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Biomedical subjects

Brian Smith

Publications and source records attributed to Brian Smith.

34 records · Page 2Linked to original sources
PubMed2005

Severe irinotecan-induced toxicities in a patient with uridine diphosphate glucuronosyltransferase 1A1 polymorphism.

Irinotecan is an analogue of camptothecin, a topoisomerase I inhibitor, that has an important role in the management of advanced colorectal cancer. It is approved as first-line therapy in combination with 5-fluorouracil and leucovorin or as monotherapy in the second-line setting. Its clinical use has been associated with variability in terms of pharmacokinetic behavior and toxicities, especially myelosuppression and diarrhea. Irinotecan is metabolized to the active compound SN-38; it is now known that the metabolism of irinotecan and the inactivation of SN-38 by glucuronidation are mediated by genetic differences, which contributes to the variability. In this article, a case is presented that illustrates this, and there is a brief discussion of the clinical pharmacology of irinotecan and some of the genetic variations that affect its cellular metabolism.

Adenocarcinoma↗
PubMed2004

5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside inhibits proinflammatory response in glial cells: a possible role of AMP-activated protein kinase.

AMP-activated protein kinase (AMPK) is tightly regulated by the cellular AMP:ATP ratio and plays a central role in the regulation of energy homeostasis and metabolic stress. A pharmacological activator of AMPK, 5-amino-4-imidazole carboxamide riboside (AICAR) inhibited lipopolysaccharide (LPS)-induced expression of proinflammatory cytokines (tumor necrosis factor alpha, interleukin-1beta, and interleukin-6) and inducible nitric oxide synthase in primary rat astrocytes, microglia, and peritoneal macrophages. AICAR attenuates the LPS-induced activation of nuclear factor kappaB via downregulation of IkappaB kinase alpha/beta activity. It also inhibits nuclear translocation of CCAAT/enhancer-binding protein (C/EBP) transcription factor by inhibiting the expression of C/EBP-delta in brain glial cells. The dominant negative form of AMPKalpha2 (D157A) and its antisense documents a possible role of AMPK in the regulation of the cellular proinflammatory process. AICAR also inhibited the production of inflammatory mediators in serum and their expression in CNS of rats injected with a sublethal dose of LPS by intraperitoneal injection. These observations in cultured cells as well as in the animal model suggest that AICAR may be of therapeutic value in treating inflammatory diseases.

AMP-Activated Protein Kinases↗
PubMed2004

Vertical facial distraction in the treatment of arhinia.

Arhinia is a rare congenital malformation characterized by lack of the formation of external and internal nasal structures. Restricted midfacial growth is secondary to the loss of the midfacial growth centers. Staged reconstruction of the nasal passage and external nose is required. Vertical distraction osteogenesis is a beneficial step in the overall reconstructive program. This provides for additional bone and soft tissue for both improved aesthetic facial proportions and later surgical interventions.

Child, Preschool↗
PubMed2003

Usefulness of intraoperative epiaortic echocardiography to resolve discrepancy between transthoracic and transesophageal measurements of aortic valve gradient - a case report.

PURPOSE: Intraoperative measurement of the aortic valve (AV) gradient in patients undergoing cardiac surgery is routinely performed using transesophageal echocardiography (TEE). In patients with severe aortic stenosis (AS), TEE Doppler beam alignment with the blood flow through the stenotic valve may be inaccurate, resulting in an underestimation of the AV gradient. We describe here the use of epiaortic echocardiography as an alternative to TEE for the intraoperative evaluation of AS. CLINICAL FEATURES: A patient diagnosed with severe AS (peak pressure gradient by transthoracic echocardiography: 108 mmHg) was undergoing AV replacement. In contrast, intraoperative TEE examination performed prior to bypass showed only a mild pressure gradient across the AV (peak pressure gradient: 38 mmHg). In order to resolve the conflicting information, epiaortic echocardiography was used to measure the AV gradient, confirming severe AS (peak pressure gradient: 98 mmHg). Most likely, Doppler beam alignment through the stenotic valve was more parallel to blood flow using epiaortic echocardiography, thus revealing the true pressure gradient. CONCLUSION: Intraoperative epiaortic measurement of AV gradients can be successfully performed in patients where TEE may be inaccurate due to difficulty in aligning a Doppler beam with the transvalvular blood flow.

Aortic Valve Stenosis↗
PubMed2003

Atomoxetine pharmacokinetics in children and adolescents with attention deficit hyperactivity disorder.

OBJECTIVE: Atomoxetine is indicated for the treatment of attention deficit hyperactivity disorder in children, adolescents, and adults. This study was conducted, in part, to evaluate the single-dose and steady-state pharmacokinetics of atomoxetine in pediatric patients. METHODS: This was an open-label, dose-titration study in pediatric patients with attention deficit hyperactivity disorder. Eligible patients could elect to participate in a single-dose or steady-state discontinuation pharmacokinetic evaluation including serial plasma sample collection over 24 hours. Plasma concentrations of atomoxetine, 4-hydroxyatomoxetine, and N-desmethylatomoxetine were determined using an atmospheric pressure chemical ionization liquid chromatography/mass spectrometry/mass spectrometry assay. Pharmacokinetic parameters were calculated using noncompartmental analysis. RESULTS: Twenty-one cytochrome P450 2D6 extensive metabolizer patients participated in these single-dose and steady-state pharmacokinetic evaluations. Atomoxetine was rapidly absorbed, with peak plasma concentrations occurring 1 to 2 hours after dosing. Half-life averaged 3.12 and 3.28 hours after a single dose and at steady state, respectively. Minimal accumulation occurred in plasma after multiple twice-daily dosing in extensive metabolizer pediatric patients, as expected based on single-dose pharmacokinetics. As the dose (in mg/kg) increased, proportional increases in area under the curve were observed. CONCLUSIONS: The pharmacokinetics of atomoxetine in extensive metabolizer patients were well characterized over a wide range of doses in this study. Atomoxetine pharmacokinetics in pediatric patients and adult subjects were similar after adjustment for body weight.

Adolescent↗
PubMed2003

Clinical practice guidelines for the maintenance of patient physical safety in the intensive care unit: use of restraining therapies--American College of Critical Care Medicine Task Force 2001-2002.

OBJECTIVE: To develop clinical practice guidelines for the use of restraining therapies to maintain physical and psychological safety of adult and pediatric patients in the intensive care unit. PARTICIPANTS: A multidisciplinary, multispecialty task force of experts in critical care practice was convened from the membership of the American College of Critical Care Medicine (ACCM), the Society of Critical Care Medicine (SCCM), and the American Association of Critical Care Nurses (AACN). EVIDENCE: The task force members reviewed the published literature (MEDLINE articles, textbooks, etc.) and provided expert opinion from which consensus was derived. Relevant published articles were reviewed individually for validity using the Cochrane methodology (http://hiru.mcmaster.ca/cochrane/ or www.cochrane.org). CONSENSUS PROCESS: The task force met as a group and by teleconference to identify the pertinent literature and derive consensus recommendations. Consideration was given to both the weight of scientific information within the literature and expert opinion. Draft documents were composed by a task force steering committee and debated by the task force members until consensus was reached by nominal group process. The task force draft then was reviewed, assessed, and edited by the Board of Regents of the ACCM. After steering committee approval, the draft document was reviewed and approved by the SCCM Council. CONCLUSIONS: The task force developed nine recommendations with regard to the use of physical restraints and pharmacologic therapies to maintain patient safety in the intensive care unit.

Adult↗
PubMed2002

Onions--a global benefit to health.

Onion (Allium cepa L.) is botanically included in the Liliaceae and species are found across a wide range of latitudes and altitudes in Europe, Asia, N. America and Africa. World onion production has increased by at least 25% over the past 10 years with current production being around 44 million tonnes making it the second most important horticultural crop after tomatoes. Because of their storage characteristics and durability for shipping, onions have always been traded more widely than most vegetables. Onions are versatile and are often used as an ingredient in many dishes and are accepted by almost all traditions and cultures. Onion consumption is increasing significantly, particularly in the USA and this is partly because of heavy promotion that links flavour and health. Onions are rich in two chemical groups that have perceived benefits to human health. These are the flavonoids and the alk(en)yl cysteine sulphoxides (ACSOs). Two flavonoid subgroups are found in onion, the anthocyanins, which impart a red/purple colour to some varieties and flavanols such as quercetin and its derivatives responsible for the yellow and brown skins of many other varieties. The ACSOs are the flavour precursors, which, when cleaved by the enzyme alliinase, generate the characteristic odour and taste of onion. The downstream products are a complex mixture of compounds which include thiosulphinates, thiosulphonates, mono-, di- and tri-sulphides. Compounds from onion have been reported to have a range of health benefits which include anticarcinogenic properties, antiplatelet activity, antithrombotic activity, antiasthmatic and antibiotic effects. Here we review the agronomy of the onion crop, the biochemistry of the health compounds and report on recent clinical data obtained using extracts from this species. Where appropriate we have compared the data with that obtained from garlic (Allium sativum L.) for which more information is widely available.

Flavonoids↗
PubMed2002

Echocardiographic evidence of right ventricular remodeling after transplantation.

Right ventricular (RV) failure is a significant source of mortality after cardiac transplantation. The use of RV assist devices (RVAD) as a bridge to recovery has been reported. However, early changes of RV structure and anatomy after RVAD implantation have yet to be described. We report a case of RV failure after transplantation requiring RVAD implantation. After 3 weeks of gradual weaning of inotropic and RVAD support, the device was explanted successfully. Transesophageal echocardiography documents RV hypertrophy and remodeling between RVAD implantation and removal, suggesting a rapid adaptive response of the right ventricle in the presence of pulmonary hypertension.

Adult↗
PubMed2002

Chronobiotic effects of the melatonin agonist LY 156735 following a simulated 9h time shift: results of a placebo-controlled trial.

INTRODUCTION: The melatonin agonist LY 156735 (LY) is a new investigational drug under development to treat circadian rhythm disorders. The present study assessed the efficacy of LY to alleviate the symptoms of shift lag and to enhance readaptation of desynchronized circadian rhythms to a new time zone. SUBJECTS AND METHODS: Eight healthy male volunteers of age 25-35 yr participated in three identical trials of 13d duration in a temporal isolation unit separated by washout intervals. A high dose (HD) of 5 mg and a low dose (LD) of 0.5 mg of LY and placebo (PL) were administered double-blinded in a three-period cross-over design. Each trial consisted of an adaptation period, a pre-shift period for baseline measurements, a simulated 9h phase-advance shift, and a post-shift period for follow-up. The time shift was performed at 23:00h of day 6 by advancing the laboratory time to 08:00h of day 7. Double-blind study medication was administered at 14:30h on day 6, and at 22:30h on days 7-10. Subjective ratings of jet lag, alertness, tenseness, and daytime fatigue were assessed using visual analog scales (VAS) and standardized questionnaires. The objective markers of readaptation included core body temperature, wrist actigraphy, cortisol and electrolyte excretion, and a battery of computerized performance tests. RESULTS: HD but not LD enhanced the readaptation speed of all physiological rhythms investigated, as demonstrated by a significantly faster movement of acrophases towards the post-shift target time. HD (p = 0.05) significantly blunted the post-shift deterioration of performance in those tests that were sensitive to shift lag. Parameters of subjective well-being were not significantly affected by either dose. CONCLUSION: This pilot study demonstrates the chronobiotic efficacy of LY when taken at a dose of 5 mg/d.

Adaptation, Physiological↗
PubMed1996

The Analgesic Interaction of Misoprostol with Nonsteroidal Anti-Inflammatory Drugs.

The purpose of this project was to evaluate the analgesic efficacy of misoprostol when combined with ibuprofen or diclofenac Na. Animal experiments using the inflamed rat paw formalin model suggested that misoprostol potentiates the analgesic effect of some NSAIDs (nonsteroidal anti-inflammatory drugs) including diclofenac Na but not propionic acid derivatives or opiates. The dental pain model was used to evaluate the clinical relevance of this interaction. Patients received a single oral dose of study medication following surgical removal of impacted teeth. Patients were medicated for moderate to severe postsurgical pain and then filled in an analgesic diary for a 6-h observation period. Several blood samples were taken over the observation period. In addition, microdialysis samples were taken directly from the extraction socket and were analyzed for immunoreactive prostaglandin E(2) levels. The studies were single-dose, parallel group and double-blind assays. In the first study, 70 patients received an oral dose of either placebo (n = 13), misoprostol 200 &mgr;g (n = 18), ibuprofen 200 mg (n = 19), or the combination of misoprostol + ibuprofen (n = 20). Misoprostol alone demonstrated a small analgesic effect compared to placebo. Both the ibuprofen and combination groups were substantially more effective than placebo but not different from each other. The combination group had higher ibuprofen blood levels during the first 45 min but had a lower C(max) and longer time to T(max). The second study evaluated oral doses of placebo (n = 11), misoprostol 200 &mgr;g (n = 21), diclofenac Na 50 mg (n = 18), and the combination of misoprostol + diclofenac Na (n = 20). Relative to placebo, misoprostol performance was similar to the first study. When the results of the two studies were combined, there was a small, but statistically significant, analgesic effect for misoprostol. Diclofenac Na was superior to both placebo and to misoprostol alone. The combination was the most effective treatment, and for hours 4--6 it was significantly better than diclofenac Na alone. Analysis of the blood samples showed an earlier and higher peak effect for the diclofenac Na group compared to the combination, and the combination again had a lower C(max). The microdialysis probe assays demonstrated that misoprostol depressed PGE(2) levels at the peripheral site of trauma over the first 2 h after surgery. These pilot studies used small samples, and the results only suggest trend effects. Both studies demonstrated that misoprostol 200 &mgr;g, a prostaglandin analog, does have an analgesic effect. When combined with ibuprofen, there was no potentiation of analgesia. In contrast, the combination of misoprostol + diclofenac Na demonstrated an enhanced peak effect, total effect for pain intensity difference and pain relief (sum pain intensity difference [SPID] and total pain relief [TOTPAR]), and

Journal Article↗
PubMedDate not supplied

Treatment of pediatric both-bone forearm fractures: a comparison of operative techniques.

Both-bone forearm fractures of the radius and ulna are a common injury in children. Closed reduction and casting has historically been the primary means of treatment in over 90% of these fractures. Unstable and irreducible fractures, however, often pose a therapeutic challenge, with little data available to compare outcomes. The authors performed a retrospective review of 50 children with both-bones fractures treated with closed reduction and cast immobilization, open reduction and internal fixation (ORIF), or intramedullary (IM) nailing. Complications were tabulated and separated by treatment modality and subdivided into minor/major complications. Statistical regression was performed. There were 54 operations in 50 patients with both-bones fractures. All fractures healed within 8 to 10 weeks, except for two delayed unions and one nonunion. The complication rate was 5% for closed treatment, 33% for ORIF, and 42% for IM nailing. Complication rates were significantly different between the closed and operative groups. When comparing treatments in pediatric both-bones fractures, there are significantly more complications with operative techniques. Patients with ORIF had more major complications, often requiring a return to the operating room. IM nailing, when done correctly, is as acceptable and safe a form of treatment.

Adolescent↗
PubMedDate not supplied

Racial and economic disparity and the treatment of pediatric fractures.

Disparity in the treatment of various medical conditions in patient groups with differing racial and economic backgrounds has increasingly been reported. This paper examines the relationship between baseline racial and economic factors and the treatment of pediatric long-bone fractures. The 2000 Healthcare Cost and Utilization Project (HCUP) Kid's Inpatient Database (KID) was used to retrospectively examine the incidence and treatment of pediatric fractures. Data were included for supracondylar humerus (n = 2,957), femoral shaft (n = 1,726) or radius and ulna forearm fracture (n = 828) as their primary diagnosis were studied. Hispanic (78%) and black (82%) patients were more likely to receive closed reduction with internal fixation (percutaneous pinning) of supracondylar humerus fractures than whites (73%, P = 0.02). Despite a fairly large sample size, differences in treatment of supracondylar humerus fractures across primary payer or income groups were not statistically significant. Patients with femur fractures and private insurance were more likely to be treated with an external fixation device (7.2%) than patients in the Medicaid (3.8%) or self-pay (4.5%) groups (P = 0.015). No statistically significant difference was found in the treatment of forearm fractures across racial, primary payer or income groups. Racial and economic disparity is an important issue in medicine today. This study did demonstrate statistically significant differences in the treatment of pediatric supracondylar humerus across racial groups, with Blacks and Hispanics being more likely to receive percutaneous pinning of these injuries than Whites. Private insurance patients were also more likely to have femoral shaft fractures treated with an external fixator device than patients with Medicaid or self-pay as their primary payer. However, the clinical significance of these differences is not clear. Further research is needed to gain a more complete understanding of disparities in medicine, and their etiologies, in order to work towards optimizing the quality of medical care for all patient groups.

Black People↗
PubMedDate not supplied

Lateral compression injuries in the pediatric elbow: Panner's disease and osteochondritis dissecans of the capitellum.

Lateral compression injuries of the elbow typically occur in throwing athletes and gymnasts. In the preadolescent and adolescent patient, these injuries predominantly include Panner's disease and osteochondritis dissecans. Panner's disease, an osteochondrosis of the capitellum, is a rare disorder that usually affects the dominant extremity in individuals younger than age 10 years. Symptomatic management of Panner's disease consisting of reduction of stressful activities of the elbow is usually sufficient to allow resolution. Although a prolonged period is required for healing, most patients demonstrate excellent long-term results. Osteochondritis dissecans of the capitellum typically occurs in adolescents and is associated with loose body formation. Panner's disease and osteochondritis dissecans likely represent a continuum of disordered endochondral ossification with presentation and prognosis dependent primarily on age at onset.

Adolescent↗