Synthetic studies on glycosphingolipids from Protostomia phyla: synthesis of amphoteric glycolipid analogues containing a phosphocholine residue from the earthworm Pheretima hilgendorfi.
(49/519)
Two kinds of amphoteric glycosphingolipid analogues from the earthworm Pheretima hilgendorfi were synthesized as follows: The key reaction is a coupling of a phosphocholine group at the position C-6 of 1 and 6 which was attempted using 2-chloro-2-oxo-1,3,2-dioxaphospholane, followed by reaction of the resulting cyclic phosphate intermediate with anhydrous trimethylamine to give 2 and 7. Subsequent debenzylation afforded target compounds (3, 8). Their ability to inhibit the histamine release in vitro was examined. (+info)
Enhancement by histamine of vascular endothelial growth factor production in granulation tissue via H(2) receptors.
(50/519)
1. Roles of histamine in the production of vascular endothelial growth factor (VEGF) in the carrageenin-induced granulation tissue in rats were analysed in vitro and in vivo. 2. Incubation of the minced granulation tissue in the presence of histamine (1 and 10 microM) increased the content of VEGF protein in the conditioned medium in a time- and concentration-dependent manner. The levels of VEGF mRNA in the minced granulation tissue were also increased by histamine in a concentration-dependent manner. 3. The increase in the content of VEGF protein in the conditioned medium by histamine (10 microM) was suppressed by the H(2) receptor antagonist cimetidine (IC(50) 0.37 microM), but not by the H(1) receptor antagonist pyrilamine maleate, the H(3) receptor antagonist thioperamide or the cyclo-oxygenase inhibitor indomethacin. 4. The histamine-induced increase in the content of VEGF protein in the conditioned medium was inhibited by the cyclic AMP antagonist Rp-cAMP (IC(50) 6.8 microM), and the protein kinase A inhibitor H-89 (IC(50) 12.5 microM), but not by the protein kinase C inhibitors Ro 31-8425 and calphostin C or the tyrosine kinase inhibitor genistein. 5. Simultaneous injection of cimetidine (400 microg) and indomethacin (100 microg) into the air pouch of rats additively reduced the carrageenin-induced increase in VEGF protein levels and angiogenesis in the granulation tissue as assessed by using carmine dye. 6. These findings indicate that histamine has an activity to induce VEGF production in the granulation tissue via the H(2) receptor-cyclic AMP-protein kinase A pathway and augments angiogenesis in the granulation tissue. (+info)
Effect of clobenpropit on regional cerebral blood flow in rat hippocampus.
(51/519)
AIM: The effect of clobenpropit on regional cerebral blood flow (rCBF) was investigated in the rat hippocampus. METHODS: rCBF was determined in the hippocampus by the hydrogen clearance method. The blood pressure was measured by a tail-cuff plethysmograph. RESULTS: Intracerebroventricular (icv) injection of clobenpropit (20, 50 microg), a representative H3-antagonist, dose-dependently and significantly increased rCBF in the hippocampus. The increase of rCBF induced by clobenpropit was enhanced by metoprine (1, 2 mg/kg), a selective histamine N-methyltransferase inhibitor; however, was antagonized by an H3-agonist, (R)-alpha-methylhistamine (5 microg), an H(1)-antagonist, mepyramine (5-10 mg/kg), and an H2-antagonist, zolantidine (10 mg/kg). Clobenpropit caused no apparent effects on blood pressure even at a high dose of 50 microg. CONCLUSION: These results suggest that brain endogenous histamine may contribute to increase rCBF in the rat hippocampus via both the post-synaptic H1-, H2-receptors and the pre-synaptic H3-receptor. (+info)
Role of tyrosine kinase activity in alpha-adrenergic inhibition of the beta-adrenergically regulated L-type Ca(2+) current in guinea-pig ventricular myocytes.
(52/519)
1. The purpose of this study was to investigate the hypothesis that tyrosine kinase activity contributes to alpha(1)-adrenergic inhibition of beta-adrenergic responses in cardiac myocytes. We addressed this question by studying the pharmacological regulation of the L-type Ca(2+) current in acutely isolated adult guinea-pig ventricular myocytes using the whole-cell patch-clamp technique. 2. The selective alpha(1)-adrenergic receptor agonist methoxamine had no effect on the basal L-type Ca(2+) current. Methoxamine also had no effect on cAMP-dependent stimulation of the Ca(2+) current mediated by H(2) histamine receptor activation. However, methoxamine did inhibit cAMP-dependent stimulation of the Ca(2+) current mediated by beta-adrenergic receptor activation. The ability of methoxamine to inhibit beta-adrenergic regulation of the Ca(2+) current was significantly antagonized by the tyrosine kinase inhibitors genistein and lavendustin A. 3. The inhibitory effect of methoxamine was also mimicked by the phosphotyrosine phosphatase inhibitor pervanadate (PVN). PVN had no effect on basal Ca(2+) current or Ca(2+) current stimulated by histamine, but it did inhibit Ca(2+) current stimulated by beta-adrenergic receptor activation. Furthermore, the ability of PVN to inhibit beta-adrenergic stimulation of the Ca(2+) current was antagonized by lavendustin A. 4. These results are consistent with the conclusion that in guinea-pig ventricular myocytes alpha-adrenergic inhibition of beta-adrenergic responses involves a tyrosine kinase-dependent signalling pathway. The fact that methoxamine and PVN antagonized cAMP-dependent responses mediated by beta-adrenergic, but not H(2) histamine, receptor activation suggests that the inhibitory effect of alpha-adrenergic stimulation and tyrosine kinase activity is at the level of the beta-adrenergic receptor. (+info)
Cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use; partial final rule for combination drug products containing a bronchodilator. Final rule.
(53/519)
The Food and Drug Administration (FDA) is issuing a final rule establishing that cough-cold combination drug products containing any oral bronchodilator active ingredient in combination with any analgesic(s) or analgesic-antipyretic(s), anticholinergic, antihistamine, oral antitussive, or stimulant active ingredient are not generally recognized as safe and effective and are misbranded for over-the-counter (OTC) use. FDA is issuing this final rule after receiving no public comments on the agency's proposed nonmonograph status of these specific combination drug products, which was issued in the form of a tentative final monograph for OTC cough-cold combination drug products. This final rule is part of the ongoing review of OTC drug products conducted by FDA. (+info)
Role of endogenous histamine in altered lung mechanics in rabbits.
(54/519)
BACKGROUND: Unlike the effects of exogenous histamine, those of endogenous histamine on the lung mechanics have not yet been characterized. The site of endogenous histamine liberation by mivacurium was determined, as were the effects of this histamine on the airway and parenchymal mechanics in control rabbits (group C) and rabbits pretreated with H1 and H2 receptor blockers (group AH). The effectiveness of the receptor blockade was ensured by challenges with exogenous histamine. METHODS: Pulmonary input impedance at low frequencies (ZL) was measured in anesthetized mechanically ventilated open-chest rabbits under control conditions and every minute after administration of an intravenous bolus of mivacurium (2 mg/kg) and exogenous histamine (10 microg/kg). Histamine levels were determined in serum samples taken from the carotid artery and jugular vein before and 1, 3, and 6 min after mivacurium injection. Parameters of airway resistance (Raw) and inertance and parenchymal damping (G) and elastance (H) were extracted from ZL spectra. RESULTS: Mivacurium induced significant increases in plasma histamine levels, with the venous concentrations being significantly higher than those in the artery. The mivacurium-induced increase in Raw (28.7 +/- 2.3%; mean +/- SD) in group C was significantly higher than that in group AH (6.6 +/- 3.4%), whereas the responses in G were not inhibited significantly (23.9 +/- 6.9% vs. 15.5 +/- 3.0%). The significant increases in Raw (70.6 +/- 12.6%) and G (21.0 +/- 4.9%) after exogenous histamine administration were virtually completely abolished by antihistamine pretreatment (3.6 +/- 3.7% and 0.3 +/- 2.6%). CONCLUSIONS: After mivacurium administration, endogenous histamine is liberated at least partly in the systemic circulation, and it induces primarily a heterogeneous airway constriction with minor changes in the parenchymal properties. This response was considerably reduced but not abolished by antihistamine pretreatment, a circumstance suggesting that mivacurium may liberate other constrictor mediators that might also contribute to the airway and parenchymal constriction. (+info)
Proarrhythmic potential of halofantrine, terfenadine and clofilium in a modified in vivo model of torsade de pointes.
(55/519)
1. This study was designed to compare the proarrhythmic activity of the antimalarial drug, halofantrine and the antihistamine, terfenadine, with that of clofilium a K(+) channel blocking drug that can induce torsade de pointes. 2. Experiments were performed in pentobarbitone-anaesthetized, open-chest rabbits. Each rabbit received intermittent, rising dose i.v. infusions of the alpha-adrenoceptor agonist phenylephrine. During these infusions rabbits also received increasing i.v. doses of clofilium (20, 60 and 200 nmol kg(-1) min(-1)), terfenadine (75, 250 and 750 nmol kg(-1) min(-1)), halofantrine (6, 20 and 60 micromol kg(-1)) or vehicle. 3. Clofilium and halofantrine caused dose-dependent increases in the rate-corrected QT interval (QTc), whereas terfenadine prolonged PR and QRS intervals rather than prolonging cardiac repolarization. Progressive bradycardia occurred in all groups. After administration of the highest dose of each drug halofantrine caused a modest decrease in blood pressure, but terfenadine had profound hypotensive effects resulting in death of most rabbits. 4. The total number of ventricular premature beats was highest in the clofilium group. Torsade de pointes occurred in 6 out of 8 clofilium-treated rabbits and 4 out of 6 of those which received halofantrine, but was not seen in any of the seven terfenadine-treated rabbits. 5. These results show that, like clofilium, halofantrine can cause torsade de pointes in a modified anaesthetized rabbit model whereas the primary adverse effect of terfenadine was cardiac contractile failure. (+info)
Review article: the non-inherited gastrointestinal polyposis syndromes.
(56/519)
The non-inherited gastrointestinal polyposis syndromes represent a group of rare disorders characterized by the presence of multiple, non-adenomatous polyps on the gastrointestinal mucosa occurring in unrelated patients. We present here a review of the clinical and histo- pathological aspects of the syndromes to include the Cronkhite-Canada syndrome, hyperplastic polyposis and lipomatous polyposis. While infrequently encountered, these diseases can have devastating clinical effects that may be aggravated by delays in diagnosis and treatment. Prompt accurate diagnosis and treatment of these uncommon disorders depend on a sound working knowledge of the distinct clinical and pathological features described herein. (+info)