Biomedical subjects
Publications and source records attributed to A Calignano.
A new series of 2-(4- and 3-substituted phenyl)-3-[3-(N,N-dimethylamino) propyl]-1,3-thiazolidin-4-ones were synthesized, characterized, and evaluated for their ability to inhibit the contractions induced by histamine on guinea pig ileum. The measurement of pA2 values suggested that the reported compounds showed H1-antagonism. The more active compounds 5, 9, and 13 exhibited activity close to that of mepyramine.
1. Following intravenous administration of morphine.HCl a reduction in mean arterial blood pressure (MABP) was produced, quaternary morphine analogue was ineffective. 2. Theophylline and 8-phenyltheophylline administration reduced morphine-induced hypotension. 3. A2 adenosine receptor agonist caused an hypotension while A1 adenosine receptor agonist was ineffective. 4. L-NG-Mono-methylarginine administration reduced the hypotensive effect of exogenous A2 agonist while it was ineffective on morphine-induced hypotension. 5. Morphine-induced hypotension was increased by pretreatment with dipyridamole, whereas tetrabenazine abolished it. 6. The present study is consistent with previous reports on the central hypotensive action of morphine and propose a role for adenosine release in morphine-induced hypotension.
1. The effect of dexamethasone in gastrointestinal constipation induced by morphine, verapamil and atropine in mice has been studied. 2. These drugs caused a dose-related inhibition of charcoal meal transit, which was reversed by dexamethasone. 3. Dexamethasone resulted more active in reversing morphine and atropine constipation, than in modifying verapamil effect. 4. The authors concluded that the interaction of dexamethasone on its receptor could release a larger amount of acetylcholine resulting in a reversion of atropine- or morphine-induced constipation. 5. The minor effect of dexamethasone on verapamil-induced constipation suggest a reduced involvement of calcium influx. 6. The above results suggest a role for steroid in gastrointestinal transit and propose a possible mechanism through which dexamethasone could reverse morphine- and atropine-induced constipation.
Administration of morphine in mice causes inhibition of the gastrointestinal transit of a charcoal meal. Morphine-induced constipation in mice seems to depend predominantly on action(s) on the central nervous system since N-methyl morphine, a quaternary derivative, inhibits intestinal transit only when administered intracerebroventricularly (i.c.v.). L- but not D-arginine, given intraperitoneally, reversed the constipation induced by both morphine and its quaternary analogue. L-arginine was ineffective when given i.c.v. and did not reverse atropine-induced constipation. These results suggest that L-arginine preferentially modulates opioid-induced constipation through a stereospecific and peripheral action(s). It is possible that the effect of L-arginine is achieved by increasing the amount of nitric oxide released by non-adrenergic, non-cholinergic nerves in the gut. Thus, L-arginine may represent a useful agent for the treatment of undesirable constipation associated with the use of narcotic analgesics.
We describe some properties on an Mr 30,000 thermolabile and trypsin-sensitive protein that activates phospholipase A2 (PLA2) and which was isolated from nervous tissue of the marine mollusk, Aplysia californica. A similar protein is present in rat cerebral cortex. This protein was partially purified from crude homogenates of nervous tissue by ion exchange chromatography on DEAE-Sephadex followed by size-exclusion high performance liquid chromatography (HPLC). It is loosely associated with membrane fractions, and is extracted by 0.05% Tween 20. Although similar in size to several previously described PLA2-stimulating proteins from non-neural mammalian cells and tissues, it differs from them in some aspects of biological activity. The protein promotes the release of eicosanoids from the membranes of intact Aplysia neurons prelabeled with [3H]arachidonic acid and appears to be an in vitro substrate for protein kinase C (PKC). PLA2-stimulating activity is greatly enhanced after exposing isolated ganglia to phorbol dibutyrate (PDBu) and is reduced by treatment with immobilized E. coli alkaline phosphatase. These observations suggest that phosphorylation of this stimulatory protein by PKC regulates PLA2 in neurons.
1. Morphine and dexamethasone significantly reduce gastrointestinal transit in mice. The degree of reduction was greater for morphine. 2. Dexamethasone pretreatment was found, however, to antagonize morphine-induced constipation. 3. Cycloheximide does not modify the dexamethasone effects. 4. RU-38486 reverses both the inhibitory action of dexamethasone on gastrointestinal transit and its reducing effect on morphine-induced constipation. 5. These results suggest that dexamethasone might act through binding to receptors not linked to DNA-responsive elements.
1. The effect of dexamethasone and its interaction with morphine has been studied on transmurally-stimulated guinea-pig ileum preparation. 2. Dexamethasone dose-dependently depressed the contractions of the ileum; this action has a rapid onset. 3. Naloxone did not reverse the inhibitory effect of dexamethasone. 4. When dexamethasone and morphine were given in combination the maximum reduction observed was equal to the sum of the single effect of two drugs given individually and naloxone antagonized only the inhibition induced by morphine. 5. Proteic synthesis inhibitors did not modify the inhibition induced by dexamethasone. 6. RU-38486, a glucocorticoid antagonist receptor, antagonized completely the inhibitory effect of DXM without affecting the inhibition induced by morphine showing that the effect of dexamethasone occurs by glucocorticoid receptor-mediated processes.
The following 2-substituted phenyl-3-(N,N-dimethylaminopropyl)-1,3-thiazolidin-4-one of general formula (A): [formula: see text] where: X = H (I), 3-F (II), 3-Cl (III), 3-Br (IV), 3-CH3 (V), 3-OCH3 (VI), 3-NO2 (VII), 4-F (VIII), 4-Cl (IX), 4-Br (X), 4-CH3 (XI), 4-OCH3 (XII), 4-NO2 (XIII) were prepared and tested for antihistamine activity. The synthetic procedure involves the cyclocondensation of the appropriate Schiff base with thioglycolic acid in refluxing dry benzene. The compounds herein presented were tested for their ability to inhibit the contraction inducted by histamine 5.10(-7) M "in vitro", on guinea pig ileum. The results are reported as contraction of test compound causing 50% of submaximal contraction induced by histamine (IC50), and related to mepyramine as control. The results of the antihistamine tests showed an interesting degree of activity of some of the new thiazolidinone-derivatives. Compounds II, III, V, X, and XI showed IC50 values near the value of the control, compound XI being the most active. These compounds seem to be worthy of further investigation.
1. When castor oil was administered by gavage to rats, the duodenum and jejunum but not ileum and colon produced large amounts (5-6 fold greater than control) of platelet activating factor (Paf). 2. Intraluminal release of acid phosphatase (AP) was also markedly increased (5-6 fold greater than control) in the duodenum and jejunum of castor oil-treated rats and there was a correlation between the elevated release of AP and intestinal hyperaemia. 3. These findings support a role for Paf as a mediator of intestinal damage induced by castor oil.
Platelet activating factor (PAF) neutrophils, platelets, macrophages, endothelial cells, and isolated tissue preparations. In the present study, we have isolated and identified PAF in the skin of guinea pigs undergoing irradiation by UV light.
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Angiotensin converting enzyme (ACE) converts angiotensin I (Angio I) to angiotensin II (Angio II) and inactivates bradykinin (BK). Glucocorticoids in the physiological range increase ACE in rabbit alveolar macrophages and bovine endothelial cells in culture. Since Angio I and BK are cleaved by ACE catalysis during passage through the pulmonary vasculature we have studied the steroid modulation of ACE in the rat lung. The conversion of Angio I to Angio II by isolated lungs from normal or adrenalectomized male Wistar rats has been evaluated. The initial conversion of Angio I to Angio II in lungs from normal rats was about 60%. In contrast the initial converting activity in lungs from adrenalectomized rats was about 30%. In both groups the converting activity progressively decreased. After 3 h it was about 30% in normal lungs and virtually undetectable in lungs from adrenalectomized rats. Dexamethasone infusion (1 microgram/ml) prevented the decrease in ACE activity observed in normal lungs and induced a gradual enhancement of converting activity in lungs from adrenalectomized animals up to the control level. The effect of dexamethasone was abolished by simultaneous infusion of cycloheximide (1 microgram/ml). These results demonstrate that glucocorticoids induce ACE synthesis in the rat lung. By this induction glucocorticoids promote the increase of both Angio II formation and BK degradation. Thus ACE induction may represent a possible mechanism whereby glucocorticoids might control vascular tone and permeability according to the general mode of action of steroid hormones.
The anti-inflammatory effect of glucocorticoids has been investigated in two standard models of experimental inflammation, i.e. rat paw oedema induced by carrageenin or dextran. Both types of oedema are suppressed by dexamethasone while indomethacin and BW755C only suppress carrageenin oedema. Dexamethasone inhibits dextran oedema according to the accepted mode of action of steroid hormones since the inhibition occurs after a 2-3 h time lag and is abolished by pretreating animals with actinomycin D. Dextran oedema and carrageenin oedema are also controlled by endogenous corticoids since adrenalectomy potentiates the paw oedema formation induced by low concentrations of phlogogenic agents. It has been shown that glucocorticoids induce both in vitro and in vivo the formation and release of antiphospholipase proteins which are anti-inflammatory in that they greatly suppress carrageenin oedema. However, these proteins have no effect on dextran oedema. We conclude that the inhibition of dextran oedema by glucocorticoids depends on the formation of another type of anti-inflammatory protein.
Gamma(glutamyl5)spermine derivative of substance P (Spm-SP) was synthesized in vitro in the presence of purified guinea pig liver transglutaminase and Ca2+. The spermine adduct of the neuropeptide was purified by HPLC on a reversed-phase column and characterized by fast atom bombardment mass spectrometry. The biological activities of Spm-SP were tested by assaying, in comparison with substance P, its ability to induce both the contractions of smooth muscle in vitro and the edema formation in vivo. Spm-SP was shown not to elicit contractile responses in the isolated rat stomach strip and duodenum and not to antagonize the spasmogenic effect evoked by the native neuropeptide. Furthermore, Spm-SP was unable, when administered into rats by plantar injection, either to provoke an acute inflammatory response in the hind limb or to antagonize the edema formation induced by a concurrent administration of substance P. These results indicate that the introduction of a large size hydrophilic moiety at the glutamine5 level negatively affects the ability of the neuropeptide to bind to its receptor(s), thus supporting the view that the hydrophobic middle portion of substance P plays a key role in receptor recognition.
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In this paper we present the formulation, preparation and characterization of new polymeric composite materials containing a nano-hybrid to be used for the controlled molecular delivery of an anti-inflammatory molecule, Diclofenac. The nano-hybrid consists of a layer of double hydroxide of an Mg-Al hydrotalcite type, in which we replaced the chloride anions present in the host galleries with Diclofenac anions by a simple ion-exchange reaction. Different amounts of the hybrid material were incorporated in polycaprolactone and processed as films of 0.15 mm thickness. The composite materials were analyzed by X-ray diffractometry, thermogravimetry and for their mechanical properties, and showed properties even better than those for the pristine polymer. The release process of the anti-inflammatory molecules was very interesting and promising for tuneable drug delivery. It consists of two stages: a first stage, very rapid as a burst in which a small fraction of the drug is released, and of a second stage that is much slower, extending for longer and longer periods. The parameters influencing the drug release were individuated and discussed.