Subject(s)
Drug Resistance, Neoplasm , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/therapy , Oncogene Proteins, Fusion/genetics , Pyrazoles/therapeutic use , Pyridines/therapeutic use , Anaplastic Lymphoma Kinase , Child, Preschool , Combined Modality Therapy , Crizotinib , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Female , Hematopoietic Stem Cell Transplantation , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/pathology , Protein Kinase Inhibitors/therapeutic use , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Receptor Protein-Tyrosine Kinases/genetics , Remission Induction , Transplantation, HomologousABSTRACT
Despite extensive research efforts over decades, the teratogenic profile of valproic acid (VPA) remains obscure. We performed cumulative and conventional meta-analyses of cohort studies to determine the time profiles of signal emergence of VPA-associated congenital malformations (CMs) and to define risk estimates of each of the CMs. Fifty-nine studies were identified and analyzed. We found that the significant risk signals began to emerge over the last 10-20 years even before large-scale studies were performed: neural tube defect (the significant risk signal emerged in 1992); genitourinary and musculoskeletal anomalies (2004); cleft lip and/or palate (2005); and congenital heart defects (2006). At present, the risks of VPA-associated CMs are 2-7-fold higher than other common antiepileptic drugs. VPA should not be used as a first-line therapy in women of childbearing age unless it is the only option for the patient.
Subject(s)
Abnormalities, Drug-Induced/etiology , Anticonvulsants/adverse effects , Maternal Exposure/adverse effects , Valproic Acid/adverse effects , Female , Humans , Odds Ratio , Pregnancy , Risk Assessment , Risk Factors , Time FactorsABSTRACT
A common pharmacogenomic test is for thiopurine S-methyltransferase (TPMT) status prior to treatment with thiopurine drugs, used to treat auto-immune conditions and pediatric cancer. Guidelines assist practitioners with decisions regarding testing and treatment. The objectives were to conduct a systematic review and critical appraisal of guidance documents with statements regarding TPMT testing and thiopurine dosing. Guidelines, clinical protocols and care pathways from all disciplines were eligible. A quality appraisal was carried out by three appraisers using the Appraisal of Guidelines for Research and Evaluation II. Of the 20 documents found, 5 recommended genotyping while 4 recommended phenotyping. Thirteen documents provided dosing recommendations based on TPMT status. The quality appraisal revealed wide variation across documents. The National Institute for Health and Clinical Excellence and Cincinnati Children's Hospital guidelines demonstrated the highest overall quality with scores of 79 and 76, respectively. Low-scoring documents failed to use systematic methods to develop recommendations or to provide evidence to support recommendations. Guidance documents that included dosing recommendations demonstrated higher quality.
