Systematic Review and Meta-Analysis of Neuropsychiatric Symptoms and Executive Functioning in Adults With Phenylketonuria.

This systematic review and meta-analysis (MA) investigates the impact of elevated blood phenylalanine (Phe) on neuropsychiatric symptoms in adults with phenylketonuria (PKU). The meta-analysis of PKU is challenging because high-quality evidence is lacking due to the limited number of affected individuals and few placebo-controlled, double-blind studies of adults with high and low blood Phe. Neuropsychiatric symptoms associated with PKU exceed general population estimates for inattention, hyperactivity, depression, and anxiety. High Phe is associated with an increased prevalence of neuropsychiatric symptoms and executive functioning deficits whereas low Phe is associated with improved neurological performance. Findings support lifelong maintenance of low blood Phe.

Systematic review to establish the safety profiles for direct and indirect inhibitors of p38 Mitogen-activated protein kinases for treatment of cancer. A systematic review of the literature.

OBJECTIVE: To identify potential tolerability issues for a novel selective p38 Mitogen-activated Protein Kinases (p38MAPK) inhibitor, we performed a systematic review of published studies and abstracts reporting safety outcomes for indirect inhibitors of p38MAPK. METHODS: A systematic review was performed to identify articles and meeting abstracts published between January 1, 1990 and March 31, 2005 that reported safety outcomes in cancer patients. Study, patient, and treatment level data were summarized using descriptive statistics without meta-analyses. RESULTS: Of 2,408 studies identified in the search, only 174 met eligibility criteria. Most studies (90%) involved thalidomide (or analog); only 12 (8%) studied sorafenib and 5 studied anti-tumor necrosis factor antibodies. In 165 treatment arms, 32% involved thalidomide (or analog) monotherapy and 2.4% involved sorafenib. The tolerability profiles of the two agents differed markedly. The most common Grade 3/4 adverse events experienced on thalidomide monotherapy were venous thrombosis (3.1% of patients), weakness/asthenia/fatigue (3.0%), neutropenia (2.7%), peripheral neuropathy/tingling/numbness (2.4%), somnolence/drowsiness/lethargy (2.4%), constipation (2.1%), and infection (2.0%). In contrast, the most common Grade 3/4 toxicities with sorafenib were diarrhea (4.8%), weakness/asthenia/fatigue (4.0%), hand-foot syndrome (3.2%), and leukopenia (2.4%). For both types of inhibitors, abnormal liver function tests were reported in about 3% of patients. CONCLUSIONS: The present review summarizes clinical safety information of anti-cancer drugs with indirect or nonspecific p38MAPK inhibitory activity. Based on our analysis, a novel p38MAPK inhibitor should be monitored for similar neurological, gastrointestinal, and cardiovascular symptoms in Phase I clinical trials.