A brief summary of alcohol intervention research at West Virginia University from 1998-2003

Injury resulting in death and disability and alcohol-related problems are two major problems in West Virginia, yet few effective preventive strategies are available. A relatively simple and effective preventive strategy, appropriate for all health care providers, can help to alter excessive alcohol consumption and its resulting harm and consequences. Over the past five years, a series of alcohol intervention projects have been conducted in the Emergency Department at West Virginia University Hospital and other medical settings. Short motivational counseling sessions, which are referred to as screening and brief intervention (SBI), were tailored to each patient's needs. SBI is a secondary prevention strategy used to help persons identified with alcohol problems to decrease their drinking and reduce the harm caused by alcohol. To date, 90% of the nearly 8,000 eligible patients have consented to participate in these studies. Follow-up rates have ranged between 45% and 61%. This article describes the methodologies and results of our SBI studies and their relevance to West Virginia health care providers.     

Potent N-(1,3-thiazol-2-yl)pyridin-2-amine vascular endothelial growth factor receptor tyrosine kinase inhibitors with excellent pharmacokinetics and low affinity for the hERG ion channel

A series of N-(1,3-thiazol-2-yl)pyridin-2-amine KDR kinase inhibitors have been developed that possess optimal properties. Compounds have been discovered that exhibit excellent in vivo potency. The particular challenges of overcoming hERG binding activity and QTc increases in vivo in addition to achieving good pharmacokinetics have been acomplished by discovering a unique class of amine substituents. These compounds have a favorable kinase selectivity profile that can be accentuated with appropriate substitution.     

Increased seizure threshold in mice lacking aquaporin-4 water channels

Mice deficient in the glial water channel aquaporin-4 (AQP4) show decreased cerebral edema and improved neurological outcome following water intoxication or ischemic challenge. In this report, we tested seizure susceptibility in AQP4 mice. AQP4 mice and wild-type controls were given the chemoconvulsant pentylenetetrazol (PTZ) and monitored for seizure activity. At 40 mg/kg PTZ, all wild-type mice exhibited seizure activity, whereas six of seven AQP4 mice did not exhibit seizure activity. At 50 mg/kg PTZ, both groups exhibited seizure activity; however, the latency to generalized (tonic-clonic) seizures was significantly lower in wild-type than AQP4 mice. These results suggest that glial water channels may modulate brain excitability and the initiation and generalization of seizure activity.     

Low density of membrane particles in auditory hair cells of lizards and birds suggests an absence of somatic motility

Hair cells are the mechanoreceptive cells of the vertebrate lateral line and inner ear. In addition to their sensory function, hair cells display motility and thus themselves generate mechanical energy, which is thought to enhance sensitivity. Two principal cellular mechanism are known that can mediate hair-cell motility in vitro. One of these is based on voltage-dependent changes of an intramembrane protein and has so far been demonstrated only in outer hair cells of the mammalian cochlea. Correlated with this, the cell membranes of outer hair cells carry an extreme density of embedded particles, as revealed by freeze fracturing. The present study explored the possibility of membrane-based motility in hair cells of nonmammals, by determining their density of intramembrane particles. Replicas of freeze-fractured membrane were prepared from auditory hair cells of a lizard, the Tokay gecko, and a bird, the barn owl. These species were chosen because of independent evidence for active cochlear mechanics, in the form of spontaneous otoacoustic emissions. For quantitative comparison, mammalian inner and outer hair cells, as well as vestibular hair, cells were reevaluated. Lizard and bird hair cells displayed median densities of 2,360 and 1,880 intramembrane particles/microm2, respectively. This was not significantly different from the densities in vestibular and mammalian inner hair cells; however, it was about half the density in of mammalian outer hair cells. This suggests that nonmammalian hair cells do not possess high densities of motor protein in their membranes and are thus unlikely to be capable of somatic motility.     

Exploratory activity and fear conditioning abnormalities develop early in R6/2 Huntington's disease transgenic mice

The Huntington's disease R6/2 transgenic mouse model, containing exon 1 of the human huntingtin gene with a greatly increased CAG repeat length, shows multiple effects of the altered polyglutamine in the resultant protein. The authors report that exploratory and fear conditioning behavioral changes appear well before the onset of obvious pathology. The first differences in exploratory and fear conditioning behavior emerge by 4 and 5 weeks of age, respectively. These behaviors correlate with the earliest neurochemical and molecular changes previously reported and provide insight into functional mechanisms by which cellular and subcellular disease changes may mediate neurological symptoms. These studies provide behavioral protocols suitable for high-throughput screening of therapeutic agents.     

Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64)

BACKGROUND: The progression of nephropathy from diagnosis of type 2 diabetes has not been well described from a single population. This study sought to describe the development and progression through the stages of microalbuminuria, macroalbuminuria, persistently elevated plasma creatinine or renal replacement therapy (RRT), and death. METHODS: Using observed and modeled data from 5097 subjects in the UK Prospective Diabetes Study, we measured the annual probability of transition from stage to stage (incidence), prevalence, cumulative incidence, ten-year survival, median duration per stage, and risk of death from all-causes or cardiovascular disease. RESULTS: From diagnosis of diabetes, progression to microalbuminuria occurred at 2.0% per year, from microalbuminuria to macroalbuminuria at 2.8% per year, and from macroalbuminuria to elevated plasma creatinine (>or=175 micromol/L) or renal replacement therapy at 2.3% per year. Ten years following diagnosis of diabetes, the prevalence of microalbuminuria was 24.9%, of macroalbuminuria was 5.3%, and of elevated plasma creatinine or RRT was 0.8%. Patients with elevated plasma creatinine or RRT had an annual death rate of 19.2% (95% confidence interval, CI, 14.0 to 24.4%). There was a trend for increasing risk of cardiovascular death with increasing nephropathy (P < 0.0001), with an annual rate of 0.7% for subjects in the stage of no nephropathy, 2.0% for those with microalbuminuria, 3.5% for those with macroalbuminuria, and 12.1% with elevated plasma creatinine or RRT. Individuals with macroalbuminuria were more likely to die in any year than to develop renal failure. CONCLUSIONS: The proportion of patients with type 2 diabetes who develop microalbuminuria is substantial with one quarter affected by 10 years from diagnosis. Relatively fewer patients develop macroalbuminuria, but in those who do, the death rate exceeds the rate of progression to worse nephropathy.     

Gentamicin pharmacokinetics during slow daily home hemodialysis

BACKGROUND: Gentamicin is commonly used in hemodialysis patients. Gentamicin pharmacokinetics during traditional hemodialysis have been described. Slow daily home (SDH) hemodialysis (7 to 9 hours a day/6 days a week) use is increasing due to benefits observed with increased hemodialysis. We determined gentamicin pharmacokinetics for SDH hemodialysis patients. METHODS: Eight patients (four male and four female) received a single intravenous dose of 0.6 mg/kg gentamicin post-hemodialysis. Blood samples were collected at 5, 10, 15, 30, and 60 minutes after dose. The next day patients underwent a typical SDH hemodialysis (high-flux F50NR dialyzer) session. Blood samples were taken at 0, 5, 15, 60, 120, 240, 360, 480 minutes during and 15, 30 and 60 minutes post-hemodialysis. Baseline and 24-hour urine samples were collected. Pharmacokinetic parameters were calculated assuming a one-compartment model. RESULTS: Patients were 42.5 +/- 13.1 years old (mean +/- SD). Inter-, intra-, and post-hemodialysis collection periods were 17.0 +/- 2.1 hours, 8.1 +/- 0.4 hours, and 1.1 +/- 0.1 hours, respectively. Intra-, and interdialytic gentamicin half-lives were different (intradialytic, 3.7 +/- 0.8 hours; interdialytic, 20.4 +/- 4.7 hours; P < 0.0001). Hemodialysis clearance accounted for 70.5% gentamicin total clearance. Renal clearance correlated with glomerular filtration rate (GFR) (renal clearance=1.2 GFR; r2=0.98; P < 0.001). Mean peak and trough of hemodialysis concentrations were 1.8 +/- 0.6 microg/mL and 0.5 +/- 0.2 microg/mL, respectively. Post-hemodialysis rebound was 3.1 +/- 8.8% at 1 hour. CONCLUSION: Pharmacokinetic model predicts 2.0 to 2.5 mg/kg dose gentamicin post-hemodialysis would provide peak (1 hour post-dose) and trough (end of SDH hemodialysis session) concentrations of 6.0 to 7.5 microg/mL and 0.7 to 0.8 microg/mL, respectively. This would provide adequate coverage for most gram-negative organisms in SDH hemodialysis patients.     

Drug record discrepancies in an outpatient electronic medical record: frequency,type, and potential impact on patient care at a hemodialysis center

BACKGROUND: Patients who require hemodialysis take many drugs. Electronic drug records may be discrepant with what patients are actually taking. Record discrepancies are a potential source of drug-related problems. We sought to determine the extent to which drug record discrepancies occur in a hemodialysis population. METHODS: This was a prospective observational study of patients enrolled in a pharmacist clinic at an outpatient hemodialysis center from August-December 2001. Patients participated in monthly drug interviews conducted by a pharmacist, during which patient drug use was determined. Data collected consisted of patient demographics, drug type, and number of drugs. Drug record discrepancies were classified and assigned a potential drug-related problem. Results were compared with the electronic drug record. Patients with documented drug record discrepancies were compared with those patients for whom no discrepancy was identified. RESULTS: Over the 5-month period, 215 drug interviews were conducted in 63 patients. One hundred thirteen drug record discrepancies were identified in 38 patients (60%). Discrepancies (mean +/- SD 1.7 +/- 1.3, range 1-7) were identified during 65 drug interviews (30.2%). Electronic drug records were discrepant by one drug record, two drug records, and more than two drug records 60.0%, 26.2%, and 13.8% of the time, respectively. Drug record discrepancies placed patients at risk for adverse drug events and dosing errors in 49.6% and 34.5%, respectively, of 113 discrepancies. Patient age negatively correlated with the number of drug record discrepancies identified (r = -0.27, p = 0.04). CONCLUSIONS: Drug record discrepancies occur frequently among patients undergoing hemodialysis. Incorporation of a pharmacist into the patient care team may increase the accuracy of the electronic drug record and avert unnecessary drug-related problems.     

Cannulation of the axillary artery for cardiopulmonary bypass: safeguards and pitfalls

BACKGROUND: The ascending aorta is the customary site for arterial cannulation for cardiopulmonary bypass. Favorable experience at our institution and elsewhere using axillary artery cannulation in treating type A aortic dissections has caused us to broaden our indications for using this site for arterial cannulation for cardiopulmonary bypass. METHODS: Medical records, operative notes, and perfusion records were reviewed in all patients in whom the axillary artery was cannulated directly or by a graft for cardiopulmonary bypass from January 1, 2000 through August 30, 2002. RESULTS: Seventy-five patients underwent axillary artery cannulation during the 32-month interval. Eleven patients had ascending aortic dissections, 20 had extensively diseased ascending aortas, and 44 were individuals undergoing repeat cardiac procedures. The right axillary artery was used in 72 patients and the left in 3. In 16 patients the artery was cannulated directly, and in 59 the arterial cannula was inserted into a prosthetic graft that had been anastomosed to the axillary artery. Axillary artery cannulation was satisfactory in 95% (71 of 75) of the cases in which it was used. CONCLUSIONS: Cannulation of the axillary artery for cardiopulmonary bypass is a dependable approach for procedures including reoperations, aortic dissections, and extensively diseased ascending aortas.     

Tissue oxygen monitoring during hemorrhagic shock and resuscitation: a comparison of lactated Ringer's solution,hypertonic saline dextran,and HBOC-201

BACKGROUND: The ideal resuscitation fluid for the trauma patient would be readily available to prehospital personnel, universally compatible, effective when given in small volumes, and capable of reversing tissue hypoxia in critical organ beds. Recently developed hemoglobin-based oxygen-carrying solutions possess many of these properties, but their ability to restore tissue oxygen after hemorrhagic shock has not been established. We postulated that a small-volume resuscitation with HBOC-201 (Biopure) would be more effective than either lactated Ringer's (LR) solution or hypertonic saline dextran (HSD) in restoring baseline tissue oxygen tension levels in selected tissue beds after hemorrhagic shock. We further hypothesized that changes in tissue oxygen tension measurements in the deltoid muscle would reflect the changes seen in the liver and could thus be used as a monitor of splanchnic resuscitation. METHODS: This study was a prospective, blinded, randomized resuscitation protocol using anesthetized swine (n = 30), and was modeled to approximate an urban prehospital clinical time course. After instrumentation and splenectomy, polarographic tissue oxygen probes were placed into the liver (liver PO2) and deltoid muscle (muscle PO2) for continuous tissue oxygen monitoring. Swine were hemorrhaged to a mean arterial pressure (MAP) of 40 mm Hg over 20 minutes, shock was maintained for another 20 minutes, and then 100% oxygen was administered. Animals were then randomized to receive one of three solutions: LR (12 mL/kg), HSD (4 mL/kg), or HBOC-201 (6 mL/kg). Physiologic variables were monitored continuously during all phases of the experiment and for 2 hours postresuscitation. RESULTS: At a MAP of 40 mm Hg, tissue PO2 was 20 mm Hg or less in both the liver and muscle beds. There were no significant differences in measured liver or muscle PO2 values after resuscitation with any of the three solutions in this model of hemorrhagic shock. When comparing the hemodynamic effects of resuscitation, the cardiac output was increased from shock values in all three animal groups with resuscitation, but was significantly higher in the animals resuscitated with HSD. Similarly, MAP was increased by all solutions during resuscitation, but remained significantly below baseline except in the group of animals receiving HBOC-201 (p < 0.01). HBOC-201 was most effective in both restoring and sustaining MAP and systolic blood pressure. There was excellent correlation between liver and deltoid muscle tissue oxygen values (r = 0.8, p < 0.0001). CONCLUSION: HBOC-201 can be administered safely in small doses and compared favorably to resuscitation with HSD and LR solution in this prehospital model of hemorrhagic shock. HBOC-201 is significantly more effective than HSD and LR solution in restoring MAP and systolic blood pressure to normal values. Deltoid muscle PO2 reflects liver PO2 and thus may serve as an index of the adequacy of resuscitation in critical tissue beds.