Management of the patient with diabetic peripheral neuropathy presenting for peripheral regional anesthesia: a European survey and review of literature.

BACKGROUND: Diabetic peripheral neuropathy (DPN) is a frequent complication of longstanding diabetes mellitus. There is no evidence-based consensus whether neuropathic patients undergoing peripheral regional anesthesia are at increased risk of neurologic damage. It is unknown whether these controversial results have been incorporated into clinical practice. We conducted a survey to test the hypothesis that the majority of respondents would consider DPN a potential risk factor for nerve damage in regional anesthesia, and would adapt their technique when performing regional anesthesia. In parallel, we sought to summarize the current knowledge-base regarding regional anesthesia and DPN. METHODS: We therefore performed 1) a literature search to review current literature and 2) an online computer-based survey among members of the European Society of Regional Anesthesia and Pain Therapy (ESRA). RESULTS: The overall response rate was 19% (584 responders/3107 invitations). About a quarter of participants would avoid regional anesthesia in patients with diabetic neuropathy, and 59% of respondents would counsel patients with diabetic neuropathy about increased risk of regional anesthesia. When techniques were modified, most participants would decrease or omit epinephrine, while fewer respondents would decrease dose of local anesthetic or perform other adjustments. More than 80% agreed with the statement that nerve blocks could be performed safely in diabetic neuropathic patients. CONCLUSION: In conclusion, we report the results of the first survey analyzing attitudes and standards of care among European anesthesiologists with regards to regional anesthesia in DPN. While literature is divided on the question whether pre-existing diabetic neuropathy is a risk factor for new neurological deficit after regional anesthesia, most of the responders of this survey take measures to reduce risks, counsel patients on a possible greater risk of neurologic complications, but only a minority of responders would avoid peripheral regional anesthesia altogether.

Pre-existent depression in the 2 weeks before an acute coronary syndrome can be associated with delayed presentation of the heart attack.

BACKGROUND: Depression is common among patients with acute coronary syndrome (ACS). AIM: To examine how depression may alter outcome of ACS. DESIGN: Observational study on how ongoing depression influences the time delay to seeking help and its effects on subsequent treatment compliance after discharge. METHODS: Depression was measured by Beck Depression Inventory (BDI) 2 weeks prior to presentation on consecutive patients with ACS. RESULTS: Of the 276 patients, 81 had BDI > or =10 and 195 had BDI score <10. The time from onset of the predominant symptom to seeking help tended to be longer in those with BDI > or =10 than in those with BDI <10 [180 (IQR 37.5-1042.5) min vs. 120 (IQR 30-735) min, P = 0.099]. Results were similar for the 68 with ST elevation myocardial infarction (MI) [238 (IQR 49-709) min vs. 60 (IQR 20-352) min, P = 0.071]. Each point increase of BDI predicted an approximately 4.2% [95% confidence interval (CI) 0.4-8.0%] increase in the time duration, P = 0.029. On multivariable analysis, the effect of BDI persisted (6.0% increase in duration per each point increase in BDI, 95% CI 2.4-9.7%, P = 0.001). Among the 68 patients who had ST elevation MI, results were similar with an 8.0% (95%CI 1.7-14.7%, P = 0.013) increase in time duration for each unit increase in BDI. Results were also similar when BDI was evaluated as a dichotomous variable. Small differences were observed for subsequent treatment compliance. CONCLUSION: Ongoing depression delays the presentation of ACS.

Metabolism and excretion of zafirlukast in dogs, rats, and mice.

The in vivo metabolism and excretion of zafirlukast [Accolate; 4, 5-cyclopentoxycarbonylamino-3-[(2-methoxy-4,2- methylphenylsulfonylaminocarbonyl)phenylmethyl]-1-methylindole], a selective peptide leukotriene receptor agonist, were investigated in mice, rats, and dogs. Leukotrienes are a class of compounds that have been identified as being responsible for the contraction of human airway and lung vascular smooth muscle. A chemical agent that is effective in blocking the induced constricting actions of leukotrienes could be used to treat inflammatory processes in the pulmonary system. Zafirlukast has been shown to be clinically efficacious and has been approved for the treatment of asthma in humans. To determine the metabolic fate of zafirlukast, the radiolabeled compound was administered orally to mice, rats, and dogs and iv to rats and dogs. Plasma, urine, and feces samples were collected, assayed for radioactivity, and profiled for metabolites. Nearly all of the [14C]zafirlukast-derived radioactivity was excreted in the feces of the test species, indicating biliary clearance as the major route of elimination from the systemic circulation. The primary routes of metabolism in all species studied involved hydrolysis of the amide linkage at the 5-aminoindole position and hydroxylation at one or more sites. Additional metabolites were formed by N-acetylation (not in dogs), demethylation of the indole nitrogen, and N-desmethylation. Accolate is a registered trademark, property of Zeneca Ltd.

Determination of zafirlukast, a selective leukotriene antagonist, human plasma by normal-phase high-performance liquid chromatography with fluorescence detection.

A high-performance liquid chromatographic (HPLC) method was developed for the determination of zafirlukast, a selective peptide leukotriene receptor antagonist, in human plasma. Zafirlukast and the internal standard, ICI 198 707, were extracted from deproteinated plasma samples using large reservoir C18 solid-phase extraction columns and analyzed by normal-phase liquid chromatography with fluorescence detection. The method had a lower limit of quantitation of 0.75 ng/ml and a linear calibration curve in the range of 0.75 to 200 ng/ml. The absolute recovery of zafirlukast was > 90%, and the within-day and between-day relative standard deviations were < 9%. The utility of the method in the characterization of the plasma concentration-time profiles of zafirlukast in clinical studies was demonstrated.

Pharmacokinetics of meropenem in patients with liver disease.

Eight subjects with chronic stable alcoholic cirrhosis and eight matched controls with normal liver function were given an initial 30-minute intravenous infusion of 1 g of meropenem; beginning 24 hours later, they received five additional 1-g doses at 6-hour intervals. No statistically significant differences were found between the first dose and steady state or between groups for any plasma pharmacokinetic parameters-including the highest observed plasma concentrations, plasma concentrations at 6 hours after dosing (C6h), terminal half-life, area under the plasma concentration-time curve (AUC), area under the first moment of the curve, plasma clearance, steady-state volume of distribution, and accumulation ratios-on the basis of either AUC or C6h. There were also no statistically significant differences in any of the measured or calculated pharmacokinetic parameters of the microbiologically inactive metabolite of meropenem (ICI 213,689). A total of 11 adverse experiences (one moderate and 10 mild) were reported by four patients; nine of these experiences, including two in controls, were rated by the investigator as "possibly" drug related. It is concluded that meropenem is well tolerated with repeated intravenous dosing and that dosage adjustments are not necessary for patients with hepatic disease.

Laryngeal mask airway for therapeutic fiberoptic bronchoscopic procedures.

These cases illustrate the advantages of the laryngeal mask as compared with an endotracheal tube or oxygen face mask for selected patients undergoing therapeutic bronchoscopic procedures. The advantages include a larger internal diameter allowing easier passage of instruments, reduced work of breathing, lack of discomfort associated with insertion, access to the vocal cords and upper trachea unimpeded by the presence of an endotracheal tube, and capnographic and volume monitoring of respiration. The LMA is thus a valuable alternative for airway management in pulmonary compromised patients undergoing therapeutic bronchoscopic procedures.

Bioequivalence of 20-mg once-daily tamoxifen relative to 10-mg twice-daily tamoxifen regimens for breast cancer.

PURPOSE: We studied the bioequivalence of a new once-daily regimen of tamoxifen citrate relative to the standard twice-daily regimen of tamoxifen citrate, an established antiestrogenic treatment for breast cancer. PATIENTS AND METHODS: Of 30 women with breast cancer, 27 completed this open, two-period, crossover randomized trial. During one 3-month period, patients took one standard 10-mg tamoxifen tablet twice daily; during the preceding or following 3-month period, patients took one of the new 20-mg tablets once daily. Pharmacokinetic profiles and safety parameters were assessed at the end of each 3-month treatment period. RESULTS: Overall, measured concentrations of tamoxifen and its principal active metabolite, N-desmethyltamoxifen, remained relatively constant over the 24-hour sampling periods at the end of each treatment sequence. For both compounds, the percentage differences of the geometric means for all pharmacokinetic parameters indicated bioequivalence of the once-daily regimen of tamoxifen relative to the standard twice-daily regimen. Both treatment sequences were well tolerated; reported adverse events occurred at similar frequencies with the two treatment regimens. CONCLUSION: The 20-mg tamoxifen tablet taken once daily was bioequivalent to the 10-mg tamoxifen tablet taken twice daily, with no difference in relative risk. The once-daily treatment is a simpler regimen and may facilitate compliance, which may enhance therapeutic outcomes during long-term treatment of breast cancer.

Pharmacokinetic and galactopoietic response to recombinant variants of bovine growth hormone.

Two studies were designed to examine the pharmacokinetic and galactopoietic potency of three molecular variants of recombinant-derived bovine GH (rbGH): [Met1, Leu127]-bGH, [Ala1, Val127]-bGH and [Ala1, Val127, His133]-bGH. Histidine substitution for arginine at residue 133 of rbGH was shown to impart thrombin resistance. In a Latin square design, nine lactating Holstein cows received a 25 mg rbGH bolus infusion via the jugular vein followed by frequent blood sampling over the next 12 h. The serum GH concentration data were found to fit a two-compartment open model. Neither primary nor secondary kinetic parameter estimates differed significantly (P > 0.05) among the three rbGH variants. Thus, the disposition of GH concentration at time t was described by the equation C(t) = (1295.5 micrograms/l) (e-(0.11/min)(t)) + (317.3 micrograms/l)(e-(0.03/min)(t)). Overall averages were: area under the curve = 27.1 mg.min per l, clearance = 0.15 litres/min per 100 kg and volume of distribution of the central compartment = 2.59 litres/100 kg. The t 1/2 for the two compartments averaged 8.2 and 29.1 min. In the second study, 36 lactating Holstein cows received i.m. injections of one of four oil-based formulation treatments: control vehicle or 500 mg of one of the three rbGH variants every 14 days for 42 days. Average and maximum serum GH concentrations and area under the curve estimates were increased by approximately 3-6 micrograms/l, 5-15 micrograms/l and 40-90 micrograms.day per 1 respectively. Ala1, Val127 rbGH treatments elicited greater blood GH concentrations than [Met1, Leu127]-bGH when administered in an oil-based formulation. Blood GH responses did not directly translate into milk response differences, possibly due to differences in biopotency or receptor availability. Thrombin resistance resulting from substitution of histidine at position 127 of rbGH did not affect blood GH pharmacokinetic parameters or milk response over other rbGH variants.

Subscapular and triceps skinfold thicknesses, body mass index and cardiovascular risk factors in a cohort of middle-aged employed men.

Associations of indices of adiposity with cardiovascular risk factors were examined in 1860 middle aged men employed by the Western Electric Company in Chicago in 1960 and 1961. Body mass index and subscapular and triceps skinfolds were examined for associations with systolic and diastolic blood pressure, serum cholesterol, and post-load serum glucose. Correlations of study variables measured one year apart suggest that triceps and subscapular skinfold measurements are less reproducible than body mass index, but more reproducible than measurements of systolic and diastolic blood pressure and serum cholesterol. Associations with blood pressure were stronger for body mass index than for skinfolds, and subscapular skinfold was associated with blood pressure independently of triceps skinfold, as well as age, heart rate, alcohol intake, and family history of cardiovascular disease. Body mass index was also generally more strongly related to serum cholesterol than skinfold measurements. Triceps skinfold was more strongly related to serum cholesterol than subscapular skinfold based on average values for the variables in 1960-61, but subscapular skinfold was more strongly related to one-year change in serum cholesterol. Subscapular skinfold was as strongly related to serum glucose as body mass index. This association was also independent of triceps skinfold and other variables. These analyses demonstrate positive associations of subscapular skinfold, an index of central adiposity, with blood pressure and serum glucose levels. Associations of subscapular and triceps skinfolds with serum cholesterol levels were not consistent in the cross-sectional and longitudinal analyses and require further investigation.

Liquid excimers: lasing Xe(2) and Kr(2) in liquid argon.

By pumping a small cryogenic cell with a 40-nsec, 1-MeV e-beam pulse, we have excited lasing in dilute mixtures of xenon or krypton in liquid argon. The lasing occurred at 175 nm for the excimer Xe(2) and at 147 nm for Kr(2).

Lasing XeO in liquid argon.

We have lased XeO at 547 nm with xenon and N(2)O concentrations of tens of parts in 10(6) in liquid argon. The solution was pumped with a short-pulse 1-MeV e beam. The resulting gain was at least 23% per centimeter.

Attention deficit disorder with hyperactivity: differential effects of methylphenidate on impulsivity.

The impulsivity component of attention deficit disorder with hyperactivity requires regulation because its effects interfere with children's school performance and persist into adulthood. The present investigation examined the effects of low to intermediate doses of methylphenidate on impulsivity (measured by the Matching Familiar Figures test, a primary index of cognitive tempo) in 14 children with attention deficit disorder with hyperactivity. The mean percentile error score in the highest dose (15 mg) group was significantly lower than those in placebo (P less than .01), 5-mg (P less than .01), and 10-mg (P less than .01) groups. Trend analysis revealed a linear relationship between dose and error score with total errors decreasing as dose increased. Changes in children's error scores were examined using both fixed-dose and milligram per kilogram data-plotting methods. This work demonstrates the need to consider specific task and child characteristics while assessing the child's responsivity to psychostimulants across a range of safe doses and a variety of behavioral domains.

Methylphenidate in hyperactive children: differential effects of dose on academic, learning, and social behavior.

Methylphenidate (Ritalin) has been shown to have differential effects on hyperactive children's behavior as a function of dose level. In the present investigation, a triple-blind, placebo-control, within-subject (crossover) experimental design was employed in which 12 hyperactive boys between 6 and 10 years received three different dosages of methylphenidate (5, 10, and 15 mg) in a randomly assigned sequence. Dosage effects were assessed on clinic-(PAL--Paired Associates Learning test) and school-(percent on task, teacher ratings, work completion rates, and accuracy) related behaviors. For 10 of the children, classified as responders to medication by the PAL using the criteria of Swanson, Kinsbourne, and colleagues, a series of ANCOVAs with repeated measures showed significant dosage effects on teacher ratings (p less than .01), percent on task (p less than .01), academic accuracy (p less than .05), and assignment completion rates (p less than .05). PAL performance was also significantly enhanced (p less than .01) after optimal dose levels were considered. Subsequent trend analysis showed a significant positive linear relationship between dose and each of the dependent variables. A comparison of fixed-dose and miligram-per-kilogram plots showed that children's performance across the different dosages were clearly individualistic and task-specific, even when similar body weights were compared. The implications of using clinic-based testing to determine optimal medication responsivity were discussed.

Tissue analysis of N-methylformamide: organ distribution.

This report describes a gas chromatographic procedure, utilizing a packed column and flame ionization detector, suitable for the quantitative measurement of N-methylformamide (N-MF) in tissue samples. N-MF is a polar solvent that induces the maturation of cancer cells in vitro and, in vivo, exhibits antitumor activity with human tumors xenografted in nude (athymic) mice. Therapeutic monitoring is essential as toxicology studies have shown this compound to be hepatotoxic. N-MF is currently undergoing phase 1 clinical trials as an anticancer drug. This method of tissue analysis was developed to aid in the understanding of N-MF disposition and distribution in a murine model. The data thus generated may help predict the clinical behavior of this drug.

Analysis of folinic acid in human serum using high-performance liquid chromatography with amperometric detection.

An assay for the separation and quantification of folinic acid in serum was developed using high-performance liquid chromatography with electrochemical detection. Folinic acid was extracted from serum using a C18 minicolumn treated with dibasic ammonium phosphate. The drug was eluted from this column with methanol, which was evaporated under a nitrogen stream at 50 degrees. The mobile phase, pH 3.5 ammonium phosphate buffer-methanol-acetonitrile (93:4:3), was pumped at a flow rate of 3.0 ml/min. The recovery of folinic acid added to human serum was 101.11 +/- 8.5% (mean +/- SD). A plot of folinic acid peak height as a function of concentration was linear over the range of 2.5 X 10(-7) to 2.5 X 10(-6) M. Neither methotrexate nor other reduced folates interfered with the analysis of folinic acid. Sample preparation and analysis can be completed within 2 min of sample collection.

Measurement of photorespiration in algae.

The rates of true and apparent photosynthesis of two unicellular green algae, one diatom and four blue-green algae were measured in buffer at pH 8.0 at subsaturating concentrations of dissolved inorganic carbon (13-27 micromolar). Initial rates of depletion from the medium of inorganic carbon and (14)C activity caused by the algae in a closed system were measured by gas chromatography and by liquid scintillation counting, respectively. The rate of photorespiration was calculated as the difference between the rates of apparent and true photosynthesis. The three eucaryotic algae and two blue-green algae had photorespiratory rates of 10 to 28% that of true photosynthesis at air levels of O(2). Reduction of the O(2) level to 2% caused a 52 to 91% reduction in photorespiratory rate. Two other blue-green algae displayed low photorespiratory rates, 2.4 to 6.2% that of true photosynthesis at air levels of O(2), and reduction of the O(2) concentration had no effect on these rates.

Measurement of carbon dioxide compensation points of freshwater algae.

A technique is described for the measurement of total dissolved inorganic carbon by acid release as CO(2) followed by its conversion to methane and detection by flame ionization in a modified gas chromatograph. This method was used to determine the dissolved inorganic carbon concentration reached at compensation point when algae were allowed to photosynthesize in a closed system in a buffer at known pH, and the CO(2) compensation point was calculated from this concentration. The CO(2) compensation points of 16 freshwater algae were measured at acid and alkaline pH in air-saturated medium: at acid pH the CO(2) compensation points ranged from 4.8 to 41.5 microliters per liter while at alkaline pH they ranged from 0.2 to 7.2 microliters per liter. Removal of O(2) from the medium caused a slight lowering of compensation point at acid pH but had little effect at alkaline pH. These low, O(2)-insensitive compensation points are characteristic of C(4) plants. It is suggested that these low CO(2) compensation points are maintained by an active bicarbonate uptake by algae especially at alkaline pH.

Systemic absorption of topical salicylic acid.

The systemic absorption of salicylic acid in humans following topical application in either hydrophilic ointment or polyethylene glycol 400 vehicle was studied. Drug absorption was minimal following application to intact skin; however, measurable levels (8 mg/dl) were attained when the stratum corneum was removed prior to application of the drug in hydrophilic ointment. A one-compartment open model with first order absorption and elimination processes was fitted to the plasma salicylate concentrations as a function of time. Computer simulations predict that plasma salicylate levels associated with toxicity in some patients may be present after repetitive application of the drug in hydrophilic ointment.