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Biomedical subjects

E Z Dajani

Publications and source records attributed to E Z Dajani.

At least 19 recordsLinked to original sources
PubMed1998

Effects of tolcapone, a catechol-O-methyltransferase inhibitor, and Sinemet on intestinal electrolyte and fluid transport in conscious dogs.

Tolcapone (T) is a novel catechol-O-methyltransferase (COMT) inhibitor recently introduced for the treatment of Parkinson's disease. In clinical efficacy studies, T has been associated with a low incidence of diarrhea. The objectives of the study were to examine whether T and its adjunctive drug Sinemet (S) could influence intestinal fluid and electrolyte transport as a possible cause for the diarrhea. The studies were conducted in conscious dogs surgically prepared with Thiry-Vella loops constructed from a 40-cm jejunal segment. A physiologically buffered test solution was perfused into the orad stoma and collected from the caudad stoma. Secretions were collected at 15-min intervals and analyzed for volume, electrolytes, lipid phosphorus, and protein. The acute oral administration of T (10 and 30 mg/kg doses) was well tolerated. Concurrent acute administration of S (25 mg/kg) with T (30 mg/kg) was also well tolerated. The acute oral administration of T induced a dose-dependent efflux of intestinal fluid and electrolytes (sodium, potassium, chloride, and bicarbonate) secretion (P < 0.05). The oral coadministration of S (25 mg/kg) with T (30 mg/kg) accelerated the onset of the stimulation of intestinal secretion. Despite the significant stimulation of intestinal secretion, none of the dogs developed diarrhea, indicating the importance of intestinal compensatory mechanisms. Neither T nor T&S affected calcium, lipid, or protein efflux rates, suggesting that the stimulated secretion was not a consequence of intestinal mucosal injury. The chronic (seven-day) administration of T and T&S was associated with reduced intestinal secretory responses when compared with the acute administration of the same drugs; S enhanced the T-induced tolerance development. The basis for such tolerance is unknown. In conclusion, the stimulatory systemic actions of tolcapone on intestinal secretion may, under certain conditions, contribute to the induction of diarrhea in susceptible patients.

Animals↗
PubMed1998

Idiopathic esophageal ulceration in acquired immunodeficiency syndrome: successful treatment with misoprostol and viscous lidocaine.

OBJECTIVE: Esophageal ulceration is a common and important cause of morbidity in patients with acquired immunodeficiency syndrome (AIDS). After known causes are excluded, a subgroup remains with unexplained esophageal ulceration, known as idiopathic esophageal ulceration (IEU). The current therapy of IEU includes corticosteroids or, less frequently, thalidomide, although no placebo-controlled trials have been reported. The aim of this retrospective study was to determine the outcome of treating IEU with misoprostol and viscous lidocaine. METHODS: A retrospective review of esophageal ulceration in AIDS identified seven subjects with IEU at our institution. IEU in these subjects was treated successfully with misoprostol, 200 microg, crushed and suspended in 2% viscous lidocaine, 15 ml, given orally a.c. and h.s. for 4 wk. RESULTS: All patients reported symptomatic improvement within 2-3 days and complete resolution of their symptoms within 15 days. Healing of esophageal ulcerations was confirmed in five of seven subjects at a repeat endoscopy 8-12 wk later. CONCLUSIONS: Misoprostol, an antiulcer drug, has GI cytoprotective properties, and viscous lidocaine, a topical anesthetic, coats mucosal surfaces. We speculate that misoprostol when delivered topically is 3-6 times more effective than when delivered systemically. Considering the rapid resolution of symptoms, healing of ulcers, and lack of side effects, we believe that misoprostol crushed and suspended in viscous lidocaine should be considered for further evaluation in prospective, placebo-controlled trials of IEU.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Chronic systemic treatment with epidermal growth factor induces smooth muscle cell hyperplasia and hypertrophy in the urinary tract of mature Goettingen minipigs.

OBJECTIVE: To determine the effect of systemic treatment with epidermal growth factor (EGF) on the induction of growth in the urinary tract. MATERIALS AND METHODS: Mature Goettingen minipigs were treated daily with vehicle (Tris-HCl; n = 5) or EGF (30 micrograms/kg) (n = 6) for 4 weeks. The total number of smooth muscle cells was counted using an optical disector in a 20 microns thick cross-section of the ureter and the mean smooth muscle cell volume estimated. Cell proliferation was detected by immunostaining for the marker Ki67. RESULTS: The ureters of the animals treated with EGF were longer and thicker than those of the controls and the median cross-sectional area of the ureter was 3.3-fold larger; the growth involved all wall layers. The median (range) number of smooth muscle cells in a 20 microns thick cross-section of the ureter was 11 (9-12) x 10(3) in the pigs treated with placebo and 55 (19-80) x 10(3) in those treated with EGF, and the median (range) volume of the smooth muscle cells was 2.3 (2.2-2.4) x 10(3) and 4.0 (3.0-4.5) x 10(3) mm3, respectively. CONCLUSIONS: There were two likely mechanisms contributing to smooth muscle cell hyperplasia, the division of fully differentiated smooth muscle cells and division of fibroblasts in the borderline between the submucosal layer and muscular coat, with ensuing differentiation into smooth muscle cells. Treatment with EGF induces the growth of all wall layers in the urinary tract with remarkable hyperplastic and hypertrophic changes of the smooth muscle cells in the muscular coat.

Actins↗
PubMed1997

Systemic treatment with epidermal growth factor in pigs induces ductal proliferations in the pancreas.

BACKGROUND & AIMS: Epidermal growth factor (EGF), transforming growth factor alpha (TGF-alpha), and the EGF receptor are often overexpressed in chronic pancreatitis and in malignant pancreatic growth. Transgenic mice overexpressing TGF-alpha develop tissue changes in the pancrease resembling changes found in chronic pancreatitis. The effects of systemic treatment with EGF on the porcine pancrease were investigated in this study. METHODS: Mature Goettingen minipigs were treated with solvent (n = 5), EGF (30 micrograms.kg-1.day-1; n = 6) for 4 weeks, or EGF (30 micrograms.kg-1.day-1; n = 5) for 5 weeks followed by 3 weeks of recovery. Pancreata were studied by routine histological examination and electron microscopy and were immunostained for proliferating cell nuclear antigen (PCNA). RESULTS: In the EGF-treated animals, mainly larger interlobular ducts of the pancreas appeared to be considerably hyperplastic, with an increased number of nuclei that stained for PCNA. The epithelia of these ducts were increased in height, with accumulations of glycoconjugates in the columnar cells and in an increased number of goblet cells. CONCLUSIONS: A new approach to experimentally induced hyperplastic changes of the excretory ducts of the pancreas is presented. Because ductal changes with glycoconjugate accumulations are common features of chronic pancreatitis and pancreatic cancer, the findings may be relevant to the pathogeneses of these conditions.

Animals↗
PubMed1996

Impedance planimetric characterization of the distal oesophagus in the Goettingen minipig.

Regional differences in biomechanical properties of the oesophagus were studied in 15 healthy Goettingen minipigs by means of impedance planimetry. The investigation was performed during anaesthesia by stepwise pressure-induced balloon distensions with concomitant measurement of pressure and luminal cross-sectional area (CSA) in the oesophagus 5 and 10 cm above the gastro-oesophageal junction. The circumferential wall tension, circumferential strain and incremental elastic modulus were computed from the measurements of pressure and CSA at steady-state conditions. Probably due to the anaesthesia, only scant peristalsis was recorded and the CSA always reached steady state during the balloon distensions. The CSAs were highest in the distal oesophagus (P < 0.001). At the highest induced pressure, the CSAs were 605 +/- 32 and 453 +/- 29 mm2 (mean +/- SEM) for the locations 5 and 10 cm from the gastro-oesophageal junction. The tension-strain distributions were non-linear and the curve obtained 5 cm above the gastro-oesophageal junction was shifted to the right when compared with the curve obtained from 10 cm above this junction. Fitting of the function tension = exp(a+b strain) to the data gave determination coefficients higher than 0.97 and P values lower than 0.001 for both measuring points. The constant a differed between the two locations in the oesophagus (P < 0.05). In conclusion, the pressure-CSA and the tension-strain distributions differed between the two measuring points suggesting that the elastic properties are different.

Anesthesia, General↗
PubMed1996

The effect of epidermal growth factor on circulating levels of IGF and IGF-binding proteins in adult Goettingen minipigs.

It has recently been demonstrated that epidermal growth factor (EGF) administration to neonatal rodents causes growth retardation with concomitant reductions in circulation levels of IGF-I. We describe the effects of systemic EGF administration for 4 weeks on circulating levels of IGF-I and IGF-binding proteins (IGFBPs) and on thyroid hormones (tri-iodothyronine, T3; thyroxine, T4) in sexually mature pigs. Goettingen minipigs of either sex were treated with placebo (n = 5) or EGF (30 micrograms/kg per day, n = 6) s.c. for 4 weeks (in relation to an oesophageal sclerotherapy regimen). Blood samples were taken under anaesthesia before and after 1, 2, 3 and 4 weeks of treatment. Circulating levels of IGF-I, insulin, glucose, T3 and T4 were analysed every week and IGFBPs every second week. IGF-I was not reduced significantly after 1 week but significantly reduced after 2 and 3 weeks of EGF treatment. A similar decline was observed for the major IGFBP, IGFBP-3, which was reduced after 2 and 4 weeks. IGFBP-1, IGFBP-2 and IGFBP-4 increased throughout the treatment period (all significantly at week 4). EGF treatment induced increased circulating T3 after 2, 3 and 4 weeks of EGF treatment. In conclusion, we report that EGF treatment for 4 weeks in Goettingen minipigs reduces circulating IGF-I and IGFBP-3, increases circulating IGFBP-1, IGFBP-2 and IGFBP-4, and induces a slight hyperthyroidism as judged from increased circulating levels of T3.

Animals↗
PubMed1996

Idiopathic esophageal ulceration in patients infected with human immunodeficiency virus.

Esophageal disease is a common and important cause of morbidity and mortality in patients with human immunodeficiency virus (HIV) infection. The etiology of HIV-related esophageal ulceration varies. After all known etiologies are excluded, a subgroup of patients remains with esophageal ulceration known as idiopathic esophageal ulceration (IEU). Establishing a diagnosis of IEU is critical and precludes unnecessary treatment with antiviral, antifungal, or antibiotic agents. A review of the current literature indicates that there are no prospective, placebo-controlled, randomized, double-blind trials on the specific treatment of IEU. Several preliminary reports suggest that corticosteroids and thalidomide may be effective. The incidence and natural history of IEU are incompletely known. It is important to establish that any potential therapeutic agents employed to treat IEU do not increase viral replication or provide viral protection. There is a need for well-designed, placebo-controlled, prospective studies to assess the risks and benefits of corticosteroids, thalidomide, and other agents in the treatment of idiopathic esophageal ulceration.

Adrenal Cortex Hormones↗
PubMed1995

Chronic treatment with epidermal growth factor causes esophageal epithelial hyperplasia in pigs and rats.

Epidermal growth factor (EGF) is an important factor for maintaining the esophageal functional integrity. Goettingen minipigs were treated with either placebo or subcutaneous EGF (30 micrograms/kg/day) for four weeks. Wistar rats were treated with either placebo or subcutaneous EGF (150 micrograms/kg/day) for four weeks. At sacrifice, esophageal samples were obtained for histology, immunochemistry, and lectin characterization. In pigs, the thickness of the esophageal epithelium was almost doubled in the EGF-treated animals. Characterization with lectins revealed a normal pattern of differentiation. Subcutaneously administered EGF was visualized on cells located basally in the esophageal epithelium. In rats, EGF-treatment increased the esophageal volume of the epithelium, the lamina propria of the mucosa, and the submucosa. In conclusion, systemic EGF challenge induces growth of the esophageal epithelium with an unaltered pattern of differentiation. This supports previous studies demonstrating a beneficial effects of systemic EGF-treatment on sclerotherapy-induced esophageal damage.

Animals↗
PubMed1995

Systemic treatment with epidermal growth factor induces anaemia in Goettingen minipigs.

1. From two independent experimental studies conducted in 48 minipigs with oesophageal sclerotherapy and concomitant treatment with epidermal growth factor, blood samples together with bone marrow biopsies were analysed for safety data. 2. Four to five weeks of systemic treatment with epidermal growth factor induced a decline in blood haemoglobin concentration in a time- and dose-dependent and reversible manner but without an effect on leucocyte or platelet counts. 3. The bone marrow expressed decreased amounts of haematopoietic tissue and reduced numbers of erythropoietic cells. 4. Four to five weeks of systemic treatment with epidermal growth factor induced reversible increases in serum concentrations of creatinine and urea, most likely reflecting renal impairment. 5. Groups in which creatinine and urea were not increased also had reduced blood haemoglobin concentrations. 6. These findings suggest that epidermal growth factor selectively impaired the erythropoiesis and stress the importance of risk-benefit analysis concerning the potential therapeutic applications of epidermal growth factor.

Anemia↗
PubMed1995

Prevention of nonsteroidal anti-inflammatory drug-induced gastroduodenal ulcers: role of mucosal protective and gastric antisecretory drugs.

One of the most serious side effects of nonsteroidal anti-inflammatory drugs (NSAIDs) is upper gastrointestinal mucosal damage that may result in erosions, ulcerations and other serious complications. NSAIDs reduce endogenous prostaglandins, and this reduction is relevant to their pharmacology and toxicity. The stomach and to some extent the duodenum are the major organs involved in the mucosal toxicity of NSAIDs. With the availability of the synthetic prostaglandin misoprostol, it has become possible to prevent NSAID-induced gastroduodenal ulcers without compromising the beneficial antirheumatic and analgesic effects of NSAID therapy. In fact, misoprostol is the only drug with established long-term efficacy in preventing NSAID-induced gastroduodenal ulcers in rheumatic patients. The purpose of this communication is to critically review the efficacy of gastric antisecretory drugs, mucosal protective drugs and misoprostol when used for the prevention of NSAID-induced ulcers, considering only data from well-controlled, randomized, double-blind clinical studies. The histamine H2-receptor antagonist ranitidine has been shown to be effective in preventing NSAID-induced duodenal ulcers, but has no efficacy in preventing NSAID-induced gastric ulcers. In a direct comparative trial with ranitidine, misoprostol (200 micrograms qid) was significantly more effective than ranitidine (150 mg bid) in preventing gastric ulcers in chronic NSAID users. The inactivity of ranitidine in preventing gastric ulcers indicates that the pathogenesis of NSAID-induced gastric ulcers is not related to gastric acid. Limited but conflicting data exist with omeprazole. The mucosal-coating drug sucralfate has not been found effective in preventing NSAID ulcers. In fact, in a direct comparative trial, misoprostol (200 micrograms qid) was significantly more effective than sucralfate (1 g qid) in preventing gastric ulcers in patients receiving chronic NSAID therapy. No meaningful data exist with organic bismuth salts, a group of drugs which has mucosal coating and protective properties. From this brief overview, we conclude: (1) mucosal-coating compounds have no therapeutic role in preventing NSAID-induced ulceration; (2) gastric antisecretory drugs are not effective in preventing NSAID-induced gastric ulcers, and (3) misoprostol is the only antiulcer drug proven to be effective for preventing NSAID-induced gastric and duodenal ulcers in patients receiving chronic NSAID. Misoprostol represents a major therapeutic advance for the management of NSAID-induced mucosal injury.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1995

Tissue distribution of 131I-labelled epidermal growth factor in the pig visualized by dynamic scintigraphy.

We visualized the metabolism of intravenously injected 131I-labelled epidermal growth factor in the pig using dynamic scintigraphy combined with repetitive samplings of blood, urine and bile. The labelled peptide was recognized in the samples by means of immunoprecipitation and high pressure liquid chromatography. The plasma elimination was extremely rapid, and it was described with a triexponential equation, C(t) = A*e -alpha*t+B*e-beta*t+C*e-gamma*t. The first two exponentials denoted the distribution phase, and the third the elimination phase. T1/2 alpha ranged from 0.4-0.7 min, T1/2 beta from 2.0-2.2 min and T1/2 gamma from 53.3-97.6 min. Concomitant with the rapidly declining plasma concentration, the gamma camera visualized the uptake by the liver and the kidneys. The liver was the principal organ for clearance and degradation of the labelled peptide, but only 0.12-0.30% of the injected dose was excreted into the bile. The renal uptake and the urinary excretion accounted for 6.6-13.0 and 2.5-4.9% of the given dose, respectively.

Animals↗
PubMed1995

Chronic systemic treatment with epidermal growth factor induces hypergastrinaemia in Goettingen minipigs.

BACKGROUND: Epidermal growth factor (EGF) is an inhibitor of gastric acid secretion. The impact of chronic systemic treatment with EGF on intragastric pH and serum gastrin concentrations has not been investigated previously. METHODS: Goettingen minipigs were treated with human recombinant EGF (hEGF) or placebo for 4 weeks. Once a week the acidity and protein concentration of gastric juice were determined, and serum gastrin concentrations measured. After 4 weeks, tissue specimens were obtained from the gastric antrum and immunostained for gastrin- and somatostatin-producing G- and D-cells. Furthermore, the development of antibodies against hEGF was evaluated. RESULTS AND CONCLUSION: Subcutaneously administered hEGF, 30 micrograms/kg/day for 4 weeks, included a fourfold increase in basal serum gastrin concentration, increased the number of antral G-cells, and decreased the density of antral D-cells. The acidity of gastric fluid was reduced, and the protein concentration increased. All animals developed low-titred antibodies towards hEGF. The antibodies did not influence the extent to which the individual animal responded to the EGF treatment.

Animals↗
PubMed1995

Epidermal growth factor attenuates the sclerotherapy-induced biomechanical properties of the oesophagus. An experimental study in minipigs.

BACKGROUND: The effect of epidermal growth factor (EGF) on the biomechanical properties of the oesophagus subjected to sclerotherapy was studied in Goettingen minipigs by means of impedance planimetry. METHODS: Seventeen animals underwent three sessions of weekly endoscopic sclerotherapy. During these 3 weeks and for the subsequent 2 weeks they were treated with either EGF or placebo. After another 3 weeks an impedance planimetric study was done. Ten healthy non-sclerosed pigs were studied as controls. Impedance planimetry was performed by stepwise pressure-induced balloon inflation for analysis of oesophageal cross-sectional area 5 and 10 cm above the gastro-oesophageal junction (GEJ). RESULTS: Systemic treatment with EGF (total daily dose of 30 micrograms/kg/day, administered subcutaneously) for 3 to 7 days per week combined with a weekly paravenous injection of 20-40 micrograms/kg attenuated the oesophageal damage caused by sclerotherapy, implying less pronounced narrowing 5 cm above and less dilation 10 cm above the GEJ. CONCLUSION: These observations suggest a potential therapeutic role for EGF in attenuating sclerotherapy-induced oesophageal injury.

Animals↗
PubMed1995

Chronic systemic treatment with epidermal growth factor in pigs causes pronounced urothelial growth with accumulation of glycoconjugates.

Epidermal growth factor (EGF) is present in large amounts in the urine, but the effects of systemically administered EGF on the urinary tract have not been described previously. In the present paper, we describe a potent growth induction of EGF on the urinary tract. Goettingen minipigs were treated with solvent (n = 5), EGF 30 micrograms/kg/day (n = 6) for 4 weeks, or EGF 30 micrograms/kg/day for 5 weeks followed by 3 weeks of recovery (n = 5). The ureters and bladders were examined by routine histology and electron microscopy and were immunostained for proliferating cell nuclear antigen. Four weeks of EGF treatment increased the median cross sectional area of the ureter fourfold with growth of all wall layers. The urothelium was widened from 5 cell layers in the controls to 10 in the EGF-treated animals. Proliferating cell nuclear antigen immunostaining revealed an increased mitotic activity in the basal zone of the urothelium. In the luminal zone, glycoconjugates accumulated in goblet cells, in cells with intracytoplasmic lumina, and beneath the luminal cell membrane in the umbrella cells. Our studies present a new experimental approach to growth induction of the urinary tract. The findings implicate the EGF system in regulating urothelial growth and glycoconjugate biosynthesis.

Animals↗
PubMed1995

Prevention and treatment of ulcers induced by nonsteroidal anti-inflammatory drugs: an update.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are most frequently used for the treatment of rheumatic disease due to their anti-inflammatory and analgesic properties. All NSAIDs have the potential to cause damage to the gastrointestinal (GI) tract and have been associated with the induction of peptic ulcers and massive life-threatening bleeding. The therapeutic approaches for the treatment and prevention of NSAID-induced ulcers is critically reviewed using data derived from carefully controlled, world-wide clinical studies with anti-ulcer drugs. Histamine (H2) antagonists, omeprazole, sucralfate and E-prostaglandin (PGE) analogs are effective for the treatment of NSAID-induced gastric and duodenal ulcers, if NSAIDs are discontinued. However, if NSAIDs are continued while GI damage is present, the PGE analogs misoprostol, arbaprostil and enprostil have shown efficacy in healing NSAID-induced ulcers. Furthermore, one limited clinical study demonstrated that omeprazole has efficacy in healing NSAID-associated ulcers. Neither H2 antagonists, sucralfate and sulglycotide (a cytoprotective drug) have shown efficacy in preventing NSAID-induced gastric ulcers. However H2 antagonists have shown efficacy in preventing NSAID-induced duodenal ulcers. In contrast, only misoprostol prevents the development of NSAID-induced gastric and duodenal ulcers. Such pharmacological observations suggest that the pathophysiologic mechanisms for the induction of NSAID-induced gastric ulcer are distinctly different from those of NSAID-induced duodenal ulcers. Mild diarrhea and GI intolerance were the predominant adverse reactions experienced by patients receiving synthetic PGEs, particularly enprostil and arbaprostil. From the published data, we conclude that misoprostol is the only anti-ulcer drug proven to be well tolerated and effective for the treatment and prevention of NSAID-induced gastric and duodenal ulcers in patients receiving chronic NSAIDs therapy.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1995

Chronic administration of epidermal growth factor to pigs induces growth, especially of the urinary tract with accumulation of epithelial glycoconjugates.

BACKGROUND: Epidermal growth factor (EGF) receptor hyperstimulation induced by systemically administered EGF or by the development of transgenic mice overexpressing transforming growth factor alpha (TGF alpha) or other EGF-related ligands is known to induce various effects, such as acceleration of developmental processes like incisor eruption, inhibition of gastric acid secretion, morphologic changes in the pancreas resembling pancreatitis, and malignancies in mammary glands and the liver. The present investigation was initiated to explore the effects of systemic EGF administration to the mature organism in a species with greater anatomic resemblance to humans than rodents. EXPERIMENTAL DESIGN: Eleven Goettingen Minipigs underwent 4 weeks of treatment either with placebo (n = 5) or human recombinant EGF 30 micrograms/kg/day (n = 6) administered subcutaneously. At the end of Week 4, the animals were sacrificed, autopsy was performed, and tissue samples were collected for histologic examination. RESULTS: EGF treatment caused macroscopic enlargement of the ureters, kidney, and heart. The ureters increased 4-fold in cross sectional area due to growth of all wall layers. The urothelium was hyperplastic with intracellular accumulations of material staining with Periodic acid-Schiff. Similar but less pronounced changes were found in the pancreas, lungs, salivary glands and esophagus. CONCLUSIONS: The most important observation of the present study is that systemic treatment with EGF for 4 weeks induces considerable growth to the urinary tract. We suggest new biologic effects of the EGF family in promoting growth of the urinary tract and in stimulating epithelial glycoconjugate biosynthesis in the urothelium and excretory ducts of the pancreas.

Animals↗