutes every 12 hours during the first 2 days followed by 200 mg given i.v. once daily. RESULTS: One hundred patients were enrolled, 96 of whom were evaluable. Approximately 48% of the patients in the group of patients treated with i.v. ITRA as well as in the F+I group completed prophylaxis. Nine patients (9%) in the study group developed either proven/probable fungal infections (Candida glabrata in 5 patients, C. tropicalis in 1 patient, C krusei in 1 patient, and Fusarium in 2 patients) compared with 3 patients (4%) with proven fungal infection in the historic control group (C. tropicalis in 1 patient and Aspergillus in 2 patients). There were no significant differences noted between the two groups with regard to the percentage of patients who developed proven/probable or possible fungal infection as well as with regard to survival. These results also were obtained after adjusting for relevant prognostic factors (creatinine and bilirubin). The most common toxicity encountered with the use of i.v. ITRA was NCI Grade 3-4 hyperbilirubinemia (6%). CONCLUSIONS: Despite its theoretic advantages, the authors found no evidence that i.v. ITRA is superior to itraconazole capsules, at least when the latter is combined with fluconazole.