Phenoxybenzamine treatment is insufficient to prevent spasm in the radial artery: the effect of other vasodilators

OBJECTIVES: After its reintroduction as an arterial graft in coronary artery surgery, the radial artery is now established as an alternative arterial conduit, with good early and midterm patency. However, because of the concern about its vasospasticity, numerous vasodilator strategies have been used. Recently the use of the irreversible alpha-adrenergic antagonist phenoxybenzamine has been proposed. Although this treatment is effective in eliminating the vasoconstriction mediated by noradrenaline, the contribution of other circulating vasoconstrictors to vasospasm could be as important. This study investigates the response of radial arteries treated with phenoxybenzamine to vasoconstrictor stimuli and possible preventative strategies. METHODS: In vitro, sections of radial artery, pretreated with phenoxybenzamine after harvesting, were stimulated with maximal concentrations of the vasoconstrictors noradrenaline, vasopressin, angiotensin II, KCl, and endothelin-1. In matched segments of artery, vasoconstrictor responses were recorded in the presence of diltiazem, glyceryl trinitrate, and papaverine and compared with phenoxybenzamine-treated samples. RESULTS: Phenoxybenzamine-treated radial artery failed to respond to noradrenaline but did respond to vasopressin, angiotensin II, endothelin-1, and KCl. Diltiazem was largely ineffective against contractile stimuli apart from KCl. Glyceryl trinitrate and papaverine significantly reduced responses to all of the vasoconstrictors tested. CONCLUSION: In phenoxybenzamine-treated sections of radial artery, circulating vasoconstrictor agonists may still contribute to the induction of spasm. Additional vasodilator strategies may be required to completely prevent vasospasm.     

Pharmacogenomics of cancer chemopreventive isothiocyanate compound sulforaphane in the intestinal polyps of ApcMin/+ mice

Sulforaphane (SFN) is an isothiocyanate that is present in widely consumed vegetables. Previous studies have shown that SFN is effective in preventing carcinogenesis induced by carcinogens in rodents. Recently it was found that SFN could also suppress the growth of intestinal polyps in the ApcMin/+ mouse. In the present study, the acute effect of SFN on the gene expression profile in small intestinal polyps of ApcMin/+ mice using Affymetrix microarray was performed. SFN is a strong inducer for phase II drug metabolizing enzymes, which is believed to contribute to its chemopreventive properties. However, the results show that genes involved in apoptosis, cell growth and maintenance rather than the predicted phase II genes were modulated. The proapoptotic genes including MBD4, TNFR-7 and TNF (ligand)-11 were up-regulated while pro-survival genes including cyclin-D2, integrin-beta1 and Wnt-9A were down-regulated. Interestingly, two genes potentially involved in colorectal carcinogenesis, 15-LOX and COX-2 were found to be increased and decreased, respectively. In conclusion, the results show, for the first time, that chemopreventive agents such as SFN regulate different set of genes involving apoptosis, cell growth/maintenance and inflammation in the small intestinal polyps of ApcMin/+ mice, which could contribute to the overall chemopreventive pharmacological effects.     

Cysteine residues in the C-terminal lobe of Src: their role in the suppression of the Src kinase

To evaluate the function of cysteine residues of the Src kinase, we constructed a series of Src mutants in which some of cysteines were replaced to alanines. With these mutants, we studied the effect of SH-alkylating agents, N-[p-(2-benzimidazolyl)phenyl] maleimide (BIPM) and N-(9-acridinyl) maleimide (NAM), on their kinase activity. Of 10 cysteine residues scattered over v-Src, either a single mutation at Cys520 or multiple mutations at the four clustered cyteines, Cys483, Cys487, Cys496 and Cys498, yielded clear resistance to the treatment with 10 microM BIPM or 1 microM NAM. In contrast, other cysteines including those in the SH2 domain and those in the catalytic cleft of the kinase domain were dispensable for the inactivation by BIPM and NAM. Similarly, deletion of SH2 and SH3 did not confer the resistance to v-Src, suggesting the inactivation by the SH-alkylating agents is SH2/SH3-independent. Although Cys520-mutated v-Src was resistant to 1 microM NAM, it was inactivated by 5 microM NAM. However, combined mutation including all of Cys483, Cys487, Cys496, Cys498 and Cys520 yielded clear resistance to 5 microM NAM. Among these mutants, those with double mutations in the four clustered cysteines yielded a temperature sensitive phenotype in the transfected cells, whereas Cys520 did not, suggesting that Cys520 has, at least in part, a discrete function. In contrast to v-Src, c-Src, which lacks cysteine at position 520, was resistant to 1 microM NAM but sensitive to 5 microM NAM. While replacement of Phe520 of c-Src to cysteine made it sensitive to 1 microM NAM, double mutation in clustered cysteines again yielded resistance to 5 microM NAM. Taken together, our results strongly suggest that the multiple cysteine residues clustered at the end of the C-terminal lobe are critical for the inhibition by the SH-alkylating agents and, thereby, have an allosteric repressor effect on the catalytic activity of Src in a SH2-phosphoTyr527 independent manner.     

Pharmacokinetics of Caffeine and Its Demethylated Metabolites in Lactation: Predictions of Milk to Serum Concentration Ratios

Pharmaceutical Research -     

Intravenous hydration versus naso-jejunal enteral feeding after esophagectomy: a randomised study.

OBJECTIVE: Patients undergoing esophagectomy are typically nutritionally depleted and cannot establish oral feeding for up to a week after surgery. We have investigated the routine use of enteral feeding via a naso-jejunal tube. METHODS: Forty consecutive patients undergoing a transthoracic esophagectomy for cancer were randomised to receive enteral feeding or intravenous crystalloid fluids after surgery. Nutritional indices were obtained prior to surgery and on the 7th post-operative day. RESULTS: There were no post-operative deaths. Non-fatal complications occurred in 10 patients, without difference in morbidity between the two groups. Lean body mass did not change in either group over the study period. No differences in any other parameters were identified between the two groups. CONCLUSION: Enteral feeding via a naso-jejunal tube is safe and well tolerated after esophagectomy. It is a simple method of providing nutritional support prior to the re-introduction of oral feeding. However it provides no measurable benefit over intravenous hydration only for patients undergoing routine esophagectomy.     

Cation-osmotic Haemolysis in Patients with Retinal Vein Occlusion

The purpose of this work was to use a new technique to assess erythrocyte deformability in patients with retinal vein occlusion. Erythrocyte microrheology changes were measured by cation-osmotic haemolysis (COH) in healthy donors and in patients with both central (n= 6) and branch (n= 16) retinal vein occlusion up to 12 months after the occlusion. The patient group consisted of five patients with ischaemic and 17 with oedematous vein occlusion. The control group consisted of the same number of age-, sex- and risk factor (hypertension)-matched donors. In patients with retinal vein occlusion, COH was significantly decreased compared to the control group. The decrease was most marked at low and high concentrations of incubating media where the differences reached high statistical significance (p<0.01–0.001). In our previous experiments we showed that COH and erythrocyte deformability (ED) are closely related and that COH reflects basic information about erythrocyte deformability. Thus, decreased COH in patients with retinal vein occlusion points to reduced ED in comparison with the control group. We, therefore, assume that impairment in ED together with other microrheological abnormalities contributes to the pathophysiology of changes in patients with retinal vein occlusion.     

Incidence of acute respiratory distress syndrome: a comparison of two definitions

OBJECTIVES: To determine the incidence and outcome of acute respiratory distress syndrome (ARDS) in children by comparing two commonly used definitions: the lung injury score and the American-European Consensus Conference definition. The causes and risk for developing ARDS were also studied. METHODS: Part prospective and retrospective analysis of 8100 consecutive hospital admissions from 1 June 1995 to 1 April 1997. RESULTS: Twenty one patients fulfilled the criteria for ARDS. Both definitions identified the same group of patients. The incidence was 2.8/1000 hospital admissions or 4.2% of paediatric intensive care unit admissions. The main causes were sepsis and pneumonia. Mortality was 13 of 21. Factors predicting death were a high admission paediatric risk of mortality (PRISM) score (30.38 v 18.75) and the presence of multiple organ dysfunction syndrome (92% v 25%). CONCLUSION: Both definitions identified similar groups of patients. The incidence in this population was higher than that reported elsewhere, but mortality and cause were similar to those in developed countries. Poor outcome was associated with sepsis, a high admission PRISM score, and simultaneous occurrence of other organ dysfunction.     

The development of the human interradicular dentine as revealed by tetracycline-labelling

The pattern of labelling of the interradicular dentine that forms the floor of the pulp chamber was studied in human deciduous second mandibular molars from patients who had undergone treatment with tetracycline during the period of formation of those teeth. Six teeth exhibited isolated mineralization centres for the interradicular dentine, indicating that this region in man, unlike in rodents, does not develop as a direct continuation of coronal dentine.