scholarly journals Pharmacokinetic of Diclofenac in the Presence and Absence of Glibenclamide in the Rat

2009 ◽  
Vol 12 (3) ◽  
pp. 280 ◽  
Author(s):  
María R. León-Reyes ◽  
Gilberto Castañeda-Hernández ◽  
Mario I Ortiz
Keyword(s):  
Oral Administration ◽  
Formalin Test ◽  
Antinociceptive Effect ◽  
Dorsal Surface ◽  
Pharmacokinetic Interaction ◽  
Pharmacokinetic Profile ◽  
Pharmacokinetic Parameters ◽  
Formalin Injection ◽  
Pharmacodynamic Interaction ◽  
Chromatography Method

ABSTRACT - PURPOSE. There is evidence that the sulfonylurea antidiabetic agent glibenclamide reduces the analgesic action of non-steroidal anti-inflammatory drugs (NSAIDs), opioids and neuromodulators in animal models. Therefore, in view of the vast clinical uses and interactions of NSAIDs with commonly used therapeutic agents, the interaction of the NSAID diclofenac and glibenclamide was investigated about pharmacokinetic profile and antinociceptive effect in rats. METHODS. Antinociception was assessed using the formalin test. Fifty microliters of diluted formalin was injected s.c. into the dorsal surface of the right hind paw. Nociceptive behavior was quantified as the number of flinches of the injected paw during 60 min after injection. Rats were treated with oral administration of vehicle or increasing doses of diclofenac (3-18 mg/kg) before formalin injection. To determine the pharmacodynamic interaction between diclofenac and glibenclamide, the effect of oral administration of glibenclamide (1-30 mg/kg) on the antinociceptive effect induced by diclofenac (18 mg/kg, p.o.) was assessed. To evaluate the pharmacokinetic interaction between diclofenac and glibenclamide, the effect of glibenclamide (10 mg/kg, p.o.) on the pharmacokinetic of diclofenac (18 mg/kg, p.o.) was studied in the rat. Blood samples were taken over 8 h and analyzed using a validated high-performance liquid chromatography method to generate the pharmacokinetic profile of diclofenac. Pharmacokinetic parameters were estimated using noncompartmental analysis. RESULTS. Systemic administration of diclofenac produced a dose-dependent antinociceptive effect in the formalin test. Systemic treatment with glibenclamide prevented diclofenac-induced antinociception. In pharmacokinetic interaction study, no significant (P>0.05) change in diclofenac concentration-time profiles in the presence of glibenclamide was detected. CONCLUSION. The experimental findings suggest that systemic glibenclamide is able to block the diclofenac-induced antinociception in the rat formalin test. Besides, this antagonism was not produced by diminution in the bioavailability of diclofenac. Likewise, the validated assay had sufficient accuracy and precision for pharmacokinetic determination of diclofenac in the rat.

Role of the NO-cGMP-K+ channels pathway in the peripheral antinociception induced by α-bisabolol

2021 ◽  
Author(s):  
Mario I Ortiz ◽  
Raquel Cariño-Cortés ◽  
Victor Manuel Muñoz Pérez ◽  
Andres Salas Casas ◽  
Gilberto Castañeda-Hernández
Keyword(s):  
Opioid Receptors ◽  
Formalin Test ◽  
Antinociceptive Effect ◽  
Dorsal Surface ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
K Channel ◽  
Formalin Injection ◽  
K Channels ◽  
The Right

The aim of this study was to examine if the peripheral antinociception of α-bisabolol involve the participation of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) synthesis followed by K+ channel opening in the formalin test. Wistar rats were injected in the dorsal surface of the right hind paw with formalin (1%). Rats received a subcutaneous injection into the dorsal surface of the paw of vehicles or increasing doses of α-bisabolol (100-300 µg/paw). To determine whether the peripheral antinociception induced by α-bisabolol was mediated by either the opioid receptors or the NO-cGMP-K+ channels pathway, the effect of pretreatment (10 min before formalin injection) with the appropriate vehicles, naloxone, naltrexone, L-NAME, ODQ, glibenclamide, glipizide, apamin, charybdotoxin, tetraethylammonium or 4-aminopyridine on the antinociceptive effects induced by local peripheral α-bisabolol (300 µg/paw) were assessed. α-bisabolol produced antinociception during both phases of the formalin test. α-bisabolol antinociception was blocked by L-NAME, ODQ, and all the K+ channels blockers. The peripheral antinociceptive effect produced by α-bisabolol was not blocked by the opioid receptor inhibitors. α-bisabolol was able to active the NO-cGMP-K+ channels pathway in order to produce its antinoceptive effect. The participation of opioid receptors in the peripheral local antinociception induced by α-bisabolol is excluded.

scholarly journals Pharmacokinetics and Pharmacodynamics of diclofenac in the presence and absence of glibenclamide in the rat

2016 ◽  
Vol 11 (3) ◽  
pp. 68 ◽  
Author(s):  
María R León-Reyes ◽  
Gilberto Castañeda-Hernández ◽  
Mario I Ortiz
Keyword(s):  
Formalin Test ◽  
Antinociceptive Effect ◽  
Dorsal Surface ◽  
Pharmacokinetic Interaction ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Female Wistar Rats ◽  
Inflammatory Drugs ◽  
The Right ◽  
Dose Dependent ◽  
Analgesic Response

PURPOSE. There are evidences that glibenclamide, a sulfonylurea antidiabetic agent, reduces the analgesic action of non-steroidal anti-inflammatory drugs (NSAIDs), opioids and neuromodulators in animal models. The purpose of this work was to examine in the rat if such interaction involves pharmacokinetic mechanisms or is solely limited to the pharmacodynamic level. METHODS. All studies were carried out in female Wistar rats. Analgesia was assessed using the formalin test. Fifty microliters of diluted formalin was injected subcutaneously into the dorsal surface of the right hind paw. Nociceptive behavior was quantified as the number of flinches of the injected paw during 60 min after injection and a reduction in formalin-induced flinching was interpreted as an analgesic response. Rats were treated with oral diclofenac (3-18 mg/kg) in presence and the absence of oral glibenclamide (1-30 mg/kg). To evaluate the possibility of a pharmacokinetic interaction, the oral bioavailability of diclofenac (18 mg/kg) was studied in presence and the absence of glibenclamide (10 mg/kg). RESULTS. Oral administration of diclofenac produced a dose-dependent antinociceptive effect in the formalin test. Coadministration of glibenclamide significantly reduced diclofenac-induced antinociception. Notwithstanding, the interaction does no appear to involve pharmacokinetic mechanisms, as oral glibenclamide failed to produce any significant alteration in oral diclofenac bioavailability. CONCLUSION. Concomitant systemic administration of glibenclamide and diclofenac results in a reduction of the analgesic effect of the NSAID in the formalin test in the rat. This interaction, however, appears due solely to a pharmacodynamic mechanisms as diclofenac pharmacokinetics are not altered.

scholarly journals Pharmacokinetics and Tissue Distribution of Benznidazole after Oral Administration in Mice

2017 ◽  
Vol 61 (4) ◽  
Author(s):  
Luísa Perin ◽  
Rodrigo Moreira da Silva ◽  
Kátia da Silva Fonseca ◽  
Jamille Mirelle de Oliveira Cardoso ◽  
Fernando Augusto Siqueira Mathias ◽  
...  
Keyword(s):  
Oral Administration ◽  
Chagas Disease ◽  
High Performance ◽  
Chronic Phase ◽  
Pharmacokinetic Profile ◽  
European Medicines Agency ◽  
Pharmacokinetic Parameters ◽  
Uv Detector ◽  
Chromatography Method ◽  
Content Type

ABSTRACT Specific chemotherapy using benznidazole (BNZ) for Chagas disease during the chronic stage is controversial due to its limited efficacy and toxic effects. Although BNZ has been used to treat Chagas disease since the 1970s, few studies about the biodistribution of this drug exist. In this study, BNZ tissue biodistribution in a murine model and its pharmacokinetic profile in plasma were monitored. A bioanalytical high-performance liquid chromatography method with a UV detector (HPLC-UV) was developed and validated according to the European Medicines Agency for quantification of BNZ in organs and plasma samples prepared by liquid-liquid extraction using ethyl acetate. The developed method was linear in the BNZ concentration, which ranged from 0.1 to 100.0 μg/ml for plasma, spleen, brain, colon, heart, lung, and kidney and from 0.2 to 100.0 μg/ml for liver. Validation assays demonstrated good stability for BNZ under all conditions evaluated. Pharmacokinetic parameters confirmed rapid, but low, absorption of BNZ after oral administration. Biodistribution assays demonstrated different maximum concentrations in organs and similar times to maximum concentration and mean residence times, with means of 40 min and 2.5 h, respectively. Therefore, the biodistribution of BNZ is extensive, reaching organs such as the heart and colon, which are the most relevant organs affected by Trypanosoma cruzi infection, and also the spleen, brain, liver, lungs, and kidneys. Simultaneous analyses of tissues and plasma indicated high BNZ metabolism in the liver. Our results suggest that low bioavailability, instead of inadequate biodistribution, could be responsible for therapeutic failure during the chronic phase of Chagas disease.

scholarly journals Pharmacokinetic Profile of μSMIN Plus™, a new Micronized Diosmin Formulation, after Oral Administration in Rats

2015 ◽  
Vol 10 (9) ◽  
pp. 1934578X1501000 ◽  
Author(s):  
Rosario Russo ◽  
Angelo Mancinelli ◽  
Michele Ciccone ◽  
Fabio Terruzzi ◽  
Claudio Pisano ◽  
...  
Keyword(s):  
Oral Administration ◽  
Plasma Concentrations ◽  
Compartmental Analysis ◽  
Pharmacokinetic Profile ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Sprague Dawley ◽  
Time Curve ◽  
Maximum Plasma Drug Concentration

Diosmin is a naturally occurring flavonoid present in citrus fruits and other plants belonging to the Rutaceae family. It is used for the treatment of chronic venous insufficiency (CVI) for its pheblotonic and vaso-active properties, safety and tolerability as well. The aim of the current in vivo study was to investigate the pharmacokinetic profile of a branded micronized diosmin (μSMIN Plus™) compared with plain micronized diosmin in male Sprague-Dawley rats. After oral administration by gastric gavage, blood samples were collected via jugular vein catheters at regular time intervals from baseline up to 24 hours. Plasma concentrations were assessed by LC/MS. For each animal, the following pharmacokinetic parameters were calculated using a non-compartmental analysis: maximum plasma drug concentration (Cmax), time to reach Cmax (Tmax), area under the plasma concentration-time curve (AUC0-last), elimination half-life (t1/2), and relative oral bioavailability (%F). The results of the current study clearly showed an improvement in the pharmacokinetic parameters in animals treated with μSMIN Plus™ compared with animals treated with micronized diosmin. In particular, μSMIN Plus™ showed a 4-fold increased bioavailability compared with micronized diosmin. In conclusion, the results from the current study provided a preliminary pharmacokinetic profile for μSMIN Plus™, which may represent a new tool for CVI management.

scholarly journals The effects of oral administration of Cola nitida on the pharmacokinetic profile of metoclopramide in rabbits

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Cecilia Nwadiuto Amadi ◽  
Wisdom Izuchukwu Nwachukwu
Keyword(s):  
Drug Interaction ◽  
Plasma Concentration ◽  
Oral Administration ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Elimination Rate ◽  
Area Under The Curve ◽  
Pharmacokinetic Profile ◽  
Pharmacokinetic Parameters ◽  
Cola Nitida

Abstract Background Cola nitida is commonly chewed in many West African cultures to ease hunger pangs and sometimes for their stimulant and euphoriant qualities. Metoclopramide is a known substrate for P-gp, SULT2A1 and CYP2D6 and studies have revealed that caffeine- a major component of Cola nitida can induce P-glycoprotein (P-gp), SULT2A1 and SULT1A1, hence a possible drug interaction may occur on co-administration. The aim of this study was to investigate the pharmacokinetic interactions of Cola nitida and metoclopramide in rabbits. Methods The study was performed in two stages using five healthy male rabbits with a 1-week washout period between treatments. Stage one involved oral administration of metoclopramide (0.5 mg/kg) alone while in the second stage, metoclopramide (0.5 mg/kg) was administered concurrently with Cola nitida (0.7 mg/kg). Blood samples were collected after each stage at predetermined intervals and analyzed for plasma metoclopramide concentration using HPLC. Results Compared with control, the metoclopramide/Cola nitida co-administration produced a decrease in plasma concentration of metoclopramide at all the time intervals except at the 7th hour. The following pharmacokinetic parameters were also decreased: area under the curve (51%), peak plasma concentration (39%), half-life (51%); while an increase in elimination rate constant (113%) and clearance rate (98%) were noted indicating rapid elimination of the drug. A minimal decrease in absorption rate (10%) was also observed. Conclusions The results of this study reveal a possible herb-drug interaction between Cola nitida and metoclopramide.

scholarly journals Spinal Antinociceptive Action of Amiloride and Its Interaction with Tizanidine in the Rat Formalin Test

2015 ◽  
Vol 20 (6) ◽  
pp. 321-326 ◽  
Author(s):  
Handong Ouyang ◽  
Peizong Wang ◽  
Wan Huang ◽  
Qiang Li ◽  
Bilin Nie ◽  
...  
Keyword(s):  
Side Effects ◽  
Adrenergic Receptor ◽  
Formalin Test ◽  
Antinociceptive Effect ◽  
Formalin Injection ◽  
Nociceptive Response ◽  
Sprague Dawley ◽  
Allosteric Site ◽  
Isobolographic Analysis ◽  
Antinociceptive Action

BACKGROUND: Amiloride has been reported to produce a wide variety of actions, thereby affecting several ionic channels and a multitude of receptors and enzymes. Intrathecal α2-adrenergic receptor agonists produce pronounced analgesia, and amiloride modulates α2-adrenergic receptor agonist binding and function, acting via the allosteric site on the α2A-adrenergic receptor.OBJECTIVES: To investigate the antinociceptive interaction of intrathecal amiloride and the α2-adrenoceptor agonist tizanidine using a rat formalin test.METHODS: Sprague-Dawley rats were chronically implanted with lumbar intrathecal catheters and were tested for paw flinching using formalin injection. Biphasic painful behaviour was recorded. Amiloride, tizanidine or an amiloride-tizanidine mixture was administered 10 min before formalin injection. To characterize any interactions, isobolographic analysis was performed. The effects of a pretreatment using intrathecally administered yohimbine was also tested.RESULTS: Intrathecally administered amiloride (12.5 μg to 100 μg) and tizanidine (0.5 μg to 5 μg), given separately, produced a significant dose-related suppression of the biphasic responses in the formalin test. Isobolographic analysis revealed that the combination of intrathecal amiloride and tizanidine synergistically reduced phase I and II activities. Intrathecally administered yohimbine antagonized or attenuated the antinociceptive effect of amiloride, tizanidine and the amiloride-tizanidine mixture. Intrathecally administered amiloride synergistically interacts with tizanidine to reduce the nociceptive response in the formalin test, most likely by activating α2-adrenoceptors in the spinal cord.CONCLUSIONS: Although intrathecal tizanidine produced pronounced analgesia, antinociceptive doses of intrathecal tizanidine also produced several side effects, including bradycardia and sedation. Amiloride produced antinociceptive action against the thermal nociceptive test without side effects in rats.

scholarly journals Pharmacokinetic Interaction Between Oltipraz and Silymarin in Rats

2009 ◽  
Vol 12 (1) ◽  
pp. 1 ◽  
Author(s):  
Min Kyung Kang ◽  
Soo Kyung Bae ◽  
Jin Wan Kim ◽  
Myung Gull Lee
Keyword(s):  
Oral Administration ◽  
Intravenous Administration ◽  
Pharmacokinetic Interaction ◽  
Pharmacokinetic Parameters ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Intravenous And Oral Administration ◽  
Single Intravenous Administration

ABSTRACT. Purpose: To evaluate the pharmacokinetic interaction between oltipraz and silymarin after intravenous and oral administration of both drugs to male Sprague–Dawley rats. Methods: Oltipraz (single doses of 10 and 30 mg/kg for intravenous and oral administration, respectively), silymarin (single doses of 50 and 100 mg/kg for intravenous and oral administration, respectively, and 14 days oral administration of 100 mg/kg), alone and together were administered to control rats. Results: The pharmacokinetic parameters of oltipraz did not significantly altered by silymarin. However, after intravenous administration of the drugs together, the AUCs of unconjugated, conjugated, and total (unconjugated plus conjugated) silibinin were significantly different (32.7% decrease, and 32.1% and 27.2% increase, respectively), and total and (CL) and non-renal (CLNR ) clearance of unconjugated silibinin were significantly faster (49.4% and 61.1% increase, respectively) than those of silymarin alone (without oltipraz). After oral administration of silymarin with or without oltipraz, however, the pharmacokinetic parameters of unconjugated, conjugated, and total silibinin were comparable. Conclusions: After single intravenous administration of the drugs together, the AUC of unconjugated silibinin was significantly smaller, but that of both conjugated and total silibinin was significantly greater. This could have been due to an increase in the formation of conjugates (glucuronidation and sulfation) of silibinin as induced by oltipraz. After simultaneous oral administration of the drugs, however, the AUCs (or AUC0−12 h) of unconjugated, conjugated, and total silibinin were comparable.

scholarly journals Analgesic characteristics of a newly developed α2δ ligand, mirogabalin, on inflammatory pain

2021 ◽  
Vol 17 ◽  
pp. 174480692110521
Author(s):  
Shuji Komatsu ◽  
Shingo Nakamura ◽  
Takahiro Nonaka ◽  
Toshihiko Yamada ◽  
Tatsuo Yamamoto
Keyword(s):  
Oral Administration ◽  
Inflammatory Pain ◽  
Analgesic Effect ◽  
Time Course ◽  
Formalin Test ◽  
Formalin Injection ◽  
Intracerebroventricular Administration ◽  
Analgesic Effects ◽  
Adrenergic Antagonist ◽  
Sites Of Action

Mirogabalin is a novel α2δ ligand approved in Japan for the treatment of peripheral neuropathic pain. However, the sites of action of α2δ ligands to produce analgesic effects on inflammatory pain remain unclear. In this study, we investigated the analgesic effect and site of action of mirogabalin using the rat formalin test, an acute inflammatory pain model. Mirogabalin was administered orally, intrathecally, and intracerebroventricularly. Open field tests were performed to evaluate the effect of oral-, intrathecally, and intracerebroventricularly administered mirogabalin on locomotor activity and orientation ability. Oral mirogabalin produced an analgesic effect when the formalin test was performed 4 h, but not 1 or 2 h, after oral administration. Intrathecal, but not intracerebroventricular, administration of mirogabalin produced analgesic effects when mirogabalin was administered 10 min before formalin injection. These analgesic effects were not antagonized by idazoxan, an α2 adrenergic antagonist; WAY100135, a 5-HT1A antagonist; or naloxone, an opioid receptor antagonist. Mirogabalin attenuated moving distances 1 and 2 h after oral administration and 10 min after intracerebroventricular administration, but not 10 min after intrathecal administration. In the oral administration group, the time course of the analgesic effect was different from that of moving distance. In the intracerebroventricular group, mirogabalin attenuated moving distances but did not produce an analgesic effect. In the intrathecal group, mirogabalin produced an analgesic effect but did not affect moving distances. These findings suggest that the analgesic effect of mirogabalin on the rat formalin test is mediated by spinal action and not by the activation of α2, 5-HT1A, or opioid receptors, and that the inhibitory effect of mirogabalin on moving distances is mediated by the supraspinal brain.

scholarly journals Antinociceptive Effects of Spinal Manipulative Therapy on Nociceptive Behavior of Adult Rats during the Formalin Test

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Stephen M. Onifer ◽  
William R. Reed ◽  
Randall S. Sozio ◽  
Cynthia R. Long
Keyword(s):  
Formalin Test ◽  
Antinociceptive Effect ◽  
Spinal Manipulative Therapy ◽  
Formalin Injection ◽  
Nociceptive Behavior ◽  
Adult Rats ◽  
Manipulative Therapy ◽  
Antinociceptive Effects ◽  
Custom Made ◽  
The Mean

Optimizing pain relief resulting from spinal manipulative therapies, including low velocity variable amplitude spinal manipulation (LVVA-SM), requires determining their mechanisms. Pain models that incorporate simulated spinal manipulative therapy treatments are needed for these studies. The antinociceptive effects of a single LVVA-SM treatment on rat nociceptive behavior during the commonly used formalin test were investigated. Dilute formalin was injected subcutaneously into a plantar hindpaw. Licking behavior was video-recorded for 5 minutes. Ten minutes of LVVA-SM at 20° flexion was administered with a custom-made device at the lumbar (L5) vertebra of isoflurane-anesthetized experimental rats (n=12) beginning 10 minutes after formalin injection. Hindpaw licking was video-recorded for 60 minutes beginning 5 minutes after LVVA-SM. Control rats (n=12) underwent the same methods except for LVVA-SM. The mean times spent licking the formalin-injected hindpaw of both groups 1–5 minutes after injection were not different. The mean licking time during the first 20 minutes post-LVVA-SM of experimental rats was significantly less than that of control rats (P<0.001). The mean licking times of both groups during the second and third 20 minutes post-LVVA-SM were not different. Administration of LVVA-SM had a short-term, remote antinociceptive effect similar to clinical findings. Therefore, mechanistic investigations using this experimental approach are warranted.

Participation of the opioid receptor – nitric oxide – cGMP – K+ channel pathway in the peripheral antinociceptive effect of nalbuphine and buprenorphine in rats

2020 ◽  
Vol 98 (11) ◽  
pp. 753-762
Author(s):  
Mario I. Ortiz ◽  
Raquel Cariño-Cortés ◽  
Gilberto Castañeda-Hernández
Keyword(s):  
Nitric Oxide ◽  
Channel Blocker ◽  
Antinociceptive Effect ◽  
Dorsal Surface ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
K Channel ◽  
Formalin Injection ◽  
Opioid Agonist ◽  
The Right

The aim of this study was to examine if the peripheral antinociceptive effects of the opioid agonist/antagonist nalbuphine and buprenorphine involve the sequential participation of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) synthesis followed by K+ channel opening in the formalin test. Wistar rats (180–220 g) were injected in the dorsal surface of the right hind paw with formalin (1%). Rats received a subcutaneous (s.c.) injection into the dorsal surface of the paw of vehicles or increasing doses of nalbuphine (50–200 μg/paw) or buprenorphine (1–5 μg/paw) 20 min before formalin injection into the paw. Nalbuphine antinociception was reversed by the s.c. injection into the paw of the inhibitor of NO synthesis (NG-nitro-l-arginine methyl ester (L-NAME)), by the inhibitor of guanylyl cyclase (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ)), by the Kir6.1–2, ATP-sensitive K+ channel inhibitors (glibenclamide and glipizide), by the KCa2.1–3, small conductance Ca2+-activated K+ channel blocker (apamin), by the KCa1.1, large conductance Ca2+-activated K+ channel blocker (charybdotoxin), and by the KV, voltage-dependent K+ channel inhibitors (4-aminopyridine (4-AP) and tetraethylammonium chloride (TEA)). The antinociceptive effect produced by buprenorphine was blocked by the s.c. injection of 4-AP and TEA but not by L-NAME, ODQ, glibenclamide, glipizide, apamin, or charybdotoxin. The present results provide evidence for differences in peripheral mechanisms of action between these opioid drugs.

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