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PubMed1998

Relationship between the skin permeation movement of propranolol and skin inflammatory reactions.

We studied inflammatory reactions induced by dermal application of the beta-blocker propranolol (PRL) in ethanol to guinea pigs in order to elucidate the relation of the reactions with the cumulative PRL permeating amount through the stratum corneum or the PRL content in the stripped skin, and to investigate the chemical mediators responsible for the reactions. The cumulative PRL permeating amount through the stratum corneum increased rapidly up to 2 h after dermal application, then increased linearly with time up to 24 h after application. Visual observation revealed formation of erythema and edema at the applied site of PRL, and histopathological examination revealed infiltration of pseudoeosinophiles of dermis and epidermis and degeneration/necrosis of epidermis. In general, it was considered that the duration and the extent of these reactions were dependent on the PRL dosage and application time. It was expected that the cumulative PRL permeating amount through the stratum corneum could be used to predict possible inflammatory reactions during development of transdermal drug delivery systems. On the other hand, contact of PRL with guinea pig skin tissues released histamine, and intradermal injection of PRL caused an increase of capillary permeability at the site of application. Also, the inhibitory effects of anti-inflammatory agents (diphenhydramine, dexamethasone, indomethacin, cyproheptadine hydrochloride, CV3988 and AA-861) to PRL-induced erythema formation demonstrated that histamine and prostaglandins were responsible for the inflammatory reactions induced by PRL.

Adrenergic beta-Antagonists↗
PubMed1983

Changes in testicular blood flow and testosterone production during aspermatogenesis after irradiation.

Exposure of the testes of anaesthetized adult rats to 527 rads of gamma-irradiation caused testis weight to fall slowly at first and then more rapidly from 21 days afterwards, reaching a minimum at 52 days, when spermatogenesis was severely disrupted. The weights of the accessory organs and the concentrations of testosterone in peripheral blood were slightly reduced; the concentrations in blood from the testicular veins were lower than control at shorter intervals after irradiation, but at later times tended to be similar or greater than control. Testicular blood flow per testis followed testis weight closely, and as a result the production of testosterone by the smaller testes (calculated as the product of plasma flow and the veno-arterial difference in testosterone concentration) was markedly reduced especially when the rats had been stimulated with human chorionic gonadotrophin (hCG). Serum FSH and LH rose appreciably as testis weight fell but there was a proportionately greater rise in FSH than LH, in comparison with surgically castrated animals. Increased amounts of extratubular, extracellular fluid were found in the aspermatogenic testes, but injection of hCG still caused increases in capillary permeability and the amount of fluid in the testis. These results indicate that during aspermatogenesis following irradiation (as with heat and efferent duct ligation) the capacity of the testes to secrete testosterone is severely limited by decreased testicular blood flow, not by the ability of the Leydig cells to release testosterone into their immediate environment.

Animals↗
PubMedDate not supplied

Radiocontrast-induced nephropathy: current status and future prospects.

Radiocontrast-induced nephropathy (RCIN), a leading cause of in-hospital acute renal failure, is an acute decrease in renal function related to intravascular administration of iodinated radiocontrast agents. Though RCIN is relatively uncommon in patients without predisposing factors, patients with preexisting renal dysfunction, diabetes mellitus and severe congestive heart failure are at increased risk for acute renal failure following radiocontrast. Three recently developed animal models have provided important insights into the pathophysiology of RCIN. Specifically, these studies have implicated transient renal ischemia, direct renal tubular toxicity and changes in glomerular capillary permeability as possible mediators of RCIN, and these pathophysiologic mechanisms are not mutually exclusive. There is currently no effective treatment for RCIN. Assuring adequate hydration may reduce the risk of RCIN. In addition, synthetic atrial natriuretic factor and/or mannitol are promising, but as yet unproven, approaches to the prophylaxis of RCIN.

Acute Kidney Injury↗
PubMed1985

Potential antiglioma activity of 9-hydroxy-2-N-methylellipticine as determined by pharmacological and human tumor clonogenic cell studies.

The antiglioma activity of elliptinium (HME) was investigated in a human glioma clonogenic cell assay. Early passage cells of three human glioma cell lines (SF126, SF375, and SF407) were exposed to HME at the clinically achievable dose of 3 microM for 3 h. At this HME concentration, clonogenic cell survival was reduced by more than 3 logs in SF126 and SF375, and by 0.8 logs in SF407. A study of the kinetics of cell kill showed that whereas at moderate (less than or equal to 1.5 microM) HME doses cell kill increased with treatment time up to a maximum at approximately 3 h, cytotoxicity was more dose than time dependent at higher doses. Flash treatment of SF375 cells with 3 microM HME resulted in more than 2 logs clonogenic cell kill. Using high-pressure liquid chromatography, we investigated the in vitro decay kinetics of HME under our in vitro drug treatment conditions and observed a very rapid, protein nondependent 40% drop in HME concentration which was dose dependent and was probably due to HME adsorption on the surface of tissue culture plasticware. Subsequent decay of the drug was very slow, with a decay rate constant of 0.022/h and a half-life of 298 h. In order to determine whether HME crosses the blood-brain barrier, we measured the rat brain capillary permeability coefficient, P, of [3H]HME and [14C]HME. The mean P value of 2.2 X 10(-6) cm/s +/- 16% (SD) suggests that HME crosses the blood-brain barrier (t 1/2 = 46 min) consistent with its molecular size and octanol-water partition coefficient.

Alkaloids↗
PubMed1982

Anti-allergic properties of ethyl-3-methoxyphenyl-4-thiazolyl-2-oxamate (F 1865).

F 1865 (ethyl-3-methoxyphenyl-4-thiazolyl-2-oxamate) has powerful oral anti-allergic properties in immediate hypersensitivity models in rats. In IgE-dependent passive cutaneous anaphylaxis (PCA) the ED50 was of 0.8 mg/kg. In IgG-dependent PCA the ED50 was of 0.6 mg/kg. This oxamate derivative inhibited the liberation of histamine during passive peritoneal anaphylaxis in rats at concentrations of 1 X 10(-6) M or higher. Doses of F 1865, active in PCA, had only weak anti-histamine and anti-serotonin effects, as measured by the increase of cutaneous capillary permeability. Likewise, its inhibitory effect on the bronchospasm due to histamine or serotonin in guinea-pigs was apparent only at doses of 1 mg/kg on i.v. administration. At doses of 100 mg/kg (X2) p.o., F 1865 was inactive against reverse passive Arthus pleurisy induced in rats by rabbit anti-bovine-albumin serum.

Amino Acids↗
PubMed1987

Some aspects of the inhibitory activity of hypolaetin-8-glucoside in acute inflammation.

Hypolaetin-8-glucoside (H-8-G) has been examined for its mode of action in several models of acute inflammation. Its anti-inflammatory activity in carrageenan-induced inflammation of the rat hind-paw is not affected either by adrenalectomy or by phentolamine given with propranolol. H-8-G and its aglycone, hypolaetin, did not antagonize the actions of histamine, 5-hydroxytryptamine (5-HT), bradykinin or prostaglandin E2 (PGE2) on various smooth muscle preparations in-vitro, but protected erythrocytes from heat-induced lysis. The glycoside was more potent than troxerutin on capillary permeability increased by histamine and exerted inhibitory effects on protein exudation, leucocyte migration and beta-glucuronidase activity in the carrageenan air pouch, thereby showing some difference from indomethacin. These results are discussed in relation to the features of non-steroidal anti-inflammatory drugs (NSAID) and flavonoid anti-inflammatory actions.

Animals↗
PubMed2001

The vascular endothelial growth factor receptor KDR/Flk-1 is a major regulator of malignant ascites formation in the mouse hepatocellular carcinoma model.

The vascular endothelial growth factor-A (VEGF-A), also known as the vascular permeability factor (VPF), has been shown to play an important role in malignant ascites formation. The effects of VEGF-A are mediated through flt-1 and kinase insert domain-containing receptor/fetal liver kinase (KDR/Flk-1) receptors. It has been shown that KDR/Flk-1 is a predominant receptor in solid hepatocellular carcinoma (HCC) development, but the role of this receptor in hepatic ascites formation has not yet been elucidated. In this study, we examined the role of KDR/Flk-1 in the murine MH134 hepatic malignant ascites formation by means of VEGF-A- and KDR/Flk-1-specific neutralizing antibodies (VEGF-A nAb and KDR/Flk-1 nAb, respectively). The mean volume of ascites, number of tumor cells in ascites, and the peritoneal capillary permeability were significantly suppressed by VEGF-A nAb and KDR/Flk-1 nAb treatment. These inhibitory effects of KDR/Flk-1 nAb were more potent than those of VEGF-A nAb. The autophosphorylation of KDR/ Flk-1 in the peritoneal wall was almost completely abolished by KDR/ Flk-1 nAb, whereas a certain level of activation was still shown by VEGF-A nAb treatment. Another VEGF-family, VEGF-C, which also binds KDR/Flk-1, was detected in the ascites. Furthermore, in the therapeutic experiment, although both VEGF-A nAb and KDR/Flk-1 nAb prolonged the survival rate of ascites-bearing mice, the latter showed a more significant impact on the survival of animals. These results suggest that KDR/Flk-1 is a major regulator of malignant hepatic ascites formation, and that in addition to VEGF-A, VEGF-C may also be involved in the malignant ascites formation via KDR/ Flk-1 activation.

Animals↗
PubMed1981

Colloids versus crystalloids as volume substitutes: clinical relevance of the serum oncotic pressure.

With some amplifications, Starling's concept of the serum colloid osmotic or oncotic pressure as the determinant of fluid partition between the intravascular and the interstitial compartment has been confirmed by modern physiological research. The relationship between serum oncotic pressure and interstitial edema is non-linear, i.e. edema becomes progressively greater per mm decrease of the oncotic pressure. The intravascular volume effect of crystalloids is inseparable from interstitial edema, because it depends on an expansion of the interstitium which increases the hydrostatic pressure in that compartment sufficiently to compensate for a lowered capillary oncotic pressure. With large crystalloid fluid loads, about 90% of the total edema accumulates in skeletal muscle, subcutaneous fat, and the skin. The skin is particularly susceptible to the development of edema associated with a hypoproteinemic fluid overload, presumably because its extracellular space is three times larger than the average whole-body value. The intestine also shows a marked reaction to a hypoproteinemic fluid overload. There is evidence for a pathogenetic significance of hypoproteinemic edema in the myocardium, the intestine, and the skin. To rid a patient of this type of edema, concentrated albumin is indispensable, and its effects are demonstrable in the above-mentioned tissues, whereas a diuretic alone is ineffective. The therapeutic implications of these mechanisms and findings are discussed. In the lung, fluid exchange and distribution between the intravascular and the interstitial compartment is influenced by additional factors, and opinions on the use of colloids versus crystalloids continue to differ, particularly with respect to those circumstances where capillary permeability is presumably or demonstrably abnormal. However, the weight of the evidence still favours the concept that in patients with a much greater than respiratory distress syndromes much greater than, the serum oncotic pressure should at any rate not be permitted to drop below a certain critical level. A condensed review of these complex and as yet incompletely clarified problems is presented.

Blood Physiological Phenomena↗
PubMed1984

Effect of beta-adrenergic blockade on in vivo norepinephrine release in canine heart.

The beta-adrenergic blockade-induced reduction in myocardial norepinephrine overflow during sympathetic stimulation was examined by use of the multiple indicator-dilution technique. A kinetic model incorporating the effects of flow, capillary permeability surface product for norepinephrine, the interstitial uptake rate constant for neurotransmitter, and plasma norepinephrine input and output values was used to estimate the rate of local release of norepinephrine into the interstitial space. The model was tested by first examining the effects of two drugs that increase myocardial norepinephrine overflow during sympathetic stimulation by differing mechanisms: desmethylimipramine, a norepinephrine uptake inhibitor, and phentolamine, an alpha-adrenergic blocker. The uptake inhibitor was demonstrated to reduce interstitial uptake and the alpha-blocker to increase local neurotransmitter release, without change in blood flow. The beta-adrenergic blocker, in contrast, reduced coronary blood flow and decreased the capillary norepinephrine permeability surface product but did not change the rate of local release. The decreased norepinephrine overflow after beta-blockade was deduced to result from the decrease in transcapillary flux and secondary increase in interstitial uptake.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

Brain water alterations after unilateral nephrectomy. A study of regional circulatory factors in squirrel monkeys.

White and regional gray matter distributions of water, blood flow, and the protein tracer pertechnetate were measured in five normal squirrel monkeys. A second group of five monkeys, which had undergone unilateral nephrectomy six months previously, were found at the time of study to have blood pressures similar to those of the control animals but increased brain water and altered distribution of blood flow which was increased in white matter. No alteration of capillary permeability to the protein traces attended these changes, which appeared to be influenced by blood pressure. Nephrectomy without hypertension influences brain water content, perhaps because of an effect on cerebral resistance vessels. In hypertensive encephalopathy renal lesions, as well as intraluminal pressure changes, may be related to cerebral edema.

Animals↗
PubMed1985

The variation with flow-rate of the extraction of bone-seeking tracers in recirculation experiments.

Radioactive microspheres were injected into the hearts of anesthetized dogs and the reference organ technique used to determine cardiac output. Blood flow to the leg bones was then obtained from microsphere uptake. Simultaneous injections of the bone-seeking radiotracers 85Sr and, in fewer animals, 18F and 99mTc methylene diphosphonate similarly gave their clearances from the blood by bone over a period of 5 min. The ratio of clearance to flow (extraction ratio) was found to be flow-dependent, falling from near unity at low flow rates to about 0.4 at higher flow rates. The results are in general accordance with the Renkin theory of capillary permeability but do not fit exactly to the concept of a constant product of permeability and surface area, perhaps due to the heterogeneity of the model. The findings confirm conclusions based on tibial nutrient artery perfusion experiments and demonstrate that skeletal blood flow cannot be measured by the clearance of bone-seeking tracers. There were substantial differences of blood flow normalized for weight between the bones of a given animal.

Animals↗
PubMed1999

Microalbuminuria and transcapillary albumin leakage in essential hypertension.

Microalbuminuria (an increased urinary albumin excretion that is not detectable by the usual dipstick methods for macroproteinuria) predicts cardiovascular events in essential hypertensive patients. A possible reason for this behavior is that albumin leaks through exaggeratedly permeant glomeruli exposed to the damaging impact of subclinical atherogenesis. To evaluate this possibility, the transcapillary escape rate of albumin (TER(alb), the 1-hour decline rate of intravenous (125)I-albumin), a parameter that estimates the integrity of systemic capillary permeability, albuminuria, blood pressure, echocardiographic left ventricular mass, lipids, and body mass index were measured in 73 uncomplicated, glucose-tolerant men with essential hypertension and normal renal function; 53 were normoalbuminuric, and 20 were microalbuminuric. Twenty-one normotensive age-matched male subjects were the controls. TER(alb) was higher in hypertensives, a behavior explained in part by a positive correlation with blood pressure values, although body mass index, lipids, and left ventricular mass showed no association. Transcapillary albumin leakage values did not differ between normoalbuminuric and microalbuminuric patients and were unrelated to albuminuria. Blood pressure, particularly systolic, and cardiac mass were higher in microalbuminuric patients in whom albuminuria correlated with both cardiovascular variables and indicated the influence of the hemodynamic load on urinary albumin levels. Thus, TER(alb), a parameter influenced by the permeability surface area product for macromolecules and the filtration power across the vascular wall, is altered in essential hypertensives. However, this abnormality is dissociated from the amount of albuminuria, which is contrary to the hypothesis that a higher albumin excretion reflects a greater degree of systemic microvascular damage in essential hypertension.

Albuminuria↗
PubMed1989

[Inhibitory effects of clonidine on edema formation after thermal injury in mice and rats].

Clonidine 1 mg/kg ip given before thermal injury significantly inhibited the edema formation in mice and rats during the early stage of burn. Clonidine 0.1 mg/kg ip gave no such effect, but it became effective after being administrated via icv. The inhibitory effects of clonidine on edema formation were abolished by pretreatment with yohimbine 5 mg/kg ip, but not with prazosin 10 mg/kg ip. The tracing by 113mIn labelled transferrin demonstrated that clonidine decreased the capillary permeability in burned tissues 1 h after burn. When clonidine 1 mg/kg was given ip to the rats 20 min before burn, it lowered the level of lipoperoxide in the serum 2 h after burn. These results suggest that the inhibitory effects of clonidine on edema formation is most probably due to the depression of sympathetic activity via alpha 2 receptor during thermal injury.

Animals↗
PubMedDate not supplied

[Humoral immunopathologic changes in the myocardium after clinical allotransplantation of the heart].

Endomyocardial diagnostic biopsies, recipient heart removed at operation, endomyocardial biopsies of allotransplants and postmortem material were studied using immunofluorescence to specify immunopathological process and to detect humoral rejection. Altogether 306 samples from 55 patients were studied. In the early postoperative period (one year) 8 out of 18 patients with heart transplants repeatedly showed immunopathologic picture of acute humoral (vascular) rejection which was characterized by a widespread immunoglobulin G and complement fixation in the capillary walls accompanied by enhanced capillary permeability and fibrin deposition in intestitial tissue. Such patients often had graft dysfunction. 1 to 5 years after transplantation in 24 out of 37 patients discrete focal immunoglobulin and complement fixation was observed as one of chronic rejection component.

Adolescent↗
PubMed1997

Antipsoriatic, anti-inflammatory, and analgesic effects of an extract of red propolis.

AIM: To study the antipsoriatic, anti-inflammatory, and analgesic effects of ethanolic extract of red propolis. METHODS AND RESULTS: This extract induced the formation of granular layer in the mouse tail test used as a model of psoriasis. Propolis 50 mg.kg-1 i.g. showed anti-inflammatory activity in the cotton-pellet granuloma assay in rats, in croton oil-induced edema in mice at a dose of 25% (2.5 microL), and in the peritoneal capillary permeability test in mice at a dose of 10 mg.kg-1. The extract (25 mg.kg-1 i.g.) showed analgesic effect in the model of acetic acid-induced writhings, whereas 40 mg.kg-1 was effective in the hot plate test in mice. CONCLUSION: Anti-inflammatory, analgesic, and antipsoriatric properties of Cuban red propolis were evident.

Animals↗
PubMed1975

Cardiovascular lesions in pancreatitis.

Data have been presented correlating changes of blood coagulability, capillary permeability, blood electrolyte content with electrocardiographic abnormalities and symptoms of coronary insufficiency. In acute pancreatitis and in acute exacerbation of chronic pancreatitis, accentuation of these vascular factors may induce symptoms of coronary disease. Data are also presented indicating abnormal blood coagulability and blood electrolyte content in patients with chronic pancreatitis. Minimal augmentation of these abnormalities may account for the "yoke" syndrome.

Acute Disease↗
PubMed1977

[Pulmonary complications after extracorporeal circulation. ECC lung syndrome].

Pulmonary complications after cardiac surgery under extracorporeal circulation remain frequent and sometimes grave, in spite of the great progress which has been made over the past 20 years in the methods of cardiorespiratory assistance. The authors analyse the clinical and radiological repercussions of perfusion on the lung, in 40 patients operated under ECC for coronary revascularisation. The simutaneous study of the arterial, and mixed venous blood gasses and of the alveolar gases, in 20 of these patients showed the constant occurrence of a shunt syndrome, without alveolar hypoventilation or disorders in peripheral circulatory flow. Ventilatory alcalosis, hypocapnia, hypoxemia and the rise in the alveolar arterial oxygen gradient is increased during the second post-operative day. Among the variables studied (duration of ECC, degree of hypothermia, duration of the intervention, duration of anesthesia, pleurotomy) only the latter intervened in a statistically significant manner in this study, in the increase in hypoxemia. 46 pulmonary biopsies carried out before and after ECC in 23 coronary patients were examined with the electron microscope. The initial alveolar involvement affects the septal microcirculation with signs of an increase in capillary permeability leading to an interstitial and epithelial destruction. The use of a membrane oxygenator prevents some of the alveolar lesions, as has been proved by the study of five pulmonary biopsies carried out in dogs submitted to ECC of long duration. Catherterization of the pulmonary artery carried out in 35 patients by means of a SWAN-GANZ catheter, before the intervention enabled supervision of the degree of importance and speed of the hemodynamic variations in the pulmonary circulation during the different phases of ECC (during the phase of ventricular fibrillation). The rise in the flow of left output can lead to the occurrence of negative pulmonary intravascular pressures which can be prejudicial for capillary trophicity. The syndrome of "ECC lung", a veritable "induced post-agressive lung" must be placed in the group of refractory hypoxemia of which it represents one of the most typical pictures.

Alkalosis, Respiratory↗
PubMed1980

Albumin: role and discriminative use in surgery.

Exogenous human serum albumin (HSA) is generally used empirically and its role in surgery is poorly defined. The function and kinetics of HSA in the body are reviewed to provide rational guidelines for its use in surgery. Starling's law of transcapillary exchange is important, especially when applied to the capillary beds of the skin and subcutaneous tissue, skeletal muscle, lungs and intestines; but it overestimates the importance of maintaining oncotic pressure in the two situations where HSA is clinically beneficial--hypovolemia and plasma volume sequestration. In hypovolemia, the harmful effects of protein dilution by massive crystalloid resuscitation are minimized initially by "edema safety factors", such as reduced oncotic pressure of interstitial fluid and increased flow of lymph, and subsequently by intravascular protein refill from extravascular sites. But in severe hypovolemia, albumin should be given early, with sufficient isotonic saline, to reduce the total volume of crystalloid required. In the first 24 hours of plasma volume sequestration, albumin infused intravenously may be lost from excessively permeable capillaries; but later, hyperoncotic HSA is useful to restore the plasma volume and to reduce interstitial edema.

Blood Pressure↗