Postoperative nausea and vomiting in children using patient-controlled analgesia: the effect of prophylactic intravenous dixyrazine

BACKGROUND: Although patient-controlled analgesia (PCA) with morphine provides a high degree of satisfactory postoperative analgesia in children, it is often associated with a high incidence of postoperative nausea and vomiting (PONV). Our aim in this study was to evaluate the prophylactic effect of dixyrazine, a phenothiazine with proven anti-emetic properties. METHODS: The incidence of nausea and vomiting was studied in 60 children using PCA after major surgery. The patients were randomised to receive either dixyrazine 0.25 mg kg-1 or placebo on the induction of anaesthesia in a double-blind, placebo-controlled design. The anaesthetic technique was standardised. The PCA pump was programmed to deliver bolus doses of morphine of 20 micrograms kg-1 with a continuous background infusion of 8-10 micrograms kg-1 h-1. Nausea, vomiting, sedation and pain scores were noted every 3 h for a period of 24 h. RESULTS: The morphine consumption of morphine was the same in both groups. During the stay in the recovery room the incidence of vomiting was 3% in the dixyrazine group compared to 30% in the placebo group (P < 0.05). On the ward, 57% versus 83% of the children vomited (P < 0.05). Rescue antiemetics were significantly lower, 30%, in the dixyrazine group compared to 60% in the placebo group (P < 0.05). Higher sedation scores were recorded for the dixyrazine group in the recovery room. No other adverse effects were found. CONCLUSION: A significant number of children using PCA with morphine after major surgery experience PONV. Although prophylactic dixyrazine reduces the incidence and severity of vomiting, the incidence still remains high.     

The prothrombin gene G20210A mutation and the platelet glycoprotein IIIa polymorphism PlA2 in patients with central retinal vein occlusion

The prothrombin gene G20210A mutation and the platelet glycoprotein IIIa polymorphism PlA2 have been shown to be associated with thromboembolic disease. We wondered if mutations were overrepresented in patients with central retinal vein occlusion. We studied 129 consecutive patients with a history of central retinal vein occlusion. We analysed for the prothrombin gene G20210A mutation and the platelet glycoprotein IIIa polymorphism PlA2 and compared the results to controls with no history of thrombosis. For the platelet glycoprotein IIIa polymorphism PlA2, 69% were normal, 26% were heterozygous, and 5% were homozygous. For the G20210A prothrombin mutation, 97% were normal and 3% were heterozygous. Neither the prothrombin gene G20210A mutation nor the platelet glycoprotein IIIa polymorphism PlA2 seem to be associated with central retinal vein occlusion.     

Synthesis of vesicular GABA from glutamine involves TCA cycle metabolism in neocortical neurons.

In contrast to the classic concept of direct conversion of glutamine to gamma-aminobutyric acid (GABA; via glutamate), this process may involve alpha-ketoglutarate as an intermediary metabolite and tricarboxylic acid (TCA) cycle activity. To obtain information about a possible differential role of these pathways for the synthesis of cytosolic and vesicular GABA, cultured neocortical neurons were incubated in medium containing [U-(13)C]glucose (0.5 mM) and in some cases unlabeled glutamine (0.5 mM). Subsequently, the cells were "superfused" for investigation of the effect of depolarization by 55 mM K+. To make sure that depolarization by 55 mM K+ released only vesicular GABA, tiagabin, a nontransportable inhibitor of the plasma membrane GABA carriers, was included in the medium to prevent GABA release from the cytoplasmic pool by reversal of the carriers. The importance of the TCA cycle for conversion of the carbon skeleton of glutamine to GABA was evident from the effect of glutamine on the labeling pattern of GABA. Percentage of labeling by GABA released into the depolarizing medium was the same as that in the corresponding cell extracts and was unaffected by the presence of glutamine during incubation. Despite the existence of multiple forms of glutamate decarboxylase, compartmentation of glutamate pools, and functionally different compartments within neurons, there appears to be full equilibration between the vesicular and cytosolic pools of GABA. However, during depolarization, the newly synthesized pool of GABA from glutamine does not rapidly equilibrate with the vesicular pool.     

Neuronal correlates of real and illusory contour perception: functional anatomy with PET

Illusory contours provide a striking example of the visual system's ability to extract a meaningful representation of the surroundings from fragmented visual stimuli. Psychophysical and neurophysiological data suggest that illusory contours are processed in early visual cortical areas, and neuroimaging studies in humans have shown that Kanizsa-type illusory contours activate early retinotopic visual areas that are also activated by real contours. It is not known whether other types of illusory contours are processed by the same mechanisms, nor is it clear to what extent attentional effects may have influenced these results, as no attempt was made to match the salience of real and illusory stimuli in previous imaging studies. It therefore remains an open question whether there are any brain regions specifically involved in the perception of illusory contours. To address these questions, we have used 15O-butanol positron emission tomography (PET) and a novel kind of illusory contour stimulus that is induced only by aligned line ends. By employing a form discrimination task that was matched for attention and stimulus salience across conditions we were able to directly contrast perception of real and illusory contours. We found that the regions activated by illusory contour perception were the same as those activated by real contours. Only one region, located in the right fusiform gyrus, was significantly more strongly activated by perception of illusory contours than by real contours. In addition, a principal component analysis suggested that illusory contour perception is associated with a change in the correlation between V1 and V2. We conclude that different kinds of illusory contours are processed by the same cortical regions and that these regions overlap extensively with those involved in processing of real contours. At the regional level, perception of illusory contours thus appears to differ from perception of real contours by the degree of involvement of higher visual areas as well as by the nature of interaction between early visual areas.     

Tolterodine in the treatment of overactive bladder: analysis of the pooled phase II efficacy and safety data

OBJECTIVES: To summarize the efficacy and safety of tolterodine from the pooled data of four multicenter, randomized, double-blind, placebo-controlled, dose-ranging, parallel-group Phase II studies in patients with urodynamically proved overactive bladder (detrusor instability or detrusor hyperreflexia) and to analyze the concentration-effect relation. METHODS: After a 1-week run-in period to establish baseline values, 319 patients were randomized to receive placebo or tolterodine 0.5, 1, 2, or 4 mg twice daily. Micturition diary and urodynamic variables and subjective urinary symptoms were assessed after 2 weeks of treatment. Patients were classified as "extensive" or "poor" metabolizers of tolterodine on the basis of serum levels of tolterodine. RESULTS: A per-protocol analysis of efficacy in 262 patients showed dose-related improvements in micturition diary and urodynamic variables. A dosage of 4 mg twice daily was, however, associated with an increase in residual urinary volume. The incidence of adverse events (mainly mild or moderate antimuscarinic effects) was comparable between placebo and tolterodine dosages of 2 mg twice daily. No serious drug-related adverse events were observed, and tolterodine had no clinically significant impact on electrocardiographic or laboratory findings. Changes in urodynamic variables were found to be related to the sum of unbound serum concentrations of tolterodine and its major active 5-hydroxymethyl metabolite. In poor and extensive metabolizers of tolterodine, exposure to the sum of these active moieties was similar, and the efficacy and safety profiles were comparable. CONCLUSIONS: The results of this pooled data analysis indicate that tolterodine offers an effective treatment for patients with urinary symptoms attributable to overactive bladder. The optimal dosage is 1 to 2 mg twice daily, irrespective of metabolic phenotype.     

Activity of standard and investigational cytotoxic drugs in primary cultures of tumor cells from patients with kidney and urinary bladder carcinomas

PURPOSE: In vitro tumor models could support the process of development of new cytotoxic drugs and selection of suitable drugs for the individual patient. We investigated whether the testing of tumor cells from patients with kidney or urinary bladder carcinoma by fluorometric microculture cytotoxicity assay (FMCA) could provide clinically relevant data for these tumor types. MATERIALS AND METHODS: A total of 45 tumor samples from patients with kidney or urinary bladder carcinoma were compared with 247 samples of other tumor types with respect to sensitivity to 8 standard and 6 investigational cytotoxic drugs in the FMCA, a 72 hour assay based on the concept of total cell kill. In bladder carcinomas, sensitivity to standard drugs was correlated to various tumor characteristics. RESULTS: The technical success rate for kidney and bladder carcinomas was high; approximately 90% of the samples could be analyzed successfully. Kidney carcinomas were highly resistant to standard drugs and bladder carcinomas essentially as sensitive as carcinomas of the breast and ovary but with a steeper dose-response relationship. In bladder carcinoma there was no clear relationship between tumor stage, grade, ploidy, mitoses or p53 expression and drug sensitivity. Except for suramin, kidney carcinomas were poorly sensitive to the investigational drugs CdA, gemcitabine, paclitaxel, vinorelbine and topotecan. In bladder carcinomas paclitaxel, gemcitabine and suramin showed promising activity. CONCLUSIONS: The FMCA seems suitable for cytotoxic drug sensitivity testing of urinary tract carcinomas. This technique may have a role in new drug development in these tumor types.     

Activated protein C resistance and anticoagulant proteins in young adults with central retinal vein occlusion

BACKGROUND: Central retinal vein occlusion is a disease that is most common in old people, and often associated with atherosclerosis, hypertension, diabetes or glaucoma. Since these diseases are much less evident in young people, we wanted to investigate the prevalence of disorders in the most common anticoagulant proteins in a group of young patients with central retinal vein occlusion. METHODS: 37 consecutive patients younger than 50 years and with a history of central retinal vein occlusion, were analysed for deficiencies of natural inhibitors of coagulation (protein C, S, and antithrombin III), plasminogen, resistance to activated protein C, and the presence of anticardiolipin or lupus anticoagulants. RESULTS: Anticoagulant protein deficiencies were found in 4 patients (11%) and activated protein C resistance in 7 patients (19%). Anticardiolipin or lupus anticoagulants were not found in the patients. CONCLUSION: Activated protein C resistance and anticoagulant protein deficiencies seem to be important factors to the etiology to central retinal vein occlusion in young patients.     

Selective inhibitors of glial GABA uptake: synthesis, absolute stereochemistry, and pharmacology of the enantiomers of 3-hydroxy-4-amino-4,5,6,7-tetrahydro-1,2-benzisoxazole (exo-THPO) and analogues

3-Methoxy-4,5,6,7-tetrahydro-1,2-benzisoxazol-4-one (20a), or the corresponding 3-ethoxy analogue (20b), and 3-chloro-4,5,6, 7-tetrahydro-1,2-benzisothiazol-4-one (51) were synthesized by regioselective chromic acid oxidation of the respective bicyclic tetrahydrobenzenes 19a,b and 50, and they were used as key intermediates for the syntheses of the target zwitterionic 3-isoxazolols 8-15 and 3-isothiazolols 16 and 17, respectively. These reaction sequences involved different reductive processes. Whereas (RS)-4-amino-3-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole (8, exo-THPO) was synthesized via aluminum amalgam reduction of oxime 22a or 22b, compounds 9, 11-13, and 15-17 were obtained via reductive aminations. Compound 10 was synthesized via N-ethylation of the N-Boc-protected primary amine 25. The enantiomers of 8 were obtained in high enantiomeric purities (ee >/= 99.1%) via the diastereomeric amides 32 and 33, synthesized from the primary amine 23b and (R)-alpha-methoxyphenylacetyl chloride and subsequent separation by preparative HPLC. The enantiomers of 9 were prepared analogously from the secondary amine 27. On the basis of X-ray crystallographic analyses, the configuration of oxime 22a was shown to be E and the absolute configurations of (-)-8 x HCl and (+)-9 x HBr were established to be R. The effects of the target compounds on GABA uptake mechanisms in vitro were measured using a rat brain synaptosomal preparation and primary cultures of mouse cortical neurons and glia cells (astrocytes). Whereas the classical GABA uptake inhibitor, (R)-nipecotic acid (2), nonselectively inhibits neuronal (IC(50) = 12 microM) and glial (IC(50) = 16 microM) GABA uptake and 4,5,6,7-tetrahydroisoxazolo?4,5-cpyridin-3-ol (1, THPO) shows some selectivity for glial (IC(50) = 268 microM) versus neuronal (IC(50) = 530 microM) GABA uptake, exo-THPO (8) was shown to be more potent as an inhibitor of glial (IC(50) = 200 microM) rather than neuronal (IC(50) = 900 microM) GABA uptake. This selectivity was more pronounced for 9, which showed IC(50) values of 40 and 500 microM as an inhibitor of glial and neuronal GABA uptake, respectively. These effects of 8 and 9 proved to be enantioselective, (R)-(-)-8 and (R)-(+)-9 being the active inhibitors of both uptake systems. The selectivity of 9 as a glial GABA uptake inhibitor was largely lost by replacing the N-methyl group of 9 by an ethyl group, compound 10 being an almost equipotent inhibitor of glial (IC(50) = 280 microM) and neuronal (IC(50) = 400 microM) GABA uptake. The remaining target compounds, 11-17, were very weak or inactive as inhibitors of both uptake systems. Compounds 9-13 and 15 were shown to be essentially inactive against isoniazide-induced convulsions in mice after subcutaneous administration. The isomeric pivaloyloxymethyl derivatives of 9, compounds 43 and 44, were synthesized and tested as potential prodrugs in the isoniazide animal model. Both 43 (ED(50) = 150 micromol/kg) and 44 (ED(50) = 220 micromol/kg) showed anticonvulsant effects, and this effect of 43 was shown to reside in the (R)-(+)-enantiomer, 45 (ED(50) = 44 micromol/kg). Compound 9 also showed anticonvulsant activity when administered intracerebroventricularly (ED(50) = 59 nmol).