Higher Risk Of Neutropenia Research Articles

High Risk of Neutropenia in HIV‐Infected Children following Treatment with Artesunate plus Amodiaquine for Uncomplicated Malaria in Uganda

Artemisinin-based combination therapies are rapidly being adopted for the treatment of malaria in Africa; however, there are limited data on their safety and efficacy among human immunodeficiency virus (HIV)-infected populations. We compared malaria treatment outcomes between cohorts of HIV-infected and HIV-uninfected children in Uganda who were observed for 18 and 29 months, respectively. Malaria was treated with artesunate plus amodiaquine, and outcomes were assessed using standardized guidelines. HIV-infected children received trimethoprim-sulfamethoxazole prophylaxis and antiretroviral therapy in accordance with current guidelines. Twenty-six HIV-infected participants experiencing 35 episodes of malaria and 134 HIV-uninfected children experiencing 258 episodes of malaria were included in the study. Twelve HIV-infected children were receiving antiretroviral therapy, 11 of whom were receiving zidovudine. Malaria treatment was highly efficacious in both the HIV-infected and HIV-uninfected cohorts (28-day risk of recrudescence, 0% and 3.6%, respectively); however, there was a trend towards increased risk of recurrent malaria among the HIV-uninfected children (2.9% vs. 13.2%; p = .08). Importantly, the risk of neutropenia 14 days after initiation of treatment with artesunate plus amodiaquine was higher among HIV-infected children than among HIV-uninfected children (45% vs. 6%; p < .001). The severity of all episodes of neutropenia in HIV-uninfected children was mild to moderate, and 16% of episodes of neutropenia in the HIV-infected cohort were severe or life-threatening (neutrophil count, <750 cells/mm(3)). In the HIV-infected cohort, the risk of neutropenia was significantly higher among children who received antiretroviral therapy than among those who did not receive antiretroviral therapy (75% vs. 26%; p < .001). Artesunate plus amodiaquine was highly efficacious for malaria treatment in HIV-infected children but was associated with a high risk of neutropenia, especially in the context of concurrent antiretroviral use. Our findings highlight an urgent need for evaluation of alternative antimalarial therapies for HIV-infected individuals.

Modeling and simulation of neutropenia to support dosing regimens for liposome-encapsulated paclitaxel easy-to-use (LEP- ETU)

13011 Background: LEP-ETU is a liposomal formulation of paclitaxel designed to reduce toxicities while maintaining or enhancing the efficacy of the drug. A PKPD model was used to characterize the time course of neutrophils in relation to blood exposure of LEP-ETU in patients with solid tumors. Simulations were performed to provide justification for dosing schedule in Phase 3 trials. Methods: Data from 63 patients in two phase I studies with advanced malignancies were utilized. LEP-ETU was infused intravenously over 90 min. at 135, 175, 225, 275, 325, and 375 mg/m2 every 21 days (Q3W). A separate cohort received 175 mg/m2 of LEP-ETU infused over 3 hours following a Q3W regimen. Population PKPD modeling and simulations were performed to assess the influence of dose and schedule (275 - 325 mg/m2 Q3W vs. 90 - 110 mg/m2 QW) on neutropenia. Results: The temporal relationship between circulating neutrophils and paclitaxel concentrations was adequately characterized using a model representative of progenitor cells undergoing differentiation and maturation into neutrophils. Mean predicted (%SEM) baseline ANC was 4.3 (6) x 109/L, representative of a normal neutrophil count. Mean transit time (%SEM) was 80 (8) hr, representing a post-mitotic time delay to neutrophil maturation. The neutrophil T1/2 was 14 hr, comparable to published values. The drug effect (Slope·Cp) on the proliferation rate constant is decreased by 9- and 91-fold when 10 or 100 units of drug is present, indicative of paclitaxel’s inhibition of progenitor cell production in bone marrow. Simulations suggest a higher risk of neutropenia with the Q3W regimen and dose-dependent severity for both the Q3W and QW regimens. The predicted incidence of grade 4 toxicity increased from 33% - 42% across the dose range of 275 - 325 mg/m2 Q3W. For a dose of 110 mg/m2 given QW, the incidence of grade 4 neutropenia was 16% compared to 42% for the same total dose of 325 mg/m2 given Q3W. Conclusions: Modeling and simulation predict that a Q3W regimen of 325 mg/m2 LEP- ETU (MTD) provides acceptable neutropenia outcomes comparable to 175 mg/m2 paclitaxel Q3W, while minimizing the Cremophor- associated adverse events. Future consideration of QW regimens may be explored. No significant financial relationships to disclose.

Pharmacogenetics of Irinotecan: Clinical Perspectives on the Utility of Genotyping

Depending upon the UDP glucuronosyltransferase 1A1 (UGT1A1) genotype, patients are more or less susceptible to the risk of severe toxicity of irinotecan. As the US FDA-approved label of irinotecan (CPT-11, Camptosar) has been recently revised to include UGT1A1 genotype among potential risk factors for toxicity, it is expected that UGT1A1 genotyping will be increasingly used in patients undergoing irinotecan treatment. At present, the label states that *28/*28 (7/7) genotype patients are at higher risk of neutropenia and should be treated at a lower dose of irinotecan. Although effective alternative drugs (i.e., oxaliplatin) exist for metastatic colorectal cancer (the main indication of irinotecan), recent studies have confirmed that irinotecan has an important place in the management of this disease. We feel that now is the time for addressing questions around the UGT1A1*28 testing that many oncologists might have had but remained unanswered. For example, does the test have adequate sensitivity/specificity? Can the test results be effectively utilized to guide therapy of metastatic colorectal cancer patients? Is it possible that the *1/*1 (6/6) patients are underdosed? How can the genetic prediction of irinotecan toxicity be improved? Is the UGT1A1*28 test fully predictive of the UGT1A1 deficiency in patients who are not of Caucasian origin? Clinicians and investigators interested in a discussion of each of these points could find this article a useful source.

Traitement des états mixtes dans le trouble bipolaire de l’humeur

Mixed states are characterized by the mixture or rapid alternation, within hours, of manic and depressive symptoms. They bear a high suicidal risk and therefore represent a major therapeutic issue. We performed a computerized bibliographic search and reviewed the efficacy of the available treatments of mixed states. It confirmed the recognized poor efficacy of lithium and the need to discontinue antidepressants. Among mood stabilizers, divalproate and its derivatives are those with the highest level of evidence. As regards new anticonvulsants, the data are yet too limited to recommend them as first line treatments. They may however be used as second line or adjunct treatments in case a monotherapy with a reference treatment has failed. Among antipsychotic drugs, clozapine has demonstrated its efficacy but also remains a second line treatment due to its high risk of neutropenia and agranulocytosis. Electroconvulsive therapy is a useful alternative in treatment resistant cases or when there is an imminent risk for suicide. Some degree of uncertainty remains for the treatment of the so called "agitated depressions" as no study has yet focused on this issue with a specifically selected sample of patients. Such a study would also enlighten the uncertain nosological status of this clinical entity and would answer as to whether they belong to the category of mixed states.

G-CSF and GM-CSF for treating or preventing neonatal infections.

The colony stimulating factors (CSFs), granulocyte-macrophage colony stimulating factor (GM-CSF) and granulocyte colony stimulating factor (G-CSF), are naturally occurring cytokines that stimulate the production and antibacterial function of neutrophils and monocytes. Two strategies have been adopted for exploring whether CSFs can provide clinical benefit for preterm infants. The first has investigated their use as a treatment to improve outcome in established systemic infection, especially when complicated by a low neutrophil count. The alternative strategy has been to use CSFs prophylactically, to prevent sepsis prospectively through stimulation of neutrophil production and bactericidal function. To determine the efficacy and safety of the haemopoietic colony stimulating factors (G-CSF or GM-CSF) in newborn infants, when used for:a) treatment of suspected or proven systemic infection to reduce mortality, orb) prophylaxis, to prevent systemic infection in infants at high risk of nosocomial infection. To determine, in subgroup analysis, the influence of pre-existing or high risk of neutropenia on the outcome of therapy. PubMed, EMBASE, MEDLINE and the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 2, 2003) were searched in April 2003 using the keywords: G-CSF, GM-CSF, infant newborn, with and without the limit Clinical Trial. In addition, reference lists of identified RCTs, meta-analyses and personal files were searched. The criteria used to select studies for inclusion were: RCT. Newborn infants in intensive care. G-CSF or GM-CSF given as treatment in conjunction with antibiotics for suspected or microbiologically proven systemic infection. G-CSF or GM-CSF given as prophylaxis with the aim of reducing the incidence of systemic infection. Treatment studies reporting all cause mortality. Prophylaxis studies reporting subsequent incidence of sepsis and / or mortality. Relative risks (RR) and risk differences (RD) with 95% confidence intervals (CI) using the fixed effect model are reported. Number needed to treat (NNT) was calculated for the outcomes that showed a statistically significant reduction in RR. Seven treatment studies of 257 infants with suspected systemic bacterial infection and three prophylaxis studies comprising 359 neonates are analysed. Treatment studies: There is no evidence that the addition of G-CSF or GM-CSF to antibiotic therapy in preterm infants with suspected systemic infection reduces immediate all cause mortality. No significant survival advantage was seen at 14 days from the start of therapy [typical RR 0.71 (95% CI 0.38,1.33); typical RD -0.05 (95% CI -0.14, 0.04)]. However all seven of the treatment studies were small, the largest recruiting only 60 infants. The subgroup analysis of 97 infants from three treatment studies who, in addition to systemic infection, had clinically significant neutropenia (< 1.7 x 10(9)/l) at trial entry, does show a significant reduction in mortality by day 14 [RR 0.34 (95% CI 0.12, 0.92); RD -0.18 (95% CI -0.33, -0.03); NNT 6 (95% CI 3-33)]. Prophylaxis studies have not demonstrated a significant reduction in mortality in neonates receiving GM-CSF [RR 0.59 (95% CI 0.24,1.44); RD -0.03 (95% CI -0.08,0.02)]. The identification of sepsis as the primary outcome of prophylaxis studies has been hampered by inadequately stringent definitions of systemic infection. However, data from one study suggest that prophylactic GM-CSF may provide protection against infection when given to preterm infants who are neutropenic or at high risk of developing postnatal neutropenia. There is currently insufficient evidence to support the introduction of either G-CSF or GM-CSF into neonatal practice, either as treatment of established systemic infection to reduce resulting mortality, or as prophylaxis to prevent systemic infection in high risk neonates. No toxicity of CSF use was reported in any systemic infection to reduce resulting mortality, or as prophylaxis to prevent systemic infection in high risk neonates. No toxicity of CSF use was reported in any study included in this review. The limited data suggesting that CSF treatment may reduce mortality when systemic infection is accompanied by severe neutropenia should be investigated further in adequately powered trials which recruit sufficient infants infected with organisms associated with a significant mortality risk.