Involvement of renal cytochromes P450 and arachidonic acid metabolites in diabetic nephropathy.

Diabetic nephropathy (DN) is one of the most serious complications of type I and type II diabetes. DN is characterized by hyperfiltration, hypertrophy, extracellular matrix accumulation, and proteinuria. This advances into renal fibrosis and loss of renal function. Reactive oxygen species (ROS) and TGF-beta have been implicated in the pathogenesis of diabetic nephropathy. Early stages of diabetic nephropathy are also associated with alterations in renal sodium handling as well as hypertension; both are processes linked by involvement of the arachidonic acid (AA) metabolites, 20-hydroxyeicosatetraenoic acid (20-HETE, produced by cytochrome P450-4a, (CYP4A) and epoxyeicosatrienoic acids (EETs). Indeed, metabolism of AA is increased in a rat model of diabetes. In this study, we demonstrate that rats with streptozotocin-induced diabetes of 1 month duration develop renal hypertrophy and increased fibronectin and TGF-beta1 expression/cortical levels concomitant with an increase in CYP4A expression and 20 HETE production. These results were also paralleled by an increase in reactive oxygen species (ROS) production and NADPH oxidase activity. Treatment of diabetic rats with HET0016, selective inhibitor of CYP 4A, prevented all these changes. Our results suggest that diabetes-induced induction of CYP4A and 20-HETE production could be a major pathophysiological mechanism leading to activation of ROS through an NADPH dependent pathway and TGF-beta1 thus resulting in major renal pathology. Inhibitors of 20-HETE production could thus have an important therapeutic potential in the treatment of diabetic nephropathy.

Temporal changes in vascular reactivity in early diabetes mellitus in rats: role of changes in endothelial factors and in phosphodiesterase activity.

The aims of this study were to study the influence of the duration of diabetes, the role of endothelial-derived vasodilators, and the role of phosphodiesterase (PDE) isoform activity in the early changes in vascular reactivity of aortic rings from diabetic rats. Diabetes mellitus was induced in female rats by intravenous streptozotocin (85 mg/kg). Two or 4 wk later, thoracic aortic rings from control and diabetic rats were isolated, and vascular responses to acetylcholine (ACh), S-nitroso-N-acetylpenicillamine (SNAP) [nitric oxide (NO) donor], DMPPO (PDE5 inhibitor), and phenylephrine (PE) were obtained in the presence and absence of endothelium or other drugs. PDE isoform activity was also measured. At 2 wk, responses to ACh and DMPPO were enhanced, whereas those to PE were attenuated in diabetic rats relative to controls. Indomethacin and SQ-29548 (a thromboxane A(2) receptor antagonist), but not N(G)-nitro-L-arginine methyl ester, corrected these differences. The responses to SNAP, and cAMP and cGMP hydrolytic activities, were similar in the two groups. In contrast, at 4 wk, ACh, DMPPO, and PE produced similar responses in the two groups: N(G)-nitro-L-arginine methyl ester rendered the response to PE lower in the diabetic group, and this was corrected by indomethacin, but not SQ-29548, treatment. The response to SNAP was greater in the diabetic group, and this was corrected by DMPPO. Activity of all PDEs was decreased at 4 wk. We conclude that, at 2 wk, there is modulation of thromboxane A(2) production, but no change in the NO system or PDE isoform activities. At 4 wk, a reduction in NO activity is superimposed; at this stage, PDE activity is reduced, together with increased production of vasodilating prostaglandins, possibly as a compensatory mechanism to maintain normal vascular reactivity.

Civilian aviation fatalities involving pilot ethanol and a previous record of substance abuse.

INTRODUCTION: Pilots are subject to the same temptations as the general population, but due to the demands of flying, the use of ethanol or other impairing substances are more likely to have severe consequences. The Federal Aviation Administration (FAA) requires pilots to report all adverse legal actions involving their use of ethanol and/or other drugs. The purpose of this study was to evaluate fatal civil aviation accidents between the years 2000 and 2007 in which ethanol was present in the pilot and the pilot had a record of previous drug and/or alcohol offenses. METHODS: Case histories and accident information for the period under study were obtained from the National Transportation Safety Board (NTSB). Toxicological information was obtained from the Civil Aerospace Medical Institute's Forensic Toxicology Research Laboratory. RESULTS: During the examined period 215 of the 2391 pilot specimens received for toxicological analysis had documented alcohol or drug related offenses. Of the 215 pilot specimens received, 23 showed evidence of ethanol consumption prior to the fatal incident and 16 of those had ethanol concentrations above the FAA's legal limit of 40 mg x dl(-1). DISCUSSION: These results confirm earlier reports that pilots with previous alcohol and/or drug offenses are more likely than others to engage in repeated substance abuse in association with flying with resultant fatal accidents. These findings support the NTSB's recommendation that the FAA implement more thorough verification of alcohol and drug offenses as a means of identifying pilots at increased risk of causing accidents.

Antiemetic and sedative levels found together in 26 civil aviation pilot fatalities, 2000-2006.

INTRODUCTION: Antiemetics and sedatives are two drug classes that may have harmful side effects when mixed. This is especially dangerous for pilots. Although many of these compounds are considered disqualifying by the FAA, their use occurs. Some pilots may be unaware of the danger of combining compounds from these two drug classes. Our laboratory was interested in evaluating the circumstances surrounding accidents in which the pilot was found positive for drugs from each of these two classes. METHODS: Epidemiological, toxicological, and aeromedical findings from pilots involved in such accidents were collected for the 7-yr period from 2000 through 2006. Case histories, accident information, and the probable cause of the aviation accidents were obtained from the National Transportation Safety Board (NTSB). Toxicological information was obtained from the Civil Aerospace Medical Institute's (CAMI's) Forensic Toxicology Research Laboratory. RESULTS: Of the 2184 fatal aviation accidents over this time period, 26 were found positive for compounds from both the antiemetic and the sedative drug classes. All 26 aircraft were operated under 14 CFR Part 91 as general aviation. All pilots were male; 21 tested positive for a disqualifying substance that may have affected their ability to control the aircraft. CONCLUSION: Although the percentage of accidents in which the pilot tests positive for a compound from each class is small, it is important for all pilots to understand the dangers of self-medicating and concomitant use of such substances. Under-reporting of medications by pilots during their certification process occurs; education is the key to preventing inadvertent drug-drug interactions.

Research productivity of the medical faculty at the American University of Beirut.

OBJECTIVE: To analyse the quality and quantity of scientific publications of the medical faculty at the American University of Beirut (AUB) during a six year period (1996-2001) METHODS: The study included all faculty members in the medical school of AUB in the year 2001. A Medline search inclusive of the years 1996-2001 was done for each faculty member and a total number of 881 publications was obtained. RESULTS: The faculty consisted of 203 members. Their average productivity rate (mean (SD)) was 1.24 (1.38) publications/faculty member/year (PFY), with a mean impact factor of 2.69 (4.63). Eighteen per cent of the faculty did not have any publication in the six year study period, and only 20% had two or more publications per year. There was a significantly higher publication rate among newly recruited faculty members (0.93 (1.40) PFY for those appointed before 1990, 1.45 (1.24) PFY for those appointed during 1990-1995, and 1.67 (1.43) for those appointed after 1995, p = 0.007), and among those who are younger in age (p<0.01). Collaboration with international investigators resulted in more original publications than work done only at AUB (65% v 35%, p<0.001), and a higher journal impact factor for the publications (3.20 (3.85) v 1.71 (2.36), p<0.05). CONCLUSIONS: This is one of the first studies that analyse the research productivity of the medical faculty in a university setting in a developing country. It shows a wide variation in the research productivity of the faculty members that seems to be related to individual as well as institutional characteristics. Further analysis is needed to define and characterise these factors.

Pre-treatment apparent diffusion coefficient mapping: differentiation of benign from malignant laryngeal lesions.

OBJECTIVE: To determine whether a threshold apparent diffusion coefficient value may help to differentiate laryngeal carcinomas from benign lesions. METHODS: Fifty-three patients with laryngeal masses were recruited; four of them were excluded because of susceptibility artefacts. In the remaining 49 patients, the pathological results showed 32 laryngeal carcinomas and 17 benign lesions. The diagnostic value of diffusion-weighted magnetic resonance imaging for the identification of malignant lesions was determined. In addition, the agreement between diffusion-weighted magnetic resonance imaging and histopathology was assessed. Moreover, the sensitivity, specificity, and negative and positive predictive values of the apparent diffusion coefficient in detecting benign and malignant lesions were analysed. An apparent diffusion coefficient histogram was also produced. RESULTS: An apparent diffusion coefficient value of 1.1 × 10-3 mm2/second produced the best result when used as the cut-off point to differentiate malignant from benign masses. CONCLUSION: An apparent diffusion coefficient threshold of 1.1 × 10-3 mm2/second is optimal for distinguishing laryngeal carcinomas from benign lesions. Apparent diffusion coefficient values were lower for patients with laryngeal carcinomas than for those with benign lesions.

Drug-related hospitalization at a tertiary teaching center in Lebanon: incidence, associations, and relation to self-medicating behavior.

OBJECTIVE: In Lebanon there is very limited restriction on drug use. Accordingly, self-medication is highly prevalent. This study examined the influence of these factors on the development of drug-related illnesses that lead to hospitalization. METHODS: Patients admitted to the medical and pediatric wards of a tertiary teaching center in Beirut, Lebanon, over a period of 6 months were interviewed and their charts were reviewed. Admissions attributable to adverse drug reactions or therapeutic failures were identified and characterized with respect to demographic factors, medical history, drug intake, and self-medicating behavior. The influence of these variables on the development of drug-related illnesses was examined by logistic regression. RESULTS: Of 1745 adults and 457 children, there were 177 (10.2%) and 36 (7.9%) drug-related illnesses, respectively. Adverse drug reactions accounted for 7.0% and 5.7% and therapeutic failures for 3.2% and 2.2% of adult and pediatric admissions, respectively. Self-medication was commonly practiced (52.6% of adults and 41.6% of children). Logistic regression analysis revealed that female sex increased the risk of adverse drug reaction in adults, whereas self-medication decreased the risk. In children, the risk of adverse drug reaction was increased in lower socioeconomic groups, whereas the risk of therapeutic failure was increased by a positive history of atopy or drug reaction. CONCLUSIONS: These results provide the first detailed analysis of the problem of drug-related illnesses in a developing country and identify a number of related or risk factors. Despite the lack of regulation of drug dispensing and the unchecked access to drugs in Lebanon, the incidence of drug-related illnesses is not different from that in Western nations. This finding may have relevance to policies of drug regulation in other countries.

Amphotericin B nephrotoxicity.

The frequency of fungal infections is increasing. Amphotericin B remains the anti-fungal drug of choice for most systemic infections, but a limiting factor for its use is the development of nephrotoxicity. Amphotericin B-induced nephrotoxicity is manifested as azotaemia, renal tubular acidosis, impaired renal concentrating ability and electrolyte abnormalities like hypokalaemia and sodium and magnesium wasting. All these abnormalities occur to varying degrees in almost all patients receiving the drug. Upon withdrawal of therapy renal function gradually returns to baseline, although in some instances permanent damage is sustained, especially when the cumulative dose exceeds 5g. Salt depletion enhances the development of nephrotoxicity. The mechanism of nephrotoxicity involves direct cell membrane actions to increase permeability, as well as indirect effects secondary to activation of intrarenal mechanisms (tubuloglomerular feedback) and/or release of mediators (thromboxane A2). The latter effects are presumably responsible for the observed acute decreases in renal blood flow and filtration rate, responses that are inhibited by several physiological and pharmacological interventions. Changes in intracellular calcium levels may also contribute to the observed effects. In the clinical situation, and in long term models of nephrotoxicity in the rat, salt loading protects against deterioration in renal function; recommendations are made for the optimisation of amphotericin B therapy by salt loading. New preparations of the drug, such as liposomal amphotericin B, may also prove useful in minimising nephrotoxicity while maintaining antifungal activity, but further research is needed with both salt loading and liposomal amphotericin B to confirm or deny their protective effect on kidney function.

Influence of phenobarbital on changes in Na(+) handling, hemodynamics and liver function due to partial portal vein ligation in rats.

This study examined the influence of phenobarbital, an inducer of hepatic enzymes, on Na(+) handling, hemodynamics and liver function (measured by the rate constant of elimination of aminopyrine in the aminopyrine breath test) after partial portal vein ligation. Rats were randomized to drink either phenobarbital + water or water only for 10 days and then underwent either sham operation or partial portal vein ligation. The aminopyrine rate constant of elimination and Na(+) balance were measured daily before and after surgery; after surgery, hemodynamic measurements were obtained daily in a subset of rats. Phenobarbital raised the baseline aminopyrine rate constant of elimination. Partial portal vein ligation, but not sham operation, caused equivalent reductions in the aminopyrine rate constant of elimination in phenobarbital- and water-treated groups, such that the aminopyrine rate constant of elimination remained higher in the former. Na(+) balance increased significantly in partial portal vein ligation + water, but not sham + water rats on day 1 and then decreased on days 2 and 3. In contrast, neither sham + phenobarbital nor partial portal vein ligation + phenobarbital rats had a significant increase in Na(+) balance. Partial portal vein ligation resulted in vasodilation on day 3 after surgery in the water-treated rats, an effect that was prevented by treatment with phenobarbital. These results support previous suggestions that a reduction in liver function triggers renal Na(+) retention in this model. Vasodilation is not necessary for the latter effect, but also appears to be dependent on a reduction in liver function.

Effect of amphotericin B on intracellular calcium levels in cultured glomerular mesangial cells.

Amphotericin B induces a reduction in the glomerular filtration rate due, in part, to a decrease in the glomerular capillary ultrafiltration coefficient (Kf), possibly resulting from mesangial cell contraction. The present study has examined the effect of amphotericin B on intracellular free calcium concentrations ([Ca2+]i) in cultured glomerular mesangial cells, using the fluorescent probe, fura-2. Under control conditions, amphotericin B caused a concentration-dependent increase in [Ca2+]i with a 231 +/- 52 nM increase at a concentration of 10(-6) M. This increase was almost completely inhibited when Ca2+ ions were omitted from the cell medium (an increase of 34 +/- 7 nM, P less than 0.0001). Replacement of extracellular Na+ ions with N-methylglucamine caused a marked inhibition of the amphotericin B-induced rise in [Ca2+]i (28 +/- 5 nM, P less than 0.0001). Diltiazem (20 microM) also suppressed the rise in [Ca2+]i seen with amphotericin B (36 +/- 6 nM, P less than 0.0001). In contrast, theophylline (20 microM) enhanced the response to amphotericin B (351 +/- 51 nM rise, P less than 0.001). The results suggest that amphotericin B-induced mesangial cell contraction is secondary to Ca2+ entry from the extracellular space through voltage-dependent calcium channels. The dependence of the response on extracellular Na+ suggests that Na+ entry induces depolarization of the membrane and opening of voltage-dependent calcium channels.

Post-junctional mechanisms involved in the potentiation of cardiac adrenergic responses by cocaine.

Cocaine cardiotoxicity is partly due to sympathetic activation of the heart resulting from inhibition of catecholamine uptake at the sympathetic nerve terminal and possible central sympathetic stimulation and/or inhibition. This study evaluated the role of postsynaptic mechanisms in potentiation by cocaine of cardiac adrenergic responses. Cardiovascular responses (arterial and left ventricular pressure, contractility and heart rate) to increasing doses of noradrenaline and to isoproterenol were obtained in anesthetized cats during a control period, after irreversible alpha-adrenoceptor blockade with phenoxybenzamine (5 mg/kg i.v.), and after cocaine (5 mg/kg, i.v.). Responses to noradrenaline were significantly reduced by phenoxybenzamine with lowering of the maximal rise of all parameters. Cocaine shifted the dose-response curve of noradrenaline to the left and enhanced its maximal effects. Some responses to isoproterenol, which is not taken up by nerve terminals, were also enhanced by cocaine. Pretreatment with chlorisondamine or verapamil prevented the cocaine-induced enhancement of the maximal response to noradrenaline and the response to isoproterenol, but it did not inhibit potentiation of submaximal doses. Lidocaine did not potentiate the response to noradrenaline or isoproterenol. Use of chlorisondamine instead of cocaine potentiated responses to all noradrenaline doses and enhanced the responses to isoproterenol. These results suggest that the potentiation by cocaine of cardiac responses to adrenergic stimuli involves presynaptic mechanisms to block noradrenaline re-uptake, and postsynaptic mechanisms to raise the maximal responses. The latter may result from inhibition of central sympathetic outflow or from activation of cardiac Ca(+) channels, leading to increased cardiac sensitivity to noradrenaline.

Gender differences in the diagnosis and treatment of acute myocardial infarction in Lebanon.

PURPOSE: To study the gender differences in presentation, diagnosis and treatment of acute myocardial infarction in Lebanon. MATERIAL & METHODS: Consecutive admissions due to myocardial infarction to 18 medical centers in various regions of Lebanon were entered into the Lebanese Myocardial Infarction Study, conducted between January and July 1996. Information was obtained on age, gender, time of onset of symptoms, delay to hospital arrival, mode of transport, and coronary risk factor analysis. The patients were followed up in hospital for analysis of modes of therapy, complications and mortality. RESULTS: Of 433 admissions, 99 were female. Compared to men, women were older, presented later, smoked less but tended to have a higher frequency of hypertension. The other coronary risk factors were similarly prevalent in males and females. Inotropic agents were used more commonly in females but thrombolytics were used less so. Women tended to develop more heart failure and had significantly higher incidence of recurrent ischemia or myocardial infarction, high level atrioventricular block and atrial arrhythmias. The overall mortality rate was higher in females than in males (16.2% vs. 8.1%, P = 0.037). CONCLUSIONS: The results reveal similarities between gender differences among Lebanese and Western populations. The higher mortality rate in women may relate to the late arrival to hospital, the older age and the more frequent complications. This emphasizes the need to educate women about coronary risk and to urge them to seek early medical care.

In-hospital mortality after acute myocardial infarction in Lebanon: incidence, associations, and influence of newer treatment regimens.

PURPOSE: To study the incidence of in-hospital mortality following acute myocardial infarction in Lebanon, and its relationship to demographic, clinical variables, and therapeutic strategies. PATIENTS & METHODS: Consecutive admissions due to myocardial infarction to 18 medical centers in various regions of Lebanon were entered into the Lebanese Myocardial Infarction Study, conducted between January and July 1996. Information was obtained on age, gender, time of onset of symptoms, delay to hospital arrival, mode of transport, and coronary risk factor analysis. The patients were followed up in hospital for analysis of modes of therapy, complications and mortality. RESULTS: There were 44 in-hospital deaths among the 433 admissions (10.2%), which is a rate lower than those previously reported from Lebanon. Less than half the patients presented within 6 hours of onset of symptoms and only 28% received thrombolytic therapy. The mortality rate was higher in older age groups, those presenting with cardiogenic shock or pulmonary edema, those with a history of angina, infarction or heart failure, and those who developed recurrent ischemia or infarction during their hospital stay. Furthermore, occurrence of ventricular arrhythmias, mechanical complications, congestive heart failure and left bundle branch block was associated with a higher mortality rate. Treatment with angiotensin converting enzyme inhibitors, beta-blockers, aspirin, heparin, nitrates and thrombolytics significantly reduced mortality rates. CONCLUSIONS: The results reveal improvement in the survival of patients after acute myocardial infarction to values similar to those reported from Western countries. Further effort should be expended to enhance early arrival to the hospital, increased thrombolytic therapy and to implement treatment strategies supported by large clinical trials such as use of aspirin, ACE inhibitors and beta-blockers.

[Reflux nephropathy]. / Refluxová nefropatie.

A corticopapillary scar is a frequent finding on urography in patients with vesicoureteral reflux. It is considered a typical sign of so-called reflux nepropathy. It develops most frequently in children aged 5-7 years and has a negative impact on the growth of the kidney. In its development three factors participate: ureterovesical reflux, intrarenal reflux associated with so-called refluxing papillas and urinary infection. The inflammatory cicatrical process may affect the whole kidney--small shrivelled kidney--or only a portion of the kidney. The development of scars is explained by the so-called bing-bang theory according to which all refluxing papillae are affected at the same time by the first urinary infection. This position develops in particular in case of inadequate treatment of acute pyelonephritis, Deformity of normal papillae caused by various factors explains, however, the development of renal scars in children aged 8-12 years or even in adults. The growing kidney tolerates poorly not only urinary infections and scar formation but also hydrodynamic disorders associated with vesicoureteral reflux. Therefore it is important to diagnose and treat vesicoureteral reflux already at an early age. For the time being it is important o consider asymptomatic bacteriuria and any urinary infection in children a clinical marker calling for examination for the possible presence of vesicoureteral reflux.

An evaluation of 25B-, 25C-, 25D-, 25H-, 25I- and 25T2-NBOMe via LC-MS-MS: method validation and analyte stability.

As potent serotonin (5-HT2A) receptor agonists, the NBOMe class of drugs including 25B-, 25C-, 25D-, 25H-, 25I- and 25T2-NBOMe is frequently abused due to the intense hallucinations that they induce. From the limited literature available, the concentration of these NBOMe compounds reported in postmortem cases is exceedingly low. In most instances, published concentrations are <0.50 ng/mL. Therefore, the need for a sensitive, rapid and comprehensive analytical method for the quantification of these compounds was evident. In addition to the more publicized analog 25I-NBOMe, evaluation of 25B-, 25C-, 25D-, 25H and 25T2- in whole blood, plasma and urine was conducted. This publication presents the data obtained from the validation of a liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of these six NBOMe analogs. The method utilizes ultra-performance liquid chromatography technology for the separation followed by positive electrospray ionization of each analog. Limits of quantification for these analogs ranged from 0.01 to 0.02 ng/mL (10-20 pg/mL) with typical linear dynamic ranges of 0.01-20 ng/mL. Data for recovery, intraday control accuracy and precision, matrix effects, ion suppression/enhancement and analyte stability are included. Validation was completed in whole blood, plasma and urine. Short run times and high sensitivity afforded by this newly validated analytical method that allows for the detection of these six analogs in the most common toxicological matrices and can be applied to both ante- and postmortem specimens.

The stability of four designer drugs: MDPV, mephedrone, BZP and TFMPP in three biological matrices under various storage conditions.

The analysis of designer drugs, including those in the synthetic cathinone and piperazine classes, may be complicated by the poor stability of these compounds in biological specimens. The stability of four of these compounds was investigated: 3,4-methylenedioxypyrovalerone, 4-methyl-N-methylcathinone (mephedrone), N-benzylpiperazine and 1-[3-(trifluoromethyl)phenyl]piperazine. Compound stability was monitored in three different biological matrices when each matrix was stored under three different conditions. These matrices and conditions included human whole blood, human serum and human urine, each stored at -20, 4 and 22°C for a period of 14 days in the dark in a sealed glass container. Analysis by liquid chromatography-tandem mass spectrometry was performed on Day 1 to establish the initial concentration for each drug in each specimen type, and then the samples were divided into three parts for storage under the various conditions. Analysis was performed in triplicate on Days 2, 4, 7 and 14 for each specimen type under each storage condition and the results were compared to those obtained on Day 1. Following analysis of the data, it became clear that mephedrone was not stable, and that care must be taken following specimen receipt to ensure minimal degradation.

Toxicological findings in 889 fatally injured obese pilots involved in aviation accidents.

Prevalence of drugs in fatally injured obese pilots involved in aviation accidents has not been evaluated. Therefore, toxicological findings in such pilots (body mass index ≥30 kg/m(2) ) were examined in a data set derived from the Civil Aerospace Medical Institute's (CAMI's) Scientific Information System for 1990-2005. Aeromedical histories of these aviators were retrieved from the CAMI medical certification and toxicology databases, and the cause/factors in the related accidents from the National Transportation Safety Board's database. In 311 of the 889 pilots, carbon monoxide, cyanide, ethanol, and drugs were found, and glucose and hemoglobin A(1c) were elevated. Of the 889 pilots, 107 had an obesity-related medical history. The health and/or medical condition(s) of, and/or the use of ethanol and/or drugs by, pilots were the cause/factors in 55 (18%) of the 311 accidents. Drugs found were primarily for treating obesity-related medical conditions such as depression, hypertension, and coronary heart disease.

Using team-based learning to teach clinical pharmacology in medical school: student satisfaction and improved performance.

Formal teaching in clinical pharmacology was never part of the curriculum at the American University of Beirut Faculty of Medicine. Based on feedback from students and on recommendations of academic bodies, we have introduced, since June 2008, twice-monthly "rational prescribing" sessions during the required internal medicine rotation in year 4 of medical school. All sessions were designed according to the innovative Team-based Learning format and concluded by having the students practice prescription writing and personal formulary development based on the World Health Organization criteria. Our 18-month experience showed that students were very satisfied with the course and the teaching approach, and that their performance on prescription writing and formulary development had improved. Although further studies are needed to explore the impact of team-based learning on additional performance measures, we recommend it as an effective alternative for teaching clinical pharmacology in medical schools.

The screening of forensic blood, urine, and tissue specimens for xenobiotics using ion-trap liquid chromatography-tandem mass spectrometry.

During the investigation of aviation accidents, postmortem specimens from accident victims including blood, urine, and tissue are submitted to the Federal Aviation Administration's Civil Aerospace Medical Institute (CAMI) for toxicological analysis. The first, and perhaps most important, step in the analysis process is the initial screening of biological specimens for illicit, medically prescribed, and over-the-counter compounds that may be present and potentially be a cause and/or factor in the accident. Currently, our general unknown screening (GUS) procedure involves, in part, both gas chromatography-mass spectrometry (GC-MS) and liquid chromatography (LC) with both diode-array detection (DAD) and fluorescence detection. Both GC and LC techniques have inherent limitations that prevent the detection of certain types of compounds. The decreased specificity and sensitivity of LC-DAD has been an impediment to the existing GUS procedure. Therefore, our laboratory set out to develop and validate an LC-MS-MS procedure that is superior to LC-DAD. The limits of detection of 359 forensically important xenobiotics have been established following solid-phase extraction from whole blood and analysis by LC-MS-MS. Although whole blood was used as the matrix during instrument validation, the method has been successfully applied to both forensic urine and tissue specimens as well.