Self-administered heroin and cocaine combinations in the rat: additive reinforcing effects-supra-additive effects on nucleus accumbens extracellular dopamine.

The concurrent use of cocaine and opiate combinations (speedball) has increased since the 1970s and now represents a growing subset of intravenous drug abusers. An isobolographic analysis was applied to the ascending limb of the dose-effect curves for rat self-administration of cocaine, heroin, and their combination to determine the nature of the interaction. The addition of heroin to cocaine shifted the dose-effect curve for self-administration to the left, and the modulation in reinforcing efficacy of the combination of cocaine and heroin was found to be additive. A second experiment used microdialysis to determine the effects of this drug combination on nucleus accumbens (NAc) extracellular levels of dopamine ([DA](e)) in rats self-administering low doses of cocaine, heroin, or cocaine/heroin combinations. These doses of cocaine and cocaine/heroin combinations significantly increased NAc [DA](e), while heroin alone did not. The ratio of the % baseline of [DA](e) (or the dialysate concentrations of DA) to cocaine in the dialysate was higher during self-administration of cocaine/heroin combinations than with cocaine alone. These data indicate that although the interaction between cocaine and heroin in maintaining self-administration is additive, a potentiation of NAc dopaminergic neurotransmission is present, suggesting that NAc [DA](e) may not be a direct measure of reinforcing efficacy and/or it is not central to the mediation of the self-administration of this drug combination.     

Characterization of P-glycoprotein and multidrug resistance proteins in rat kidney and intestinal cell lines.

The activity of P-glycoprotein (Pgp/MDR1/ABCB1) and multidrug resistance proteins (MRP/ABCC) influence the pharmacokinetics and bioavailability of many drugs. Few suitable cell lines for the study of drug transport exist. Additional non-human cell lines may help clarify species differences and contribute to the current knowledge of drug transport. The aim of the present study was to characterize three rat epithelial cell lines for transporter expression and activity. Transporter expression was assessed in intestinal IEC-6 and renal GERP and NRK-52E cells using RT-PCR and Western blot analysis. Pgp and Mrp transport activity were analyzed by measuring calcein accumulation and glutathione-S-bimane efflux, respectively. The three cell lines showed Pgp expression and Pgp-dependent transport, both decreasing with culture time after reaching confluency. Besides Pgp, cells expressed Mrp1, Mrp3, Mrp4, and Mrp5, while Mrp2 and Mrp6 were absent. In addition, they showed temperature- and Mrp-dependent efflux of glutathione-S-bimane. Exposure to a panel of different inhibitors showed that this efflux was probably mediated by Mrp4. In conclusion, the three rat epithelial cell lines investigated showed Pgp and Mrp expression and transport. Mrp dependent transport was most likely mediated by Mrp4. In future, these cell lines may be used as in vitro models to study drug transport.     

Early complications of stenting in patients with congenital heart disease: a multicentre study.

AIMS: Stenting has become an established interventional cardiology procedure for congenital heart disease. Although most stent procedures are completed successfully, complications may occur. This multicentre study evaluated early complications after stenting in patients with congenital heart disease, including potential risk factors. METHODS AND RESULTS: In this combined Dutch-Belgian retrospective study, 309 consecutive patients had undergone 366 catheterizations and received 464 stents in 13 different anatomical positions (418 sites). Seventy-two stenting-related complications (19%) occurred, of which 24 (5.7%) were major. Seven procedure-related deaths were documented (2.3%). Stent malpositioning and embolization were most common (7.7%). The use of non-premounted stents tended to be associated with higher complication rates. Centre inexperience with stenting and stenting of native vs. post-surgical stenosis tended to be associated with increased major complication rates. CONCLUSION: After stenting, complications are common for congenital heart disease. The vast diversity of stenotic sites combined with relatively small patient populations makes these procedures sensitive to complications. Combining operator experience may reduce the risks of stenting in congenital heart disease. The availability of premounted stents for greater vessel diameters will likely reduce incidences of stent migration and embolization.     

Dose escalation study of rhenium-186 hydroxyethylidene diphosphonate in patients with metastatic prostate cancer

Rhenium-186 hydroxyethylidene diphosphonate (¹⁸⁶Re-HEDP) has been used for the palliative treatment of metastatic bone pain. A phase 1 dose escalation study was performed using ¹⁸⁶Re-HEDP Twenty-four patients with hormone-resistant prostate cancer entered the study. Each patient had at least four bone metastases and adequate haematological function. Groups of at least three consecutive patients were treated with doses starting at 1295 MBq and increasing to 3515 MBq (escalated in increments of 555 MBq). Thrombocytopenia proved to be the dose-limiting toxicity, while leucopenia played a minor role. Early death occurred in one patient (10 days after administration) without clear relationship to the ¹⁸⁶Re-HEDP therapy. Transient neurological dysfunction was seen in two cases. Two patients who received 3515 MBq ¹⁸⁶Re-HEDP showed grade 3 toxicity (thrombocytes 25–50 × 10⁹/1), defined as unacceptable toxicity. After treatment alkaline phosphatase levels showed a transient decrease in all patients (mean: 26% ± 10% IUA; range: 11%–44%). Prostate-specific antigen values showed a decline in eight patients, preceded by a temporary increase in three patients. From this study we conclude that the maximally tolerated dose of ¹⁸⁶Re-HEDP is 2960 MBq. A placebo-controlled comparative study on the efficacy of ¹⁸⁶Re-HEDP has been initiated.     

Glottic and supraglottic carcinoma: a retrospective comparison of radiotherapy alone with sandwich therapy in 366 patients

From 1971 through 1982, 442 patients with laryngeal carcinoma were seen at the Leiden University Hospital. They were treated either with radiotherapy alone, sandwich therapy (pre- and postoperative radiotherapy) or by surgery followed by postoperative irradiation. Three hundred and sixty-six patients with glottic or supraglottic tumours could be analysed with respect to two different treatments, complications of treatment and some prognostic factors. Two endpoints of analysis were used: disease-free interval and survival to cancer death. In patients with glottic or supraglottic carcinoma, the survival of patients with advanced disease, treated with radiotherapy only, was worse as compared to the survival of the same category of patients who were treated with sandwich therapy (p less than 0.005). In patients with small glottic tumours, radiotherapy alone was mostly used. In small supraglottic tumours, the survival with both therapy policies was equal. Persistent hoarseness in patients with small glottic tumours, treated with radiotherapy only, is of predictive value for the development of a recurrence (p less than 0.001). There was no influence on prognosis of histological differentiation of the tumour. It appeared that interruption of radiotherapy for more than two days had an adverse effect on survival in patients with glottic carcinoma (p = 0.0001). Finally, the occurrence of second malignancies was analysed. It was found that 19% had a second malignancy. Almost 60% of them were lung cancers.