Melatonin treatment for insomnia in pediatric patients with attention-deficit/hyperactivity disorder.

OBJECTIVE: To evaluate the efficacy and safety of melatonin for the treatment of insomnia in pediatric patients with attention-deficit/hyperactivity disorder (ADHD). DATA SOURCES: Literature was accessed through MEDLINE (1948-August 2009), EMBASE (1950-August 2009), and Scopus (1960-August 2009) using the terms melatonin, attention-deficit/hyperactivity disorder (ADHD), pediatric, insomnia, sleep disorder, and sleep. In addition, reference citations from publications identified were reviewed for relevant information. STUDY SELECTION AND DATA EXTRACTION: All English-language articles and human studies were identified and evaluated. Results from all identified randomized trials (n = 5), safety studies (n = 1), long-term follow-up studies (n = 1), post hoc retrospective analyses (n = 1), meta-analyses (n = 2), review articles (n = 9), and letters (n = 1) were summarized. DATA SYNTHESIS: Pediatric insomnia is prevalent in children with ADHD and impacts academic performance, social functioning, overall health, and family life. First-line therapy includes ruling out differential diagnoses, optimizing ADHD stimulant treatment, and initiating good sleep hygiene and behavioral therapy. Adjuvant pharmacotherapy is then an option and melatonin is often prescribed. Melatonin regulates circadian rhythm sleep disorders such as sleep-onset insomnia (SOI) in children with ADHD. Four studies in children with ADHD and insomnia showed improvement in sleep onset and sleep latency. Studies included children 6-14 years old and melatonin doses ranged from 3 to 6 mg administered within a few hours of a scheduled bedtime. In all studies, adverse events were transient and mild. The available melatonin studies are limited by small size and short duration; variable SOI criteria, ADHD criteria, and treatment assessments; and lack of generalizability. CONCLUSIONS: Available data suggest that melatonin is a well-tolerated and efficacious treatment option for pediatric patients with chronic SOI and ADHD. Regulated melatonin products and larger, well-designed trials to establish optimal dosing regimens and long-term safety are needed.

Role of gabapentin in the treatment of uremic pruritus.

OBJECTIVE: To evaluate the efficacy of gabapentin for the treatment of uremic pruritus (UP). DATA SOURCES: Literature retrieval was accessed through MEDLINE (1950-March week 3, 2008; In-Process & Other Non-Indexed Citations, April 1, 2008) and International Pharmaceutical Abstracts (1970-March 2008) using the terms gabapentin, pruritus, itch, urem$ (truncated), dialysis, and kidney disease. The Google Scholar search engine was used to identify articles that MEDLINE did not capture with the described search terms. Additionally, reference citations from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION: All articles in English and studies conducted in humans were identified and evaluated. DATA SYNTHESIS: UP is an unpleasant itching sensation that affects approximately 30% of patients on hemodialysis (HD). The current mainstays of therapy include antihistamines and topical therapies, although many patients remain symptomatic despite these treatments. Alternative therapeutic approaches, including topical, oral, and intravenous drugs; dialysis modifications; homeopathic therapies; and physical treatments have been used, but few evidence-based studies exist to support their utility. Gabapentin has been evaluated for the treatment of UP in 2 small, randomized, placebo-controlled studies, 1 pilot evaluation, and 1 index case. Gabapentin has demonstrated efficacy in the treatment of multiple types of itch and shows promise in treating patients with UP who are unresponsive to standard therapies. All of the controlled studies consisted of 4 weeks of active treatment, and no patients discontinued gabapentin due to adverse events. The most common adverse events noted in these trials were consistent with gabapentin's safety profile (dizziness, somnolence, fatigue, nausea). CONCLUSIONS: Available data support the use of gabapentin as a well-tolerated and effective treatment option for patients with UP who are unresponsive to traditional therapies. Further well-designed trials are warranted to establish the most appropriate dosing regimen in patients on HD.

Characterization and clinical management of clozapine-induced fever.

OBJECTIVE: To characterize clozapine-induced fever and suggest clinically relevant management recommendations. DATA SOURCES: Literature was accessed through MEDLINE (1966-June 2007) using the terms clozapine, fever, and adverse effects. In addition, reference citations from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION: All English-language articles about human studies of fever associated with the use of clozapine were evaluated. DATA SYNTHESIS: Mild to high-grade fever frequently accompanies clozapine therapy. Fever usually occurs within 10-15 days after treatment initiation and has been reported to last between 2 and 4 days. The mechanism and clinical implications of clozapine-induced fever are unclear. The primary concern for clinicians, with regard to these fevers, is the possibility of 2 serious conditions: agranulocytosis with infection or neuroleptic malignant syndrome (NMS). However, the presence of fever during clozapine therapy does not appear to predict agranulocytosis, NMS, or an increased rate of drug discontinuation at 1 year. CONCLUSIONS: Available data suggest that clozapine-induced fevers are benign; once infectious and other medical causes for fever are ruled out, clozapine therapy can be continued.

Ruboxistaurin, a protein kinase C beta inhibitor, as an emerging treatment for diabetes microvascular complications.

OBJECTIVE: To review current clinical data regarding the pharmacologic actions of ruboxistaurin (LY333531) mesylate, an inhibitor of protein kinase C (PKC) beta, and its role to potentially reduce the development and/or the progression of diabetic microvascular complications. DATA SOURCES: Primary literature was obtained via a MEDLINE search (1966-August 2004) and through review of pertinent abstracts and presentations at major medical meetings. STUDY SELECTION AND DATA EXTRACTION: Literature relevant to PKC physiology, the pharmacokinetics of ruboxistaurin, and data evaluating the use of ruboxistaurin in treating diabetic microvascular complications in human and relevant animal models was reviewed. DATA SYNTHESIS: PKC is part of a group of intracellular signaling molecules activated in response to various specific hormonal, neuronal, and growth factor stimuli. Hyperglycemia leads to PKC beta 1 and 2 isoform activation, which experimentally has been shown to contribute to the development and progression of diabetic microvascular complications (retinopathy, nephropathy, neuropathy) through various biochemical mechanisms. Animal and/or human studies using ruboxistaurin mesylate, a novel, highly selective inhibitor of PKC beta, have shown delay in the progression and, in some cases, reversal of diabetic retinopathy, nephropathy, and neuropathy. CONCLUSIONS: Ruboxistaurin mesylate, by inhibiting excessive activation of certain PKC isoforms, has the potential to reduce the burden of microvascular complications for patients with diabetes.

Incretin mimetics as emerging treatments for type 2 diabetes.

OBJECTIVE: To review the physiology, pharmacology, and clinical efficacy of glucagon-like peptide (GLP-1) and the incretin mimetics exenatide and liraglutide in clinical studies. DATA SOURCES: Primary literature obtained via MEDLINE (1966-April 2004) and International Pharmaceutical Abstracts (1970-April 2004) searches; abstracts obtained from meeting sources and manufacturers. STUDY SELECTION AND DATA EXTRACTION: All English-language studies and abstracts evaluating GLP-1, exenatide, and liraglutide in the treatment of patients with type 2 diabetes were reviewed. Data from animal studies were also included if human data were not available. Primary and review articles related to the physiology, development, and evaluation of GLP-1s were reviewed. DATA SYNTHESIS: GLP-1, exenatide (exendin-4, AC2993), and liraglutide (NN2211) are incretin mimetics that have been shown in human studies to be an effective treatment to improve glycemic control in patients with type 2 diabetes. Mechanisms by which these compounds improve glycemic control include enhancing glucose-dependent pancreatic secretion of insulin in response to nutrient intake, inhibiting glucagon secretion, delaying gastric emptying, and promoting early satiety. GLP-1 has been shown to promote pancreatic progenitor cell differentiation and improve beta-cell function and lifespan. Reported adverse effects of exenatide and liraglutide include nausea, vomiting, and transient headache, as well as increased risk of hypoglycemia when used with sulfonylureas. CONCLUSIONS: Clinical studies show that GLP-1, exenatide, and liraglutide improve glycemic control for patients with type 2 diabetes through unique mechanisms not available with current pharmaceutical products. Ongoing Phase III studies will help to further position these compounds as treatment options for patients with type 2 diabetes.

Intravenous proton-pump inhibitors versus H2-antagonists for treatment of GI bleeding.

OBJECTIVE: To evaluate the evidence supporting the use of intravenous proton-pump inhibitors in the treatment of gastrointestinal (GI) hemorrhage in comparison with histamine(2) (H(2))-receptor antagonists. DATA SOURCES: Clinical literature was accessed through a MEDLINE search (1966-October 2002). Data from abstracts and fully published articles were retrieved for analysis. Key search terms included pantoprazole, omeprazole, proton-pump inhibitors, gastrointestinal hemorrhage, histamine(2)-receptor antagonists, ranitidine, and cimetidine. DATA SYNTHESIS: There are limited published clinical outcome data evaluating the use of intravenous pantoprazole in patients with upper GI hemorrhage. However, there are several gastric pH studies suggesting that intravenous pantoprazole is effective in quickly obtaining and maintaining a pH >6. When considering the results from studies of high-dose intravenous omeprazole, in addition to the pantoprazole data, the relative efficacy of intravenous proton-pump inhibitors appears to be superior to that of intravenous H(2)-receptor antagonists in providing a more predictable and sustained pH control. CONCLUSIONS: Intravenous proton-pump inhibitors are suitable, possibly superior, alternatives to intravenous H(2)-receptor antagonists in treatment of upper GI bleeding.