| 1. |
- Arce, Maximiliano, et al.
(författare)
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Coagulation Factor Xa Promotes Solid Tumor Growth, Experimental Metastasis and Endothelial Cell Activation
- 2019
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 11:8
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Tidskriftsartikel (refereegranskat)abstract
- Hypercoagulable state is linked to cancer progression; however, the precise role of the coagulation cascade is poorly described. Herein, we examined the contribution of a hypercoagulative state through the administration of intravenous Coagulation Factor Xa (FXa), on the growth of solid human tumors and the experimental metastasis of the B16F10 melanoma in mouse models. FXa increased solid tumor volume and lung, liver, kidney and lymph node metastasis of tail-vein injected B16F10 cells. Concentrating on the metastasis model, upon coadministration of the anticoagulant Dalteparin, lung metastasis was significantly reduced, and no metastasis was observed in other organs. FXa did not directly alter proliferation, migration or invasion of cancer cells in vitro. Alternatively, FXa upon endothelial cells promoted cytoskeleton contraction, disrupted membrane VE-Cadherin pattern, heightened endothelial-hyperpermeability, increased inflammatory adhesion molecules and enhanced B16F10 adhesion under flow conditions. Microarray analysis of endothelial cells treated with FXa demonstrated elevated expression of inflammatory transcripts. Accordingly, FXa treatment increased immune cell infiltration in mouse lungs, an effect reduced by dalteparin. Taken together, our results suggest that FXa increases B16F10 metastasis via endothelial cell activation and enhanced cancer cell-endothelium adhesion advocating that the coagulation system is not merely a bystander in the process of cancer metastasis.
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| 2. |
- Çevik Aras, Hülya, 1975, et al.
(författare)
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Melatonin-induced protein synthesis in the rat parotid gland
- 2011
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Ingår i: Journal of physiology and pharmacology. - 0867-5910. ; 62:1, s. 95-99
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Tidskriftsartikel (refereegranskat)abstract
- Melatonin occurs in large amounts in the intestinal mucosa and is released during a meal. Recent studies of ours reveal that exogenous melatonin evokes the in vivo secretion of protein and amylase from the rat parotid gland. The aim of the present study was to investigate the effect of melatonin on the protein synthesis of the parotid gland of pentobarbitone-anaesthetized rats as estimated by the rate of incorporation of [3H]leucine into trichloroacetic acid-insoluble material of the gland. Compared with the parotid protein synthesis (set at 100 %) of those rats exposed to an intravenous infusion of melatonin (25 mg/kg during 1 hour), under muscarinic and α- and β-adrenoceptor blockade, the synthesis in the corresponding glands of saline-treated control rats was less (by 25%). The synthesis was also less when the melatonin administration was combined with the melatonin 2-preffering receptor antagonist luzindole (24%), the non-selective nitric oxide synthase inhibitor L-NAME (18%) and the neuronal nitric oxide synthase inhibitor N-PLA (21%). Almost all the melatonin receptor-mediated effect was due to nitric oxide generation via the activity of neuronal type nitric oxide synthase. The present findings lend further weight to the idea that salivary glandular activity associated with food intake is hormonally influenced and they also suggest clinical implications for melatonin in the treatment of xerostomia. Since melatonin is known to exert anti-inflammatory actions in the oral cavity, the stimulatory effect of melatonin may include the synthesis of proteins of importance for the oral defence.
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| 3. |
- Ekström, Jörgen, 1944, et al.
(författare)
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Clozapine: agonistic and antagonistic salivary secretory actions.
- 2010
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Ingår i: Journal of dental research. - : SAGE Publications. - 1544-0591 .- 0022-0345. ; 89:3, s. 276-80
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Tidskriftsartikel (refereegranskat)abstract
- Individuals receiving clozapine treatment for schizophrenia complain of drooling. Reports on salivary flow measurements are contradictory in humans and lacking in animals. Clozapine has affinity for several different receptor types and may, hypothetically, both stimulate and inhibit salivary secretion. In rats, intravenous clozapine evoked a long-lasting secretion, being more prominent from submandibular than from parotid glands. Chronic denervation enhanced the responses. Clozapine acted on muscarinic (M1-) receptors of acinar cells, independent of central nervous mechanisms, pre-synaptic intraglandular events, or circulating catecholamines. A fraction of the methacholine- and parasympathetic-nerve-evoked secretion was abolished by clozapine at doses below those evoking secretion. Sympathetic-nerve-evoked secretion was partially reduced by clozapine, due to antagonistic action on alpha-adrenoceptors; the beta-adrenoceptor-mediated response persisted. Subsecretory doses of clozapine enhanced secretion induced by the beta-adrenoceptor agonist isoprenaline. The overall actions of clozapine suggest that, in clozapine-treated humans, salivation is increased during sleep and at rest, but is decreased during meals.
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| 4. |
- Ekström, Jörgen, 1944, et al.
(författare)
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How to explain the Clozapine-induced sialorrhea?
- 2010
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Ingår i: International Symposium on Morphological Sciences;Taotmina-Messina;18-22 september 2010.
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Konferensbidrag (refereegranskat)abstract
- About one-third of the schizophrenic patients receiving clozapine-therapy complain of hypersalivation, which is particularly troublesome during the night, and which may lead to discontinuation of the treatment. Objective measurements of the salivary flow are few, and data are, in fact inconsistent. The reported hypersalivation has, by some authors, even been attributed to a dysfunctional swallowing reflex. Animal experiments on the in vivo salivary effect of clozapine have been lacking until recently. We have established, using the anaesthetized rat as model, that clozapine, indeed, causes secretion from parotid and submandibular glands. The effect is small and "direct", indepentent of central nervous mechanisms, pre-synaptic intraglandular events and circulating catecholamines. It is exerted via muscarinic-M1-receptors, since it is abolished by pirenzepine. Clozapine exerts dual effects, since it inhibits secretion mediated via muscarinic-M3-receptors and α-adrenergic receptors and consequently, reduces both parasympathetic and sympathetic nerve evoked secretion. A main metabolite of clozapine is N-desmethylclozapine. Compared to its parent compound, we found this drug to exert stronger agonistic action via muscarinic M1-receptors and weaker antagonistic actions via M3-receptors and α-adrenergic receptors. Theoretically, N-desmethylclozapine adds its excitatory effect to that of clozapine. Moreover, the secretory response to the two drugs are gradually enhanced in surgically denervated glands. Thus theoretically, chronic blockade of M3- and α-receptors sensitizes the muscarinic-M1-receptors to clozapine and its metabolite as consequence of the prolonged pharmacological denervation. To conclude, during sleep the excitatory action of clozapine and N-desmethylclozapine will dominate, while during a meal, under reflex secretion, their inhibitory action is likely to dominate.
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| 5. |
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| 6. |
- Ekström, Jörgen, 1944, et al.
(författare)
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N-Desmethylclozapine exerts dual and opposite effects on salivary secretion in the rat.
- 2010
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Ingår i: European journal of oral sciences. - : Wiley. - 1600-0722 .- 0909-8836. ; 118:1, s. 1-8
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Tidskriftsartikel (refereegranskat)abstract
- N-Desmethylclozapine is a major metabolite of the atypical antipsychotic drug clozapine, used in the treatment of therapy-resistant schizophrenia. Patients under clozapine treatment report a troublesome sialorrhea. Recent experiments show clozapine to exert mixed agonist/antagonist actions on salivary secretion in rats. The present study was performed to define the secretory role of N-desmethylclozapine and to compare it with that of its parent compound. N-Desmethylclozapine evoked secretion by acting directly on the muscarinic acetylcholine M1-receptors of 'silent' duct-cannulated parotid and submandibular glands of the anaesthetized rat. In chronic surgically denervated glands, the secretory response was enlarged. The methacholine-evoked secretion, as well as the parasympathetic nerve-evoked secretion, were reduced by N-desmethylclozapine and involved blockade of M3-receptors, while the sympathetic nerve-evoked response was reduced, involving blockade of alpha(1)-adrenergic receptors. Synergistic interactions between N-desmethylclozapine and the beta-adrenergic receptor agonist, isoprenaline, occurred. Compared with clozapine, the excitatory efficacy of N-desmethylclozapine was higher and the inhibitory efficacy was lower (parasympathetic activity) or about the same (sympathetic activity). Theoretically, in humans treated with clozapine, an increase in the N-desmethylclozapine : clozapine ratio would contribute to salivation during the night and at rest, and, furthermore, the magnitude of the reduction in the reflexly elicited secretion is likely to diminish.
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| 7. |
- Ekström, Jörgen, 1944, et al.
(författare)
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Parasympathetic vasoactive intestinal peptide (VIP): a likely contributor to clozapine-induced sialorrhoea
- 2014
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Ingår i: Oral Diseases. - : Wiley. - 1354-523X. ; 20:3
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Tidskriftsartikel (refereegranskat)abstract
- Objective The parasympathetic transmitter vasoactive intestinal peptide (VIP) increases salivary gland blood flow and evokes protein secretion and, in some species, such as rats, a small fluid secretion. It interacts synergistically with muscarinics for protein and fluid output. Human salivary acini are supplied with VIP-containing nerves. We hypothesise that VIP and clozapine, acting together, evoke a volume of saliva greater than the sum of those induced by each drug given separately. It was further considered whether, in the current test situation, circulatory events influenced the magnitude of the secretory response. Saliva from parotid glands deprived of their autonomic innervation, and saliva and blood from innervated submandibular glands were collected in adrenoceptor antagonist-pretreated pentobarbitone-anaesthetised rats. Initially, the individual and then the combined effects of intravenous doses of VIP and clozapine were established. The submandibular volume response to the combination was 2-3 times higher, while blood pressure and glandular blood flow did not differ from those to VIP alone. The synergism occurred independent of nerves as shown in denervated parotid glands. From the current preclinical data, we speculate that VIP of parasympathetic origin, by its synergistic interaction with clozapine, may contribute to the clozapine (muscarinic M1-receptor)-induced sialorrhoea in schizophrenics.
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| 8. |
- Godoy, Tania, et al.
(författare)
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Atypical antipsychotics - effects of amisulpride on salivary secretion and on clozapine-induced sialorrhea
- 2012
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Ingår i: Oral Diseases. - : Wiley. - 1354-523X. ; 18:7, s. 680-691
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Tidskriftsartikel (refereegranskat)abstract
- Oral Diseases (2012) 18, 680691 Objective: Amisulpride is suggested for treatment of clozapine-induced sialorrhea. However, objective measurements of its effectiveness are lacking and, preclinically, amisulpride has no effect. We currently hypothesise that amisulpride acts by reducing the nervous- rather than the clozapine-driven salivary secretion. Material and Methods: Effects of intravenous amisulpride (as well as of clozapine and raclopride, a dopamine D2/D3 antagonist) were investigated in rats, including those subjected to chronic preganglionic parasympathetic denervation (submandibular glands) or combined postganglionic parasympathetic and sympathetic denervation (parotid glands). In duct-cannulated glands, secretion was evoked reflexly, at low and maximum flow rates, and by electrical stimulation of the parasympathetic and sympathetic innervations, and administration of autonomimetics (including substance P). Results: Unlike clozapine, amisulpride had no effect on the reflexly evoked secretion at maximum rate. With respect to reflex secretion at low rate and to the secretion evoked by muscarinic, a-adrenergic, beta-adrenergic and substance P receptors, amisulpride (in contrast to raclopride) dose dependently potentiated the responses. Amisulpride had no effect on gland blood flow. Conclusions: No support for any inhibitory influence of amisulpride was found. Conversely, amisulpride universally enhanced secretion, suggesting that amisulpride is a potential drug for dry-mouth treatment. The mechanism behind the potentiation is currently unknown.
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| 9. |
- Godoy, Tania, et al.
(författare)
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Clozapine-induced salivation: interaction with N-desmethylclozapine and amisulpride in an experimental rat model
- 2011
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Ingår i: European Journal of Oral Sciences. - : Wiley. - 0909-8836. ; 119:4, s. 275-281
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Many drugs (e.g. amisulpride) have been used to treat troublesome clozapine-induced salivation; however, varying success has been achieved in this respect, probably because, until recently, the salivatory action of clozapine has been largely unexplained. In the rat, clozapine and its main metabolite, N-desmethylclozapine, were found to exert mixed secretory actions: excitatory, through muscarinic acetylcholine M1-receptors giving rise to a long-lasting, low-level flow of saliva; and inhibitory, through muscarinic M3-receptors and α(1) -adrenoceptors reducing the parasympathetically and sympathetically nerve-evoked flow of saliva. The aim of the present study was to define the interactions between clozapine and N-desmethylclozapine, and clozapine and amisulpride, with respect to the excitatory response. Submandibular glands, sensitized by chronic parasympathetic preganglionic denervation, were studied in pentobarbitone-anaesthetized rats. To prevent clozapine from being metabolized to N-desmethylclozapine by hepatic enzymes, the liver was, under terminal anaesthesia, excluded from the circulation. The weak receptor-stimulating clozapine prevented the strong receptor-stimulating N-desmethylclozapine, at specific ratios in humans and in rats, from exerting its full agonistic action. In conclusion, the contribution of N-desmethylclozapine to the clozapine-induced sialorrhoea was, at most, only partly additive. Furthermore, the present experimental set-up failed to demonstrate any anti-salivatory action of amisulpride on the clozapine-induced flow of saliva.
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| 10. |
- Godoy, Tania, et al.
(författare)
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Salivary secretion effects of the antipsychotic drug olanzapine in an animal model
- 2013
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Ingår i: Oral Diseases. - : Wiley. - 1354-523X. ; 19:2, s. 151-161
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Olanzapine, introduced as an alternative to clozapine in schizophrenia therapy, is thought to display a receptor affinity similar to that of clozapine. Antipsychotics are well-known xerogenic drugs. However, clozapine exerts both antagonistic and agonistic salivary effects (‘clozapine-induced sialorrhea’), the latter probably via muscarinic M1 type of receptor. We hypothesise that olanzapine also has dual salivary effects. Material and methods: Effects of intravenous olanzapine were examined in rats, including those subjected to chronic preganglionic parasympathetic denervation (submandibular glands) or combined postganglionic parasympathetic and sympathetic denervation (parotid glands). Secretion was evoked reflexly, and by intravenous methacholine and the tachykinin substance P. Results: At 0.01–1 mg kg−1, olanzapine dose dependently reduced secretion in response to methacholine or reflex stimulus but not that to substance P. At 10 mg kg−1, olanzapine evoked a long-lasting secretion, independent of the autonomic innervation as well as of α- and β-adrenergic receptors and muscarinic receptors. The secretion was reduced, but not abolished, by a substance P receptor antagonist. Conclusions: Like clozapine, olanzapine evoked secretion. The response to olanzapine was greater and, in contrast to clozapine, involved non-traditional gland receptors (such as substance P receptors). The findings imply that olanzapine plays an excitatory role via tachykinin receptors in humans.
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