5 results on '"Ortiz MI"'
Search Results
2. Pharmacokinetic-pharmacodynamic modelling of the analgesic effects of lumiracoxib, a selective inhibitor of cyclooxygenase-2, in rats.
- Author
-
Vásquez-Bahena, DA, Salazar-Morales, UE, Ortiz, MI, Castañeda-Hernández, G, Trocóniz, IF, Vásquez-Bahena, D A, Salazar-Morales, U E, Ortiz, M I, Castañeda-Hernández, G, and Trocóniz, Iñaki F
- Subjects
PHARMACOKINETICS ,PHARMACODYNAMICS ,ANALGESICS ,DRUG efficacy ,CYCLOOXYGENASE 2 inhibitors ,NOCICEPTORS ,HYPERALGESIA ,LABORATORY rats ,ANIMAL experimentation ,BIOAVAILABILITY ,BIOLOGICAL models ,CHAOS theory ,COMPARATIVE studies ,DICLOFENAC ,DOSE-effect relationship in pharmacology ,INFLAMMATORY mediators ,RESEARCH methodology ,MEDICAL cooperation ,NONSTEROIDAL anti-inflammatory agents ,ORAL drug administration ,POLYSACCHARIDES ,RATS ,RESEARCH ,TIME ,CYCLOOXYGENASE 2 ,EVALUATION research - Abstract
Background and Purpose: This study establishes a pharmacokinetic/pharmacodynamic (PK/PD) model to describe the time course and in vivo mechanisms of action of the antinociceptive effects of lumiracoxib, evaluated by the thermal hyperalgesia test in rats.Experimental Approach: Female Wistar fasted rats were injected s.c. with saline or carrageenan in the right hind paw, followed by either 0, 1, 3, 10 or 30 mg*kg(-1) of oral lumiracoxib at the time of carrageenan injection (experiment I), or 0, 10 or 30 mg*kg(-1) oral lumiracoxib at 4 h after carrageenan injection (experiment II). Antihyperalgesic responses were measured as latency time (LT) to a thermal stimulus. PK/PD modelling of the antinociceptive response was performed using the population approach with NONMEM VI.Results: A two-compartment model described the plasma disposition. A first-order model, including lag time and decreased relative bioavailability as a function of the dose, described the absorption process. The response model was: LT=LT(0)/(1 +MED). LT(0) is the baseline response, and MED represents the level of inflammatory mediators. The time course of MED was assumed to be equivalent to the predicted profile of COX-2 activity and was modelled according to an indirect response model with a time variant synthesis rate. Drug effects were described as a reversible inhibition of the COX-2 activity. The in vivo estimate of the dissociation equilibrium constant of the COX-2-lumiracoxib complex was 0.24 microg*mL(-1).Conclusions: The model developed appropriately described the time course of pharmacological responses to lumiracoxib, in terms of its mechanism of action and pharmacokinetics. [ABSTRACT FROM AUTHOR]- Published
- 2010
- Full Text
- View/download PDF
3. Lack of effects of acemetacin on signalling pathways for leukocyte adherence may explain its gastrointestinal safety.
- Author
-
Chávez-Piña AE, Vong L, McKnight W, Dicay M, Zanardo RC, Ortiz MI, Castañeda-Hernández G, and Wallace JL
- Subjects
- Animals, Cell Adhesion physiology, Dose-Response Relationship, Drug, Indomethacin pharmacology, Male, Rats, Rats, Wistar, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Gastric Mucosa metabolism, Indomethacin analogs & derivatives, Leukocytes metabolism, Signal Transduction physiology
- Abstract
Background and Purpose: Acemetacin is a non-steroidal anti-inflammatory drug which is rapidly bioconverted to indomethacin, but produces significantly less gastric damage than indomethacin. This study was performed to investigate several possible mechanisms that could account for the gastrointestinal tolerability of acemetacin., Experimental Approach: The gastric and intestinal damaging effects of acemetacin and indomethacin were examined in the rat. Effects of the drugs on blood levels of leukotriene B(4) and thromboxane B(2), on leukocyte-endothelial adherence in post-capillary mesenteric venules, and on gastric expression of tumour necrosis factor-alpha (TNF-alpha) were determined. The two drugs were also compared for gastric toxicity in rats pretreated with inhibitors of COX-2 and NOS., Key Results: Acemetacin induced significantly less gastric and intestinal damage than indomethacin, despite markedly suppressing COX activity. Indomethacin, but not acemetacin, significantly increased leukocyte adherence within mesenteric venules, and gastric expression of TNF-alpha. Pretreatment with L-nitro-arginine methyl ester or lumiracoxib increased the severity of indomethacin-induced gastric damage, but this was not the case with acemetacin., Conclusions and Implications: The increased gastric and intestinal tolerability of acemetacin may be related to the lack of induction of leukocyte-endothelial adherence. This may be attributable to the reduced ability of acemetacin to elevate leukotriene-B(4) synthesis and TNF-alpha expression, compared to indomethacin, despite the fact that acemetacin is rapidly bioconverted to indomethacin after its absorption.
- Published
- 2008
- Full Text
- View/download PDF
4. The atypical 5-HT2 receptor mediating tachycardia in pithed rats: pharmacological correlation with the 5-HT2A receptor subtype.
- Author
-
Centurión D, Ortiz MI, Saxena PR, and Villalón CM
- Subjects
- Animals, Antihypertensive Agents pharmacology, Blood Pressure physiology, Dose-Response Relationship, Drug, Free Radical Scavengers pharmacology, Heart Rate drug effects, Heart Rate physiology, Injections, Intravenous, Male, Norepinephrine pharmacology, Norepinephrine physiology, Rats, Rats, Wistar, Receptor, Serotonin, 5-HT2A, Reserpine pharmacology, Serotonin pharmacology, Serotonin physiology, Serotonin Receptor Agonists pharmacology, Vasoconstrictor Agents pharmacology, Receptors, Serotonin physiology, Tachycardia metabolism
- Abstract
1. In pithed rats, 5-HT mediates tachycardia both directly (by 5-HT(2) receptors) and indirectly (by a tyramine-like effect). The receptor mediating tachycardia directly has been classified as an 'atypical' 5-HT(2) receptor since it was 'weakly' blocked by ketanserin. Moreover, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT(2) agonist, failed to mimic 5-HT-induced tachycardia. Since 5-HT(2) receptors consist of 5-HT(2A), 5-HT(2B) and 5-HT(2C) subtypes, this study investigated if these subtypes mediate the above response. 2. In pithed rats, intraperitoneally (i.p.) pre-treated with reserpine (5 mg kg(-1)), intravenous (i.v.) administration of 5-HT, 5-methoxytryptamine (5-MeO-T), 1-(3-chlorophenyl) piperazine (mCPP) and 5-carboxamidotryptamine (5-CT) (10, 30, 100 and 300 microg kg(-1) each), produced dose-dependent tachycardic responses. Interestingly, DOI (10 - 1000 microg kg(-1), i.v.) induced only slight, dose-unrelated, tachycardic responses, whilst the 5-HT(2C) agonist, Ro 60-0175 (10 - 1000 microg kg(-1), i.v.), produced a slight tachycardia only at 300 and 1000 microg kg(-1). In contrast, sumatriptan and 1-(m-trifluoromethylphenyl)- piperazine (TFMPP) were inactive. The rank order of potency was: 5-HT > or =5-MeO-T> mCPP > or =5-CT > or =DOI > Ro 60-0175. 3. The tachycardic responses to 5-HT, which remained unaffected after i.v. saline (0.3 and 1 ml kg(-1)) or propranolol (3 mg kg(-1)), were selectively blocked by the 5-HT(2A) antagonists ketanserin (30 and 100 microg kg(-1)) or spiperone (10 and 30 microg kg(-1)) as well as by the non-selective 5-HT(2) antagonists, ritanserin (10 and 30 microg kg(-1)) or mesulergine (100 microg kg(-1)). Remarkably, these responses were unaffected by the antagonists rauwolscine (5-HT(2B)), SB204741 (5-HT(2B/2C)) or Ro 04-6790 (5-ht(6)) (300 and 1000 microg kg(-1) each). 4. These results suggest that the 'atypical' 5-HT(2) receptors mediating tachycardia in reserpinized pithed rats are pharmacologically similar to the 5-HT(2A) receptor subtype.
- Published
- 2002
- Full Text
- View/download PDF
5. Evidence for 5-HT(1B/1D) and 5-HT(2A) receptors mediating constriction of the canine internal carotid circulation.
- Author
-
Centurión D, Ortiz MI, Sánchez-López A, De Vries P, Saxena PR, and Villalón CM
- Subjects
- Animals, Blood Pressure drug effects, Blood Pressure physiology, Carotid Artery, Internal drug effects, Dogs, Female, Heart Rate drug effects, Heart Rate physiology, Male, Receptor, Serotonin, 5-HT1B, Receptor, Serotonin, 5-HT1D, Receptor, Serotonin, 5-HT2A, Receptors, Serotonin drug effects, Regional Blood Flow drug effects, Regional Blood Flow physiology, Serotonin pharmacology, Serotonin Antagonists pharmacology, Serotonin Receptor Agonists pharmacology, Vasoconstriction drug effects, Carotid Artery, Internal physiology, Receptors, Serotonin physiology, Vasoconstriction physiology
- Abstract
The present study has investigated the preliminary pharmacological profile of the receptors mediating vasoconstriction to 5-hydroxytryptamine (5-HT) in the internal carotid bed of vagosympathectomised dogs. One minute intracarotid infusions of the agonists 5-HT (0.1 - 10 microg min(-1)), sumatriptan (0.3 - 10 microg min(-1); 5-HT(1B/1D)), 5-methoxytryptamine (1 - 100 microg min(-1); 5-HT(1), 5-HT(2), 5-HT(4), 5-ht(6) and 5-HT(7)) or DOI (0.31 - 10 microg min(-1); 5-HT(2)), but not 5-carboxamidotryptamine (0.01 - 0.3 microg min(-1); 5-HT(1), 5-ht(5A) and 5-HT(7)), 1-(m-chlorophenyl)-biguanide (mCPBG; 1 - 1000 microg min(-1); 5-HT(3)) or cisapride (1 - 1000 microg min(-1); 5-HT(4)), resulted in dose-dependent decreases in internal carotid blood flow, without changing blood pressure or heart rate. The vasoconstrictor responses to 5-HT, which remained unaffected after saline, were resistant to blockade by i.v. administration of the antagonists ritanserin (100 microg kg(-1); 5-HT(2A/2B/2C)) in combination with tropisetron (3000 microg kg(-1); 5-HT(3/4)) or the cyclo-oxygenase inhibitor, indomethacin (5000 microg kg(-1)), but were abolished by the 5-HT(1B/1D) receptor antagonist, GR127935 (30 microg kg(-1)). Interestingly, after administration of GR127935, the subsequent administration of ritanserin unmasked a dose-dependent vasodilator component. GR127935 or saline did not practically modify the vasoconstrictor effects of 5-MeO-T. In animals receiving GR127935, the subsequent administration of ritanserin abolished the vasoconstrictor responses to 5-MeO-T unmasking a dose-dependent vasodilator component. The vasoconstriction induced by sumatriptan was antagonized by GR127935, but not by ritanserin. Furthermore, ritanserin (100 microg kg(-1)) or ketanserin (100 microg kg(-1); 5-HT(2A)), but not GR127935, abolished DOI-induced vasoconstrictor responses. The above results suggest that 5-HT-induced internal carotid vasoconstriction is predominantly mediated by 5-HT(1B/1D) and 5-HT(2A) receptors.
- Published
- 2001
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.