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Biomedical subjects

H McLeod

Publications and source records attributed to H McLeod.

At least 19 recordsLinked to original sources
PubMed2002

Quality collaboratives: lessons from research.

Quality improvement collaboratives are increasingly being used in many countries to achieve rapid improvements in health care. However, there is little independent evidence that they are more cost effective than other methods, and little knowledge about how they could be made more effective. A number of systematic evaluations are being performed by researchers in North America, the UK, and Sweden. This paper presents the shared ideas from two meetings of these researchers. The evidence to date is that some collaboratives have stimulated improvements in patient care and organisational performance, but there are significant differences between collaboratives and teams. The researchers agreed on the possible reasons why some were less successful than others, and identified 10 challenges which organisers and teams need to address to achieve improvement. In the absence of more conclusive evidence, these guidelines are likely to be useful for collaborative organisers, teams and their managers and may also contribute to further research into collaboratives and the spread of innovations in health care.

Cooperative Behavior↗
PubMed1999

Phase I and pharmacokinetic study of tomudex combined with 5-fluorouracil plus levofolinic acid in advanced head and neck cancer and colorectal cancer.

In vitro studies have shown a schedule-dependent synergism between Tomudex and 5-fluorouracil (5-FU). Incubation of different types of head and neck and colorectal cancer cells with levofolinic acid (LFA) plus 5-FU for 4 or 24 h, after 24-h incubation with Tomudex, produces a clear synergism. The purpose of this study was to evaluate the tolerability and activity of a combination of Tomudex, LFA, and 5-FU in advanced head and neck and colorectal cancer. Furthermore, the potential for 5-FU pharmacomodulation by Tomudex was also evaluated through an intrapatient assessment of dihydropyrimidine dehydrogenase (DPD) activity and 5-FU AUC with and without pretreatment with Tomudex. Eligible patients were treated with Tomudex at the starting dose of 1.5 mg/m2 on day 1, LFA at a fixed dose of 250 mg/m2 on day 2, immediately followed by bolus 5-FU at the starting dose of 600 mg/m2. Tomudex and 5-FU doses were alternately escalated. Courses were repeated every 2 weeks. In the second course, LFA and 5-FU were administered on day 1 and Tomudex on day 2; further treatment was given according to the sequence used in the first course. Plasma 5-FU concentrations were analyzed on courses 1 and 2 using a high-performance liquid chromatography assay with UV detection. DPD activity was measured in peripheral blood mononuclear cells on courses 1 and 2 using incubation of cytosol with [14C]FU and quantitation of metabolite formation. Fifty-eight patients were enrolled in the study. Dose escalation was stopped at step 8, because of the occurrence of dose-limiting toxicity in two of three patients. The dose level immediately before (3 mg/m2 Tomudex, 1050 mg/m2 5-FU) was selected for further evaluation. Tomudex and 5-FU mean dose intensities actually delivered at the seventh step were 1.32 and 462 mg/m2/week, respectively. Six of 40 patients with metastatic colorectal cancer obtained an objective response (15%; 95% confidence interval, 6-30%). In particular, three complete responses and three partial responses were observed. Six of 17 patients with locally advanced or metastatic head and neck cancer obtained an objective response (1 complete response + 5 partial responses; 35%; 95% confidence interval, 14-62%). Median duration of response in colorectal cancer patients was 12 months. 5-FU AUC was not significantly different between the two courses (median intrapatient difference, 9.3%; P = 0.28). DPD activity in course 1 was significantly higher than course 2 (P = 0.041) in the 16 patients in which values were evaluable. The combination of Tomudex, LFA, and 5-FU is well tolerated and active in colorectal and head and neck cancer. The Tomudex mean dose intensity actually delivered is higher than usually achieved in monotherapy. The absence of a clear pharmacokinetic interaction suggests that the synergism of Tomudex and 5-FU might occur at the cellular level.

Adult↗
PubMed1998

Evaluation of total purchasing pilots in England and Scotland and implications for primary care groups in England: personal interviews and analysis of routine data. The Total Purchasing National Evaluation Team.

OBJECTIVES: To evaluate the reported achievements of the 52 first wave total purchasing pilot schemes in 1996-7 and the factors associated with these; and to consider the implications of these findings for the development of the proposed primary care groups. DESIGN: Face to face interviews with lead general practitioners, project managers, and health authority representatives responsible for each pilot; and analysis of hospital episode statistics. SETTING: England and Scotland for evaluation of pilots; England only for consideration of implications for primary care groups. MAIN OUTCOME MEASURES: The ability of total purchasers to achieve their own objectives and their ability specifically to achieve objectives in the service areas beyond fundholding included in total purchasing. RESULTS: The level of achievement between pilots varied widely. Achievement was more likely to be reported in primary than in secondary care. Reported achievements in reducing length of stay and emergency admissions were corroborated by analysis of hospital episode statistics. Single practice and small multipractice pilots were more likely than large multipractice projects to report achieving their objectives. Achievements were also associated with higher direct management costs per head and the ability to undertake independent contracting. Large multipractice pilots required considerable organisational development before progress could be made. CONCLUSION: The ability to create effective commissioning organisations the size of the proposed primary care groups should not be underestimated. To be effective commissioners, these care groups will need to invest heavily in their organisational development and in the short term are likely to need an additional development budget rather than the reduction in spending on NHS management that is planned by the government.

Budgets↗
PubMed1997

Exploring novel chemotherapy treatments using the WWW.

A JAVA application, The Oncologists Workbench, which allows oncologists to estimate the influence of new cancer treatment schedules is being developed. The requirement for a rational approach to the design of chemotherapeutic regimens is well established [1]. Our prototype allows oncologists using the World Wide Web (WWW) to graphically construct treatment regimens while considering various toxic side effects. A simulation engine makes predictions of tumour growth based on previous clinical knowledge of response to treatment. The oncologist can then examine the predicted tumour response information with a specially constructed interactive viewer. These interlinked tools allow oncologists to develop and predict the effectiveness of novel chemotherapeutic regimens. This work is part of an ongoing collaboration between oncologists, mathematicians and computer scientists to provide tools for improving cancer chemotherapy.

Antineoplastic Agents↗
PubMed1997

Alterations in porcine gastric mucin during the development of experimental ulceration.

Bile duct ligation in the pig results in ulceration of the pars oesophagea (oesophagogastric junction) within 48 h with 100% reproducibility. This work describes novel observations made during development of such ulcers using an endoscope introduced at intervals postoperatively via a Thomas gastric cannula. Macroscopic and histological changes were recorded and compared with quantitative and qualitative changes in crude mucus scrapings and purified mucins. Crude mucus scrapings of the cardiac gland region had a higher protein content in the ulcerated states than in the normals. After bile duct ligation, the (degraded) mucin glycopeptide/total protein ratio was higher in partially purified mucus from pre-ulcerated and ulcerated stomachs as compared with normal samples. The quantity of purified mucin was less in samples from ulcerated stomachs, and the N-acetylgalactosamine and fucose contents were also decreased. It is possible that these changes resulted in the failure of the mucus barrier and the development of oesophagogastric junction ulceration.

Animals↗
PubMed1995

Regeneration after in situ flushing of partially hepatectomised rat livers.

The effect of various components of the transplant procedure upon the regenerative process in reduced liver grafts is not known. In this study, partially hepatectomised rat liver remnants were flushed with 5 ml of either Ringer's lactate, Euro Collins solution or University of Wisconsin solution at 4 degrees C and then 5 ml Ringer's lactate at 4 degrees C. After partial hepatectomy alone, the peak increase in thymidine kinase was measured at 24 hours (36,021 +/- 8,060 disintegrations per minute per milligram protein; the mitotic index was 25 +/- 7). In all the groups in which the remnant was flushed, peak thymidine kinase and mitotic index were measured at 48 hours. The pattern of ornithine decarboxylase activity was disorganised in all groups. Flushing of the liver remnant therefore delays the regenerative response by 24 hours. In large animals, including humans, regeneration appears to commence within the first 5 days after resection. A comparable delay doubling this time might coincide with the onset of rejection and further compromise liver function.

Animals↗
PubMed1994

The effect of administration of FK506 on delayed regeneration in flushed partially hepatectomized livers.

It has been shown previously that liver regeneration after partial hepatectomy in rats is delayed if the liver is subjected to either concurrent ischaemia, flushing with cold solution, or grafting. We have shown recently that treatment with CsA preoperatively overcomes the suppressive effect of flushing and returns the regenerative response to a normal time scale. The present study was designed to investigate whether administration of FK506 would also return the observed delayed regenerative response to normal. Long-Evans rats weighing 250-350 g were subjected to standard 68% partial hepatectomy. Group 1 had no further treatment; in group 2, the liver remnant was flushed with 10 ml cold (4 degrees C) Ringers lactate solution, and in group 3, FK506 (1 mg/kg/day) was administered by intramuscular injection for 3 days before the partial hepatectomy and flushing as in group 2; a final dose was given after completion of the procedures. Animals were killed in sets of 6 per group at 4, 24, 48, 72, and 96 hr after surgery and blood samples were taken for measurement of plasma aspartate amino-transferase. Liver biopsies were analyzed for measurement of thymidine kinase and ornithine decarboxylase activity and for counting of mitotic figures. While the highest recorded thymidine kinase activity occurred in group 1 at 24 hr, this was delayed to 48 hr in both group 2 and 3 and counts remained high up to 96 hr in group 3. Mitotic indices were only significantly elevated (compared with group 1 at 96 hr), while ornithine decarboxylase activity did not correlate with these changes being significantly lower than in groups 2 and 3 at 4 hr and in group 3 also at 24 hr. Plasma aspartate aminotransferase was also significantly higher in group 3. It is concluded that the administration of FK506 preoperatively to rats subjected to partial hepatectomy and flushing did not restore the delayed regenerative response to normal but enhanced the response (as measured by thymidine kinase but not by mitotic indices) which commenced at 48 hr and was still present at 96 hr.

Animals↗
PubMed1994

Does liver transplantation in the rat cause a regenerative response. The effect of arterialisation of the graft.

This study was conducted to determine the pattern of early regenerative response to orthotopic intact liver transplantation in the rat and to investigate whether the response differed in grafts with or without revascularisation of the arterial bed. Outbred male Long Evans (LE-LE allogeneic, non rejector) rats weighing 300-350g were subjected to orthotopic intact liver allograft using a "sleeve" anastomosis for the hepatic artery. Total warm ischaemia ranged from 19 to 34 minutes and no storage was employed. Comparison was made with a group of control rats which were subjected to 25 minutes total inflow occlusion and regeneration was measured with tissue thymidine kinase (TK) and mitotic figures. Samples were taken at 1, 2, 4, 7, 10 and 20 days post-operatively. Plasma aspartate aminotransferase (AAT) and light microscopy were used to evaluate hepatocyte necrosis. There was a brief sharp increase in TK and AAT in the first 24 hours after sham operation but no appearance of mitotic figures. A similar but more prolonged increase in TK occurred in the arterialized transplant group with the highest levels recorded on day 4. The level remained significantly elevated above pre-operative until 10 days and declined within 20 days. Mitotic figures appeared at 2 days, reached significance at 7 and 10 days and had disappeared by 20 days. The pattern of changes was accentuated in animals in which the artery was not reanastomosed and the increases in TK and AAT were still significant at 20 days. Whilst similar degrees of peri-portal cellular infiltrate occurred in both groups of rats, bile duct proliferation was most obvious in non-arterialized animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Anastomosis, Surgical↗
PubMed1993

Effect of flushing of the liver graft upon plasma calcium and magnesium concentrations.

Previous studies of total and ionized calcium in the plasma of liver transplant recipients have been conducted in patients with preexisting liver disease or who received blood transfusion. The intraoperative decline in plasma total and ionized calcium has been attributed to the effects of liver disease and/or the citrate in transfused blood. The present study was conducted in normal porcine recipients of liver stored either with EuroCollins or University of Wisconsin (UW) solution for 6 hr, compared with livers flushed with Ringer's lactate without storage. No blood transfusion was given. Mean total plasma calcium levels declined significantly after storage with UW solution to a nadir approximately 65-70% of preoperative levels. This decline persisted for two to five days. Mean levels of plasma ionized calcium declined lowest after flushing with UW solution but only to 82% of preoperative (NS). There was an increase in plasma total magnesium in the recipients of livers flushed with EuroCollins or UW solutions, which resolved within 30 min and which was probably related to magnesium content of the flushing solution. It is concluded that while the changes in plasma total and ionized calcium are moderate and of little clinical significance, they could be aggravated under clinical conditions by massive blood transfusion. Changes in plasma magnesium seemed to be directly attributable to the magnesium content of flushing solutions but the same relationship did not exist for changes in plasma calcium.

Animals↗
PubMed1993

Liver regeneration after hepatic ischemia and reduced liver autotransplantation in the rat.

Current knowledge of liver regeneration after reduced liver transplantation is limited. Warm ischemia is one component of the reduced liver transplantation procedure that could have an impact on the regenerative response. To study this effect, we performed partial hepatectomy on male Long-Evans rats, with animals divided into four groups: group 1 underwent partial hepatectomy only; group 2 underwent partial hepatectomy and 40 min of ischemia; group 3 underwent partial hepatectomy, 40 min of ischemia and portocaval shunt surgery; and group 4 underwent partial hepatectomy and orthotopic autograft surgery. Group 5 consisted of sham-operated animals. Animals were killed 4, 24, 48, 72 and 96 hr after surgery. Thymidine kinase activity, mitotic index, a liver mass index and ornithine decarboxylase levels were used as parameters of liver regeneration. Aspartate transaminase was recorded. Maximal thymidine kinase and mitotic index were observed in group 1 animals at 24 hr. In groups 2, 3 and 4 maximal thymidine kinase activity and mitotic activity were observed 24 hr later at 48 hr. The magnitude of the peak response in these groups appeared to correlate with the duration of portal venous occlusion, with greatest increases occurring in those groups where portal stasis was most prolonged. The increase in liver mass for these groups was also delayed with respect to group 1 animals. The anticipated peak in ornithine decarboxylase levels was seen at 4 hr in group 1. The ornithine decarboxylase response in the other groups was disorganized, with delay of the recorded peaks.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Clinical pharmacokinetics and pharmacodynamics of anticancer drugs in children.

Pharmacokinetic variability in children with cancer is substantial and confounds drawing conclusions regarding optimal therapy based only on dose-response relationships. Careful pharmacokinetic studies performed during drug development in conjunction with an assessment of patient characteristics, such as age, renal and hepatic function, and concomitant therapy, is essential for defining those factors that may alter drug disposition. By integrating pharmacokinetic studies with measures of efficacy and toxicity, a pharmacodynamic framework can be established for guiding therapy to minimize differences in systemic exposure among subpopulations of patients (eg, impaired renal function and neonates). In selected instances when pharmacokinetic variability cannot be predicted by patient covariates, the potential for individualizing dosages based on patient-specific pharmacokinetic parameters is now a clinically feasible option. The need for and benefits of incorporating such strategies into routine therapy represents an exciting area for further clinical research.

Adult↗
PubMed1992

Ex vivo versus in situ resection of segmental liver grafts in pigs--a comparison in immediate and four-hour-stored grafts.

This study compared the function of reduced grafts prepared in situ or ex vivo and transplanted immediately or after 4 hr of cold storage. Measurements of acid/base balance, plasma electrolytes, albumin, and urea showed no differences between groups. There was no difference between the increase and decline of plasma AST in recipients of grafts transplanted immediately after either ex vivo or in situ reduction; the increase in plasma AST of recipients of stored grafts was up to 10-fold and persisted until the end of the study at 7 days, with some decline. Plasma fibrinogen decreased intraoperatively but levels were restored within 24 hr in all groups; plasma prothrombin and partial thromboplastin times were not significantly disturbed. The patterns of decline and return of tissue adenine nucleotides were similar in all groups. While the regenerative response measured by tissue thymidine kinase and mitotic figures was not different between the groups, comparison with results from a group of partially hepatectomized animals showed a 3-4-fold depression in response in reduced liver grafts. The contributions of the effects of ischemia, flushing, and preservation to the depressed regenerative response of reduced liver grafts need to be determined. The present studies suggest however, that with regard to functional assessment, results are not affected either by ex vivo or in situ reduction of the graft, or by cold storage for 4 hr.

Adenine Nucleotides↗