Excavated mass and doubletracking in the sigmoid colon due to colocolic fistula complicating diverticulitis.

We report on a patient admitted for work up of prostatic carcinoma in which CT study showed an excavated mass involving the sigmoid colon and the bladder dome. Barium enema showed a double track pattern associated with diverticular disease. By surgery the mass was separated from the urinary bladder and the sigmoid resected. On pathological exam diverticulitis was evident as well as an organised colocolic fistula in the thickened fibrotic subserosal fat.The usefulness of opacifying the colon is highlighted.

The venous thrombectomy: obsolete or forgotten?

This report describes the surgical management of three patients with an extended ilio-femoral deep venous thrombosis. In the first patient a residual occlusion of the common iliac vein was treated conservatively and this patient developed severe chronic venous insufficiency. In the second patient a residual (sub)occlusion of the common iliac vein was treated with a stent and this patient remained asymptomatic with two years follow-up. In the third patient no residual or underlying anatomical abnormality was found with a good result at one year. Venous thrombectomy still has a place in the treatment of deep venous thrombosis and the long term results may be improved by application of endovascular techniques.

Hippocampal and cerebellar extracellular amino acids during pilocarpine-induced seizures in freely moving rats.

Limbic seizures were provoked in freely moving rats by intrahippocampal administration of the muscarinic receptor agonist pilocarpine via a microdialysis probe (10 mM for 40 min at 2 microliters/min). Changes in extracellular hippocampal and cerebellar glutamate, aspartate and gamma-aminobutyric acid (GABA) levels were monitored during and after pilocarpine administration. Effects of systemic or local administration of anticonvulsants on the seizures and concomitant changes in amino-acid concentrations, were investigated. Pilocarpine-induced seizures were completely abolished after intraperitoneal premedication for 7 days with phenobarbital (15 mg/kg per day) and after intrahippocampal administration of 10 mM phenobarbital and 1 mM carbamazepine (180 min at 2 microliters/min). Rats premedicated with carbamazepine (5 mg/kg per day) still developed seizures. The changes in extracellular hippocampal amino-acid levels suggest that glutamate, aspartate and GABA are not involved in seizure onset, but may play a role in seizure maintenance and/or spread in the pilocarpine animal model of epilepsy. The increases in extracellular amino acids in ipsi- and contralateral cerebellum following limbic seizures provoked in the hippocampus, probably play a role in the 'reversed' diaschisis phenomenon.

Characterization of LY344864 as a pharmacological tool to study 5-HT1F receptors: binding affinities, brain penetration and activity in the neurogenic dural inflammation model of migraine.

LY344864 is a selective receptor agonist with an affinity of 6 nM (Ki) at the recently cloned 5-HT1F receptor. It possesses little affinity for the 56 other serotonergic and non-serotonergic neuronal binding sites examined. When examined for its ability to inhibit forskolin-induced cyclic AMP accumulation in cells stably transfected with human 5-HT1F receptors, LY344864 was shown to be a full agonist producing an effect similar in magnitude to serotonin itself. After an intravenous dose of 1 mg/kg, rat plasma LY344864 levels declined with time whereas brain cortex levels remained relatively constant for the first 6 hours after injection. Oral and intravenous LY344864 administration potently inhibited dural protein extravasation caused by electrical stimulation of the trigeminal ganglion in rats. Taken together, these data demonstrate that LY344864 is a selective 5-HT1F receptor agonist that can be used to explore both the in vitro and in vivo functions of this receptor.

Liquid chromatographic assay using a microcolumn coupled to a U-shaped optical cell for high-sensitivity ultraviolet absorbance detection of oxcarbazepine and its major metabolite in microdialysates.

An isocratic LC assay using a microcolumn (800 microns I.D.) coupled to a U-shaped optical flow cell (cell volume 70 nl; optical path length 8 mm) for high-sensitivity UV absorbance is described for the detection of oxcarbazepine and its major and active metabolite, 10,11-dihydro-10-hydroxycarbamazepine in microdialysates. Using the combination microcolumn-capillary UV detector, a ten-fold increase in sensitivity was obtained resulting in a limit of detection of 10 pg/10 microliters. This assay is sufficiently sensitive to allow quantification of drug and metabolite in 10-microliters aliquots of rat blood and hippocampus microdialysates, using carbamazepine-10,11-epoxide as external standard.

Quantitative microdialysis for studying the in vivo L-DOPA kinetics in blood and skeletal muscle of the dog.

In this study the microdialysis technique, using alpha-methyldopa as internal standard (IS), is introduced for the in vivo determination of L-DOPA, dopamine (DA), and their metabolites dihydroxyphenylacetic acid (DOPAC) and 3-O-methyldopa (3-OMD) in blood plasma and skeletal muscle extracellular fluid (ECF), in anaesthetised beagle dogs, after i.v. administration of L-DOPA. In a first calibration experiment, the in vivo relative losses (RL) of the compounds and the IS were determined. These were lower in skeletal muscle than in blood plasma. K was defined as the ratio of the RL of the IS to the RL of the compound of interest and was shown to be constant for a certain compound within one tissue. However, except for DA, a significant difference was seen in K values between blood plasma and skeletal muscle. In a second step, the method was validated in blood plasma. The AUC0-->3 values for the non-protein bound L-DOPA did not differ significantly between the dialysis (141.3 +/- 16.0 nmol.h/ml) and traditional whole blood sampling (145.3 +/- 18.7 nmol.h/ml), confirming that microdialysis combined with accurate calibration is a reliable technique for studying the kinetics of drugs in vivo in different tissues.

Brain, liver and blood distribution kinetics of carbamazepine and its metabolic interaction with clomipramine in rats: a quantitative microdialysis study.

The aim of this work was to study the transport across the blood-brain barrier (BBB), blood and liver distribution kinetics, metabolic interaction and local liver metabolism of carbamazepine (CBZ) in the rat, using microdialysis with the internal standard technique as in vivo calibration method. CBZ and its major metabolite, carbamazepine-10,11-epoxide (CBZ-EPO), are homogenously distributed to hippocampus and cerebellum. The ratios of the areas under the concentration-time curve (AUC) for both brain regions to blood AUC were not different from unity for CBZ; they were 0.46 +/- 0.08 (hippocampus) and 0.45 +/- 0.05 (cerebellum) for CBZ-EPO. In addition, the disposition of CBZ and CBZ-EPO in blood and liver, after a single dose of CBZ, was studied in control animals and in rats after pretreatment with clomipramine (CLOMI). A 2-fold increase in the blood AUC of CBZ and a decrease to 33% of the blood AUC of CBZ-EPO in the pretreated group demonstrate the metabolic inhibition of CBZ-EPO formation by clomipramine. The ratios of the AUCCBZ-EPO to the AUCCBZ, as a measure of CBZ-EPO formation, were not different for blood and liver within the control and the clomipramine-pretreated groups, but the ratios were significantly lower for liver and blood in the clomipramine group compared with the control animals. In addition, CBZ was administered locally in the extracellular fluid of the liver via the microdialysis probe. The liver metabolic ratio, expressed as the ratio of the formed CBZ-EPO concentration to the CBZ concentration administered, ranged from 18.2 +/- 1.2% to 19.6 +/- 1.6%.

Narrow-bore liquid chromatographic assay for oxcarbazepine and its major metabolite in rat brain, liver and blood microdialysates.

An isocratic narrow-bore high-performance liquid chromatographic assay with UV detection is described for the detection of oxcarbazepine and its major metabolite, 10,11-dihydro-10-hydroxycarbamazepine, using carbamazepine as the internal standard. This method is sufficiently sensitive to allow quantification of oxcarbazepine and its metabolite in rat brain, liver and blood microdialysates.

In vitro and in vivo microdialysis calibration for the measurement of carbamazepine and its metabolites in rat brain tissue using the internal reference technique.

Microdialysis, as in vivo sampling technique, can be used for determining exogenous compounds in the extracellular fluid of freely moving animals and in humans. Usually, calibration of the microdialysis probe is determined by in vitro relative recovery (RR) (dialysate extraction fraction). However, due to different diffusion properties of the compound in tissue, the RR in vivo is different from the RR in vitro. In this study, the evaluation of the internal reference technique as in vivo calibration method was established. To determine the RR in vivo, the relative loss (RL) was defined as the loss of a compound from the perfusate. RL was determined in vitro and in vivo by adding an internal standard (IS) to the perfusate. This internal reference technique was applied for the determination of carbamazepine (CBZ) and its 2 major metabolites, carbamazepine-10,11-epoxide (CBZ-EPO) and trans-10,11-dihydroxy-10,11-dihydro-carbamazepine (CBZ-DIOL) using 2-methyl-5H-dibenz(b,f)azepine-5-carboxamide (m-CBZ) as IS. In vitro and in vivo, the loss of m-CBZ and the recovery of CBZ are identical. The ratios of the RR of CBZ-EPO and CBZ-DIOL to the RL of m-CBZ are constant, in vitro and in vivo. Therefore, m-CBZ can be used as IS for CBZ, CBZ-EPO and CBZ-DIOL determinations in brain tissue. It is shown that the internal reference technique is a useful method to estimate the true concentration of exogenous compounds in the extracellular space of tissues.

Distributional transport kinetics of zidovudine between plasma and brain extracellular fluid/cerebrospinal fluid in the rabbit: investigation of the inhibitory effect of probenecid utilizing microdialysis.

The effect of probenecid (PBD) on the distributional transport of zidovudine (AZT) between plasma, cerebrospinal fluid (CSF) and brain extracellular fluid (ECF) was investigated by using microdialysis. New Zealand White rabbits received AZT, in a crossover design, during control and treatment periods. PBD was coadministered at one of two rates. One additional study involved a repeated control to investigate the possible existence of a period effect. In the low- and high-dose treatment groups, PBD decreased the total body clearance of AZT by 47.7 +/- 8.9 and 51.7 +/- 9.7%, respectively. PBD also decreased the clearance of AZT from CSF and thalamus ECF, prolonging the half-lives of AZT disappearance from the brain. Additionally, PBD elevated the AZT area under the concentration-time curve in the ventricular CSF 3- to 5-fold and the area under the thalamic ECF concentration-time curve by 5- to 6-fold, whereas the area under the plasma concentration-time curve increased only 2-fold. During PBD treatment the ratio area under the thalamic ECF concentration-time curve/area under the ventricular CSF concentration-time curve approached unity. These results provide evidence that AZT is actively transported outwardly across the CSF- and brain ECF-blood barriers, and this transport system is sensitive to PBD. A pharmacokinetic model that considers the effect of PBD on the AZT clearance from brain to plasma suggests that 73% of this pathway is subject to competitive inhibition by PBD.

The use of microdialysis for the determination of plasma protein binding of drugs.

Microdialysis sampling was used for the determination of the protein binding and the free therapeutic drug concentration of drugs in plasma in vitro. Several drugs with varying extent of protein binding and for which the plasma monitoring is important were studied. To mimic the in vivo situation, an artificial blood vessel was constructed and filled with spiked plasma circulating at the flow rate of human blood at 37 degrees C. The microdialysis probe (16 mm membrane length, 20000 MW cut off) was placed in the vessel and perfused with 0.9% NaCl at 5 microliters min-1. Dialysates were collected every 10 min and were analysed by reversed-phase LC with UV detection. The free concentration of the drug was calculated by correcting the concentration in the dialysate for the recovery of the probe, which was also determined in the artificial blood vessel after the experiment. The data confirm that microdialysis is a valid alternative technique for the determination of protein binding or free therapeutic plasma concentration of drugs on a comparative basis. Reference to literature values indicates that the results of the proposed method correspond reasonably well with accepted values.