Gabapentin enacarbil for treatment of restless legs syndrome in adults.

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, precautions, dosing recommendations, and patient counseling for gabapentin enacarbil for the treatment of restless legs syndrome (RLS) in adults. DATA SOURCES: A literature search was conducted using the terms gabapentin enacarbil, XP13512/GSK1838262, and restless legs syndrome. MEDLINE, Books@Ovid, Journals@Ovid Full Text, BIOSIS Previews, and EMED databases were the primary search sites (2004-October 2011). All English-based articles and abstracts obtained from the literature searches were reviewed. Additional information was obtained from references cited in the articles. STUDY SELECTION AND DATA EXTRACTION: All gabapentin enacarbil information related to RLS was considered. Study selection included human trials evaluating safety and efficacy of gabapentin enacarbil for the treatment of RLS. DATA SYNTHESIS: Gabapentin enacarbil is a prodrug of gabapentin that is Food and Drug Administration (FDA) approved for the treatment of moderate-to-severe primary RLS in adults. In placebo-controlled trials, gabapentin enacarbil demonstrated efficacy in reducing the symptoms of RLS. Most clinical trials assessed gabapentin enacarbil at dosages greater than the FDA-approved 600-mg dosage. For the approved dose of 600 mg, the most commonly reported adverse effects are somnolence and dizziness. CONCLUSIONS: Clinical trials have evaluated gabapentin enacarbil for safety and efficacy in treating moderate-to-severe RLS symptoms for up to 64 weeks. It offers a pharmacokinetic advantage over gabapentin by having improved absorption and a longer duration of action, but clinically significant differences are yet to be determined. Potential disadvantages of gabapentin enacarbil include cost, concerns of suicide risk and pancreatic cancer, and a lack of data for the FDA-approved 600-mg dosage. Overall, gabapentin enacarbil is a viable therapeutic option for adults with moderate-to-severe RLS for whom more conventional therapies have failed.

Octogenarian Motor Vehicle Collisions: Injury Patterns Matter.

INTRODUCTION: Motor vehicle collision (MVC) is the second most common mechanism of injury among octogenarians and is on the rise. These "oldest old" trauma patients have higher mortality rates than expected. This study examined potential factors influencing this increased mortality including comorbidities, medications, injury patterns, and hospital interventions. METHODS: A 10-year retrospective review was conducted of patients aged 80 and over who were injured in an MVC. Data collected included patient demographics, comorbidities, medication use prior to injury, collision details, injury severity and patterns, hospitalization details, outcomes, and discharge disposition. RESULTS: A total of 239 octogenarian patients were identified who were involved in an MVC. Overall mortality was 18.8%. An increased mortality was noted for specific injury patterns, patients injured in a rural setting, and those who were transfused, intubated, or admitted to the ICU. No correlation was found between mortality and medications or comorbidities. CONCLUSIONS: The high mortality rate for octogenarian patients involved in an MVC was related to injury severity, type of injury, and in-hospital complications, and not due to comorbidities and prior medications.

Cyclic vomiting syndrome: diagnostic approach and current management strategies.

Cyclic vomiting syndrome (CVS) is a disorder characterized by episodes of nausea and vomiting lasting for 1-5 days followed by asymptomatic periods. The etiology of CVS is unknown, but it shares similar characteristics to migraine headaches. CVS is generally classified as having four phases: prodromal, acute/vomiting/hyperemesis, recovery, and remission/interepisodic. Current management strategies include trigger avoidance, abortive and prophylactic medication therapies, and supportive care. The goal of therapy for the remission phase is prophylaxis of further episodes. Antidepressant, antiepileptic, and antimigraine medications show an overall reduction or remission of CVS symptoms in more than 70% of patients. This article provides a summary of diagnostic strategies and reviews current management strategies for CVS.

OnabotulinumtoxinA Injections for the Treatment of Cyclic Vomiting Syndrome.

Cyclic vomiting syndrome (CVS) is a disorder characterized by episodes of nausea and vomiting lasting 1 to 5 days, followed by asymptomatic periods. The etiology and pathophysiology of CVS are unknown, but CVS shares similar characteristics to those of migraine headaches. Tricyclic antidepressants have the most evidence and are generally effective for prophylaxis of further episodes in patients with CVS. Second-line pharmacotherapies typically target specific comorbid symptoms or conditions and may include antiepileptic or antimigraine drugs, benzodiazepines, antispasmodics, proton pump inhibitors, antiemetics, and analgesics. OnabotulinumtoxinA (ONABoNT-A) injections have not been studied in the population with CVS but are regarded as a pharmacotherapeutic option for migraine headaches. We describe a 45-year-old woman with a 5-year history of CVS who had failed previous typical prophylactic migraine and CVS pharmacotherapies and was referred to the neurology clinic for management of both of these conditions. On review, the neurologist noted a correlation of the patient's headaches with her CVS symptoms. ONABoNT-A injections were started at 155 units intramuscularly every 12 weeks for her migraine headaches, which also dramatically improved her CVS. The main adverse effect reported by the patient was numbness and weakness in her left shoulder after the injections, which are symptoms consistent with ONABoNT-A injection use; however, these symptoms typically resolved a few days later. Regarded as a pharmacotherapeutic option for migraine headache prophylaxis, ONABoNT-A injections have demonstrated modest efficacy in preventing migraine headaches. Clinicians should be aware that ONABoNT-A injections may also have a role in the prophylaxis of CVS.

Octogenarians and motor vehicle collisions: postdischarge mortality is lower than expected.

BACKGROUND: Motor vehicle collisions (MVCs) are the second leading cause of injury among octogenarians. Physicians and families lack outcomes-based data to assist in the decision-making process concerning injury treatment in this population. The purpose of this study was to evaluate 1-year postdischarge mortality in octogenarian MVC patients, cause of death, and patterns predictive of mortality. METHODS: A 10-year retrospective review was conducted of trauma patients 80 years and older who were involved in an MVC and were subsequently discharged alive. Data collected included demographics, injury severity and patterns, hospitalization details, and outcomes. State death database and hospital records were queried to determine cause of death for patients who died within 12 months of hospital discharge. Analyses were conducted to explore if a relationship existed between severity of injury and injury patterns to 12-month postdischarge mortality. RESULTS: Among the 199 patients included in this study, mean (SD) age and Injury Severity Score (ISS) was 84.2 (3.3) years and 9.3 (8.2), respectively. Twenty-two patients (11.1%) died within 12 months. Among these patients, cause of death was directly related to trauma in nine (40.9%), likely related to trauma in seven (31.8%), and unrelated to trauma in six (27.3%). More severely injured patients (ISS >15, p = 0.0041) and those admitted to the intensive care unit (ICU) (p = 0.0051) were more likely to die within 12 months of discharge. Results indicated a trend toward higher mortality in patients with pneumonia. Rib, hip, and pelvic fractures; spinal injuries; intubation upon hospital arrival; and need for mechanical ventilation were not associated with higher postdischarge mortality rates. CONCLUSION: The commonly held belief that the majority of octogenarians with MVC-related trauma die within 1 year of hospital discharge is refuted by this study. Only injury severity, ICU admission, and ICU duration were predictive of mortality within 12 months following discharge. LEVEL OF EVIDENCE: Prognostic study, level III.

Indiplon in the management of insomnia.

Indiplon is a novel pyrazolopyrimidine, nonbenzodiazepine gamma-aminobutyric acid (GABA) agonist studied for the treatment of insomnia. This article reviews the chemistry, pharmacology, clinical pharmacokinetics, drug interactions, clinical trials, safety, tolerability, contraindications, use in special populations, and dosing of indiplon. OVID, International Pharmaceutical Abstracts (IPA), and PubMed databases were searched (1966 to February 2009) for the keywords indiplon, NBI-34060, and insomnia. References of key articles were also reviewed to identify additional publications. Only English language articles were selected for review. Indiplon has been shown to have high affinity and selectivity for the GABAalpha(1) receptor subunit associated with sedation. In clinical studies, indiplon has demonstrated efficacy in improving latency to sleep onset, latency to persistent sleep, total sleep time, wake time after sleep onset, number of awakenings after sleep onset, and overall sleep quality when compared to placebo. Indiplon has a favorable safety profile with limited rebound insomnia and no tolerance. Neurocrine Biosciences, Incorporated received an Approvable Letter from the United States Food and Drug Administration in December 2007 for the indiplon IR 5 mg and 10 mg capsules based on meeting three additional requirements. At the time of this writing, indiplon remains unapproved.

Medical education and communication companies involved in CME: an updated profile.

INTRODUCTION: Medical Education and Communication Companies (MECCs) represent approximately 21% of the providers accredited by the Accreditation Council for Continuing Medical Education (ACCME), yet relatively little is known about these organizations in the greater continuing medical education (CME) community. Two prior studies described them, but powerful changes in the regulatory environment have impacted the structure and organization of these companies. METHODS: The investigators administered a 32-item questionnaire to a select sample of 157 MECCs involved in CME, achieving a response rate of 50.3%. RESULTS: Of the responding organizations, 87% were accredited by the ACCME, with 27% also holding accreditation from the Accreditation Council for Pharmacy Education and the American Nurses Credentialing Center Commission on Accreditation. Eighty-six percent reported no immediate involvement of the company in promotional activities. Fifty-three percent of the survey responders reported being part of a larger organization that included companies involved in promotion, and 88% of these organizations reported implementation of firewalls designed to protect the independence of certified education. DISCUSSION: The survey reveals a sector that is largely privately held and moving from an organizational model that included both certified and promotional activities to one that includes only certified education. These changes, along with the implementation of firewalls to protect certified education from the promotional interests of other companies within their own corporate structure, may help to alleviate concerns about the independence of CME produced by MECCs. However, because MECCs continue to receive the majority of their support from commercial interests, the influence of funding is likely to be an area of lingering concern.

Biomechanical comparison of expandable and locked intramedullary femoral nails.

OBJECTIVES: The expandable intramedullary (IM) nail does not require locking and fluoroscopy use is minimized. However, the lack of cross-locking screws may adversely affect the fixation's rotational stability. The purpose of our study was to compare the rotational stability afforded by an expandable nail with that of a standard locked nail. METHODS: In a cadaver model of a diaphyseal femoral fracture (OTA type 32-A3), we compared first-generation expandable IM nails with standard locked IM nails in osteoporotic and nonosteoporotic femora (10 pairs each) and second-generation expandable nails with standard locked IM nails only in nonosteoporotic femora (10 pairs). To simulate torsional loads during walking, we applied an external rotation moment of -1 to 10 Nm at 1 Hz to each construct for 5000 cycles. Failure was defined as 15 degrees of rotation at the fracture site. We used McNemar's test to check for significant (P < 0.05) differences in failure between groups. RESULTS: Of the first-generation expandable nails, 90% failed (9/10 in osteoporotic and 9/10 in nonosteoporotic femora) within the first 1000 cycles. Of the respective locked nails, significantly fewer failed in nonosteoporotic femora than in osteoporotic femora (0/10 and 3/10, respectively). Of the second-generation nails, 8/10 failed within 100 cycles of testing. Of the comparative locked nails, none failed at 5000 cycles. CONCLUSIONS: We concluded that the expandable IM femoral nail, when tested in purely axial rotation, has poor rotational stability compared with the standard locked IM femoral nail.

Patellar tendon length after knee arthroplasty with and without preservation of the infrapatellar fat pad.

Our aim was to assess whether there was any significant difference in change in patellar tendon length after knee arthroplasty, when the infrapatellar fat pad was either preserved or excised. Three-year radiographic follow-up was studied on 73 primary knee arthroplasty patients. The infrapatellar fat pad was completely preserved in 38 cases and completely excised in 35. At 3 years there was a significant patellar tendon shortening of 4.2% (P = .0004) in the fat pad excision group and no significant change in the fat pad preservation group (P = .82). The difference between the 2 groups was significant (P = .004). Our results show that patella tendon length does not always shorten after knee arthroplasty and that preservation of the infrapatellar fat pad may be a factor in preventing such shortening.

Sodium oxybate for cataplexy.

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, precautions, dosing recommendations, and patient counseling of sodium oxybate for the treatment of cataplexy in patients with narcolepsy. DATA SOURCES: OVID and PubMed databases were searched (1966-January 2006) using the key words sodium oxybate, gamma-hydroxybutyrate, narcolepsy, and cataplexy. Only English-language articles were selected. STUDY SELECTION AND DATA EXTRACTION: All information on sodium oxybate related to narcolepsy and cataplexy was considered. Study selection included human trials evaluating safety and efficacy of sodium oxybate for the treatment of cataplexy. DATA SYNTHESIS: Sodium oxybate is approved by the Food and Drug Administration for the treatment of excessive daytime sleepiness and cataplexy in patients with narcolepsy. In placebo-controlled trials, sodium oxybate demonstrated efficacy in reducing the number of cataplexy attacks. The dosing regimen includes a split dose given at bedtime and 2.5-4 hours later due to its short elimination half-life. The drug is generally well tolerated, with headache, nausea, dizziness, pain, and somnolence being the most common adverse events. CONCLUSIONS: Sodium oxybate is safe and effective for the treatment of cataplexy. Potential disadvantages include a multiple dosing regimen, abuse potential, cost, and a closed distribution system. Potential advantages demonstrated in clinical trials include significant decreases in the number of weekly cataplexy attacks, improvement in daytime sleepiness, and improvement in the Clinical Global Impression of Change score and nighttime awakenings. Overall, sodium oxybate provides a new option for the treatment of cataplexy.

Impact of vaccine-induced mucosal high-avidity CD8+ CTLs in delay of AIDS viral dissemination from mucosa.

Natural HIV transmission occurs through mucosa, but it is debated whether mucosal cytotoxic T lymphocytes (CTLs) can prevent or reduce dissemination from the initial mucosal site to the systemic circulation. Also, the role of CTL avidity in mucosal AIDS viral transmission is unknown. To address these questions, we used delay in acute-phase peak viremia after intrarectal challenge as an indicator of systemic dissemination. We found that a peptide-prime/poxviral boost vaccine inducing high levels of high-avidity mucosal CTLs can have an impact on dissemination of intrarectally administered pathogenic SHIV-ku2 in macaques and that such protection correlates better with mucosal than with systemic CTLs and particularly with levels of high-avidity mucosal CTLs.

Shared modes of protection against poxvirus infection by attenuated and conventional smallpox vaccine viruses.

The concern about bioterrorism with smallpox has raised the possibility of widespread vaccination, but the greater prevalence of immunocompromised individuals today requires a safer vaccine, and the mechanisms of protection are not well understood. Here we show that, at sufficient doses, the protection provided by both modified vaccinia Ankara and NYVAC replication-deficient vaccinia viruses, safe in immunocompromised animals, was equivalent to that of the licensed Wyeth vaccine strain against a pathogenic vaccinia virus intranasal challenge of mice. A similar variety and pattern of immune responses were involved in protection induced by modified vaccinia Ankara and Wyeth viruses. For both, antibody was essential to protect against disease, whereas neither effector CD4+ nor CD8+ T cells were necessary or sufficient. However, in the absence of antibody, T cells were necessary and sufficient for survival and recovery. Also, T cells played a greater role in control of sublethal infection in unimmunized animals. These properties, shared with the existing smallpox vaccine, provide a basis for further evaluation of these replication-deficient vaccinia viruses as safer vaccines against smallpox or against complications from vaccinia virus.