Alcohol-Induced Retrograde Facilitation?

Somewhat counterintuitively, alcohol consumption following learning of new information has been shown to enhance performance on a delayed subsequent memory test. This phenomenon has become known as the retrograde facilitation effect (Parker et al., 1981). Although conceptually replicated repeatedly, serious methodological problems are associated with most previous demonstrations of retrograde facilitation. Moreover, two potential explanations have been proposed, the interference and the consolidation hypothesis. So far, empirical evidence for and against both hypotheses is inconclusive (Wixted, 2004). To scrutinize the existence of the effect, we conducted a pre-registered replication that avoided common methodological pitfalls. In addition, we used Küpper-Tetzel and Erdfelder's (2012) multinomial processing tree (MPT) model to disentangle encoding, maintenance, and retrieval contributions to memory performance. With a total sample size of N = 93, we found no evidence for retrograde facilitation in overall cued or free recall of previously presented word pairs. In line with this, MPT analyses also showed no reliable difference in maintenance probabilities. However, MPT analyses revealed a robust alcohol advantage in retrieval. We conclude that alcohol-induced retrograde facilitation might exist and be driven by an underlying retrieval benefit. Future research is needed to investigate potential moderators and mediators of the effect explicitly.

On the transience of egocentric working memory: evidence from testing the contribution of limbic brain regions.

Rats trained on a nonmatching-to-turn rule revealed that egocentric working memory is readily disrupted, hard to use, and transient. In Experiment 1, rats failed to acquire the rule in a plus-maze. Experiment 2 used 2 different plus-mazes to remove any intramaze cues. Task acquisition occurred only when rats could use direction cues (i.e., nonegocentric cues). In Experiments 3 and 4, a J maze was used to minimize the retention interval and eliminate handling rats within a trial. All rats acquired the nonmatching rule, although a 3-s retention delay severely impaired performance. Fornix lesions transiently disrupted performance of the J-maze task (Experiments 3 and 4), but neither fornix (Experiment 1) nor retrosplenial (Experiment 2) lesions impaired the plus-maze tasks.

Perilymphatic fistula: surgical experience in the United States.

One survey sent to 6953 individual otolaryngologic practices and 106 departments of otolaryngology at teaching hospitals in the United States, and a more limited survey of 75 patients operated on for perilymphatic fistula (PLF) at the House Ear Institute, addressed aspects of managing PLF: surgical incidence, reliability of diagnostic test, preoperative observations, and disability after surgery. Of surgeons sampled, 93% estimated incidence of PLF surgery to be less than or equal to 1 per 1000 otolaryngologic outpatient visits. The most reliable diagnostic indicators were history, symptomatology, and tympanometric and electronystagmographic fistula tests. About 72% of surgeons reported less than 4 weeks' average delay before surgery. Most surgeons and patients (greater than or equal to 70%) rated length of disability before return to work, exposure to noise, travel by airplane, swimming, and heavy lifting, at several weeks to several months. Diving was the most restricted activity. Results suggest that incidence of surgery and disability with PFL in the United States is very limited.

Perinatal pharmacokinetics of acetylsalicylic acid.

Pregnant women were treated with infusions of acetylsalicylic acid (ASA). The plasma concentrations of total salicylate or those of ASA and salicylic acid (SA) were determined. The ASA steady state was reached after 2 h of infusion whereas 3 days seemed necessary to reach the steady state of SA. In a further study during the late phase of cervical dilatation (12 min - 2 h before birth) healthy pregnant women were given 1 g ASA as a single i.v. bolus injection. The resulting plasma levels of ASA and SA in the mothers during delivery, the plasma concentrations in umbilical cord blood and in blood obtained from the newborn several hours after birth were measured. With increasing time the SA concentrations in the umbilical cord blood plasma approached those of the mothers. On the other hand, the umbilical cord blood concentrations of ASA did not approach the maternal concentrations, probably because of the ASA esterase activity at the placental barrier. The plasma concentrations in the newborn indicated that the newborn is able to degrade ASA and to excrete SA. However, the velocities are lower than the respective velocities in adults.

[Isoniacid intoxication: correlation between blood level and coagulation status? (author's transl)]. / Isoniacid (INH) Intoxikation: Beziehung zwischen Blutspiegel und Gerinnungsstörungen?

In a 1,10 year old boy intoxication by isoniazid (INH) produced an initial fall of prothrombin and a prolonged fall of the clotting factor VII. The rest of the coagulation factors as well as the inhibitor activity remained uninfluenced. Since the decrease of the liver-dependent clotting factors occurred immediately after ingestion the apparently rare INH induced liver injury is considered as dose-dependent. On the other hand, however, since the serum half-life of INH amounted to 2,98 hours whereas the decrease of factor VII persisted over 46 hours and there appears to be no correlation between liver injury and INH plasma levels. This discrepancy may be attributable to the fact that only the acetylated intermediates of INH may have a hepatotoxic potential.

[The biliary excretion of azlocillin]. / Die biliäre Exkretion von Azlocillin.

The excretion of azlocillin into the human biliary tract was investigated in 8 patients with a T-tube in the common bile duct after intravenous injection of 2 g. Samples of serum and common duct bile were assayed from 15 min to 12 hours after injection. Biliary tract levels generally run parallel to serum levels but were about 15 times higher than those. Peak levels in T-tube bile averaged 1137 mg/l 60 to 90 min after administration. 12 hours after administration there were still mean concentrations of 13 mg/l to be found. It is concluded that azlocillin concentrations in bile exceed for a long time the minimum inhibitory concentrations for gram-negative and gram-positive causative organisms (above all E. coli, enterococci, Klebsiella spp., Proteus spp., staphylococci) of biliary tract-infections.

Methods for the determination of glandular kallikrein by means of a chromogenic tripeptide substrate.

A chromogenic peptide substrate H-D-Val-Leu-Arg-pNA (S-2266) has been used for the determination of glandular kallikrein derived from pancreas, urine and saliva. The conditions used have been optimized. The methods developed are simple and shown to have good reproducibility.

Quantitative studies on the occurrence of praziquantel in milk and plasma of lactating women.

10 healthy lactating women were treated orally with the anthelmintic praziquantel (Biltricide), and the resulting timedependent concentrations of the unchanged substance in plasma and milk were determined simultaneously. 5 of the women ("1st trial") received the single dose of 50 mg/kg; the other 5 women ("2nd trial") were treated three times at 4 hour intervals with 20 mg/kg. During the 1st trial a maximal plasma-concentration of 1.30 mg/l (arithmetic mean) was found. Subsequently the mean plasma-concentration decreased continuously and after 24 h it was only 0.4% of the maximum. During the 2nd trial the highest mean value (1.92 mg/l) was found 10 h after the first administration; after 32 h (24 h after the last administration) the mean value was 0.6% of the maximum mean value. The mean areas under the concentration/time-curves were 5.25 h. mg/l and 13.8 h . mg/l, respectively. The plasma half-life was estimated to be 3 hours. In both trials the concentration/time-curves of the milk corresponded qualitatively to those of the plasma. However, in each person and at each time, the concentration in the milk were essentially lower than those in the plasma. On the average, the plasma-concentrations were four times higher than the milk-concentrations. The mean values of the milk-concentrations increased and decreased correspondingly with those of the plasma-concentrations. At the end of the investigation (24 and 32 h, respectively, from the beginning) they were lower than the limit of determination (4 microgram/l). The mean excretion with the milk of the 10 women was 0.0008% of the given dose. From the comparative concentration/time-course, it could be demonstrated that the milk does not represent a deep department but readily equilibrates with the plasma. Equilibration obviously takes place by passive diffusion and not by active secretion.

A fluorometric method for the determination of praziquantel in blood-plasma and urine.

Some physicochemical data of praziquantel which may have analytical relevance are reported. For the quantitative determination praziquantel is extracted from plasma or urine by means of organic solvents and then hydrolyzed in an aqueous alkaline solution. The hydrolyzed product is reacted with dansyl-chloride (5-dimethylaminonaphthalene-sulfonylchloride). The dansylated compound is separated and quantified fluorometrically. The limit of determination is 3 micrograms/l in blood plasma and 30 micrograms/d in urine. For both fluids, the imprecision is approximately 7.5%. The method is suitable for the determination of praziquantel in patients or healthy volunteers treated with therapeutic doses.

Extramicrosomal drug metabolism.

Drug metabolizing enzymes which are not located in the microsomes such as oxidoreductases are reviewed. It has been reported that a cytoplasmic NAD+-dependent dehydrogenase could be involved in the dehydrogenation of secondary or primary alcohols, and that peroxidases, located in all extranuclear cell-fractions, are able to oxidize certain drugs. Among the conjugating enzymes, mainly the glucuronidases and 0-Methyltransferases have been reported to be localised in the microsomes. Sulfatation, mercapturic acid formation and acetylation seem to occur in the supernatant of animal liver cells. Binding to glycine has been found in the mitochondria. Examples of combined action of microsomes and other cell fractions are presented. Esterases are found in the microsomes and cytoplasmic fraction of animal cells and also in the extracellular fluid (blood-plasma). They are more stable than monooxygenases whose activity depends on the intact microsomal structure and are therefore readily accessible in human biological material. Metabolic problems involving human esterases can often easily be solved by in vitro experiments. Results concerning the biochemical degradation of propanidid, mefrusid, acetyl salicylic acid and an acetyl salicylic acid ester are reported.

Pharmacokinetic investigations in adult humans after parenteral administration of the lysine salt of acetyl-salicylic acid.

The lysine salt of acetylsalicylic acid was administered intravenously to four volunteers and intramuscularly to three of them. The drug was tolerated without any observed side effects. Immediately after intravenous application most of the plasma salicylate was acetylsalicylic acid. The highest concentration of acetylsalicylic acid was found after 2 minutes, highest levels of salicylic acid after 60 minutes. Elimination of acetylsalicylic acid was relatively quick within the first period after intravenous administration according to a half-life of 8 minutes. Half-life of salicylic acid was determined to be 3 hours. Intramuscular application results in a constant blood level for a longer period. Bioavailability of acetylsalicylic acid was slightly lower after intramuscular application than after intravenous administration.

[Quantitative determination of the main metabolites of acetylsalicylic acid/2nd communication: the concentrations of salicylic acid and its metabolites in patients with renal insufficiency (author's transl)]. / Quantitative Bestimmung der Hauptmetaboliten der Acetylsalizylsäure 2. Mitteilung: Die Konzentrationen an Salizylsäure und ihren Metaboliten bei niereinsuffizienten Patienten

Quantitative Determination of the Main Metabolites of Acetylsalicylic Acid / 2nd Communication: The concentrations of salicylic acid and its metabolies in patients with renal insufficiency 9 patients suffering from renal insufficiencies of varing degrees and treated regularly by hemodialysis were given 1.5 g Colfarit (microcapsulated acetyl salicylic acid) as a single dose. The concentrations of salicylic acid (SA), salicyluric acid (SU), further salicylic acid conjugates (SAC) and salicyluric acid conjugates (SUC) were determined in the blood plasma. Likewise urea and creatinine were determined. SA concentration decreased continually and, at the end of the trial (72 h after application), had vanished almost completely from the plasma of most patients. SU increased at first and decreased afterwards. With the exception of the dailysis time SAC and SUC increased during the trial. After 3 days the SUC level was more than 50% of total salicylate (SSS) in most patients. SSS (the sum of SA + SU + SAC + SUC) did not change very much before dialysis, but showed a rather high decrease during the first hours of dialysis. tafter dialysis the SSS levels rose again, apparently as a consequence of a redistribution and of the synthesis of conjugates with decreased tissue affinity. It could be shown that SSS in the blood plasma does not parallel SSS in the whole body. The interindividual variation of SA metabolism as well as the variation of the biological blank values was rather high. The results are discussed with regard to salicylate pharmacokinetics in renal insufficiency and to normal salicylate metabolism.

[Quantitative determination of the main metabolites of acetylsalicylic acid. 1. A method for the quantitative determination of salicylic acid and its metabolites. Studies in healthy individuals]. / Quantitative Bestimmung der Hauptmetaboliten der Acetylsalizylsäure. 1. Eine Methode zur quantatativen Bestimmung der Salizylsäure und ihrer Metaboliten; Untersuchungen bei Gesunden

For special purposes a combination of methods is described which allows to determine salicylic acid (including acetylsalicylic acid) and its main metabolites in blood plasma and urine separately and quantitatively. Salicylic acid (SA) and salicyluric acid (SU) are extracted from the acidified fluid with ether and afterwards reextracted in an aqueous phase. By fluorometry at different wavelengths, it is possible to differentiate between SA and SU. The conjugates of SA and SU are hydrolyzed with sulfuric acid and then extracted in the form of SA and SU. The four analyses (SA, SU and their conjugates) are of satisfying accuracy and sensitivity. To test the validity of the method in vivo, the concentrations of SA and its conjugates were determined in the plasma and urines of healthy volunteers. By a simplified, but nevertheless accurate, modification of the described method total salicylate in the urine can be determined.

Antinociceptive action and plasma levels of acetylsalicylic acid in the dog.

1. The analgesic potency of acetylsalicylic acid (ASA) is four times greater when administered intravenously than when administered orally. 2. The onset of the ASA analgesia after oral administration is significantly slower (30-60 min) than after intravenous (5-15 min) application. However, the duration of ASA-analgesia after oral administration is significantly longer (5 h) than after i.v. (2-4 h) application. 3. The onset and duration of ASA-analgesia in dogs after oral and i.v. administration cannot be correlated with plasma levels of ASA. During the period of analgesia, ASA can be detected only in extremely low concentrations, since it appears to be very rapidly hydrolysed to SA. 4. The development of an accurate and reproducible method for the separate determination of ASA and SA in plasma facilitated the direct correlation of plasma levels of these substances with ASA-induced analgesia.

Influence of intravenously administered acetylsalicylic acid on platelet functions. A pharmacodynamic and pharmacokinetic study.

The influence of intravenously administered acetylsalicylic acid (ASA) on the kinetics of platelet function was examined in 10 patients. Simultaneously, assays of salicylate in plasma were performed. A significant inhibition of platelet aggregation as well as PF 3 and PF 4 availabilities could be demonstrated 2 min after injection. A decrease of platelet adhesion was significant after 15 min. The inhibition of platelet functions was still present after 24 h and was partially demonstrable after 72 h. The concentration of salicylate in plasma 2 min after injection of ASA was only about two thirds of the level calculated from mere distribution in circulation. After 1 h, half of the initial salicylate had disappeared from plasma. No salicylate could be found after 24 hours. ASA also depressed platelet functions when added to platelet-rich plasma in vitro in a concentration of 100 mug/ml. Inhibition of platelet aggregation and of PF 4 availability were dependent on the time of incubation. Their onset was much slower in vitro than in vivo. No inhibition of the PF 3 availability could be found in vitro. The inhibition of platelet functions by ASA is demonstrable almost immediately after injection while the duration of this inhibition is considerably longer than the elimination time of salicylate from plasma. This allows the conclusion that a direct intravascular reaction between ASA and platelets occurs and that the inhibition of platelet functions is irreversible.