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Biomedical subjects

G Tierney

Publications and source records attributed to G Tierney.

14 recordsLinked to original sources
PubMed2002

Marimastat as maintenance therapy for patients with advanced gastric cancer: a randomised trial.

This randomised, double-blind, placebo-controlled study was designed to evaluate the ability of the orally administered matrix metalloproteinase inhibitor, marimastat, to prolong survival in patients with non-resectable gastric and gastro-oesophageal adenocarcinoma. Three hundred and sixty-nine patients with histological proof of adenocarcinoma, who had received no more than a single regimen of 5-fluorouracil-based chemotherapy, were randomised to receive either marimastat (10 mg b.d.) or placebo. Patients were treated for as long as was tolerable. The primary endpoint was overall survival with secondary endpoints of time to disease progression and quality of life. At the point of protocol-defined study completion (85% mortality in the placebo arm) there was a modest difference in survival in the intention-to-treat population in favour of marimastat (P=0.07 log-rank test, hazard ratio=1.23 (95% confidence interval 0.98-1.55)). This survival benefit was maintained over a further 2 years of follow-up (P=0.024, hazard ratio=1.27 (1.03-1.57)). The median survival was 138 days for placebo and 160 days for marimastat, with 2-year survival of 3% and 9% respectively. A significant survival benefit was identified at study completion in the pre-defined sub-group of 123 patients who had received prior chemotherapy (P=0.045, hazard ratio=1.53 (1.00-2.34)). This benefit increased with 2 years additional follow-up (P=0.006, hazard ratio=1.68 (1.16-2.44)), with 2-year survival of 5% and 18% respectively. Progression-free survival was also significantly longer for patients receiving marimastat compared to placebo (P=0.009, hazard ratio=1.32 (1.07-1.63)). Marimastat treatment was associated with the development of musculoskeletal pain and inflammation. Events of anaemia, abdominal pain, jaundice and weight loss were more common in the placebo arm. This is one of the first demonstrations of a therapeutic benefit for a matrix metalloproteinase inhibitor in cancer patients. The greatest benefit was observed in patients who had previously received chemotherapy. A further randomised study of marimastat in these patients is warranted.

Adenocarcinoma↗
PubMed2000

An evaluation of mattresses and mats in two dairy units.

In order to investigate the relative merits of mats and mattresses in terms of cow comfort, production and performance, 29 cows were housed on ethylethene vinyl acetate (EVA) mats and 29 on mattresses of loose rubber crumb with a polypropylene cover, at each of two similar dairy units (SAC Auchincruive and Myerscough). Both mats and mattresses were newly installed at the start of the trial. The cows were housed in the autumn after calving. Milk yield was recorded daily. Cows were weighed and scored for body condition, locomotion, dirtiness and hock and knee injury at fortnightly intervals. Feed offered was recorded daily and refusals were weighed weekly. Monthly milk records of milk yield, milk composition and somatic cell count data were available for both herds. In addition, 24 h behavioural observations of 15 core cows in each group were made at weeks 0, 2, 4, 6, 8, 16, and 32 post-housing. There was no difference between cows on mats and mattresses in milk yield, composition or quality; in feed intake; in weight loss or body condition score; in severe hock or knee injury, or in the incidence of lameness. Cows on mattresses tended to have slightly higher total dirtiness scores than those on mats (7.06 vs. 6.95, P=0.074) and had dirtier udders (mattress, 7.50 vs. mat, 6.52, P<0.05). However, over the whole housing period, cows on mattresses spent longer feeding, ruminating and lying and a greater proportion of their lying time was spent ruminating. They spent less time standing doing nothing (idling) than cows on mats and less time idling in cubicles. Cows on mattresses appeared to adapt to housing more quickly than those on mats. Overall, neither mat nor mattress gave advantages in terms of production or performance, cows were slightly cleaner on mats but behavioural indices suggest that cow comfort was greater on mattresses.

Journal Article↗
PubMed1997

An experimental study of intra aortic balloon pumping within the intact human aorta.

OBJECTIVE: Intra-aortic balloon pumping is a therapeutic technique which carries a significant morbidity related to the interaction between the balloon catheter and the aorta. The aim of this study was to visualise directly the dynamic action of the balloon catheter within the cadaveric human aorta in an artificial circulation. METHODS: An artificial circulation was constructed using of PVC tubing, a filter and a roller pump. A series of five intact cadaveric human aortas were then individually studied by placing each in series within the circuit. A balloon catheter was advanced via the left common iliac artery into the descending aorta under direct angioscopic vision. Balloon pumping was then commenced. The circuit was perfused with normal saline at a flow rate of 3 l/min. Pump actions of 1:1 and 1:2 were simulated. Each aorta at the end of the experiment was subjected to histological examination. RESULTS: The balloon only appeared to make direct contact with the wall of the aorta during deflation when it was swept to one side by the circulating fluid. During maximal inflation the only points of contact were the tip of the catheter and the entry site. Side branches of the aorta were not occluded by the balloon. There was considerable atheromatous debris visualised within the lumen of the aorta. Atheromatous plaques were seen to fissure and disrupt by a pressure wave action and not by direct contact with the balloon. CONCLUSION: The balloon catheter moves relative to the wall of the aorta during inflation and deflation. Contact between the balloon and the aorta only occurs during deflation. Side branches of the aorta are not occluded by the catheter. Plaque disruption and embolus formation appear to result from pressure wave action rather than direct contact with the balloon. This may have implications for future balloon design. Further investigation of this poorly understood interaction between the balloon and the aortic wall is required.

Adult↗
PubMed1992

Cross-reactive immunodeterminants on Streptococcus sanguis and collagen. Predicting a structural motif of platelet-interactive domains.

Cross-reactive immunodeterminants on a fibril-associated surface antigen of Streptococcus sanguis and types I and III collagen participate in the induction of aggregation of human platelets. To further understand the basis for this apparent molecular mimicry, antitype-specific collagen antibodies, anti-KPGEPGPK (an analogue of platelet-interactive domains on collagen) and a panel of KPGEPGPK-like synthetic peptides were used as probes. When collagen or S. sanguis cells were pretreated with the anti-collagen antisera, the induction of aggregation of platelet-rich plasma was greatly delayed or abrogated. These anti-collagen antibodies also neutralized KPGEPGPK and purified S. sanguis platelet-interactive antigens as inhibitors of S. sanguis or collagen-induced aggregation of platelets in plasma. In immunoblot analyses, these anti-collagen antibodies reacted with S. sanguis platelet-interactive antigens. Additionally, antisera against the platelet-interactive antigen of S. sanguis selectively reacted with undigested type I collagen and with fragments CB3 and CB6 of cyanogen bromide-treated type I collagen. Finally, when platelets were pretreated with synthetic peptides containing specific amino acid substitutions within the KPGEPGPK sequence, the time to onset of platelet-rich plasma aggregation by both agonists was altered. The hierarchical pattern of responses of platelets to these peptides and predictions of the structural changes produced by simulated insertions of each peptide into the CB4 sequence of type III collagen suggested conformational requirements for interactions with platelets. Thus, these data show that cross-reactive immunodeterminants of S. sanguis and collagen induce platelet aggregation. The platelet-interactive domains are predicted to be characterized by a structural motif with the consensus sequence X-P-G-E-P/Q-G-P-X.

Amino Acid Sequence↗
PubMed1992

A study of the interaction between the hypotensive actions of doxazosin and enalaprilat in anaesthetized rats.

OBJECTIVE AND DESIGN: This study was designed to test whether previous work, which showed that the angiotensin converting enzyme (ACE) inhibitor enalaprilat potentiated the alpha 1-adrenoceptor antagonist activity of doxazosin in isolated rat tail arteries, could be extended to demonstrate a synergistic hypotensive effect of these two drugs. METHODS: Groups of untreated or chronically deoxycorticosterone acetate (DOCA)-salt-treated female Sprague-Dawley rats were used. Rats were anaesthetized with Inactin (barbiturate); drugs were administered via a jugular venous catheter; blood pressure was monitored via a carotid arterial catheter. RESULTS: In previously untreated rats, pretreatment with enalaprilat shifted the dose-response curve for the hypotensive effect of doxazosin to the left, indicating synergism. In rats dosed with DOCA-salt (which suppresses renin and angiotensin II production): (1) there was no synergism between the hypotensive actions of enalaprilat and doxazosin; (2) doxazosin was more potent than in untreated rats; and (3) enalaprilat lowered blood pressure, suggesting a hypotensive mechanism separate from ACE inhibition. CONCLUSION: In the absence of angiotensin II (resulting from enalaprilat administration or from chronic DOCA-salt), doxazosin had a greater hypotensive action than in the presence of angiotensin II. This is consistent with the concept that angiotensin II modulates alpha 1-adrenoceptor activity.

Anesthesia↗
PubMed1991

Interactions between enalaprilat and doxazosin at rat tail artery alpha 1-adrenoceptors.

Using paired isolated perfused rat tail artery segments, it was found that enalaprilat, an ACE inhibitor, augmented 1.6-fold the contractile responses to phenylephrine (PE), an alpha 1-adrenoceptor agonist. Similarly, enalaprilat potentiated 1.9-fold the alpha 1-adrenoceptor antagonist activity of doxazosin in paired rat tail artery segments. In rats treated with deoxycorticosterone acetate (DOCA) 20 mg/kg i.m. twice weekly for 5 weeks, plasma renin activity fell from a control value of 5.73 +/- 0.93 to 0.04 +/- 0.01 ng of AI/ml/h. The inhibition of circulating renin activity in these animals was associated with a loss of the potentiating effects of enalaprilat upon the alpha 1-adrenoceptor antagonist action of doxazosin. The results are interpreted as indicating that angiotensin II (AII) can modulate the functional activity of alpha 1-adrenoceptors in vascular smooth muscle.

Adrenergic alpha-Antagonists↗
PubMed1991

Investigations into interactions between doxazosin and enalaprilat at alpha 1-adrenoceptors in anaesthetized rats.

1. In anaesthetized intact Sprague-Dawley rats, the angiotensin-converting enzyme inhibitor enalaprilat, 1 mg/kg, had no significant effect on the pressor responses to the alpha 1-adrenoceptor agonist phenylephrine (PE). Doxazosin 1 mg kg was found to be a potent alpha 1-adrenoceptor antagonist. 2. The combination of enalaprilat 1 mg/kg plus doxazosin 1 mg/kg was 3.3-fold more potent in antagonizing alpha 1-adrenoceptors than doxazosin 1 mg/kg alone. 3. After treatment of rats with deoxycorticosterone acetate (DOCA) twice weekly for 5 weeks, the alpha 1-adrenoceptor antagonist action of doxazosin in anaesthetized rats was not potentiated by enalaprilat 1 mg/kg. 4. Since DOCA treatment suppresses renin activity, these findings strongly support the hypothesis that angiotensin II can modulate the functional activity of alpha 1-adrenoceptor in vascular smooth muscle.

Adrenergic alpha-Antagonists↗
PubMed1990

The malignancy grading method is not a reliable assessment of malignancy in mesothelioma.

The ploidy of a series of pleural lesions--reactive proliferations, malignant mesotheliomas and metastatic tumours--was measured on a Leitz Miamed DNA image analyser using Feulgen-stained slides. The technique successfully recognized all the metastatic tumours as malignant; this corresponds to previous work. However, it was not successful in classifying mesothelial lesions as benign or malignant, resulting in a very high false-negative rate and a moderately high false-positive rate. Mesothelial lesions appear to have a wide range of ploidy values irrespective of their biological behaviour. Thus, for primary mesothelial tumours, the ploidy value cannot be used as a reliable diagnostic index.

False Negative Reactions↗
PubMed1989

An in vitro study of interactions between doxazosin and enalaprilat at vascular alpha 1-adrenoceptors.

1. Isolated perfused male Sprague-Dawley rat tail artery segments were used to investigate interactions between the alpha-1-adrenoceptor antagonist, doxazosin, and the angiotensin converting enzyme (ACE) inhibitor, enalaprilat, using phenylephrine (PE) as the alpha 1-adrenoceptor agonist. 2. In concentrations of up to 10(-5) mol/L, enalaprilat had no effect on arterial responses to PE. 3. Doxazosin produced a concentration-dependent competitive alpha 1-adrenoceptor antagonism, yielding a mean pA2 value of 8.72. 4. In the continuous presence of 10(-6) mol/L enalaprilat, doxazosin with a pA2 value of 9.10 was a 2.4-fold more potent alpha 1-adrenoceptor antagonist than in the absence of enalaprilat. 5. These results are interpreted to indicate that endogenously produced angiotensin II can modulate the activity of alpha 1-adrenoceptors in vascular smooth muscle.

Adrenergic alpha-Antagonists↗