Decision-making performance is related to levels of anxiety and differential recruitment of frontostriatal areas in male rats.

In humans, high levels of anxiety are associated with poor performance in the Iowa Gambling Task (IGT). The IGT measures decision-making under conditions of uncertainty. In this study, we investigated the association between anxiety and decision-making in rats. Rats were screened for anxiety on the elevated plus maze (EPM) and subsequently tested in a rat analogue of the IGT (r-IGT). We explored the role of frontostriatal areas related to r-IGT performance using c-fos immunohistochemistry following the last training-session. High levels of anxiety were associated with poor r-IGT performance: high anxious rats made fewer choices for the advantageous option and collected fewer sucrose pellets in the r-IGT than low anxious rats. Analysis of win-stay/lose-shift behaviour of choices for the advantageous option revealed that good performing-low anxious subjects showed an increase in win-stays and a decrease in lose-shifts across trial blocks while poor performing-high anxious subjects did not. Furthermore, decision-making performance and, indirectly, anxiety levels were related to neural activity in parts of the medial prefrontal cortex, that is prelimbic and infralimbic cortex, and in parts of the striatum, that is nucleus accumbens shell and core. These data suggest a similar frontostriatal circuitry underlying affective decision-making in humans and rats.

Spatial, contextual and working memory are not affected by the absence of mossy fiber long-term potentiation and depression.

The mossy fibers of the hippocampus display NMDA-receptor independent long-term plasticity. A number of studies addressed the role of mossy fiber long-term plasticity in memory, but have provided contrasting results. Here, we have exploited a genetic model, the rab3A null-mutant, which is characterized by the absence of both mossy fiber long-term potentiation and long-term depression. This mutant was backcrossed to 129S3/SvImJ and C57Bl/6J to obtain standardized genetic backgrounds. Spatial working memory, assessed in the eight-arm radial maze, was unchanged in rab3A null-mutants. Moreover, one-trial cued and contextual fear conditioning was normal. Long-term spatial memory was tested in the Morris water maze. Two different versions of this task were used, an 'easy' version and a 'difficult' one. On both versions, no differences in search time and quadrant preferences were observed. Thus, despite the elimination of mossy fiber long-term plasticity, these tests revealed no impairments in mnemonic capabilities. We conclude that spatial, contextual and working memory do not depend on mossy fiber plasticity.

Delayed effect of the vasopressin metabolite VP4-8 on the social memory of sexually naive male rats.

RATIONALE: Endogenous vasopressin is involved in the social memory of the male rat and administration of exogenous vasopressin improves social memory. These findings are mainly based on studies using sexually experienced males that were tested in the social recognition test. OBJECTIVE: The present study was aimed to establish whether the modulation of social memory by vasopressin fragments depends on the sexual experience of the male rat. For this purpose, the social discrimination test was used, since this test is more suitable than the social recognition test for measuring social memory in sexually naive males. METHODS: Male rats were tested in the social discrimination test and treated subcutaneously with the vasopressin metabolite [pGlu4,Cyt6]vasopressin-(4-8) (VP4-8). VP4-8 shares with vasopressin the effects on memory processes but lacks the peripheral effects of vasopressin. RESULTS: VP4-8 (1 microgram/kg) acutely improved the social memory of sexually experienced male rats, confirming previous reports. However, in sexually naive males VP4-8 failed to improve social memory in doses ranging from 0.1 microgram/kg to 1 microgram/kg. Instead, 1 microgram/kg VP4-8 or 6 micrograms/kg desglycinamide-vasopressin were found to exert a delayed effect in sexually naive rats. This delayed effect resulted in an improved social memory 2 days after administration. CONCLUSIONS: Vasopressin sensitisation is discussed as a possible underlying mechanism of the observed delayed effect of vasopressin fragments. It is concluded that in male rats sexual experience can influence the modulation of social memory by vasopressin.

Roles of the basolateral amygdala and hippocampus in social recognition in rats.

Lesions of the amygdala or hippocampus have a large impact on social behavior of rats. In this study we investigated whether a social recognition test was also affected by those lesions. An NMDA-induced lesion of the basolateral amygdala did not impair the ability to distinguish a familiar from an unfamiliar juvenile rat. It was argued that the cortico-medial amygdala may be more important for social recognition than the basolateral amygdala. Fimbria-transected rats could no longer distinguish a familiar from an unfamiliar juvenile. Moreover, during all encounters they spent less time investigating the juvenile. The precise nature of this deficit, especially the reason for the overall reduced social investigation time, could not be specified with the classical procedure of the social recognition test.

Barrel rotation induced by central arginine8-vasopressin treatment: involvement of neurohypophyseal peptide receptors.

Two series of experiments were done to investigate the mechanism underlying arginine8-vasopressin (AVP)-induced barrel rotation in rats. In the first series, the effect of intracerebroventricular (ICV) administration of various neurohypophyseal hormone antagonists on AVP-induced barrel rotation was studied. The more vasopressin was given, the more the rats exhibited barrel rotation. ICV pretreatment with a V1 vasopressin receptor antagonist, d(CH2)5[Tyr(Me)2]AVP, prevented barrel rotation, while similar treatment with a V2-antagonist, d(CH2)5[dIle2Ile4]AVP, did not affect vasopressin-induced barrel rotation. However, Des-Gly,NH2d(CH2)5[Tyr)Me2)Thr4Orn8]-vasotocin, a specific oxytocin antagonist, potentiated the effect of AVP on barrel rotation. The second experiment was performed in rats equipped with a telemetry system to measure heart rate (HR), core temperature (CT), and gross locomotor activity. Also, in this experiment the incidence of AVP-induced barrel rotation was dose-dependent, as was the number of rats that died. Barrel rotation was accompanied by a significant decrease in CT and HR, while rats that did not develop hypothermia did not show barrel rotation. These results suggest that a V1 receptor is involved in barrel rotation. Since AVP-induced hypothermia is also mediated by a V1 receptor, it is postulated that hypothermia is a prerequisite for barrel rotation to occur. Further experiments are needed to substantiate this hypothesis.

Plasma and bone concentrations of cefuroxime and flucloxacillin. Oral versus parenteral administration in 20 arthroplasties.

Our objective was to determine and to compare the range of bone levels of cefuroxime and flucloxacillin achieved after oral and intravenous administration in 20 arthroplasty patients, allocated to 4 groups: 1 x 500 mg or 7 x 500 mg oral cefuroxime was followed by 2000 mg Flucloxacillin i.v.; 1 x 500 mg and 7 x 500 mg oral flucloxacillin was followed by 1500 mg cefuroxime i.v. Bone samples of hip and knee were obtained. Oral administration did not result in a measurable bone concentration of any of the antibiotics. Intravenous administration resulted in measurable bone concentrations of both cefuroxime and flucloxacillin, with large inter-individual variations. The bone concentrations of intravenous cefuroxime were higher than those of flucloxacillin, despite the lower dose. Oral pretreatment had no effect on the bone concentrations after intravenous administration. No accumulation of the drugs in bone was observed.

High-performance liquid chromatography of ergometrine and preliminary pharmacokinetics in plasma of men.

An isocratic high-performance liquid chromatographic (HPLC) method with fluorescence detection has been developed for the measurement of ergometrine in human plasma. The quantitation limit in plasma was 75 pg/ml. An example of the plasma concentration-time curves obtained after both oral and intravenous administration of ergometrine in one volunteer is shown. This HPLC method makes it possible to describe the pharmacokinetic parameters of oral ergometrine.

[Screening for familial occurrence of abdominal aortic aneurysm]. / Screening op familiair voorkomen van aneurysma aortae abdominalis.

To detect familial occurrence of abdominal aortic aneurysms (AAA), the siblings of patients with an AAA were screened by ultrasonography. 128 siblings of 32 patients operated on for AAA were invited. 56 brothers and 52 sisters accepted the invitation. An AAA was diagnosed in 16 brothers (28.6%) and in 3 sisters (5.8%). Six of these siblings were operated on because of an aneurysmal diameter 20 mm in excess of that of the rest of the abdominal aorta, the others were included in a follow-up programme. We conclude that the prevalence of the AAA among brothers is higher in comparison with previously known risk groups and that the family of patients with an AAA are to be considered for screening first.

Antipyretic effect of central arginine8-vasopressin treatment: V1 receptors specifically involved?

Intracerebroventricular (i.c.v.) administration of the neurohypophyseal neuropeptide arginine8-vasopressin (AVP) results in a dose-dependent attenuation of endotoxin-induced fever (EIF) in rats. Specific antagonists of the neuropeptided(CH2)5[Tyr(Me)2]AVP for V1 receptors, d(CH2)5[dlle2lle4]AVP for the V2 receptors and Des-Gly,NH2d(CH2)5[Tyr)Me2)Thr4Orn8]vasotocin, an antagonist of the oxytocin receptors (AOXT), failed to modify EIF when administered i.c.v. Relatively high doses (100 ng) of all three peptide antagonists effectively blocked the antipyretic effect of AVP. Administered in smaller doses (10 or 30 ng), however, a more specific interaction was observed, i.e. the V1 antagonist being the only effective compound in preventing the effect of AVP. Although the data indicate that peptide-antagonist interactions should be interpreted carefully, the present experiments confirm previous observations on the involvement of V1-type receptors in the antipyretic action of AVP and suggest additional interactions with V2 vasopressinergic and oxytocinergic receptors.

Direct high pressure liquid chromatographic analysis and preliminary pharmacokinetics of enantiomers of oxazepam and temazepam with their corresponding glucuronide conjugates.

Three high pressure liquid chromatographic systems for the separation of oxazepam, temazepam and their glucuronides (system A), the separation of their R,S glucuronide diastereomers (system B) and the chiral separation of the parent drugs (system C) are described. Preliminary pharmacokinetics of R,S-oxazepam and R,S-temazepam in a human volunteer reveal that the protein binding of the glucuronides is lower than that of the parent drugs, but that there is no difference in protein binding between the R-oxazepam/temazepam and S-oxazepam/temazepam and their corresponding glucuronides. The S-glucuronide is the main metabolite formed and excreted by man. The plasma ratio R/S-glucuronide is 1:1 for both oxazepam and temazepam. The renal clearance of R-temazepam, and S-temazepam are similar, and those of R-oxazepam and S-oxazepam tend to be different.

HPLC analysis and pharmacokinetics of the enantiomers of R,S-oxazepam and R,S-temazepam with their corresponding glucuronide conjugates in urine and plasma of man.

R,S-Oxazepam and R,S-temazepam can be separated in their enantiomers by means of a chiral AGP column. The corresponding R- and S-glucuronide conjugates can be separated on a normal reversed-phase C18 column. Man conjugates the S-enantiomer of oxazepam and temazepam both better than the R-enantiomer. The urinary recovery of the glucuronides following either R,S,-oxazepam or R,S-temazepam almost amounts to 100% of the dose administered.

Pharmacokinetics, metabolism, and renal excretion of articaine and its metabolite articainic acid in patients after epidural administration.

Articaine is metabolized into articainic acid. The half-lives of articaine are 0.54 +/- 0.05 and 2.44 +/- 0.30 h and that of its metabolite, 2.44 +/- 0.30 h. Of the administered dose approximately 2-5% is excreted unchanged, 40-70% is excreted as articainic acid, and 4-15% as articainic acid glucoronide. The percentage of the total dose recovered in the urine varies between 50% and 91%. Protein binding of articaine in patients varies between 50% and 70%, and that of articainic acid between 60% and 90%. Renal clearance of articaine varies between 12 and 28 ml min-1, while that of articainic acid is between 84 and 160 ml min-1.

Clinical effects and pharmacokinetics of articainic acid in one volunteer after intravenous administration.

Articainic acid, a major metabolite of articaine, was administered to a volunteer. Since the renewed interest in the utilization of articaine in epidural anaesthesia, it has been important to assess the clinical effects of this metabolite. It was noted that articainic acid had no effect on EEG, ECG, blood pressure and heart rate. Pharmacokinetic parameters are given.

Pharmacokinetics of nalidixic acid in man: hydroxylation and glucuronidation.

Nalidixic acid is metabolized by hydroxylation to 7-hydroxymethylnalidixic acid[[ and then by oxidation to 7-carboxynalidixic acid.[[ The half-lives of the two elimination phases of nalidixic acid are 0.75 and 2.5 h. The apparent half-lives of the metabolite 7-hydroxymethylnalidixic acid are 2.5 and 5.5 h. Plasma protein binding of nalidixic acid is 95% and that of 7-hydroxymethylnalidixic acid 65%. The renal clearance of nalidixic acid varies between 2 and 25 ml/min and that of 7-hydroxymethylnalidixic acid between 37 and 162 ml/min. Of nalidixic acid 42% is glucuronidated and 40% hydroxylated. Of the hydroxy metabolite 57% is glucuronidated and 32% excreted unchanged. 7-Carboxynalidixic acid is excreted in the urine and is not glucuronidated. The variations in the glucuronidation/hydroxylation ratio of nalidixic acid and the glucuronidation/renal excretion ratio of the 7-hydroxymethyl metabolite belong to a normal distribution.

The penetration of ofloxacin into lung tissue.

After a single oral 600 mg dose, ofloxacin concentrations were measured in lung tissue, whole blood and plasma in 11 patients undergoing thoracotomy for a bronchial malignancy. To correct for blood contamination in the tissue samples, the tissue haemoglobin content was measured using a method based on the binding of haemoglobin by haptoglobin. Ofloxacin concentrations in plasma and whole blood did not differ significantly. The calculated blood content in the tissue samples was 0.12 +/- 0.05 ml/g lung tissue. After correction for blood admixture, the mean lung tissue concentration 2 h after administration of ofloxacin was 17.7 +/- 9.2 micrograms/g. At the same time the mean plasma concentration was 8.7 +/- 4.2 mg/l (P less than 0.02). The high concentration of ofloxacin obtained in lung tissue does not result from the preparation technique. After a single 600 mg dose the tissue concentrations proved to exceed MIC values for most pathogens frequently involved in respiratory tract infections.

Pharmacokinetics, renal clearance and metabolism of ciprofloxacin following intravenous and oral administration to calves and pigs.

The pharmacokinetics of ciprofloxacin, a quinoline derivative with marked bactericidal activity against gram-negative bacteria, was studied in calves and pigs following intravenous and oral administration. Ciprofloxacin was rapidly and well distributed in the body, exhibited a short elimination half-life of 2.5 h in both species, and was rapidly absorbed after oral administration (Tmax:2 to 3 h). The oral bioavailability in calves was 53 +/- 14% and for 1 pig 37.3%. The renal clearance of the unbound ciprofloxacin for both species was of the same order, indicated a predominantly tubular secretion pattern, and accounted for about 46% of the total drug elimination. No complete drug mass balance could be demonstrated. Small amounts of two metabolites were detected in the urine of calves, but not in pig urine.

Pharmacokinetics of enoxacin and its penetration into bronchial secretions and lung tissue.

Pharmacokinetic data were obtained from four healthy volunteers after oral administration of a single 400 or 600 mg dose of enoxacin. Enoxacin was absorbed quickly and absorption was increased when enoxacin was ingested after a meal. Renal clearance of enoxacin and 4-oxo-enoxacin decreased after simultaneous administration of probenecid. In addition, pharmacokinetic parameters of enoxacin and its 4-oxo metabolite were determined for plasma and sputum from 19 patients treated with enoxacin, 400 or 600 mg bd, for a respiratory tract infection. The half-life of both enoxacin and 4-oxo-enoxacin was 5-6 h; during treatment with 400 and 600 mg bd, the plasma concentrations exceeded MIC values for most bacteria isolated in respiratory tract infections, including most Pseudomonas aeruginosa strains; Streptococcus pneumoniae was an exception. Diffusion from plasma to sputum was approximately 100%. Of an ingested dose, 60-65% was recovered in the urine in 24 h. In a third study, a single 600 mg dose of enoxacin was given to 15 patients undergoing thoracotomy. Subsequent lung tissue concentrations of enoxacin were significantly higher than plasma concentrations at the same time after ingestion.