Lidocaine has a narrow antiarrhythmic dose range against ventricular arrhythmias induced by programmed electrical stimulation in conscious postinfarction dogs

Summary The aim of the present study was to investigate the dose-dependent antiarrhythmic efficacy of lidocaine against electrically induced tachycardias in conscious, chronically instrumented postinfarction dogs. Programmed electrical stimulation (PES) was performed in 16 dogs 8 to 21 days after a 4 h occlusion of the left anterior descending coronary artery (LAD). Infusion of saline in 8 control animals with sustained ventricular tachycardia (SVT) inducible at baseline did not affect subsequent inducibility. In the treatment group 7 of 8 animals responded with SVT and one exhibited ventricular fibrillation at baseline. After an initial bolus of 1 mg/kg lidocaine intravenously (i.v.), the drug was infused at infusion rates of 40, 80 and 120 g/kg/min (i.v.). During 80 g/kg/min lidocaine (mean plasma level 3.5 g/ml) 7 out of 8 animals displayed an antiarrhythmic response; both the lower and the higher infusion rate were associated with a smaller antiarrhythmic efficacy (3 of 8 animals responded to 40 g/kg/min and 4 of 8 to 120 g/kg/min). Licocaine did not affect ventricular refractory periods, but induced an increase in intraventricular conduction time at all infusion rates, from 66.2 ms at baseline to 67.7 ms (p<0.05), 67.7 ms (p<0.05), 70.0 ms (p<0.01) respectively.In conclusion the present study demonstrates that lidocaine is of considerable value in the management of PES-induced ventricular arrhythmias in the postinfarction phase. However there is only a small optimal therapeutic plasma level range, where lidocaine exhibits its antiarrhythmic efficacy against this type of arrhythmia; this makes a carefully titration of the drug necessary both in the experimental and in the clinical setting. Send offprint requests to K. Krejcy at the above address     

Marked increase of plasma hyaluronan after major thermal injury and infusion therapy

Hyaluronan (HYA) is an important structural element in skin and is presumably participating in regulation of the interstitial fluid volume. HYA is transported via the lymphatics from the tissues to the blood, where its concentration is normally very low. Fluid flux through the interstitium is markedly increased after thermal injury. The present study was performed to determine whether major thermal injury would affect plasma levels of HYA. In halothane-anesthetized sheep subjected to 40% BSA full-thickness scald burns, plasma HYA concentration increased from 116 +/- 19 (mean +/- SEM) to 172 +/- 18 ng/ml within 1 hr after injury (P less than 0.05). After 3 hr of fluid therapy plasma HYA concentration was further elevated to 10 times baseline (1417 +/- 322 ng/ml) (P less than 0.01). To clarify whether this rise represented an increased "washout" of interstitial HYA, attributable either to the burn injury or the subsequent fluid therapy, awake sheep were subjected to overhydration. Following a 3-hr infusion of lactated Ringer's 2.5 liter/hr, plasma HYA concentration increased to 2-3 times baseline. Lung lymph flow and its concentration of HYA increased, leading to an increase in the lymphatic flux of HYA to 10-20 times baseline. In peripheral lymph HYA flux increased 2-3 times baseline. Infusion of lactated Ringer's markedly increased lymphatic removal of HYA. However, plasma concentrations of HYA were 3 times higher after thermal injury than following fluid challenge alone, suggesting that thermal injury per se may also increase input of HYA into the systemic circulation.     

Untersuchungen zur beziehung zwischen vinylchlorid (VCM)-aufnahme und metabolitenausscheidung bei 15 VCM-exponierten

Summary Fifteen workers employed in a PVC producing plant were investigated concerning their individual vinyl chloride (VCM) exposure and the urinary excretion of the VCM metabolite thiodiglycolic acid (TdGA). The urine concentrations found were in the range 0.94–20.4 g/ml. These could be compared with exposure data calculated from VCM air analyses performed by personal air sampling and corrected with respect to the exposure times of the workers. The amounts of TdGA excreted within 24 h were correlated with the effective VCM body concentrations calculated from the exposure data as mean values for 12 h periods (Spearman coefficient P=<0.005). This correlation resembles a function of the Michaelis-Menten type. It could be shown that during short exposure periods of less than 5 min, the metabolite formation in relation to the exposure data was lower than during longer periods of exposure although, as would be expected, there were some fluctuations of the exposure level. Therefore, the VCM body concentrations could not normally reach steady state values.

---

Untersuchungen zur beziehung zwischen vinylchlorid (VCM)-aufnahme und metabolitenausscheidung bei 15 VCM-exponiertenII. Messungen zur ausscheidung des VCM-metaboliten thiodiglykolsaure im harn

Zusammenfassung In einer Feldstudie an 15 Beschäftigten eines PVC-produzierenden Betriebes wurde der Zusammenhang zwischen der Höhe der Exposition gegenüber monomerem Vinylchlorid (VCM) und der Ausscheidung des VCM-Harnmetaboliten Thiodiglykolsäure (TdGA) untersucht. Die ermittelten Harnkonzentrationen, die sich zwischen 0,94 und 20,4 g/ml bewegten, konnten mit Expositionsdaten verglichen werden, die durch personal air sampling unter Berücksichtigung der Aufenthaltszeiten im Expositionsbereich gewonnen werden waren.Aus den mit Personendosimetern gewonnenen Analysedaten wurden unter Berücksichtigung pharmakokinetischer Gesetzmäßigkeiten die effektiven VCM-Körperkonzentrationen als 12-h-Mittelwerte kalkuliert. Mit diesen waren die im 24-h-Harn ausgeschiedenen Mengen an TdGA deutlich korreliert (P=<0,005; Spearman-Koeffizient). Die Korrelation entspricht in guter Näherung einer Funktion vom Michaelis-Mengen-Typ. Unter Berücksichtigung der Arbeitsprotokolle konnte aus den Meßdaten abgeleitet werden, daß bei Ansteigen der VCM-Luftkonzentration für Zeiträume von weniger als 5 min die Metabolitenausscheidung relativ zur kalkulierten mittleren Körper-konzentration geringer ansteigt als bei längerfristigen Expositions schwankungen. Offenbar schwankte die VCM-Raumluftkonzentration derart, daß die VCM-Körperkonzentrationen den Gleichgewichtswert in der Regel nicht erreichten.

---

Abkürzungen VCM Vinylchlorid Monomer - TdGA Thiodiglykolsäure - p.a.s. personal air sampling Mit Unterstützung der Berufsgenossenschaft der Chemischen Industrie     

Anticoagulant action of melagatran: a comparison between neonates and adults using calibrated automated thrombography (CAT)

In the present study, we comparatively evaluated the anticoagulant efficacy of the new direct thrombin inhibitor melagatran in cord vs. adult plasma. In contrast to heparin, melagatran does not require antithrombin as a cofactor. Thus, anticoagulant treatment with melagatran is of special interest in neonatal patients, whose plasma is relatively deficient in antithrombin. We evaluated the anticoagulant action of increasing amounts of melagatran (0.1–2.0 μmol/l) in both cord and adult plasma by means of calibrated automated thrombography (CAT) with respect to the lag time until the onset of thrombin formation, time to thrombin peak maximum (TTP), endogenous thrombin potential (ETP), and thrombin peak height. Melagatran exhibited approximately the same ability to prolong lag times or TTPs in both cord and adult plasma. Similar concentrations (IC₅₀) of melagatran were required to double the lag times (0.44±0.04 μmol/l vs. 0.52±0.05 μmol/l) or to double the TTPs (0.91±0.08 μmol/l vs. 1.06±0.09 μmol/l) in cord vs. adult plasma. Melagatran exhibited a higher ability to suppress ETPs or thrombin peak heights in cord vs. adult plasma. Markedly lower concentrations (IC₅₀) of melagatran were required to suppress ETPs (0.27±0.03 μmol/l vs. 0.70±0.06 μmol/l) or thrombin peak heights by 50% (0.29±0.03 μmol/l vs. 0.53±0.04 μmol/l) in cord vs. adult plasma. We conclude that our results suggest a higher ability of melagatran to suppress thrombin formation in cord vs. adult plasma. Thus, lower amounts of melagatran might be required in neonates undergoing antithrombotic therapy.     

A phase II randomized double blinded trial evaluating the efficacy of curcumin with pre-operative chemoradiation for rectal cancer

BackgroundIn vivo studies demonstrate that curcumin increases radioresponse of colorectal cancers. To demonstrate efficacy in humans, we performed a randomized double-blind study of locally advanced rectal cancer (LARC) patients receiving pre-operative chemoradiation therapy (CRT) ± curcumin. We used pathologic complete response (pCR) rate as a surrogate for clinical outcome.MethodsFrom 2008–2010, LARC patients were randomized to placebo/curcumin in a 1:2 ratio. Patients received CRT [50.4 gray in 28 fractions; capecitabine (825 mg/m² twice daily)] followed by surgery. Curcumin (4 grams orally, twice daily) or placebo was given throughout CRT and 6 weeks afterward. Toxicity was monitored weekly. Blood samples taken pre- and 1-hour post-ingestion and tissue biopsies (both collected at CRT week 2) were analyzed for pharmacokinetics. The primary outcome was surgical pCR rate.ResultsOf 22 enrolled patients, 15 received curcumin. Median age was 61 years and the majority were male (n=13; 59%). The median serum curcumin concentrations before (3.04 ng/mL; range, 1.24–18.88 ng/mL) and 1 hour after (3.32 ng/mL; range, 0.84–5.36 ng/mL) curcumin intake did not differ significantly (P=0.33). Serum curcumin concentrations both increased and decreased 1-hour post-administration (range as percentage of baseline: 8.8–258.1%). Twelve curcumin patient tissue biopsies had median curcumin concentration of 33.7 ng/mg tissue (range, 0.1–4,765.7 ng/mg). Two placebo and 1 curcumin patient achieved pCRs (P=0.18). One grade 3 toxicity (infection) was experienced.ConclusionsThe addition of curcumin to CRT did not increase pCR rates for LARC patients. The unpredictable bioavailability of curcumin contributes to continued uncertainties regarding curcumin efficacy.Trial RegistrationClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT00745134","term_id":"NCT00745134"}}NCT00745134.     

Tabakgenuß und Adrenalinspiegel

Zusammenfassung Mit der fluorimetrischen Bestimmungsmethode wird der Einfluß des Tabakgenusses auf den Adrenalingehalt des Blutes untersucht. Der Anstieg des Adrenalinspiegels während des Rauchens ist um so größer, je weniger Nikotin die Zigarre oder Zigarette enthält. Schwere Sorten ließen nach dem Rauchen eine Senkung erkennen. Tabakkauen führte nur zu einer Senkung des Adrenalinspiegels. Aus den Versuchen wird geschlossen, daß Nikotin den Adrenalinspiegel senkt, jedoch entsteht bei der Tabakverbrennung ein ergotropwirkender Faktor, der in nikotinfreien Tabaksorten allein zur Geltung kommt.Mit 5 Textabbildungen     

THE ANTIBACTERIAL PROPERTIES OF SULFUR

1. Saturated solutions of sulfur in alcohol (alcohol-sulfur) when diluted with broth are inhibitory to the growth of various Gram-positive bacteria and to C. hominis. By an arbitrary method of unitage with S. aureus as the test organism, our alcohol-sulfur contains 1,600 to 2,000 units per cc. and one unit contains between 0.24 and 0.34 gamma sulfur. The activity of a preparation is in general directly proportional to its sulfur content. 2. Solutions of sulfur in carbowax (carbowax-sulfur) when diluted with broth are likewise inhibitory to the growth of various Gram-positive bacteria and to C. hominis. When S. aureus is used as test organism, 1 unit contains between 0.1 and 0.2 gamma sulfur. The activity of these preparations is also in general directly proportional to their sulfur content. 3. Carbowax-sulfur when incorporated in agar in 1–500 to 1–2,000 dilution inhibits the growth of various Gram-positive aerobic and anaerobic bacteria, C. hominis, and certain dermatophytes. 4. Our experiments appear to show that both alcohol-sulfur and carbowax-sulfur owe their inhibitory properties to the sulfur particles that are dispersed throughout the medium when these sulfur preparations are diluted with broth. The inhibitory effect of these particles may or may not be due to a combination of the sulfur particles with substances in the medium in which they are suspended. 5. Evidence suggests that the activity of both alcohol-sulfur and carbowax-sulfur is due to sulfur in the same form. The inhibitory effect is characterized by prolonged bacteriostasis with similar activity over a wide range of dilutions. There is no evidence of true bactericidal action even with the highest concentrations used.     

Property Criteria for Automotive Al-Mg-Si Sheet Alloys

In this study, property criteria for automotive Al-Mg-Si sheet alloys are outlined and investigated in the context of commercial alloys AA6016, AA6005A, AA6063 and AA6013. The parameters crucial to predicting forming behavior were determined by tensile tests, bending tests, cross-die tests, hole-expansion tests and forming limit curve analysis in the pre-aged temper after various storage periods following sheet production. Roping tests were performed to evaluate surface quality, for the deployment of these alloys as an outer panel material. Strength in service was also tested after a simulated paint bake cycle of 20 min at 185 °C, and the corrosion behavior was analyzed. The study showed that forming behavior is strongly dependent on the type of alloy and that it is influenced by the storage period after sheet production. Alloy AA6016 achieves the highest surface quality, and pre-ageing of alloy AA6013 facilitates superior strength in service. Corrosion behavior is good in AA6005A, AA6063 and AA6016, and only AA6013 shows a strong susceptibility to intergranular corrosion. The results are discussed below with respect to the chemical composition, microstructure and texture of the Al-Mg-Si alloys studied, and decision-making criteria for appropriate automotive sheet alloys for specific applications are presented.