Overview of the preclinical pharmacological properties of Nigella sativa (black seeds): a complementary drug with historical and clinical significance.

Nigella sativa (N. sativa, black seeds; or sometimes known by many other names such as the blessed seed by the Arabs, black cumin in the Holy Bible, black caraway and Kalonji in South Asia) has been traditionally used for many years not only as a food but also as complementary drug. It is the objective of this communication to review the evidence-based pre-clinical pharmacological actions of N. sativa as a basis of its existing and potential new human clinical uses. Primary PubMed literature searches and secondary Medline searches were conducted to define N. sativa pre-clinical pharmacological and toxicological actions using a retrospective narrative review of the published studies. The ground seeds, its oil and its various extracts exhibit very broad pharmacological actions in laboratory studies, which are predictive of human clinical efficacy. In laboratory studies, N. sativa possesses anti-inflammatory, analgesic, anti-diabetic, anti-hyperlipidemic, anti-convulsant, anti-microbial, anti-ulcer, anti-hypertensive, anti-asthmatic and anti-cancer activities. Its mode of action is mediated via several mechanisms, which include anti-oxidant, immunomodulating, cytoprotective and an inhibitory effect on some mediators of inflammation. Although the seeds contain many chemical components, thymoquinone and alpha-hederin are proven to be pharmacologically active. Despite N. sativa broad and worldwide pharmacological characterization, only limited non-clinical safety studies were reported. N. sativa has many potentially important therapeutic applications. The black seeds clearly warrant formal preclinical drug development consideration to investigate the pharmacology of its components, to standardize the contents of the dosage forms, to define the methods of the pharmaceutical preparation, to determine its pharmacokinetics characteristics and its safety profile. It is our opinion that N. sativa should be considered for clinical development initially for unmet therapeutic uses, especially in the fields of oncology, neurology, rheumatology, pulmonary medicine, infectious diseases and endocrinology.

Cardiovascular and gastrointestinal toxicity of selective cyclo-oxygenase-2 inhibitors in man.

It is well established that the use of traditional nonsteroidal anti-inflammatory drugs (NSAIDs) increase the vulnerability of the gastrointestinal (GI) mucosa for the development of peptic lesions and serious ulcer complications. In addition, selective and traditional NSAIDs have also been associated with increased frequency of cardiovascular toxicity, especially in susceptible patients. The objective of this communication is to provide an overview of the salient GI and cardiovascular (CV) toxicity for these drugs. Traditional NSAIDs inhibit the constitutional cyclooxygenase-1 (COX-1) enzyme responsible for eicosanoids biosynthesis not only in joints, a beneficial effect, but also in the stomach, a detrimental effect. Selective NSAIDs were specifically designed to preferentially inhibit the cyclooxygenase-2 (COX-2), an inducible enzyme mediating the production of inflammatory eicosanoids in the joints but sparing the endogenous protective eicosanoids in the stomach. Selective COX-2 inhibitors (COXIBs) have been shown to possess much improved GI tolerability and reduced GI related adverse events when compared with nonselective COX-1 inhibitors. An unexpected CV toxicity had emerged during the COXIBs post marketing outcome studies. Many subsequent studies were carried out to define the CV risks associated with COXIBs and NSAIDs. All COX inhibitors had shown this CV toxicity. In many clinical studies, rofecoxib use was associated with significantly more elevated CV risk when compared with celecoxib and non selective NSAIDs. The COX inhibitors associated CV toxicity has multiple manifestations, which include the induction of myocardial infarction (MI), edema, thrombosis, blood pressure destabilization and death. Patients at risk of CV disease or with a history of CV disease were the most significant determinants of CV events after receiving COX inhibitors. This CV toxicity not only led to the marketing withdrawal of rofecoxib and valdecoxib but also resulted in more restricted, but essentially identical, product labels in the United States for celecoxib and traditional NSAIDS. This CV toxicity is dose and treatment duration dependent and appears to be compound specific rather than COX specific. Additional comprehensive, long-term, prospective investigations comparing the CV and GI safety profile of marketed NSAIDs against each other and against selective inhibitors are needed to address the controversy of COX inhibitors.

Prostaglandins and brain-gut axis.

Prostaglandins (PGs) have well documented physiological and pharmacological actions on the gastrointestinal (GI) tract. This communication reviews the evidence for peripheral and central nervous system (CNS) physiological actions of PGs in order to determine their role in the brain-gut axis, if any. PGs are widely distributed in nearly all cells peripherally and centrally. Laboratory and clinical evidence indicate that there is a direct relationship between altered GI physiological functions and peripheral PGs biosynthesis. Either local or parenteral administration of natural E-series PGs alters GI physiological functions particularly those relating to mucosal defense. Furthermore, the cyclooxygenase enzymes (COX), which are responsible for the PGs biosynthesis, have been localized in the brain as well as peripherally. However, increased levels of PGs in the brain have been associated with pathological processes such as inflammation, pain, fever and addiction. Although PGs have been shown to modulate CNS effects of catecholaminergic, serotoninergic and cholinergic neurons, there is no meaningful information concerning their direct central effect on GI function. The evidence for a clear physiological role of central PGs on the GI tract is not convincing. At this time, we conclude that PGs primarily manifest their activity on the GI tract by peripheral rather than by central mechanisms.

Novel therapeutic approaches to gastric and duodenal ulcers: an update.

Over the last 25 years, a remarkable revolution in the pathophysiology and treatment of gastric and duodenal ulcers has occurred. Effective therapies were developed not only to heal ulcers, but also to cure most patients. The two principal causes for gastric and duodenal ulcers are either infection with Helicobacter pylori or the use of non-steroidal anti-inflammatory drugs (NSAIDs). With H. pylori eradication, gastric and duodenal ulcers are rapidly becoming historical diseases. This communication reviews the salient pharmacology of the novel anti-ulcer drugs currently in development, with particular emphasis on the treatment of gastric and duodenal ulcers. Intense research is currently focused on the development of proton pump inhibitors primarily for the treatment and prevention of gastroesophageal reflux disease. The older proton pump inhibitors, omeprazole and lansoprazole, are effective in healing gastric and duodenal ulcers. Furthermore, both drugs are effective in eradicating H. pylori when given with various antibiotics. Pantoprazole, rabeprazole and esomeprazole are new proton pump inhibitors, which appear to have comparable therapeutic profiles with omeprazole and lansoprazole. Rebamipide is a new mucosal protective drug, which is effective in healing gastric ulcers. Polaprezinc and nocloprost are also mucosal protective drugs, which are in clinical development. However, none of these three cytoprotective drugs have been evaluated for their efficacy in eradicating H. pylori when given in combination with antibiotics. Likewise, no published literature exists on the use of these drugs for preventing NSAID-induced ulcers. With the rapid eradication of H. pylori currently happening in the developed world, the therapeutic challenge is now directed toward preventing NSAID-associated ulcer. Significant reduction of NSAID-induced ulcers is achieved by using continuous prophylactic anti-ulcer therapy (misoprostol or omeprazole) or by using NSAIDs possessing selective COX-2 inhibitory activity. However, outcome clinical studies are needed to compare the adjuvant anti-ulcer therapies given with COX-1 inhibitors versus the selective COX-2 inhibitors given alone.

Selective COX-2 inhibitors and gastrointestinal mucosal injury: pharmacological and therapeutic considerations.

It is well recognized that nonsteroidal antiinflammatory drugs (NSAIDs) induce gastrointestinal (GI) ulcerations, perforation and bleeding, which clearly limit their therapeutic value. The recent introduction of NSAIDs with selective cyclooxygenase-2 (COX-2) inhibitory effect is a major pharmacologic milestone in therapeutics. Selective COX-2 inhibitors exhibit considerable dissociation between their antiinflammatory/analgesic action and their GI toxicity. However, from a therapeutic consideration, there are still several unresolved and confusing issues with these drugs such as: the pharmacologic classification of the COX-2 selectivity; therapeutic value as antirheumatic/analgesic drugs; potential toxicity in patients at risk for the development of ulcer-related complications or patients with inflammatory bowel disease and potential renal toxicity. Although existing clinical efficacy studies with celecoxib and rofecoxib, two selective COX-2 inhibitors, were associated with considerably lower ulcerogenic rates when compared with nonselective NSAIDs, there are no long term outcome studies with these drugs similar to the MUCOSA trial performed with misoprostol. Furthermore, the selectivity of COX-2 inhibitors appears to be specific to the stomach and duodenum but not the kidney. While awaiting additional long term studies with selective COX-2 inhibitors, we recommend instituting prophylactic therapy with misoprostol in patients at risk for the development of ulcer related complications. In conclusion, we believe that the introduction of selective COX-2 inhibitors will revolutionize the treatment of pain and inflammation. However, additional basic and clinical studies are required to address the pharmacologic and therapeutic uncertainties for this class of drugs.

Gastroesophageal reflux disease: pathophysiology and pharmacology overview.

Gastroesophageal reflux disease (GERD) is one of the most frequently encountered illnesses in the Western Hemisphere. GERD encompasses a spectrum of disorders in which reflux of gastric content into the esophagus causes symptoms and/or damage to the esophagus, oropharynx, or respiratory tract. This article provides a brief update on the pathophysiology and pharmacology of drugs used for the treatment of GERD. The etiology of GERD is multi-factorial and is believed to be principally a consequence of altered motility states in the esophagus and stomach. The drugs used for the treatment of GERD are continuously evolving, but as yet no drug has been shown to cure this chronic, relapsing disease. Antacids, prokinetics, and gastric antisecretory agents are the principal drugs currently used to treat GERD in conjunction with life-style modifications. Due to their ultrashort duration of buffering action, antacids are primarily used as self-medication for temporary relief of mild GERD symptoms. The prokinetic drug cisapride effectively resolves symptoms and heals mild-to-moderate esophagitis, with efficacy similar to that of the histamine H2-receptor antagonists. H2-receptor antagonists exhibit moderate inhibition of gastric acid secretion and are effective for resolving symptoms and healing mild-to-moderate esophagitis. In addition, H2-receptor antagonists slightly augment the therapeutic efficacy of cisapride for healing mild-to-moderate esophagitis. However, use of H2-receptor antagonists at higher doses and higher frequency approaches the efficacy of proton pump inhibitors in healing erosive esophagitis. Given their potent and long-lasting acid-reducing efficacy, proton pump inhibitors have become the drugs of choice for many patients with GERD. Despite progress in the medical treatment of GERD, there are still several unresolved questions relating to cost-effective strategies with specific drugs, how long pharmacologic therapy should be maintained, and when surgical intervention is warranted. Additional studies are clearly needed to address the unresolved treatment issues in GERD.

1',1'-Dimethylheptyl-delta-8-tetrahydrocannabinol-11-oic acid: a novel, orally effective cannabinoid with analgesic and anti-inflammatory properties.

1',1'-Dimethylheptyl-Delta-8-tetrahydrocannabinol-11-oic acid (CT-3) is a novel cannabinoid that is under development by Atlantic Pharmaceuticals as an anti-inflammatory and analgesic drug. The objective of the study was to investigate the effects of CT-3 on overt symptom complex (Irwin's test), nociception, gastrointestinal (GI) ulceration, and pharmacological availability after intragastric (i.g.) and intraperitoneal (i.p.) administration. Analgesic studies were assessed in the hot-plate (55 degrees C) and the tail clip tests in mice and in the tail clip test in rats. In addition, pharmacological interaction of CT-3 with the solvent dimethyl sulfoxide (DMSO) was investigated in rats. In mice, CT-3 decreased spontaneous motor activity and induced dose-dependent, analgesic activity in the tail clip and hot-plate tests, with potency similar to morphine sulfate after i.g. and i.p. administration. However CT-3 showed more prolonged duration of analgesic action than morphine. In rats, CT-3 showed marked analgesia in the tail clip test and had similar i.p. and i.g. median effective dose (ED(50) values; 5 mg/kg). CT-3 was devoid of GI ulceration when administered with DMSO either acutely at doses below 100 mg/kg or chronically at a dosage of 30 mg/kg/day for 5 days. In contrast, indomethacin induced GI ulceration and deaths. The concurrent use of DMSO with CT-3 decreased its analgesic action, increased its adverse central nervous system effects, and induced GI ulceration. The evidence indicates that CT-3 exhibits a large dissociation between its anti-inflammatory/analgesic effects and its ulcerogenic actions. CT-3 warrants clinical development as a novel anti-inflammatory and analgesic drug.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.