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Biomedical subjects

A R Moossa

Publications and source records attributed to A R Moossa.

At least 73 records · Page 4Linked to original sources
PubMed1997

Conversion of highly malignant colon cancer from an aggressive to a controlled disease by oral administration of a metalloproteinase inhibitor.

In this study, we describe the activity of CT1746, an orally-active synthetic MMP inhibitor that has a greater specificity for gelatinase A, gelatinase B and stromelysin than for interstitial collagenase and matrilysin, in a nude mouse model that better mimics the clinical development of human colon cancer. The model is constructed by surgical orthotopic implantation (SOI) of histologically-intact tissue of the metastatic human colon tumor cell line Co-3. Animals were gavaged with CT1746 twice a day at 100 mg/kg for 5 days after the SOI of Co-3 for 43 days. In this model CT1746 significantly prolonged the median survival time of the tumor-bearing animals from 51 to 78 days. Significant efficacy of CT1746 was observed on primary tumor growth (32% reduction in mean tumor area at day 36), total spread and metastasis (6/20 treated animals had no detectable spread and metastasis at autopsy compared to 100% incidence of secondaries in control groups). Efficacy of CT1746 could also be seen on reducing tumor spread and metastasis to individual organ sites such as the abdominal wall, cecum and lymph nodes compared to vehicle and untreated controls. We conclude that chronic administration of a peptidomimetic MMP inhibitor via the oral route is feasible and results in inhibition of solid tumor growth, spread and metastasis with increase in survival in this model of human cancer, thus converting aggressive cancer to a more controlled indolent disease.

Amides↗
PubMed1995

Liver colonization competence governs colon cancer metastasis.

Tumors that metastasize do so to preferred target organs. To explain this apparent specificity, Paget, > 100 years ago, formulated his seed and soil hypothesis; i.e., the cells from a given tumor would "seed'' only favorable "soil'' offered by certain groups. The hypothesis implies that cancer cells must find a suitable "soil'' in a target organ--i.e., one that supports colonization--for metastasis to occur. We demonstrate in this report that ability of human colon cancer cells to colonize liver tissue governs whether a particular colon cancer is metastatic. In the model used in this study, human colon tumors are transplanted into the nude mouse colon as intact tissue blocks by surgical orthotopic implantation. These implanted tumors closely simulate the metastatic behavior of the original human patient tumor and are clearly metastatic or nonmetastatic to the liver. Both classes of tumors were equally invasive locally into tissues and blood vessels. However, the cells from each class of tumor behave very differently when directly injected into nude mouse livers. Only cells from metastasizing tumors are competent to colonize after direct intrahepatic injection. Also, tissue blocks from metastatic tumors af fixed directly to the liver resulted in colonization, whereas no colonization resulted from nonmetastatic tumor tissue blocks even though some growth occurred within the tissue block itself. Thus, local invasion (injection) and even adhesion to the metastatic target organ (blocks) are not sufficient for metastasis. The results suggest that the ability to colonize the liver is the governing step in the metastasis of human colon cancer.

Adenocarcinoma↗
PubMed1995

Host organ specifically determines cancer progression.

In order to further understand the role of the host organ in tumor progression, we have transplanted into nude mice histologically intact human colon cancer tissue on the serosal layers of the stomach (heterotopic site) and the serosal layers of the colon (orthotopic site). Xenograft lines Co-3, which is well differentiated, and poorly differentiated COL-3-JCK were used for transplantation. After orthotopic transplantation of the human colon tumors on the nude mouse colon, the growing colon tumor resulted in macroscopically extensive invasive local growth in 4 of 10 mice, serosal spreading in 9 of 10 mice, musclaris propria invasion in 1 of 10 mice, submucosal invasion in 3 of 10 mice, mucosal invasion in 3 of 10 mice, lymphatic duct invasion in 4 of 10 mice, regional lymph node metastasis in 4 of 10 mice, and liver metastasis in 1 of 10 mice. In striking contrast, after heterotopic transplantation of the human colon tumor on the nude mouse stomach, a large growing tumor resulted but with only limited invasive growth and without serosal spreading, lymphatic duct invasion, or regional lymph node metastasis. It has become clear from these studies that the orthotopic site, in particular the serosal and subserosal transplant surface, is critical to the growth, spread, and invasive and metastatic capability of the implanted colon tumor in nude mice. These studies suggest that the original host organ plays the same critical role in tumor progression.

Animals↗
PubMed1995

Metabolic effects of troglitazone on fat-induced insulin resistance in the rat.

Troglitazone is a new orally active hypoglycemic agent that has been shown to ameliorate insulin resistance and hyperinsulinemia in both diabetic animal models and non-insulin-dependent diabetes mellitus (NIDDM) subjects. To determine whether this drug could prevent the development of diet-induced insulin resistance and related abnormalities, we studied its effect on insulin resistance induced by high-fat feeding in rats. Normal male Sprague-Dawley rats were fed a high-fat diet for 3 weeks with and without troglitazone as a food mixture (0.2%) or were fed normal chow. In vivo insulin action was measured using a euglycemic-hyperinsulinemic clamp at two different insulin infusion rates, 4 (submaximal stimulation) and 40 (maximal stimulation) mU/kg/min. Fat feeding markedly reduced the submaximal glucose disposal rate ([GDR], 26.4 +/- 1.3 v 37.5 +/- 1.4 mg/kg/min, P < .01) and maximal GDR (55.9 +/- 1.3 v 64.5 +/- 1.3 mg/kg/min, P < 0.5), reduced the suppressibility of submaximal hepatic glucose production ([HGP], 3.2 +/- 0.9 v 1.5 +/- 0.5 mg/kg/min, P < .05), and resulted in hyperlipidemia. Troglitazone treatment did not affect any of these parameters. Insulin resistance induced by fat feeding is the first experimental model in which troglitazone failed to correct or partially correct the insulin resistance.

Animals↗
PubMed1995

Diagnosis and staging of pancreatic neoplasms.

The relative value of current approaches to the diagnosis and staging of pancreatic cancer is discussed. A rational sequence of testing is recommended based on the clinical presentation of the patient and the local institutional expertise and facilities that are available.

Angiography↗
PubMed1995

Kinetics of insulin action in vivo. Identification of rate-limiting steps.

To examine the kinetic steps in insulin's in vivo action, we have assessed the temporal relationship between arterial insulin, interstitial insulin, glucose disposal rate (GDR), and insulin receptor kinase (IRK) activity in muscle and between portal insulin, hepatic glucose production (HGP), and IRK activity in liver. Interstitial insulin, as measured by lymph-insulin concentration (muscle only), and IRK activity were used as independent methods to determine the arrival of insulin at its tissue site of action. Euglycemic clamps were conducted in seven mongrel dogs and consisted of an activation phase with a venous insulin infusion (7.2 nmol.kg-1.min-1, 100 min) and a deactivation phase. Liver and muscle biopsies were taken to assess IRK activity. Arterial, portal, and lymph insulin rose to 636 +/- 12, 558 +/- 18, and 402 +/- 24 pmol/l, respectively. GDR increased from 13.9 +/- 0.6 to 41.7 +/- 2.8, and HGP declined from 14.4 +/- 0.6 to 1.1 +/- 0.6 mumol.kg-1.min-1. Muscle and liver IRK activity increased significantly from 5.9 +/- 0.9 to 14.6 +/- 0.6 and 5.5 +/- 0.7 to 23.7 +/- 1.9 fmol P/fmol insulin receptor (IR), respectively. The time to half-maximum response (t1/2a) for stimulation of GDR (19.8 +/- 4.8 min) and suppression of HGP (21.5 +/- 3.7 min) were similar. The t1/2a for stimulation of GDR, muscle IRK, and rise in lymph insulin were not significantly different from one another and were all markedly greater than that for the approach to steady state of arterial insulin (2.3 +/- 1.2 min, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Islet amyloid polypeptide (amylin) increases the renal excretion of calcium in the conscious dog.

Islet amyloid polypeptide (IAPP) is a member of the calcitonin/CGRP family and has been isolated from the beta-cell of pancreatic islets. Recent evidence suggests that this peptide may be involved in calcium metabolism in that its administration resulted in lowering of serum calcium levels. To determine the mechanism of IAPP-induced hypocalcemia, the peptide was infused at 50 pmol/min/kg for 90 minutes in conscious male mongrel dogs. Infusion of the peptide resulted in a modest decline in the total serum calcium concentration (10.4 +/- 0.2 to 9.4 +/- 0.2 mg/dl; P < 0.05) and a concomitant increase in urinary calcium excretion (3.6 +/- 0.6 to 6.9 +/- 2.0 mg/dl; P < 0.01). Based on an extracellular volume of 7 liter in a 28 kg dog, the total decrement in calcium due to IAPP was 41.3 +/- 2.4 mg, whereas the total increase in urinary calcium was 3.2 +/- 0.7 mg. There were no detectable changes in calcitonin. We conclude that IAPP lowers serum calcium and increases the renal excretion of calcium independently of calcitonin. However, the calciuria can only account for a small component of the hypocalcemic effect and therefore, an additional calcium lowering effect of IAPP exits.

Amyloid↗
PubMed1994

Metabolic effects of troglitazone on fructose-induced insulin resistance in the rat.

Troglitazone is a new orally active hypoglycemic agent that has been shown to reduce insulin resistance and hyperinsulinemia in both diabetic animal models and non-insulin-dependent diabetes mellitus (NIDDM) subjects. To determine whether this drug could prevent the development of fructose-induced insulin resistance and related abnormalities, we studied the effects of troglitazone on the insulin resistance induced by fructose feeding in rats. Normal male Sprague-Dawley rats were fed a high-fructose diet for 3 weeks with and without troglitazone as a food admixture (0.2%) or were fed normal chow to serve as a control group. In vivo insulin resistnace was measured by the euglycemic hyperinsulinemic clamp technique at two different insulin infusion rates, 29 (submaximal stimulation) and 290 (maximal stimulation) pmol.kg-1.min-1. Fructose feeding markedly reduced submaximal glucose disposal rate (GDR) (113.8 +/- 8.3 vs. 176.0 +/- 5.6 mumol.kg-1.min-1, P < 0.05) and maximal GDR (255.9 +/- 5.6 vs. 313.6 +/- 10.5 mumol.kg-1.min-1, P < 0.05), reduced the suppressibility of submaximal hepatic glucose production (HGP; 45.5 +/- 5.0 vs. 11.7 +/- 5.0 mumol.kg-1.min-1, P < 0.05), and resulted in hypertriglyceridemia and hypertension. Troglitazone treatment completely restored the GDR (submaximal 158.2 +/- 5.6, maximal 305.3 +/- 6.1 mumol.kg-1.min-1) and submaximal HGP (9.4 +/- 2.8 mumol.kg-1.min-1) to control levels and also normalized the elevated plasma triglyceride concentration and systolic blood pressure levels in fructose-fed rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Complications of laparoscopic cholecystectomy: coordinated radiologic and surgical management in 21 patients.

The authors describe their experience in management of bile duct injuries (n = 11), bile leaks or abscesses (n = 11), and bleeding (n = 1) as complications of laparoscopic cholecystectomy in 21 patients. Clinical presentations included jaundice, sepsis, pain, abdominal distention, and persistent gallstones. Twelve patients underwent operative cholangiography, three underwent conversion to open cholecystectomy, and 12 reoperations were performed in nine patients before interventional radiologic procedures, which included diagnostic percutaneous transhepatic cholangiography (n = 13), percutaneous biliary drainage (PBD) (n = 13), percutaneous stricture dilation (n = 3), stent insertion (n = 1), percutaneous abscess or biloma drainage (n = 19), and gallstone removal (n = 1). Each procedure was technically successful. Clinical improvement occurred in 18 of 19 patients. PBD was used as an operative guide before reconstructive surgery in two patients. Reoperation was unnecessary in 10 of 21 patients (48%). One patient died of fungal sepsis and pulmonary complications. This radiologic-surgical approach provided rapid and safe management of these complications.

Adult↗
PubMed1992

Systemic and local toxicity in the rat of methyl tert-butyl ether: a gallstone dissolution agent.

Methyl tert-butyl ether (MTBE) is an organic solvent that has been used to dissolve gallstones via a percutaneous transhepatic catheter into the gallbladder. To test whether MTBE might cause serious tissue injury if accidentally infused outside the gallbladder, the effect of MTBE (0.2 ml/kg) injected into the hepatic parenchyma, or administered intravenously or intraperitoneally, was examined in the rat. The toxicity of isopropyl acetate (IPA), an organic solvent with a similar chemical structure, was examined similarly. Intracaval injection of MTBE caused the highest mortality (100%). Mortality was less (59%) after intrahepatic injection and still less (17%) after peripheral vein injection. Most animals died instantaneously from cardiorespiratory arrest. Almost all animals that were injected with MTBE intrahepatically or intravenously showed localized areas of congestion, hemorrhage, and interstitial edema in the lungs. These changes were more severe in rats which survived for 24 hr than in those which died sooner. In those rats receiving intrahepatic injections, most rats which survived for 24 hr had liver necrosis at the site of injection. Intraperitoneal injection of MTBE produced 100% survival with only 1/5 rats showing a mild pulmonary injury at autopsy. IPA had toxic effects similar to those evoked by MTBE. To test whether tumor necrosis factor was involved in organ injury, serum levels were measured; they remained unchanged. These experiments indicate that two organic solvents, MTBE and IPA, are cytotoxic to local tissues and cause severe, and often fatal, lung damage when infused into a central vein. Less toxicity occurred if solvents were given into a peripheral or portal vein or intraperitoneally.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetates↗
PubMed1992

Laparoscopic injuries to the bile duct. A cause for concern.

The authors report six patients who had injuries to their common hepatic bile duct at laparoscopic cholecystectomy over a 16-month period. Five of the six complications could be attributed to laser injuries during dissection in the region of Calot's triangle. The authors discuss the possible mechanism of these injuries, their perioperative management, and the methods of surgical reconstruction. The follow-up period ranges from 3 months to 21 months. Liver function parameters and isotope biliary excretion scans are back to normal in all six patients. The potential hazards of laparoscopic surgery demand that extraordinary care be used not only during the actual surgical procedure, but also in the preoperative decision concerning the dissection method to be employed.

Adult↗
PubMed1992

Recovery and hypersecretion of insulin and reversal of insulin resistance after withdrawal of short-term cyclosporine treatment.

We have previously demonstrated decreased insulin release and insulin resistance in dogs treated with cyclosporine (20 mg/kg/day). In this study we examine the changes caused by a lower CsA dose and evaluate the reversal of these changes. Six animals were treated for 2 weeks with oral CsA (15 mg/kg/day), after which CsA was discontinued. Glucagon stimulation tests (GST) and euglycemic clamp studies (ECS) were used to evaluate changes in insulin release and insulin resistance. GST were performed before CsA, after 2 weeks of CsA, and 3, 9, and 15 days after discontinuing CsA. ECS were performed before CsA, after 2 weeks of CsA, and 2, 4, 8, and 14 days after discontinuing CsA. The mean serum CsA level after 2 weeks of treatment was 188 +/- 28 ng/ml. GST demonstrated decreased insulin release during CsA with recovery and hypersecretion after CsA withdrawal. ECS showed peripheral insulin resistance during CsA with a rapid recovery and a temporary increase in insulin sensitivity after CsA withdrawal. Comparisons were made with our previous study group given 20 mg/kg/day of CsA. In summary, CsA induces a dose-dependent impairment of glucose homeostasis due to inhibition of insulin release and development of peripheral insulin resistance. Withdrawal of short-term CsA at commonly used therapeutic doses results in reversal of and temporary overcompensation for these changes. CsA withdrawal after long-term treatment results in a slower normalization of the insulin response as compared with after short-term treatment. The hypersecretory reaction of the beta cell may be of help in further investigations of mechanisms of CsA- and FK506-induced inhibition of insulin release.

Animals↗
PubMed1991

Human gallbladder morphology after gallstone dissolution with methyl tert-butyl ether.

The effects of methyl tert-butyl ether exposure on the human gallbladder in five patients who were treated for gallstones by contact dissolution is described. Two patients underwent cholecystectomy within 1 week of methyl tert-butyl ether treatment, one patient 2 weeks after, another 10 weeks after, and one 12 weeks after. Indications for cholecystectomy were bilirubinate stones (resistant to methyl tert-butyl ether), catheter dislodgement, bile leakage, and gallstone recurrence (2 patients). Gallstones were dissolved completely in three patients, there was approximately 50% stone reduction in one patient, and no dissolution occurred in the fifth patient. Each gallbladder was examined grossly and histologically. Electron microscopic evaluation was performed in one cases. Typical inflammatory findings of chronic cholecystitis were observed in each gallbladder and were most conspicuous in the submucosa; the mucosal and serosal surfaces were intact. Mild acute inflammatory changes were noted in the submucosa in the two patients with the shortest interval between methyl tert-butyl ether administration and cholecystectomy. There were no ulcerations in the mucosa and no unusual wall thickening or fibrosis in any patient. These observations support the safety of methyl tert-butyl ether perfusion in the human gallbladder; the mild acute changes may be a transient and reversible phenomenon.

Cholecystectomy↗
PubMed1991

Lack of effect of islet amyloid polypeptide in causing insulin resistance in conscious dogs during euglycemic clamp studies.

In this study, we administered constant intravenous infusions of human islet amyloid polypeptide (hIAPP) to conscious dogs during euglycemic glucose-clamp studies. The doses of hIAPP used (5 and 50 pmol.kg-1.min-1) raised the circulating IAPP levels approximately 12- and 50-fold above basal levels, respectively. Studies were conducted at two different insulin infusion rates, resulting in steady-state plasma insulin levels of approximately 600 and 2800 pM. According to our results, the hIAPP infusions did not lead to any measurable change in the insulin-stimulated glucose disposal rate at either insulin infusion rate. Additionally, we observed no effect of IAPP on hepatic glucose production. Although we did not observe any effect of hIAPP on any of the aspects of glucose or insulin metabolism measured, we did find a consistent hypocalcemic effect of this peptide at the 50-pmol.kg-1.min-1 infusion rate. Shortly after the onset of hIAPP infusion, serum calcium levels fell by 10-15% and remained at these levels throughout the course of the hIAPP infusion. In summary, 1) infusion of hIAPP at doses of 5 or 50 pmol.kg-1.min-1 in conscious dogs raised the circulating IAPP level 12- to 50-fold above basal; 2) during these infusion studies, no effect of hIAPP was observed on any of the aspects of glucose or insulin homeostasis measured; 3) 50 pmol.kg-1.min-1 hIAPP lead to a prompt reduction in plasma calcium concentrations with intravenous administration.

Amyloid↗
PubMed1990

Iatrogenic injury to the bile duct. Who, how, where?

We reviewed 81 patients with bile duct injuries that occurred at cholecystectomy and/or common bile duct exploration. Thirty-two of the strictures were recurrent. The median follow-up was 9 years. High injuries were inflicted during the performance of cholecystectomy while low injuries were related to common bile duct exploration. Mitigating circumstances appear to be as follows: (1) inadequate access, exposure, and assistance; (2) absence of operative cholangiogram; (3) patient's obesity; and (4) early dissection of Calot's triangle. Noncontributory factors include the following: (1) level of training of surgeon, and (2) type of institution where the operation was performed. Following repair, 15 patients eventually died and 8 suffered intermittent cholangitis and/or cirrhosis. Mortality and morbidity were related to the following: (1) level of stricture; (2) number of previous attempts at repair; and (3) adequacy of reconstruction. Mucosa-to-mucosa anastomosis without tension is essential for optimal results.

Adult↗
PubMed1990

Effect of pancreas allografts on the ultrastructure of sciatic nerves in diabetic rats.

In a long-term study using cyclosporin-A (Cy-A) as immunosuppressant in a dose of 10 mg/kg/day, pancreas-duodenum was transplanted from Brown-Norway donors to alloxan-diabetic Lewis rats (n = 190). The pancreas transplants (PT) were performed after 1, 3, 6, 9, 12, and 15 months of diabetes. Recipient rats were sacrificed between 3 and 12 months of graft retainment. The mean axonal cross-sectional area and relative percentage of small, medium, and large myelinated fibers was evaluated. Also studied were unmyelinated fiber, ovoid body, and glycogen inclusion densities. Control rats consisted of non-diabetic rats (n = 36), similar rats receiving Cy-A (n = 42), diabetic rats (n = 103), and diabetic rats receiving Cy-A (n = 45). It was found that PT had a beneficial effect on the axonal cross-sectional area of myelinated nerves, the relative percentage of the various sizes of nerve fibers, and the ovoid body density, especially so in early diabetes. The effects in late diabetes were less spectacular. PT did not prove beneficial to the glycogen inclusion and unmyelinated fiber densities.

Animals↗
PubMed1990

Effect of pancreatic allografts on vascular basement membrane thickness in the diabetic rat.

Diabetic Lewis rats received pancreaticoduodenum allotransplants from Brown-Norway donors. Cyclosporine A (Cy-A) was used in a dose of 10 mg/kg/day for immunosuppression. These transplanted rats (n = 190) were compared with nondiabetic Lewis rats (n = 36), nondiabetic Lewis rats receiving 10 mg/kg/day Cy-A (n = 42), diabetic rats (n = 103), and diabetic rats receiving 10 mg/kg/day Cy-A (n = 45). The percentage area of periodic acid-Schiff (PAS) positive basement membrane (BM) of rectus muscle microvasculature was compared in each of the groups. It was found that the percentage area of PAS positive BM increased markedly over 15 months of uncontrolled diabetes. Cy-A did not have a significant effect on either normal or diabetic skeletal muscle vascular BM. Rats with established diabetes showed some reversal in the percentage area of PAS positive BM, when pancreas transplantation was performed at 9, 12, and 15 months of diabetes. Pancreas transplantation may appear beneficial even after the development of BM thickening of skeletal muscle vascular BM.

Abdominal Muscles↗