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Biomedical subjects

D M Nott

Publications and source records attributed to D M Nott.

At least 19 recordsLinked to original sources
PubMed2001

Somatostatin analogs in oncology: a look to the future.

In the past 15 years considerable advances have been made in our understanding of the molecular pharmacology of the mechanisms whereby somatostatin and its analogs mediate their direct and indirect antineoplastic effects. However, some important issues remain to be resolved, in particular the functional roles of the individual somatostatin receptors (SSTR-1-5) in tumor tissue and up- or downregulation of the hSSTRs with prolonged administration of somatostatin analogs. Answers to these questions are essential before we can maximize the therapeutic efficacy of somatostatin analogs in cancer. For example, is continuous administration more or less effective than intermittent therapy? The role of somatostatin analogs in the management of acromegaly and to a lesser extent neuroendocrine tumors is firmly established. The development of depot preparations of all 3 somatostatin analogs currently available for clinical use will undoubtedly improve both patient compliance and quality of life in patients with these conditions. There are only likely to be minor differences in the therapeutic efficacy of octreotide, lanreotide and vapreotide since all three analogs exert the majority of their antineoplastic effects via hSSTR-2 and hSSTR-5 and at the end of the day, price may well dictate which of these drugs oncologists use to provide symptomatic palliation of acromegaly and neuroendocrine tumors. Apart from some notable exceptions, somatostatin analog therapy has proven to be very disappointing in the management of advanced malignancy. Improvements in the management of solid tumors are likely to come only from combination therapy of somatostatin analogs with cytotoxic agents or other hormones in both advanced malignancy and in the adjuvant setting. Clinical trials with clear-cut objective outcome measures and health-related quality of life assessment are needed to evaluate the therapeutic efficacy of combination treatment in advanced malignancy and as an adjuvant to surgery. Particular attention needs to be paid to possible adverse effects of somatostatin analog therapy on the immune response to cancer. Further studies are required to establish whether the adverse effects of somatostatin analog therapy alone or in combination with cytotoxics or other hormones can be reversed with appropriate immunomodulatory treatment. Targeted somatostatin analog radiotherapy and chemotherapy are currently being investigated and the results of these studies are awaited with interest. Novel approaches using combinations of somatostatin analogs with antiangiogenic drugs or gene therapy are of particular interest and may provide important advances in the management of cancer in the not too distant future.

Animals↗
PubMed2000

Treatment of iatrogenic femoral artery pseudoaneurysms using ultrasound-guided injection of thrombin.

AIM: To evaluate the use of ultrasound-guided percutaneous injection of thrombin for treatment of femoral artery pseudoaneurysms. METHOD: Nine patients with a confirmed femoral false aneurysm were included in the study. 0.5-1 ml of a 2000 U/ml solution of activated bovine thrombin was injected under ultrasound visualization into the neck of the aneurysm to induce thrombosis. The parent artery and adjacent major vessels were checked during and after the procedure to exclude propagation of thrombus. A check ultrasound examination was undertaken on the following day. RESULTS: Eight patients were successfully treated by a single injection. One patient required a second injection due to recurrence of their pseudoaneurysm 4 days after the initial treatment. The procedure was well tolerated in all cases and no complications were encountered. CONCLUSION: This small series provides further evidence that ultrasound-guided thrombin injection is a promising new method for the treatment of femoral false aneurysms.Hughes, M. J. et al. (2000). Clinical Radiology55, 749-751.

Aneurysm, False↗
PubMed1999

Extraperitoneal laparoscopic aortic control with endovascular visualization of a stent-graft combination.

OBJECTIVES: to demonstrate the feasibility of minimally invasive approaches to the aorta using retroperitoneal laparoscopy and to clamp the aorta to give views for perfemoral aortic angioscopy. METHODS: using retroperitoneal laparoscopy facilitated by balloon dissection the authors developed a new approach to the infrarenal abdominal aorta, in six pigs, to allow control of aortic blood flow. Aortic stent-grafts were then deployed via femoral arteriotomy, and after flushing the blood from the aorta, the stent-grafts were visualized by angioscopy. RESULTS: accurate positioning and patency of the stent-grafts was ascertained by direct vision angioscopy in all cases. CONCLUSIONS: this series shows that extraperitoneal laparoscopic aortic dissection is feasible and direct endovascular visualization of the aortic lumen can be performed. This may find a role as an adjunct to endovascular techniques such as endovascular stent-graft placement, by aortic angioscopy following minimally-invasive aortic clamping.

Animals↗
PubMed1998

Platelet activation and serotonin release during colorectal surgery.

In vitro studies show serotonin has a profound vasospastic effect on human mesenteric arteries. A similar response has been shown in vivo in atherosclerotic primates. If platelet serotonin stores are released as a consequence of platelet activation during colorectal surgery, a similar effect may significantly alter the perfusion of newly formed anastomoses leading to ischaemia and anastomotic breakdown. Here we have studied the effects of surgery and anaesthesia on intraplatelet and plasma serotonin levels during the peri- and postoperative period following colorectal surgery. A series of six consecutive patients undergoing colorectal resection and anastomosis were selected. Peripheral venous blood samples, taken at specified times before and after surgery and prepared in a platelet stabilizing buffer solution, were analysed using a validated enzyme immunoassay technique. Intraplatelet serotonin levels were seen to fall post-operatively, whilst plasma serotonin levels were shown to rise, implying significant platelet activation and serotonin during the peri-operative period. This study demonstrates the increased bioavailability of serotonin during the peri-operative period in colorectal surgery patients. If the in vitro effects of this amine are mirrored in vivo, increased plasma levels of serotonin may have an important role in anastomotic dehiscence secondary to ischaemia.

Journal Article↗
PubMed1998

Pharmacokinetics of octreotide in patients with cirrhosis and portal hypertension; relationship between the plasma levels of the analogue and the magnitude and duration of the reduction in corrected wedged hepatic venous pressure.

In healthy subjects octreotide is largely metabolised by the liver suggesting that the plasma half-life of the somatostatin analogue may be prolonged in patients with hepatic dysfunction. The aim of this study was therefore (a) to determine the pharmacokinetics of octreotide following its subcutaneous injection in 6 patients with cirrhosis and portal hypertension and (b) compare the magnitude and duration of the effects of intravenous administration of 250 micrograms somatostatin and 50 micrograms octreotide on corrected wedged hepatic venous pressure (WHVP) and to relate the findings to the plasma levels of the analogue 1 h after administration in 13 patients with cirrhosis and portal hypertension. Following subcutaneous administration of 50 micrograms octreotide the circulating half life (range 2.4 to 4.79 h) was prolonged whereas the clearance (range 2.101 to 4.775 L/h) was decreased compared to healthy controls. Intravenous bolus administration of 250 micrograms somatostatin or 50 micrograms octreotide resulted in a reduction in WHVP of approximately the same magnitude and duration despite appreciable quantities of the analogue in the blood 1 h after administration (1944 +/- 226 pg/ml). These results indicate that the circulating half-life of octreotide is prolonged in cirrhotics suggesting that the dosage regimens should be modified in such patients to avoid accumulation of the analogue in the blood which may result in undesirable side-effects or toxicity. Furthermore, since the magnitude and duration of the reduction in WHVP elicited by IV octreotide is similar to that observed with somatostatin, the analogue, like the native hormone, must be administered by continuous IV infusion to produce a sustained response and hence a therapeutic effect in the management of acute variceal bleeding.

Blood Pressure↗
PubMed1996

Increasing hepatic arterial flow to hypovascular hepatic tumours using degradable starch microspheres.

The effect of degradable starch microspheres (DSM) on the intrahepatic distribution of a low molecular weight marker, 99Tcm-labelled methylene diphosphonate (MDP), was studied in rats with hypovascular HSN liver tumours. MDP was injected regionally, via the hepatic artery, alone or co-administered with DSM, with or without subsequent occlusion of either the hepatic artery or the portal vein. Tumour vascularity was measured with 57Co-labelled microspheres. Co-injection with DSM immediately significantly increased hepatic retention of marker in both tumour (T) (median 22.40 (range 16.82-39.58)% injected dose) and normal liver (N) (9.08 (4.85-12.59) %ID) the greater effect seen in T (P < 0.01). After DSM degradation, very little MDP remained in N (0.61 (0.28-1.40) %ID) but there was significant retention in T (10.01 (6.73-20.28) %ID, P < 0.01). Clamping the hepatic artery had minimal effect on the retention of MDP when administered alone. Regional injection of 16.5 microM 57Co microspheres resulted in a N:T ratio of 2.25:1. Concomitant injection of the 40 microM DSM was 57Co microspheres reversed this ratio to 1:2. The results indicate that DSM selectively enhances the retention of MDP to a hypovascular hepatic tumour, not by causing intra-tumour stasis, but by directing a greater arterial flow to hypovascular areas in the liver.

Animals↗
PubMed1996

Smoking, hypertension, and colonic anastomotic healing; a combined clinical and histopathological study.

BACKGROUND: Large bowel anastomotic breakdown occurs as a result of perianastomotic ischaemia. Preservation of the macroscopic arterial supply to the perianastomotic tissues is vital, but little is known about the influence of microvascular disease on anastomotic healing. AIMS: To study the associations between risk factors for macrovascular disease, the presence of colonic microvascular disease, and the incidence of anastomotic dehiscence. PATIENTS: 147 consecutive colonic surgery patients. METHODS: The prevalence of smoking, hypertension, diabetes, and ischaemic heart disease were established retrospectively from patient notes. These risk factors were correlated with histopathological assessment of resection margin vasculature and clinical follow up. RESULTS: Smoking and hypertension were significantly associated with an increased incidence of anastomotic dehiscence and microvascular disease. Microvascular disease was positively correlated with an increased incidence of anastomotic dehiscence. CONCLUSIONS: Microvascular disease predisposes to anastomotic breakdown. This effect may in part be due to vasospasm in the diseased vessels, which are hypersensitive to serotonin, a vasoactive amine known to be present in increased quantities in the serum of smokers, hypertensives, and after surgery. Treatment with serotonin antagonists in the perioperative period may be beneficial to anastomotic healing, helping to maintain microvascular flow.

Aged↗
PubMed1995

Octreotide inhibits the growth and development of three types of experimental liver metastases.

A study was performed to assess the effects of octreotide on the growth and development of liver metastases in rats. Tumour was induced by intraportal injection of three tumorigenic cell lines (the fibrosarcoma HSN and colonic adenocarcinomas K12/Tr and WB2054M) in syngeneic rats. Octreotide treatment (2 micrograms subcutaneously for 3 or 4 weeks) was started 18 h and 1 week after tumour induction; a delay in treatment of 1 week allowed micrometastases to develop. Treatment with octreotide significantly (P < 0.001) reduced the median hepatic replacement of liver by tumour compared with that of control rats given saline (controls: HSN 76.4 per cent, K12/Tr 17.5 per cent, WB2054M 43.9 per cent; octreotide treatment delayed 18 h: HSN 2.7 per cent, K12/Tr 0.6 per cent, WB2054M 1.3 per cent; octreotide treatment delayed 1 week: HSN 9.3 per cent, K12/Tr 2.5 per cent, WB2054M 2.3 per cent). These results clearly indicate that octreotide significantly inhibits the growth and development of experimental liver metastases. Further studies are required both to delineate the mechanism of action and to investigate these effects in a clinical setting.

Animals↗
PubMed1995

Assessment of feasibility for endovascular prosthetic tube correction of aortic aneurysm.

Abdominal aortic aneurysm (AAA) can now be corrected by perfemoral introduction of a prosthetic tube graft with fixation using expandable metal stents. This technique requires a satisfactory iliac system, through which the graft can reach its destination, and suitable lengths of non-aneurysmal aorta below the renal arteries and above the aortic bifurcation for stent attachment. The feasibility for placement of endovascular grafts was assessed in 44 consecutive patients admitted for transabdominal AAA repair. The proximal and distal aneurysmal necks and the iliac arteries were assessed before operation by colour flow Doppler ultrasonography (duplex scanning), computed tomography and intravenous digital subtraction angiography, using intraoperative measurements as the 'gold standard'. At operation 32 of 44 patients had a suitable proximal neck and five of 44 a suitable distal neck for endovascular grafting. Duplex scanning was the most accurate modality for preoperative assessment of the aneurysm necks. According to this technique 32 of 44 patients had a satisfactory iliac system for introduction of an endovascular graft. Overall only four of 44 patients were considered suitable for endovascular correction of AAA using a tube graft-stent combination.

Aged↗
PubMed1995

Microvascular disease and anastomotic dehiscence in the colon.

Platelet-derived serotonin released in response to tissue manipulation during surgery may contribute to mesenteric arterial vasospasm leading to postoperative anastomotic leakage after colorectal resection. Organ bath experiments were used to demonstrate the efficacy of naftidrofuryl fumarate (NFT) to oppose serotonin-induced vasoconstriction of human mesenteric arteries. Cumulative dose-response curves were derived with and without NFT at 10(-9) and 10(-6) mol/l concentrations. The difference in maximal contractility between the three sets of curves (n = 8 for each) was significant (P < 0.0001). Sensitivity to serotonin in each of the three curves was measured by calculating the concentration for half-maximal response; differences were again significant (P < 0.0001). NFT reduced serotonin-induced contractility in a dose-dependent fashion in rings of human mesenteric arteries in vitro. This suggests a possible role for NFT in reducing mesenteric vasospasm in colorectal surgery.

Anastomosis, Surgical↗
PubMed1995

In vitro evaluation of endovascular stents to assess suitability for endovascular graft fixation.

OBJECTIVE: To compare and ascertain the suitability for endovascular aortic graft fixation of the Palmaz stent, the Strecker stent, the modified Gianturco-Z stent, the Wallstent and a new stent made of the shape memory alloy nitinol. DESIGN, SETTING AND MATERIALS: In vitro studies using a simple tensiometer to assess the forces required to distract each stent from porcine aorta; and using a high-pressure, pulsatile-flow pump to measure flow rates required to dislodge stents holding grafts within porcine aortas, with assessment using endovascular ultrasound. RESULTS: The Palmaz, the modified Gianturco-Z and the nitinol stents resisted significantly greater distraction forces than the Wallstent, but endovascular ultrasound examination revealed that the modified Gianturco-Z stent was seen to move away from the aortic wall at high flow rates precluding adequate fixation. The Strecker stent could not be assessed using these techniques. CONCLUSIONS: A nitinol stent may be suitable for aortic graft fixation, has characteristics similar to the Palmaz stent and has shape memory effect which may overcome the difficulties of introduction of wider diameter stents through narrow arteries.

Alloys↗
PubMed1995

Effect of octreotide infusion on hepatic and tumour blood flow in two experimental models of liver metastases.

OBJECTIVE: To investigate the effects of octreotide infusion on hepatic and tumour blood flow in rats with experimentally induced liver tumours. DESIGN: Blood flow was determined in tumour-bearing rats using a dual reference microsphere technique before and after intravenous infusion of octreotide. METHODS: Tumours were induced in syngeneic rats by intraportal injection of K12-Tr and WB2054-M adenocarcinoma cells. Hepatic arterial and portal venous inflow, tumour blood flow and systemic arterial pressure were determined before and after octreotide infusion (0.05 microgram/min). RESULTS: In rats with K12-Tr tumours there was no change in tumour blood flow, hepatic arterial flow or portal venous inflow after octreotide infusion. In contrast, in rats with WB2054-M tumours, octreotide infusion resulted in a significant reduction in the blood flow to the hepatic tumour (from 0.37 to 0.135 ml/min/g) but had no effect on hepatic artery or portal venous inflow. CONCLUSION: The reduction in blood flow to tumours derived from WB2054-M cells could, at least in part, explain the inhibitory effect of octreotide on the growth and development of these tumours. However, octreotide had no effect on blood flow to tumours derived from K12-Tr cells, suggesting that the analogue must inhibit tumour growth by other mechanisms.

Adenocarcinoma↗
PubMed1995

Fluctuations in the secretion of pancreatic enzymes between consecutive doses of octreotide: implications for the management of fistulae.

OBJECTIVE: To determine whether variations in pancreatic enzyme secretion between consecutive subcutaneous administrations of octreotide explain why octreotide takes longer than somatostatin to facilitate the closure of gastrointestinal fistulae. METHODS: Pancreatic enzyme secretion was studied over a 3-day period in a patient with a catheter left in the pancreatic duct postoperatively. On days 1 and 3 the patient did not receive octreotide (control days) but on day 2 he received subcutaneous octreotide 100 micrograms every 8 h. Pancreatic juice was collected at 2-h intervals over the 3-day period. RESULTS: On the day of octreotide treatment, the patient's pancreatic secretory volume and protein output were significantly reduced (P < 0.001, Mann-Whitney U-test) compared with the 2 control days. The pancreatic secretory volume decreased markedly after the first injection of octreotide and remained low for the duration of the treatment period. The enzyme concentration of the pancreatic juice was also markedly reduced after the first injection of octreotide. However, approximately 4h after each octreotide injection the protein concentration of the pancreatic juice began to rise progressively, peaking approximately 6h after each administration of the analogue. CONCLUSION: Subcutaneous administration of octreotide produces a sustained decrease in the volume of pancreatic juice secreted, but enzyme secretion rises progressively between consecutive administrations of the analogue. The net effect is therefore the production of low volumes of pancreatic juice with a high enzyme concentration between consecutive injections of octreotide, which may delay the healing of the fistula tract. This may explain why longer treatment periods are required to achieve fistula closure with octreotide than with somatostatin, particularly in the case of pancreatic fistulae.

Humans↗