ABSTRACT
Cardiac tamponade is an uncommon disorder in pediatric patients. We report a case of cardiac tamponade secondary to accumulation of cerebrospinal fluid due to ventriculo-atrial derivation (VAD) disfunction. An 11-month-old girl was assisted because of respiratory distress and tachycardia, without fever. She had a ventriculoatrial derivation, because of hydro-cephalus since two month earlier. The echocardiogram showed a pericardial effusion and the distal VAD located inside the right cardiac ventricle. The distal VAD was retired and replaced between superior cava vein and right atrium. The patient recovered ad integrum without pericardial effusion. In cases of patients with VAD presenting a clinical disorder, it should be ruled out VAD dysfunction or inappropriate placement.
Subject(s)
Cardiac Tamponade/etiology , Heart Atria/injuries , Heart Atria/surgery , Ventriculostomy/adverse effects , Female , Humans , InfantABSTRACT
El taponamiento cardíaco es una entidad poco frecuente en pediatría. Comunicamos un caso de taponamiento cardíaco por la acumulación de líquido cefalorraquídeo secundario a unaválvula de derivación ventrículo-atrial (VDVA). Ingresó una niña de 11 meses de edad con dificultad respiratoria de 12 h de evolución, afebril, taquicárdica, portadora de una válvula de derivación ventrículo atrial por hidrocefalia desde hacía dos meses. En el ecocardiograma se observó derrame pericárdico y la punta de la VDVA en la cavidad pericárdica. Se realizó la extracción de la VDVA y su recolocación en la desembocadura de la vena cava superior en la aurícula derecha. La paciente presentó buena evolución con un ecocardiograma posterior sin evidencia de derrame. Ante un paciente con VDVA que se presente con clínica de descompensación de algún tipo, se debería descartar en primer lugar que la causa no sea secundaria a la VDVA.
Subject(s)
Humans , Female , Infant , Cardiac Tamponade , Pericardiocentesis , PericardiumABSTRACT
El taponamiento cardíaco es una entidad poco frecuente en pediatría. Comunicamos un caso de taponamiento cardíaco por la acumulación de líquido cefalorraquídeo secundario a unaválvula de derivación ventrículo-atrial (VDVA). Ingresó una niña de 11 meses de edad con dificultad respiratoria de 12 h de evolución, afebril, taquicárdica, portadora de una válvula de derivación ventrículo atrial por hidrocefalia desde hacía dos meses. En el ecocardiograma se observó derrame pericárdico y la punta de la VDVA en la cavidad pericárdica. Se realizó la extracción de la VDVA y su recolocación en la desembocadura de la vena cava superior en la aurícula derecha. La paciente presentó buena evolución con un ecocardiograma posterior sin evidencia de derrame. Ante un paciente con VDVA que se presente con clínica de descompensación de algún tipo, se debería descartar en primer lugar que la causa no sea secundaria a la VDVA.(AU)
Subject(s)
Humans , Female , Infant , Cardiac Tamponade , Pericardium , PericardiocentesisABSTRACT
El taponamiento cardíaco es una entidad poco frecuente en pediatría. Comunicamos un caso de taponamiento cardíaco por la acumulación de líquido cefalorraquídeo secundario a unaválvula de derivación ventrículo-atrial (VDVA). Ingresó una niña de 11 meses de edad con dificultad respiratoria de 12 h de evolución, afebril, taquicárdica, portadora de una válvula de derivación ventrículo atrial por hidrocefalia desde hacía dos meses. En el ecocardiograma se observó derrame pericárdico y la punta de la VDVA en la cavidad pericárdica. Se realizó la extracción de la VDVA y su recolocación en la desembocadura de la vena cava superior en la aurícula derecha. La paciente presentó buena evolución con un ecocardiograma posterior sin evidencia de derrame. Ante un paciente con VDVA que se presente con clínica de descompensación de algún tipo, se debería descartar en primer lugar que la causa no sea secundaria a la VDVA.(AU)
Subject(s)
Humans , Female , Infant , Cardiac Tamponade , Pericardium , PericardiocentesisABSTRACT
A new group of derivatives of salicylic acid containing NO-donor furoxans, and the related des-NO-furazans, were synthesized and evaluated as new aspirin-like molecules. Their stability was assessed in acid (pH 1) and physiological solutions (pH 7.4), and in human serum. No compound exhibited COX-inhibitory activity against COX-1 and COX-2 isoforms, when tested up to 100µM, respectively, on isolated platelets and on monocytes. Phenylsulfonyl- and cyano-substituted furoxans inhibited platelet aggregation induced by collagen in human platelet-rich plasma, through a cGMP dependent mechanism. Furoxan derivatives displayed cGMP-dependent vasodilator activities, tested on rat aorta strips precontracted with phenylephrine. All products showed anti-inflammatory activity similar to that of ASA, tested on rats by the carrageenan-induced paw edema assay. Unlike ASA, all products showed markedly reduced gastrotoxicity in a rat lesion model.
Subject(s)
Anti-Inflammatory Agents/chemistry , Aspirin/chemistry , Nitric Oxide Donors/chemistry , Oxadiazoles/chemistry , Salicylic Acid/chemistry , Animals , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Collagen/chemistry , Collagen/metabolism , Cyclooxygenase 1/chemistry , Cyclooxygenase 1/metabolism , Cyclooxygenase 2/chemistry , Cyclooxygenase 2/metabolism , Disease Models, Animal , Drug Stability , Edema/chemically induced , Edema/drug therapy , Humans , Hydrogen-Ion Concentration , Nitric Oxide Donors/pharmacology , Nitric Oxide Donors/therapeutic use , Oxadiazoles/pharmacology , Oxadiazoles/therapeutic use , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors/chemical synthesis , Platelet Aggregation Inhibitors/chemistry , Platelet Aggregation Inhibitors/pharmacology , Rats , Vasodilator Agents/chemical synthesis , Vasodilator Agents/chemistry , Vasodilator Agents/pharmacologySubject(s)
Anti-Inflammatory Agents/chemistry , Arachidonate 5-Lipoxygenase/chemistry , Hydroxyurea/analogs & derivatives , Lipoxygenase Inhibitors/chemistry , Nitric Oxide/metabolism , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/therapeutic use , Arachidonate 5-Lipoxygenase/metabolism , Drug Design , Edema/chemically induced , Edema/drug therapy , Hydroxyurea/chemical synthesis , Hydroxyurea/chemistry , Hydroxyurea/therapeutic use , Leukotriene B4/metabolism , Lipoxygenase Inhibitors/chemical synthesis , Lipoxygenase Inhibitors/therapeutic use , Rats , Structure-Activity RelationshipABSTRACT
BACKGROUND AND PURPOSE: We compare the pharmacological profiles of a new histamine H4 receptor agonist 2-(2-guanidinoethyl)isothiourea (VUF 8430) with that of a previously described H4 receptor agonist, 4-methylhistamine. EXPERIMENTAL APPROACH: Radioligand binding and functional assays were performed using histamine H4 receptors expressed in mammalian cell lines. Compounds were also evaluated ex vivo in monocyte-derived dendritic cells endogenously expressing H4 receptors and in vivo in anaesthetized rats for gastric acid secretion activity. KEY RESULTS: Both VUF 8430 and 4-methylhistamine were full agonists at human H4 receptors with lower affinity at rat and mouse H4 receptors. Both compounds induced chemotaxis of monocyte-derived dendritic cells. VUF 8430 also showed reasonable affinity and was a full agonist at the H3 receptor. Agmatine is a metabolite of arginine, structurally related to VUF 8430, and was a H4 receptor agonist with micromolar affinity. At histamine H3 receptors, agmatine was a full agonist, whereas 4-methylhistamine was an agonist only at high concentrations. Both VUF 8430 and agmatine were inactive at H1 and H2 receptors, whereas 4-methylhistamine is as active as histamine at H2 receptors. In vivo, VUF 8430 only caused a weak secretion of gastric acid mediated by H2 receptors, whereas 4-methylhistamine, dimaprit, histamine and amthamine, at equimolar doses, induced 2.5- to 6-fold higher output than VUF 8430. CONCLUSIONS AND IMPLICATIONS: Our results suggest complementary use of 4-methylhistamine and VUF 8430 as H4 receptor agonists. Along with H4 receptor antagonists, both agonists can serve as useful pharmacological tools in studies of histamine H4 receptors.
Subject(s)
Guanidines/pharmacology , Receptors, G-Protein-Coupled/agonists , Thiourea/analogs & derivatives , Agmatine/pharmacology , Animals , Cell Line , Chemotaxis/drug effects , Chlorocebus aethiops , Dendritic Cells/physiology , Gastric Acid/metabolism , Histamine Agonists/pharmacology , Humans , Male , Methylhistamines/pharmacology , Mice , Radioligand Assay , Rats , Rats, Wistar , Receptors, Histamine , Receptors, Histamine H2/metabolism , Receptors, Histamine H3/metabolism , Receptors, Histamine H4 , Thiourea/pharmacologyABSTRACT
From a series of small fragments that was designed to probe the histamine H(4) receptor (H(4)R), we previously described quinoxaline-containing fragments that were grown into high affinity H(4)R ligands in a process that was guided by pharmacophore modeling. With a scaffold hopping exercise and using the same in silico models, we now report the identification and optimization of a series of quinazoline-containing H(4)R compounds. This approach led to the discovery of 6-chloro-N-(furan-3-ylmethyl)2-(4-methylpiperazin-1-yl)quinazolin-4-amine (VUF10499, 54) and 6-chloro-2-(4-methylpiperazin-1-yl)-N-(thiophen-2-ylmethyl)quinazolin-4-amine (VUF10497, 55) as potent human H(4)R inverse agonists (pK(i) = 8.12 and 7.57, respectively). Interestingly, both compounds also possess considerable affinity for the human histamine H(1) receptor (H(1)R) and therefore represent a novel class of dual action H(1)R/H(4)R ligands, a profile that potentially leads to added therapeutic benefit. Compounds from this novel series of quinazolines are antagonists at the rat H(4)R and were found to possess anti-inflammatory properties in vivo in the rat.
Subject(s)
Histamine Agonists/chemistry , Quinazolines/chemistry , Receptors, G-Protein-Coupled/agonists , Animals , Anti-Inflammatory Agents/chemistry , Chemistry, Pharmaceutical/methods , Drug Design , Humans , Hydrogen-Ion Concentration , Inhibitory Concentration 50 , Kinetics , Models, Chemical , Models, Molecular , Molecular Conformation , Rats , Receptors, Histamine , Receptors, Histamine H4ABSTRACT
Using a previously reported flexible alignment model we have designed, synthesized, and evaluated a series of compounds at the human histamine H 4 receptor (H 4R) from which 2-(4-methyl-piperazin-1-yl)-quinoxaline ( 3) was identified as a new lead structure for H 4R ligands. Exploration of the structure-activity relationship (SAR) of this scaffold led to the identification of 6,7-dichloro 3-(4-methylpiperazin-1-yl)quinoxalin-2(1 H)-one (VUF 10214, 57) and 2-benzyl-3-(4-methyl-piperazin-1-yl)quinoxaline (VUF 10148, 20) as potent H 4R ligands with nanomolar affinities. In vivo studies in the rat reveal that compound 57 has significant anti-inflammatory properties in the carrageenan-induced paw-edema model.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Drug Design , Receptors, Histamine/drug effects , Anti-Inflammatory Agents/chemistry , Humans , Ligands , Magnetic Resonance Spectroscopy , Models, Molecular , Receptors, Histamine/metabolism , Spectrometry, Mass, Electrospray Ionization , Structure-Activity RelationshipABSTRACT
A new class of products in which the phenol group of salicylic acid is linked to alkanoyl moieties bearing nitrooxy functions has been synthesized and studied for their polyvalent actions. The products were stable in acid and neutral media, while they were hydrolyzed in human serum. Their half-lives were dependent upon the structure of alkanoyl moieties. The products showed anti-inflammatory activities similar to aspirin when tested in the carrageenan-induced paw edema assay in the rat. Interestingly, unlike aspirin, they showed reduced or no gastrotoxicity in a lesion model in rats at equimolar doses. A number of them were able to inhibit platelet aggregation induced by collagen in human platelet-rich plasma. All of the products were capable of relaxing rat aortic strips precontracted with phenylephrine in a concentration-dependent manner. Selected members of this new class of nonsteroidal anti-inflammatory drugs might represent possible safer alternatives to aspirin in different clinical settings.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemistry , Nitric Oxide Donors/chemistry , Nitro Compounds/chemistry , Platelet Aggregation Inhibitors/chemistry , Salicylic Acid/chemistry , Vasodilator Agents/chemistry , Animals , Anti-Inflammatory Agents, Non-Steroidal/classification , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Aorta, Thoracic/drug effects , Aspirin/pharmacology , Carrageenan , Drug Evaluation, Preclinical , Edema/chemically induced , Edema/drug therapy , Humans , Hydrolysis , Male , Molecular Structure , Nitric Oxide Donors/classification , Nitric Oxide Donors/pharmacology , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors/classification , Platelet Aggregation Inhibitors/pharmacology , Rats , Rats, Wistar , Salicylic Acid/classification , Salicylic Acid/pharmacology , Solutions/chemistry , Stereoisomerism , Vasodilator Agents/classification , Vasodilator Agents/pharmacology , Water/chemistryABSTRACT
The effects of the highly selective histamine H4 receptor antagonists JNJ7777120 and VUF6002 were investigated on the carrageenan-induced inflammation and thermal hyperalgesia in rats. JNJ7777120 (10 and 30 mg/kg, s.c.) and VUF6002 (10 mg/kg, s.c.) significantly reduced paw edema and hyperalgesia provoked by subplantar injection of carrageenan; the effect was evident against the early (2 h) phase of inflammation. An inactive analog of VUF6002, VUF6007 (10 mg/kg, s.c.) slightly aggravated paw edema, while leaving unaltered carrageenan-induced nociception. These findings indicate that histamine H4 receptors participate in the early phase of acute inflammation induced by carrageenan in rats, influencing both edema and thermal hyperalgesia.
Subject(s)
Analgesics/pharmacology , Anti-Inflammatory Agents/pharmacology , Benzimidazoles/pharmacology , Histamine Antagonists/pharmacology , Hyperalgesia/prevention & control , Indoles/pharmacology , Inflammation/prevention & control , Piperazines/pharmacology , Receptors, G-Protein-Coupled/antagonists & inhibitors , Animals , Carrageenan , Disease Models, Animal , Edema/metabolism , Edema/prevention & control , Hot Temperature , Hyperalgesia/etiology , Hyperalgesia/metabolism , Inflammation/chemically induced , Inflammation/complications , Inflammation/metabolism , Male , Pain Measurement , Rats , Rats, Wistar , Receptors, G-Protein-Coupled/metabolism , Receptors, Histamine/metabolism , Receptors, Histamine H4 , Time FactorsABSTRACT
The effects of the cannabinoid (CB)-receptor agonists WIN55,212-2 and HU-210 and the selective CB(1)-receptor antagonist SR141716A were tested on in vitro and in vivo acid secretion assays from the rat. In the isolated gastric fundus from immature rats, WIN55,212-2 (0.001-30 microM), HU-210 (0.001-10 microM), or SR141716A (0.1-10 microM) did not change the basal acid output or acid responses to histamine, pentagastrin, or electrical field stimulation. HU-210 (0.3 micromol/kg, intravenously) inhibited the acid response to pentagastrin in anesthetized adult, young, or immature rats with lumen-perfused stomachs; moreover, HU-210 reduced vagally induced acid secretion in adult animals, its antisecretory effect being reversed by SR141716A (0.65 micromol/kg, intravenously). In vitro and in vivo data indicate that CB(1) receptors are not located on parietal cells but, rather, on vagal pathways (possibly at preganglionic sites) supplying the gastric mucosa. The lack of effect of CB-receptor ligands in vitro cannot be ascribed to the use of immature rats, since HU-210 inhibited stimulated acid secretion in vivo, irrespective of the animal age.
Subject(s)
Dronabinol/analogs & derivatives , Gastric Acid/metabolism , Gastric Fundus/drug effects , Morpholines/pharmacology , Naphthalenes/pharmacology , Receptor, Cannabinoid, CB1/agonists , Age Factors , Animals , Benzoxazines , Dronabinol/pharmacology , Gastric Fundus/metabolism , Gastric Mucosa/drug effects , Gastric Mucosa/metabolism , Ligands , Male , Piperidines/pharmacology , Pyrazoles/pharmacology , Rats , Rats, Wistar , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Receptor, Cannabinoid, CB1/physiology , Rimonabant , Tissue Culture TechniquesABSTRACT
The discovery of a second isoform of cyclooxygenase has led to a re-evaluation of the mechanisms underlying the adverse effects of nonsteroidal anti-inflammatory drugs, focusing in particular on the gastrointestinal system. We investigated the involvement of cyclooxygenase-1 and -2 in the regulation of gastric acid secretion and cardiovascular functions in anesthetized rats, after acute intravenous administration of the selective cyclooxygenase-1 inhibitor SC-560, the selective cyclooxygenase-2 inhibitor celecoxib and the nonselective inhibitor indomethacin. Indomethacin, celecoxib and SC-560 did not significantly modify basal acid secretion. Indomethacin and celecoxib were also ineffective on the acid secretion stimulated by pentagastrin; by contrast, SC-560 significantly enhanced the acid secretion stimulated by pentagastrin, electrical vagal stimulation or histamine. The stimulatory effects of SC-560 were prevented by cervical vagotomy, atropine and famotidine. Indomethacin caused either no change, increasing or decreasing effects on mean arterial pressure and heart rate. By contrast, SC-560 was unable to change cardiovascular parameters at 5 mg/kg, while inducing a marked bradycardia at 10 mg/kg. Celecoxib was ineffective. Our findings indicate that cyclooxygenase-1-derived prostaglandins are involved in the regulation of stimulated acid secretion and of basal heart rate; the role of prostaglandins in the acute control of systemic blood pressure under resting conditions seems to be negligible.
Subject(s)
Blood Pressure/drug effects , Cyclooxygenase 1/physiology , Cyclooxygenase 2/physiology , Cyclooxygenase Inhibitors/adverse effects , Gastric Acid/metabolism , Heart Rate/drug effects , Hemodynamics/drug effects , Animals , Celecoxib , Indomethacin/adverse effects , Male , Pentagastrin/adverse effects , Pyrazoles/adverse effects , Rats , Rats, Wistar , Sulfonamides/adverse effects , VagotomyABSTRACT
BACKGROUND/AIMS: The compound amtolmetin guacyl (AMG) has been characterized in both animal and human studies as a novel non-selective non-steroidal anti-inflammatory drug (NSAID) endowed with lower ulcerogenicity in comparison with traditional NSAIDs due to a unique mechanism of action, namely the increase in endogenous production of gastric nitric oxide. METHODS: Conscious rats were treated either acutely (4 h) or chronically (3 and 14 days) with intragastric AMG (50 and 150 mg/kg), the non-selective NSAID tolmetin (TOL, 30 and 100 mg/kg) or the COX-2-selective NSAID celecoxib (CXIB, 20 and 60 mg/kg). Macroscopically visible and histologic lesions were evaluated. The ultrastructure of mucosal microvasculature was assessed. RESULTS: (1) TOL and CXIB caused quantitatively greater endothelial damage and inflammatory cell infiltration than that induced by AMG; (2) AMG and CXIB, unlike TOL, did not cause epithelial damage after acute or chronic treatment, and (3) gastric lesions induced by TOL underwent adaptation during chronic treatment. CONCLUSION: Endothelial cell damage in the gastric microvasculature is an early event following both non-selective and COX-2-selective inhibitors. The low gastric mucosal toxicity of AMG is confirmed after acute and chronic treatment.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/toxicity , Cyclooxygenase Inhibitors/toxicity , Gastric Mucosa/drug effects , Glycine/analogs & derivatives , Glycine/toxicity , Pyrroles/toxicity , Analysis of Variance , Animals , Male , Microscopy, Electron , Rats , Rats, WistarABSTRACT
A new series of NSAIDs in which aspirin is joined by an ester linkage to furoxan moieties, with different ability to release NO, were synthesized and tested for NO-releasing, antiinflammatory, antiaggregatory, and ulcerogenic properties. Related furazan derivatives, aspirin, its propyl ester, and its gamma-nitrooxypropyl ester were taken as references. All the products described present an antiinflammatory trend, maximized in derivatives 12, 16, and 17, they are devoid of acute gastrotoxicity, principally due to their ester nature, and show an antiplatelet activity primarily determined by their ability to release NO. They do not behave as aspirin prodrugs in human serum.
