Effect of a single dose of the selectin inhibitor TBC1269 on early and late asthmatic responses

BACKGROUND : Selectins participate in the initial phase of leucocyte migration from circulation to inflamed tissues and may play a role in inflammatory cellular influx into airways in asthma. In the sheep asthma model, TBC1269, a pan-selectin antagonist, reduced late allergen response by 74%. OBJECTIVE : To determine whether a single dose of TBC1269 inhibits early (EAR) and late (LAR) asthmatic responses, and whether it inhibits sputum leucocyte influx after inhalation allergen challenge in atopic asthmatic subjects treated with bronchodilators only. METHODS : Twenty-one asthmatic subjects (mean+/-SD, age=32.5+/-6.7 years, 8 males, FEV1 percent predicted=84+/-15%) with known late asthmatic response based on a screening inhalation allergen challenge were randomly assigned to receive intravenous treatment with either placebo (n=11) or TBC1269 (n=10, 30 mg/kg) infused over 15 min immediately prior to a second (post-treatment) allergen challenge at least 4 weeks after the screening challenge. After each challenge, EAR and LAR were monitored for 7 h. In addition, sputum was induced 1 day before and 1 day after each allergen challenge. RESULTS : TBC1269 did not attenuate the EAR compared with placebo (largest fall in FEV1 within 1 h of 34.1+/-13.9% vs. 31.8+/-12.2% for TBC1269 and placebo groups respectively, P=0.61) or the LAR (largest fall in FEV1 between 3 and 7 h of 39.3+/-15.3% vs. 32.6+/-13.8%, P=0.24). TBC1269 had only minor effects on allergen-induced sputum eosinophilia. CONCLUSION : We conclude that TBC1269 administered before allergen challenge as a single intravenous dose does not attenuate early or late asthmatic responses to allergen in asthmatic subjects.     

The lipoprotein profile of women with hyperprolactinaemic amenorrhoea

The aim of this study was to evaluate the lipoprotein profile in women with hyperprolactinaemic amenorrhoea and to establish whether effective dopamine agonist therapy might have a beneficial effect. Blood samples were collected from women with hyperprolactinaemic amenorrhoea and from controls matched for age, body mass index and smoking. Follow-up blood samples were collected from women on dopamine agonist therapy as treatment for their hyperprolactinaemia. Plasma cholesterol, high density lipoprotein cholesterol, low density lipoprotein (LDL) cholesterol, very low density lipoprotein cholesterol, triglycerides, serum oestradiol and prolactin were measured. No statistically significant differences were found in the lipoprotein profile of the patient (n = 15) and control (n = 15) groups. During treatment with the dopamine agonist, bromocriptine (n = 9), significant reduction in total cholesterol [4.87 (3.98-5.87) versus 5.60 (4.55-6.61) mmol/l, P = 0.024] and LDL cholesterol [3.22 (2.01-4.23) versus 3.72 (2.59-4.93) mmol/l, P = 0.033] was noted. We conclude that beneficial alterations in the lipoprotein profile may occur in response to effective dopamine agonist therapy, presumably as a consequence of return of ovarian function and alleviation of oestrogen deficiency. Women with hyperprolactinaemic amenorrhoea should be encouraged to take effective therapy to improve their lipoprotein profile and potentially reduce their cardiovascular risk.     

Short-term Course and Outcome of Patients Treated with Electroconvulsive Therapy: Irish and British Surveys Compared

Comparison of two independently conducted electroconvulsive therapy (ECT) surveys in Great Britain and Ireland shows remarkable uniformity of opinion and practice in the selection of patients for treatment, treatment technique, and clinical outcome 14 and 28 days after completion of a course of treatment. Short-term outcome reported by a self-selected group of treating psychiatrists in each survey was remarkably similar. Between 75% and 80% of patients were satisfied with the results of ECT as were their treating psychiatrists. The data provide information hitherto unavailable from controlled efficacy studies and indicate the short-term course and outcome of patients treated with ECT in contemporary clinical practice.     

Permanent life support by kidneys perfused with a vitrifiable (7.5 molar) cryoprotectant solution

BACKGROUND: Vitrification (glass formation) is a potential method for indefinite term organ preservation that eliminates all of the conventional problems of freezing and thawing. A 7.5 M mixture of cryoprotectants known as VS4 is sufficiently concentrated, in combination with applied pressure, to preclude ice formation entirely during cooling to below the glass transition temperature (about -125 degrees C), at which point vitrification takes place, arresting further changes over time. METHODS: Rabbit kidneys were perfused with VS4 according to three different protocols. The kidneys were evaluated using an autograft model with immediate contralateral nephrectomy. RESULTS: All three methods permitted long-term survival, but the best results were obtained when the highest concentrations were perfused at about -3 degrees C. Using the latter protocol, the survival rate was 10/10, serum creatinine returned to a normal baseline after transient elevation, other clinical chemistry results normalized, and no histological damage was apparent 3 weeks after autografting. CONCLUSIONS: The results described provide the strongest evidence to date that it may be possible to bank kidneys for unlimited periods in the absence of ice for later transplantation.     

Preclinical in vivo antitumor activity of vinflunine, a novel fluorinated Vinca alkaloid

Vinflunine, or 20′,20′-difluoro-3′,4′-dihydrovino‐relbine, is a novel Vinca alkaloid obtained by hemisynthesis using superacidic chemistry. The most impressive structural modification of this vinorelbine derivative was the selective introduction of two fluorine atoms at the 20′ position, a part of the molecule previously inaccessible by classic chemistry. The antitumor activity of vinflunine was evaluated against a range of transplantable murine and human tumors. Vinflunine exhibited marked activity against murine P388 leukemia grafted i.v. when given i.p. in single or multiple doses according to various schedules or in single i.v. or p.o. doses. Increases in life span achieved with vinflunine, as assessed by T/C ratios, ranged from 200% to 457% and proved markedly superior to those of 129–186% obtained with the other Vinca alkaloids tested. Against s.c.-implanted B16 melanoma, multiple i.p. administration of vinflunine proved active in terms of both survival prolongation and tumor growth inhibition, with optimal T/C values and relative areas under the tumor growth curves (rAUC) being 24% and 36%, respectively. The extent of this activity was superior to that noted for vinorelbine under the same experimental conditions. Growth inhibition of human tumor xenografts LX-1 (lung) and MX-1 (breast) was also observed following four weekly i.p. injections of vinflunine as reflected by optimal T/C values of 23% and 26%, respectively, and significant differences in the rAUCs noted for treated versus control animals. It was also noticeable that vinflunine induced considerably more prolonged inhibitory effects on tumor growth than did vinorelbine. These results demonstrate that vinflunine is well tolerated and is definitively active against a range of experimental animal tumor models. Vinflunine activity has been documented in terms of both survival prolongation and tumor growth inhibition, with definite superiority over vinorelbine being shown in each tumor model evaluated. Received: 13 July 1997 / Accepted: 21 October 1997     

Transampullary pancreatic duct stenting decreases pancreatic fistula rate following left pancreatectomy

BACKGROUND/AIMS: Significant improvements in mortality following pancreatic surgery have been noted by high-volume centers in recent years. Despite this, morbidity from pancreatic resection remains high, with postoperative pancreatic fistula remaining a common problem following distal pancreatectomy (DP). Rates of pancreatic fistula following distal pancreatectomy have ranged from 0 to 61% in a recent meta-analysis of surgical techniques and impact upon pancreatic fistula rates. We postulated that intraoperative placement of a transampullary pancreatic duct stent (TAPDS) at the time of distal pancreatectomy, would decrease ampullary complex-mediated elevation in pancreatic duct pressures, improve healing of the ligated pancreatic duct and result in a decrease in pancreatic fistula following distal pancreatectomy. METHODOLOGY: Sixteen consecutive patients underwent distal pancreatectomy plus TAPDS and were compared to 43 control patients who underwent distal pancreatectomy by the same surgeon, with identical management of the pancreatic remnant. Distal pancreatectomy was performed as the primary operation or as part of an en-bloc resection for a primary malignancy other than pancreatic adenocarcinoma. In patients who underwent transampullary pancreatic duct stenting (TAPDS), the pancreatic duct was identified after transection of the pancreatic parenchyma. A soft, pediatric feeding tube was inserted directly into the pancreatic duct and carefully fed into the duodenum (confirmed by palpation). The stent was placed distally, one centimeter from the cut-edge of the pancreatic duct, which was then ligated as described earlier. Closure of the pancreatic parenchyma was identical to those patients who did not undergo TAPDS placement. Common perioperative outcomes were assessed, including pancreatic fistula. RESULTS: No statistically significant differences where found between the rates of intraabdominal abscess, intraabdominal hemorrhage or need for reoperation. Pancreatic fistula rates and average length of stay were significantly decreased in patients undergoing distal pancreatectomy with TAPDS (p<0.05 and p<0.0001 respectively). CONCLUSIONS: Statistically significant reductions in pancreatic fistula and average length of stay were noted in patients who underwent stenting of the pancreatic duct with TAPDS.