Propranolol block of epinephrine-induced hypokaliaemia in man

Propranolol abolished the epinephrine-induced decrease in plasma potassium, in man. Propranolol also inhibited the rise in plasma lactic acid but only slightly affected the rise in blood glucose levels.     

Synergistic effects of imatinib and carboplatin on VEGF, PDGF and PDGF-Rα/ß expression in squamous cell carcinoma of the head and neck in vitro

Head and neck squamous cell carcinoma (HNSCC) is an aggressive epithelial malignancy. The development of new treatment modalities in order to improve long-term survival of patients with HNSCC is imperative. Numerous studies have demonstrated that carcinogenesis and tumor cell dissemination is influenced by the tumor microenvironment. The protein-kinase-receptors (PTKs) are essential elements of the intracellular signal transduction pathway and regulate cell growth, development and apoptosis. Cell proliferation, migration, induction of tumor vascularization and carcinogenesis, invasion is regulated by a variety of angiogenic factors, such as PDGF (platelet-derived growth factor), VEGF (vascular endothelial growth factor) and their respective tyrosine kinase receptors (PDGF-R and VEGF-R). They present promising targets for anti-cancer therapy through abrogation of impaired signaling pathways. Indeed, imatinib, a small molecule drug targeting these protein kinases, has antiproliferative effects in several cancer types. The purpose of this study was to investigate the potential synergism of imatinib and carboplatin on the expression of PDGF, PDGF-R α/? and VEGF in different HNSCC cell lines. Several tumor cell lines were subjected to increasing concentrations of carboplatin (3 and 7.5 μmol/l) and imatinib (18 and 30 μmol/l) and ELISA, immunohistochemical methods and RQ-PRC after 48, 72, 120 and 240 h were used to assess their expression levels. While PDGF-Rα/? expression was unimpaired at lower imatinib concentrations (18 μmol/l), PDGF-Rα/? expression was suppressed at 30 μmol/l, and suppression was enhanced by the presence of carboplatin. By RQ-PCR, a significant reduction of PDGF-Rα/? expression was detected (p<0.5). We observed explicit significant reduction in VEGF levels with increasing concentrations of imatinib and with the combination of the two chemotherapeutic drugs (p<0.5). We report for the first time evidence of synergism of imatinib and carboplatin in suppressing VEGF, PDGF and PDGF-Rα/? expression in HNSCC.     

Down-regulation of MMP-2 expression due to inhibition of receptor tyrosine kinases by imatinib and carboplatin in HNSCC

Squamous cell carcinoma of the head and neck (HNSCC) is the most common neoplasm arising in the upper aerodigestive tract. Unfortunately, the survival for this type of cancer has not improved significantly in the past 25 years. To enhance the survival rate multimodal therapy regimens have been set up. In these regimens chemotherapy plays a pivotal role in the majority of advanced cases. Transmembrane protein- tyrosine kinases (PTK) are fundamental elements of the signal transduction. In consequence, they might be promising targets for cancer therapy. Imatinib (STI 571) was originally designed to inhibit the BCR-ABL tyrosine kinase in chronic myeloid leukemia. But imatinib also has an inhibitory impact on the PTK receptor c-kit and on its PTK activity. Furthermore, growth and invasion of HNSCC are strongly influenced by the extracellular matrix (ECM). The ECM is altered by matrix metalloproteinases (MMP). In this study, we incubated different HNSCC cell lines with rising concentrations of imatinib and/or carboplatin. After an incubation time of up to 10 days, we evaluated c-kit, MMP-2 and MMP-14 by ELISA techniques and immunohistochemical methods. Especially the combination of 7.5 μmol carboplatin with 30 μmol imatinib resulted in a significant decrease in MMP-2 expression in all observed cell lines (p<0.05). We did not demonstrate a significant alteration in c-kit expression by imatinib and carboplatin. We observed an increase in apoptosis in HNSCC cells by the combination of the two observed chemotherapeutic drugs. In all cell lines tested, expression of c-kit and MMP could be demonstrated. Our results indicate that MMP-2 expression was suppressed in the presence of imatinib. Thus, imatinib may exert in part its inhibitory effect on malignant cell growth via the blockage of the signal transduction of PTK receptors. Further studies are warranted, especially one keeping in mind the moderate toxicity of imatinib.     

Pretreatment with verapamil in patients with persistent or chronic atrial fibrillation who underwent electrical cardioversion.

OBJECTIVES: To evaluate, in a prospective and randomized fashion, the efficacy of a pretreatment with verapamil (V) in reducing recurrences of atrial fibrillation (AF) after electrical cardioversion (C). BACKGROUND: The increased vulnerability for AF recurrence is probably due to AF-induced changes in the electrophysiologic properties of the atria. This electrical remodeling seems to be due to intracellular calcium overload. METHODS: One hundred seven patients with persistent or chronic AF underwent external and/or internal C. All patients received oral propafenone (P) (900 mg/day) three days before and during the entire period of follow-up (three months). In the first group, patients received only the P. In the second group, in adjunct to P, oral V (240 mg/day) was initiated three days before C and continued during the follow-up. Finally, in the third group, oral V was administered three days before and continued only for three days after electrical C. RESULTS: During the three months of follow-up, 23 patients (23.7%) had AF recurrence. Mantel-Haenszel cumulative chi-square reached a significant level only when comparing AF free survival curves of group I versus group II and group III (chi-square = 5.2 and 4, respectively; p < 0.05). Significantly, 15 (65.2%) AF relapses occurred during the first week after cardioversion with a higher incidence in group I (10/33 patients, 30.3%) than group II (2/34 patients, 5.9%; p = 0.01) and group III (3/30 patients, 10%; p = 0.04). CONCLUSIONS: Six days of oral V administration centered on the C day, combined with P, significantly reduce the incidence of early recurrences of AF compared with P alone.