Biomedical subjects
Publications and source records attributed to S Szabo.
We present a case of an extensive subtentorial subdural empyema of otorhinological origin. Although 3%-6% of all intracranial suppurations are infratentorial, there is no report on extensive multiloculated subtentorial empyema so far.
Vascular factors play an important role in the pathogenesis and prevention of acute gastric mucosal lesions. Endothelin-3 (ET-3), a potent vasoactive peptide, was infused intra-arterially to induce gastric microvascular and hemorrhagic mucosal lesions, and to enhance the damaging effects of dilute HCl and ethanol. ET-3 antibody was injected intravenously to decrease hemorrhagic mucosal lesions induced by ethanol. Locally infused ET (0.01, 0.1, and 1.0 nmol.100 g-1.min-1 for up to 15 min) was followed in some cases by intragastric dilute ethanol or HCl, which alone caused no or only mild vascular and mucosal lesions. Monastral blue was used to visualize and quantify vascular injury. ET-3 produced dose-dependent vascular lesions that affected the walls of mucosal capillaries and venules and induced mucosal congestion and focal endothelial labeling in vessels of the gastric muscular layers. The highest dose of ET induced hemorrhagic gastric mucosal lesions, mortality, and periods of hyper- and hypotension in the rat. Medium and low doses of ET-3 caused vascular injury, and dose-dependently potentiated the vascular and hemorrhagic mucosal lesions caused by dilute HCl and ethanol. Indomethacin slightly enhanced damage induced by ET and 50% ethanol, suggesting a limited mediatory role of prostaglandins in the ET-induced mucosal lesions. Anti-ET-3 serum dose-dependently decreased but did not abolish the hemorrhagic gastric mucosal lesions induced by 75% ethanol. Thus, ET-3 causes endothelial damage in capillaries and venules of rat stomach and predisposes to mucosal damage even after exposure to dilute ethanol or HCl. ET is more potent than leukotrienes and histamine and thus may play an important role in the mechanisms of acute gastric mucosal injury and protection where the vascular network appears to be a major target.
The sulphydryl containing drug cysteamine protects gastric mucosa in vivo against acute injury. It is not known whether this protection includes a direct effect on gastric cells. Using gastric epithelial cell monolayers derived from a well differentiated human cell line, we evaluated whether cysteamine protects against taurocholate or indomethacin induced damage in conditions which completely exclude the influence of vascular, hormonal, and neural factors. The effect of cysteamine on prostaglandin production by monolayer cells in vitro was also assessed. Cysteamine decreased damage brought about by sodium taurocholate and indomethacin by 40% (p less than 0.01) and 50% (p less than 0.01) respectively. The sulphydryl blocker iodoacetamide prevented the protective effect of cysteamine. Pretreatment with indomethacin, which inhibited prostaglandin E2 output by 60%, did not prevent protection by cysteamine; incubation with cysteamine decreased prostaglandin E2 production by cultured cells. We conclude that (i) cysteamine directly protected gastric epithelial cells in vitro (ii) this protection occurred with indomethacin, which interferes with cellular metabolism of prostaglandins, and taurocholate, whose damaging action at neutral pH is unrelated to interference with prostanoid metabolism, (iii) cysteamine protection in vitro is unrelated to endogenous prostaglandins and is probably mediated by endogenous sulphydryl compounds.
This review provides evidence that gastroduodenal mucosal injury is a complex process because of the heterogeneous structure and multiple functions of the gut. The action of exogenous etiologic agents is usually mediated in part, or amplified by endogenous mediators which very often exert biphasic, i.e., damaging and protective effects. The pathogenetic pathways involve direct/indirect chemical injury, vascular damage and its consequences, and acute or chronic inflammatory processes following infectious, chemical or ischemic injury. The role of oxygen, free radicals, calcium and proteases as well as the components and forms of gastroduodenal injury, e.g., reversible and irreversible cell injury, tissue necrosis, acute and chronic inflammation are also briefly discussed. Only a slight or moderate direct cytoprotection was demonstrated in vitro using isolated, mixed rat gastric mucosal cells by the known gastroprotective drugs including PG and SH compounds. Thus, the terms of organo or gastroprotection are more descriptive then the misleading "gastric cytoprotection".
Cysteamine, a potent duodenal ulcerogen, stimulates gastric acid and gastrin secretion and decreases immunoreactive somatostatin (IRS) from the gut and hypothalamus of the rat. To elucidate the structural requirements for this effect, we tested a series of cysteamine analogs for their IRS decreasing activity in comparison with their nucleophilic and reducing potencies. Adult female rats were sacrificed 4 hr after p.o. administration of the test chemicals given in molar equivalents to 30 mg/100 g of cysteamine-HCl. IRS decreasing activity in gastric mucosa, expressed as percentage of controls is listed in descending order: cystamine (55%), cysteamine (59%), 2-dimethylaminethanethiol (59%), ethylamine (66%), 1,3-propanedithiol (70%), propylamine (75%) and 3-aminothiophenol (79%). The following thiols and amines had no IRS decreasing effect (80% of controls): L-cysteine, ethanethiol, 1-propanethiol, penicillamine, dimercaprol, 1-4-dithiothreitol, ethanolamine, propionitrile, n-butyronitrile, o-, m- or p-aminophenol. The aryl 2-, 3- or 4-aminothiophenols, unlike most of their aminophenol analogs also decreased immunoreactive prolactin in the pituitary by 38 to 78%. IRS decreasing activity was independent of the reducing potency of cysteamine derivatives but was correlated significantly (r = 0.793, P < .01) with electron affinity of -SH, -NH2, -OH and -CN radicals in terminal alkyl chemicals. The structural requirement for decreasing activity is the presence of either -SH and -NH2 on a 2 to 3 carbon alkyl or aryl molecule. Both radicals when present together increase potency.(ABSTRACT TRUNCATED AT 250 WORDS)
This brief overview of our recent results implicates vascular factors in the mechanisms of acute and chronic actions of sucralfate. Pretreatment of rats with sucralfate and its components, such as SOS and sodium sulfate, prevented the ethanol-induced microvascular injury and maintained blood flow in the gastric mucosa. Thus, preservation of microvascular integrity seems to be one of the mechanisms of acute gastroprotection by sucralfate. Chronic experiments with subcutaneously implanted sponges containing sucralfate or SOS revealed that both compounds stimulated angiogenesis, whereas only sucralfate enhanced the area of granulation tissue. These processes may have a role in the ulcer-healing action of sucralfate.
Binary tree-structured statistical classification algorithms and properties of 56 model alkyl nucleophiles were brought to bear on two problems of experimental pharmacology and toxicology. Each rat of a learning sample of 745 was administered one compound and autopsied to determine the presence of duodenal ulcer or adrenal hemorrhagic necrosis. The cited statistical classification schemes were then applied to these outcomes and 67 features of the compounds to ascertain those characteristics that are associated with biologic activity. For predicting duodenal ulceration, dipole moment, melting point, and solubility in octanol are particularly important, while for predicting adrenal necrosis, important features include the number of sulfhydryl groups and double bonds. These methods may constitute inexpensive but powerful ways to screen untested compounds for possible organ-specific toxicity. Mechanisms for the etiology and pathogenesis of the duodenal and adrenal lesions are suggested, as are additional avenues for drug design.
OBJECTIVE: To determine whether early effects of zidovudine treatment on CD4+ lymphocyte count and concentrations of beta 2 microglobulin, neopterin, or HIV p24 antigen or antibody are correlated with survival in patients with AIDS or AIDS related complex. DESIGN: Retrospective study of changes in laboratory markers and survival. SETTING: Multicentre trial at university hospital clinics. SUBJECTS: 90 Patients with AIDS or AIDS related complex. INTERVENTION: Patients started zidovudine 200 mg orally every four hours. Fifty six of the patients died a median 17 months after starting zidovudine; the remaining 34 patients were followed up for a median 25.5 months. MAIN OUTCOME MEASURES: Changes in CD4+ lymphocyte count and serum concentrations of p24 antigen and antibody, beta 2 microglobulin, and neopterin; survival of the patient. RESULTS: The pretreatment characteristics that independently predicted poor survival were determined using a multivariate proportional hazards model: a diagnosis of AIDS (v AIDS related complex), age over 45 years, and the logarithm of serum neopterin concentration. When these baseline characteristics were controlled for the logarithm of CD4+ lymphocyte count at weeks 8-12 of treatment (p = 0.007) and an increase in serum beta 2 microglobulin concentration at weeks 8-12 (p = 0.05) also independently correlated with survival. In the 38 patients with a better pretreatment prognosis, 24 month survival estimated by the product-limit method was 88% for those with a good response on both surrogate markers during early treatment compared with only 50% for those with a poor response on either marker. In the 38 with a worse pretreatment prognosis, 24 month survival was estimated to be 49% for those with a good response on both surrogate markers compared with only 18% for those with a poor response on either. CONCLUSION: These data suggest that CD4+ lymphocyte count at 8-12 weeks and, perhaps, change in serum beta 2 microglobulin concentration could be surrogate end points for clinical outcome in trials of antiretroviral drugs for patients with HIV disease.
Adaptation course to NaCl was estimated using a flow chamber for stimulus delivery and changes in the perceived taste magnitude as the criterion. The adapting stimulus of different durations was applied to one side of the tongue. Magnitude estimates were made by comparing the intensity of taste at the end of each adaptation time with the perceived intensity of the same stimulus applied briefly to the unadapted side of the tongue. The course of adaptation followed a negatively accelerated decreasing function. The relationship between taste magnitude and the duration of the adapting stimulus can be approximated by a logarithmic equation and, somewhat less accurately, also by an exponential equation, which can be related to the Beidler theory of taste stimulation. Some advantages of the closed flow technique and comparison of taste magnitudes on the adapted and unadapted sides of the tongue are discussed.
The influence of adaptation to taste stimuli of 1 quality on tastants with other qualities was investigated by comparing the reaction time (RT) to a test solution after adapting-solution flow with the RT to the same test solution after water flow. Adapting solutions were strong concentrations of NaCl, HCl, QHCl, and sucrose; test solutions were the same compounds but in lower concentrations. Adaptation to sucrose significantly shortened RT to NaCl and HCl, and to a lesser degree to QHCl. A similar cross-enhancement was found in sucrose when other compounds served as adapting solutions, In all other taste combinations, only a cross-adaptation effect was observed. Results are discussed in relation to some adaptation phenomena, water taste data, and magnitude-estimation data.
The complete purification of the first angiogenic molecule, basic fibroblast growth factor (bFGF), was carried out in the authors' laboratory in 1983. Application of this peptide to chronic wounds enhances angiogenesis and accelerates wound healing. The authors showed that an acid-stable form of bFGF (i.e., bFGF-CS23) could be administered orally to rats with duodenal ulcers. The peptide promoted a ninefold increase of angiogenesis in the ulcer bed and accelerated ulcer healing more potently than cimetidine. Basic fibroblast growth factor did not reduce gastric acid. The authors now show that bFGF exists as a naturally occurring peptide in rat and human gastric and duodenal mucosa. This endogenous bFGF is present also in the bed of chronic ulcers in rats. Sucralfate binds bFGF and protects it from acid degradation. The sucralfate is angiogenic, based on its affinity for bFGF. When sucralfate is administered orally to rats, it significantly elevates the level of bFGF in the ulcer bed. Cimetidine, by its capacity to reduce gastric acid, also elevates bFGF in the ulcer bed. A hypothetical model is proposed in which prevention of ulcer formation or accelerated healing of ulcers by conventional therapies may be FGF dependent. Acid-stable bFGF-CS23 may be considered as a form of replacement therapy in the treatment of duodenal ulcers.
Of the multiple actions of sucralfate, not all are equally relevant. In fact, certain actions of the drug contribute to healing of acute ulcers or to ulcer prevention, whereas other actions are more important in accelerating the healing of gastric and duodenal ulcers. The action of sucralfate can now be defined by the '1 x 1 x 1' mechanism of action--that is, one action of sucralfate is important for acute prevention, one is relevant to both acute and chronic protection, and one is important for chronic ulcer healing. Maintenance of mucosal vascular integrity and of blood flow, which ensures rapid epithelial restitution to repair superficial defects, are the most important acute actions of sucralfate. On the other hand, increased bicarbonate and mucus secretion seem to be relevant in both acute and chronic protection of the gastroduodenal mucosa. Finally, the enhanced binding by sucralfate of fibroblast growth factor and epidermal growth factor stimulates angiogenesis, granulation tissue, and epithelization for ulcer healing. This 1 x 1 x 1 theory of the mechanism of action of sucralfate concentrates on the relevant effects of this drug (which has more than a dozen actions) and may help to elucidate the molecular mechanism of action.
Recovery from adaptation to NaCl was tested by comparing some relevant parameters of response to the adapting and test stimuli separated by different recovery intervals. The time course of response was determined using magnitude estimations and using the flow chamber for stimulus delivery. The course of recovery for all parameters used was a negatively accelerated function of the rest time, but the recovery rate of different parameters did not prove to be equal. Recovery was fastest for the initial maximum taste magnitude, followed by the time needed for the taste to disappear. The taste effect summed over time and the time required for the taste magnitude to decrease to 30% of its preadapted maximum were the slowest to recover. Although the recovery processes proceeded at a rapid rate during the initial period, all parameters remained depressed over a rather long period.
Acetaminophen protects gastric mucosa in vivo against acute drug-induced damage and has also been shown to protect gastric epithelial cells in vitro. Protection afforded by acetaminophen in vitro is not associated with increased prostaglandin output. The present study evaluated whether protection of gastric epithelial cells by acetaminophen in vitro may be mediated by endogenous sulphydryls. Monolayers from a well-differentiated human gastric epithelial cell line were studied. Sodium taurocholate was used as a damaging agent and cell damage was assessed by the 51Cr release assay. Acetaminophen dose-dependently protected gastric cell monolayers against damage induced by sodium taurocholate. The sulphydryl blocker iodoacetamide dose-dependently decreased the concentration of nonprotein glutathione and cysteine and counteracted the protection afforded by acetaminophen. This suggests that sulphydryl compounds may mediate the protection of gastric epithelial cells by acetaminophen in vitro.
This article emphasizes and reviews the premise that because the pathogenesis of acute gastric mucosal injury is multifactorial, several protective mechanisms should also be considered in analyzing gastric mucosal defense. The first part of the article reviews the pathogenesis of acute gastric mucosal injury by major etiologic factors such as hypoxia and chemical and biological agents, and emphasizes the common endogenous mediators of damage (e.g, endothelins, leukotrienes, thromboxane, platelet-activating factor, monoamines, free radicals, proteases, ammonia, hydrochloric acid, and bile acids--in decreasing potency). The second part of the review is devoted to the gastroprotective mechanisms that are analyzed by anatomical (histologic) location and biochemical processes. The endogenous mediators of acute gastroprotection include prostaglandins, sulfhydryl (SH) compounds, non-SH antioxidants, polyamines, and epidermal growth factor, whereas the protective and mediatory role of glucocorticoids, somatostatin, pentagastrin, histamine, gangliosides, and calcitonin gene-related peptide need further studies. A list of endogenous and exogenous chemicals that exert biphasic, damaging, and protective effects on the gastric mucosa in also included. The final common pathway of acute gastroprotection at the structural and functional level seems to be the preservation of subepithelial microvascular integrity leading to maintenance of mucosal blood flow that allows the energy-dependent rapid restitution (cell migration) from surviving gastric neck cells to repair the superficial epithelial defect. Very new data on the contribution of a histodilutional barrier and release of proteases to gastroprotective processes are also discussed.
This review provides evidence that gastroduodenal mucosal injury is a complex process because of the heterogenous structure and multiple functions of the gut. The action of exogenous etiologic agents is usually mediated in part or amplified by endogenous mediators that very often exert biphasic, i.e., damaging and protective, effects. The pathogenetic pathways involved are direct/indirect chemical injury, vascular damage and its consequences, and acute or chronic inflammatory processes following infectious, chemical, or ischemic injury. The role of oxygen, free radicals, calcium, and proteases as well as the components and forms of gastroduodenal injury, e.g., reversible and irreversible cell injury, tissue necrosis, and acute and chronic inflammation, are also briefly discussed.
We tested the hypothesis that the gastrotoxicity of ethanol and other damaging agents is influenced through the modulation of alcohol dehydrogenase (ADH) by using either the ADH-inhibitor pyrazole or the noninhibitor derivatives of pyrazole. In time course experiments, the protection by both compounds was evident up to 48 hr before ethanol administration. Both drugs were also protected, from about 24 hr, from gastric mucosal damage induced by aspirin and hydrochloric acid. In order to examine the role of endogenous prostaglandins and sulfhydryls in this protection, indomethacin and N-ethylmaleimide were used, of which only the sulfhydryl alkylator antagonized (by about 50%) the protection by pyrazole and 3-methylpyrazole. Studies with monastral blue B revealed the protective role of both pyrazole and 3-methylpyrazole against early vascular injury in the gastric mucosa. We conclude that because both the ADH-inhibitor pyrazole and the noninhibitor derivatives of pyrazole exert gastro-protection, and because both compounds protect against aspirin and HCI, ADH inhibition is not involved in this protection. We also suggest that although prostaglandins appear to have minimal involvement in the mechanism of protection, endogenous sulfhydryls may be important mediators. Furthermore, the functional and structural mechanism of this protection seems to be the prevention of acute vascular injury.
Dopamine is an important enteric neuromodulator. Herein we review the data that support a role for dopaminergic involvement in experimental duodenal and gastric ulceration; gastric, pancreatic, and duodenal secretion; gastrointestinal motility; and gastric and intestinal submucosal blood flow regulation. There also is support for a role for dopamine and dopamimetic agents in the treatment of certain experimental gastrointestinal diseases because some highly selective dopamine agonists are gastroprotective when given either parenterally or centrally. Based upon these observations, we suggest that dopamine is a key element of the "brain-gut axis" and represents a potentially important target for pharmacotherapeutic exploitation.