Liposomal Cytarabine Induces Less Neurocognitive Dysfunction Than Intrathecal Methotrexate in an Animal Model.

Liposomal cytarabine is currently being tested clinically as an alternative to intrathecal (IT) methotrexate (MTX) for preventing relapse within the central nervous system among patients with acute lymphoblastic leukemia. To compare the toxicity and cognitive deficits caused by IT MTX versus liposomal cytarabine, juvenile Long Evans rats were treated with IT injections of MTX 1 mg/kg×4 doses over 8 days, or liposomal cytarabine 0.8 mg once. Mean concentrations of free cytarabine in cerebrospinal fluid remained above the cytotoxic threshold of 0.4 µM for 2 weeks after dosing. Animals treated with liposomal cytarabine exhibited normal recognition and spatial memory 4 weeks after injection. In contrast, exposure to IT MTX led to impaired cognitive function. In addition, mean hematocrit on day 11 was significantly lower in the MTX-treated animals (30.8%; 95% confidence interval, 27.0%-34.7%; n=6) compared with that in the liposomal cytarabine-treated animals (39.5%; 95% confidence interval, 38.4%-40.6%; n=6; P<0.0001). Our data suggest that liposomal cytarabine induces fewer neurocognitive deficits and less acute hematologic toxicity compared with IT MTX. Liposomal cytarabine may therefore have therapeutic advantages over IT MTX, if it is equally effective in preventing relapse.

Combined and alternating paracetamol and ibuprofen therapy for febrile children.

BACKGROUND: Health professionals frequently recommend fever treatment regimens for children that either combine paracetamol and ibuprofen or alternate them. However, there is uncertainty about whether these regimens are better than the use of single agents, and about the adverse effect profile of combination regimens. OBJECTIVES: To assess the effects and side effects of combining paracetamol and ibuprofen, or alternating them on consecutive treatments, compared with monotherapy for treating fever in children. SEARCH METHODS: In September 2013, we searched Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; LILACS; and International Pharmaceutical Abstracts (2009-2011). SELECTION CRITERIA: We included randomized controlled trials comparing alternating or combined paracetamol and ibuprofen regimens with monotherapy in children with fever. DATA COLLECTION AND ANALYSIS: One review author and two assistants independently screened the searches and applied inclusion criteria. Two authors assessed risk of bias and graded the evidence independently. We conducted separate analyses for different comparison groups (combined therapy versus monotherapy, alternating therapy versus monotherapy, combined therapy versus alternating therapy). MAIN RESULTS: Six studies, enrolling 915 participants, are included.Compared to giving a single antipyretic alone, giving combined paracetamol and ibuprofen to febrile children can result in a lower mean temperature at one hour after treatment (MD -0.27 °Celsius, 95% CI -0.45 to -0.08, two trials, 163 participants, moderate quality evidence). If no further antipyretics are given, combined treatment probably also results in a lower mean temperature at four hours (MD -0.70 °Celsius, 95% CI -1.05 to -0.35, two trials, 196 participants, moderate quality evidence), and in fewer children remaining or becoming febrile for at least four hours after treatment (RR 0.08, 95% CI 0.02 to 0.42, two trials, 196 participants, moderate quality evidence). Only one trial assessed a measure of child discomfort (fever associated symptoms at 24 hours and 48 hours), but did not find a significant difference in this measure between the treatment regimens (one trial, 156 participants, evidence quality not graded).In practice, caregivers are often advised to initially give a single agent (paracetamol or ibuprofen), and then give a further dose of the alternative if the child's fever fails to resolve or recurs. Giving alternating treatment in this way may result in a lower mean temperature at one hour after the second dose (MD -0.60 °Celsius, 95% CI -0.94 to -0.26, two trials, 78 participants, low quality evidence), and may also result in fewer children remaining or becoming febrile for up to three hours after it is given (RR 0.25, 95% CI 0.11 to 0.55, two trials, 109 participants, low quality evidence). One trial assessed child discomfort (mean pain scores at 24, 48 and 72 hours), finding that these mean scores were lower, with alternating therapy, despite fewer doses of antipyretic being given overall (one trial, 480 participants, low quality evidence)Only one small trial compared alternating therapy with combined therapy. No statistically significant differences were seen in mean temperature, or the number of febrile children at one, four or six hours (one trial, 40 participants, very low quality evidence).There were no serious adverse events in the trials that were directly attributed to the medications used. AUTHORS' CONCLUSIONS: There is some evidence that both alternating and combined antipyretic therapy may be more effective at reducing temperatures than monotherapy alone. However, the evidence for improvements in measures of child discomfort remains inconclusive. There is insufficient evidence to know which of combined or alternating therapy might be more beneficial.Future research needs to measure child discomfort using standardized tools, and assess the safety of combined and alternating antipyretic therapy.

Combined and alternating paracetamol and ibuprofen therapy for febrile children.

BACKGROUND: Health professionals frequently recommend fever treatment regimens for children that either combine paracetamol and ibuprofen or alternate them. However, there is uncertainty about whether these regimens are better than the use of single agents, and about the adverse effect profile of combination regimens. OBJECTIVES: To assess the effects and side effects of combining paracetamol and ibuprofen, or alternating them on consecutive treatments, compared with monotherapy for treating fever in children. SEARCH METHODS: In September 2013, we searched Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; LILACS; and International Pharmaceutical Abstracts (2009-2011). SELECTION CRITERIA: We included randomized controlled trials comparing alternating or combined paracetamol and ibuprofen regimens with monotherapy in children with fever. DATA COLLECTION AND ANALYSIS: One review author and two assistants independently screened the searches and applied inclusion criteria. Two authors assessed risk of bias and graded the evidence independently. We conducted separate analyses for different comparison groups (combined therapy versus monotherapy, alternating therapy versus monotherapy, combined therapy versus alternating therapy). MAIN RESULTS: Six studies, enrolling 915 participants, are included. Compared to giving a single antipyretic alone, giving combined paracetamol and ibuprofen to febrile children can result in a lower mean temperature at one hour after treatment (MD -0.27 °Celsius, 95% CI -0.45 to -0.08, two trials, 163 participants, moderate quality evidence). If no further antipyretics are given, combined treatment probably also results in a lower mean temperature at four hours (MD -0.70 °Celsius, 95% CI -1.05 to -0.35, two trials, 196 participants, moderate quality evidence), and in fewer children remaining or becoming febrile for at least four hours after treatment (RR 0.08, 95% CI 0.02 to 0.42, two trials, 196 participants, moderate quality evidence). Only one trial assessed a measure of child discomfort (fever associated symptoms at 24 hours and 48 hours), but did not find a significant difference in this measure between the treatment regimens (one trial, 156 participants, evidence quality not graded). In practice, caregivers are often advised to initially give a single agent (paracetamol or ibuprofen), and then give a further dose of the alternative if the child's fever fails to resolve or recurs. Giving alternating treatment in this way may result in a lower mean temperature at one hour after the second dose (MD -0.60 °Celsius, 95% CI -0.94 to -0.26, two trials, 78 participants, low quality evidence), and may also result in fewer children remaining or becoming febrile for up to three hours after it is given (RR 0.25, 95% CI 0.11 to 0.55, two trials, 109 participants, low quality evidence). One trial assessed child discomfort (mean pain scores at 24, 48 and 72 hours), finding that these mean scores were lower, with alternating therapy, despite fewer doses of antipyretic being given overall (one trial, 480 participants, low quality evidence) Only one small trial compared alternating therapy with combined therapy. No statistically significant differences were seen in mean temperature, or the number of febrile children at one, four or six hours (one trial, 40 participants, very low quality evidence). There were no serious adverse events in the trials that were directly attributed to the medications used. AUTHORS' CONCLUSIONS: There is some evidence that both alternating and combined antipyretic therapy may be more effective at reducing temperatures than monotherapy alone. However, the evidence for improvements in measures of child discomfort remains inconclusive. There is insufficient evidence to know which of combined or alternating therapy might be more beneficial.Future research needs to measure child discomfort using standardized tools, and assess the safety of combined and alternating antipyretic therapy.

Cochrane in context: Combined and alternating paracetamol and ibuprofen therapy for febrile children.

BACKGROUND: Health-care professionals frequently recommend fever treatment regimens for children who either combine paracetamol and ibuprofen or alternate them.However, there is uncertainty about whether these regimens are better than using single agents and about the adverse effect profile of combination regimens. OBJECTIVES: To assess the results and side effects of combining paracetamol and ibuprofen, or alternating them in consecutive treatments, compared with monotherapy for treating fever in children. SEARCH METHODS: In September 2013, we searched Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; LILACS and International Pharmaceutical Abstracts (2009-2011). SELECTION CRITERIA: We included randomized controlled trials that compared alternating or combined paracetamol and ibuprofen regimens with monotherapy in children with fever. DATA COLLECTION AND ANALYSIS: One review author and two assistants independently screened the searches and applied the inclusion criteria. Two authors assessed risk of bias and graded the evidence independently. We conducted various analyses for different comparison groups (combined therapy versus monotherapy, alternating therapy versus monotherapy and combined therapy versus alternating therapy). MAIN RESULTS: Six studies, enrolling 915 participants, are included. Compared to administering a single antipyretic alone, administering combined paracetamol and ibuprofen to febrile children can result in a lower mean temperature at 1 hour after treatment (mean difference -0.27 ∘C, 95% confidence interval -0.45 to -0.08, two trials, 163 participants, moderate quality evidence). If no further antipyretics are given, combined treatment probably also results in a lower mean temperature at 4 hours (mean difference -0.70 ∘C, 95% confidence interval -1.05 to -0.35, two trials, 196 participants, moderate quality evidence), and in fewer children remaining or becoming febrile for at least 4 hours after treatment (relative risk 0.08, 95% confidence interval 0.02 to 0.42, two trials, 196 participants, moderate quality evidence). Only one trial assessed a measure of child discomfort (fever, associated symptoms at 24 and 48 hours), but did not find a significant difference in this measure between the treatment regimens (one trial, 156 participants, evidence quality not graded). In practice, caregivers are often advised to initially provide a single agent (paracetamol or ibuprofen), and then provide a further dose of the alternative if the child;s fever fails to resolve or recurs. Giving alternating treatment in this manner may result in a lower mean temperature at 1 hour after the second dose (mean difference -0.60 ∘C, 95% confidence interval -0.94 to -0.26, two trials, 78 participants, low quality evidence), and may also result in fewer children remaining or becoming febrile for up to 3 hours after it is given (relative risk 0.25, 95% confidence interval 0.11 to 0.55, two trials, 109 participants, low quality evidence). One trial assessed child discomfort (mean pain scores at 24, 48 and 72 hours), finding that these mean scores were lower, with alternating therapy, despite fewer doses of antipyretic being given overall (one trial, 480 participants, low quality evidence) Only one small trial compared alternating therapy with combined therapy. No statistically significant differences were seen in mean temperature or in the number of febrile children at 1, 4 or 6 hours (one trial, 40 participants, very low quality evidence). In all the trials, there were no serious adverse events that were directly attributed to the medications used. AUTHORS' CONCLUSIONS: There is some evidence that both alternating and combined antipyretic therapies may be more effective at reducing temperatures than monotherapy alone. However, the evidence for improvements in measures of child discomfort remains inconclusive. There is insufficient evidence to decide which of combined or alternating therapy might be more beneficial. Future research needs to measure child discomfort using standardized tools, and assess the safety of combined and alternating antipyretic therapies.