scholarly journals Synergistic Interaction between Metformin and Sulfonylureas on Diclofenac-Induced Antinociception Measured Using the Formalin Test in Rats

2013 ◽  
Vol 18 (5) ◽  
pp. 253-258 ◽  
Author(s):  
Mario I Ortiz
Keyword(s):  
Formalin Test ◽  
Synergistic Interaction ◽  
Second Phase ◽  
Dependent Manner ◽  
Additive Effects ◽  
Multiple Sources ◽  
Systemic Injection ◽  
Patients With Diabetes ◽  
Effective Doses ◽  
Dose Dependent

BACKGROUND: There is evidence that biguanides and sulfonylureas block diclofenac-induced antinociception (DIA) in rat models. However, little is known about the interaction between these hypoglycemics with respect to DIA.OBJECTIVE: To determine whether metformin-sulfonylurea combinations affect DIA during the formalin test.METHODS: Rats received the appropriate vehicle or diclofenac before 1% formaldehyde was injected into the paw. Rats were also pretreated with vehicle, glibenclamide, glipizide, metformin or glibenclamide/metformin and glipizide/metformin combinations before the diclofenac and formaldehyde injections, and the effect on antinociception was assessed. Isobolograms of the combinations were constructed to test for a synergistic interaction.RESULTS: Systemic injection of diclofenac resulted in antinociception during the second phase of the test. Systemic pretreatment with the combinations of glibenclamide (0.56 mg/kg to 10 mg/kg)/metformin (10 mg/kg to 180 mg/kg) and glipizide (0.56 mg/kg to10 mg/kg)/metformin (10 mg/kg to 180 mg/kg) blocked DIA. The derived theoretical effective doses for 50% of subjects (ED50) for the glibenclamide/metformin and glipizide/metformin combinations were 32.52 mg/kg and 32.42 mg/kg, respectively, and were significantly higher than the actual observed experimental ED50values (7.57 mg/kg and 8.43 mg/kg, respectively).CONCLUSION: Pretreatment with glibenclamide, glipizide or metformin blocked DIA in a dose-dependent manner, and combining either sulfonylurea with metformin produced even greater effects. The observed ED50s for the combinations were approximately fourfold lower than the calculated additive effects. These data indicate that sulfonylureas interact to produce antagonism of DIA. Combination therapy is a common second-line treatment for patients with diabetes and metabolic syndrome, a group that experiences pain from multiple sources. The results suggest that at least some anti-inflammatory agents may not be effective in this group.

Effect of galanin on glucose-, arginine-, or potassium-stimulated insulin release

1989 ◽  
Vol 256 (5) ◽  
pp. E619-E623
Author(s):  
T. Yoshimura ◽  
J. Ishizuka ◽  
G. H. Greeley ◽  
J. C. Thompson
Keyword(s):  
Insulin Release ◽  
High Glucose ◽  
Second Phase ◽  
Dependent Manner ◽  
Perfused Pancreas ◽  
Isolated Perfused Pancreas ◽  
Second Phases ◽  
High Concentrations ◽  
Dose Dependent ◽  
Stimulation Of

We have examined the effect of galanin infusion on glucose-stimulated release of insulin from the isolated perfused pancreas of the rat to better characterize the effect of galanin on the first and second phases of insulin release. The effects of galanin on insulin release stimulated by L-arginine or high concentrations of potassium were also examined. When perfusion of galanin was started 4 min before the start of perfusion of high glucose (16.7 mM), galanin (10(-8)-10(-11) M) inhibited both the first and second phases of insulin release in a dose-dependent manner. When perfusion of galanin (10(-8) or 10(-9) M) was started simultaneously with high glucose (16.7 mM), only the second phase of insulin release was suppressed (P less than 0.05). Galanin (10(-9) M) failed to inhibit insulin release stimulated by L-arginine (10 and 5 mM) or potassium (25 and 20 mM). These findings suggest that the inhibitory action of galanin on glucose-stimulated insulin release is exerted on early intracellular events that occur during the stimulation of insulin release and that are common to both phases. Because galanin does not inhibit insulin release stimulated by L-arginine or potassium, galanin may inhibit glucose-stimulated closure of potassium channels.

Oxytocin affects apical sodium conductance in rabbit cortical collecting duct

1993 ◽  
Vol 265 (4) ◽  
pp. F487-F503 ◽  
Author(s):  
T. Inoue ◽  
M. Naruse ◽  
M. Nakayama ◽  
K. Kurokawa ◽  
T. Sato
Keyword(s):  
Receptor Antagonist ◽  
Collecting Duct ◽  
Rat Kidney ◽  
Physiological Role ◽  
Free Calcium ◽  
Second Phase ◽  
Dependent Manner ◽  
Cortical Collecting Duct ◽  
Acetoxymethyl Ester ◽  
Dose Dependent

The physiological role of oxytocin (OT) in the kidney is still unclear, although autoradiographic data have shown the existence of OT receptors in the rat kidney. We examined the effect of OT in the microperfused rabbit cortical collecting duct (CCD) by using conventional cable analysis and microscope photometry. On addition of 10(-9) M OT to the bath, the lumen-negative transepithelial voltage (VT) transiently increased and the transepithelial resistance (RT) and the fractional resistance of the apical membrane (FRA) (1st phase) both decreased. After this initial change, the lumen-negative VT gradually decreased below its baseline level and RT and FRA (second phase) both increased. These electrical changes were dose dependent and were prevented by the addition of 10(-5) M amiloride to the lumen. Although responses to OT were not prevented by 10(-9) M arginine vasopressin (AVP) or 10(-6) M of a V1-receptor antagonist (OPC-21268) or V2-receptor antagonist (OPC-31260), they were inhibited by the addition of the specific OT antagonist des-Gly-NH2-[d(CH2)3,Tyr(Me),Thr]OVT. Additional studies of intracellular free calcium ([Ca2+]i) revealed that 10(-8)-10(-6) M OT caused an increase in [Ca2+]i in CCD in a dose-dependent manner. Also, pretreatment with 2 x 10(-8) M bis-(aminophenoxy)ethane-tetraacetic acid-acetoxymethyl ester, an intracellular Ca2+ chelator, abolished the electrical and [Ca2+]i responses to OT. Pretreatment with 5 x 10(-4) M 8-(4-chlorophenylthio)-adenosine 3',5'-cyclic monophosphate (CPT-cAMP) partially prevented the electrical responses to OT, thus reducing the decrease in lumen-negative VT below its basal level and the increase in RT after the 1st phase. These data show that OT affects the apical Na+ conductance of collecting duct cells through OT receptors distinct from the AVP receptors and that the effect of OT may, at least in part, be brought about by a mechanism(s) dependent on the increase in [Ca2+]i and cAMP production.

scholarly journals Antinociceptive Interaction and Pharmacokinetics of the Combination Treatments of Methyleugenol Plus Diclofenac or Ketorolac

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 5106
Author(s):  
Héctor Isaac Rocha-González ◽  
María Elena Sánchez-Mendoza ◽  
Leticia Cruz-Antonio ◽  
Francisco Javier Flores-Murrieta ◽  
Xochilt Itzel Cornelio-Huerta ◽  
...  
Keyword(s):  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Dependent Manner ◽  
Analgesic Drugs ◽  
Isobolographic Analysis ◽  
Combination Treatments ◽  
Significant Difference ◽  
Effective Doses ◽  
Inflammatory Drugs ◽  
Dose Dependent

Although nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the main types of drugs used to treat pain, they have several adverse effects, and such effects can be reduced by combining two analgesic drugs. The aim of this study was to evaluate the nociceptive activity of methyleugenol combined with either diclofenac or ketorolac, and determine certain parameters of pharmacokinetics. For the isobolographic analysis, the experimental effective dose 30 (ED30) was calculated for the drugs applied individually. With these effective doses, the peak plasma concentration (Cmax) was found and the other parameters of pharmacokinetics were established. Methyleugenol plus diclofenac and methyleugenol plus ketorolac decreased licking behavior in a dose-dependent manner in phase II, with an efficacy of 32.9 ± 9.3 and 39.8 ± 9.6%, respectively. According to the isobolographic analysis, the experimental and theoretical ED30 values were similar for methyleugenol plus diclofenac, suggesting an additive effect, but significantly different for methyleugenol plus ketorolac (3.6 ± 0.5 vs. 7.7 ± 0.6 mg/kg, respectively), indicating a probable synergistic interaction. Regarding pharmacokinetics, the only parameter showing a significant difference was Cmax for the methyleugenol plus diclofenac combination. Even with this difference, the combinations studied may be advantageous for treating inflammatory pain, especially for the combination methyleugenol plus ketorolac.

scholarly journals Anticonvulsant effects of nimodipine alone and combination with phenytoin on MES induced seizures

2018 ◽  
Vol 7 (6) ◽  
pp. 1160
Author(s):  
Raina Jain ◽  
Ashish Jain
Keyword(s):  
Synergistic Effect ◽  
Anticonvulsant Activity ◽  
Hind Limb ◽  
Channel Blockers ◽  
Dependent Manner ◽  
The Novel ◽  
Antiepileptic Activity ◽  
Effective Doses ◽  
Dose Dependent ◽  
Anticonvulsant Effects

Background: To evaluate the anticonvulsant activity of Nimodipine alone and in combination with Phenytoin, in MES induced seizures.Methods: The study was conducted in mice and MES seizure was induced by Techno electroconvulsometer. In first part of study, animals were treated with Nimodipine (20mg/kg i.p. and 40mg/kg i.p.) and Phenytoin (0.5 mg/100g i.p. and 1.0mg/100g i.p.), MES was induced and durations of various phases were noted. Duration of Tonic hind limb extension (THLE) was taken as index for antiepileptic activity. In second part, the animals were treated with combination of sub effective doses of Nimodipine (20mg/kg i.p.) and Phenytoin (0.5mg/100g i.p.), MES was induced and durations of various phases were noted.Results: Nimodipine produced significant antiepileptic activity, in dose dependent manner. Phenytoin produced significant antiepileptic effect in dose of 1.0mg/100g but failed to produce any such effect in dose of 0.5mg/100g, when administered alone. But when sub effective doses.Of Nimodipine and Phenytoin were combined, a synergistic effect was seen.Conclusions: Nimodipine possess significant antiepileptic activity, alone, as well as it potentiates the antiepileptic effect of Phenytoin, suggesting the novel application of already proven safe and efficacious calcium channel blockers.

Comparison of ramp and square-wave exposure to thyrotrophin-releasing hormone or depolarizing K+ on cytosolic Ca2+ concentration and prolactin secretion in GH4C1 cells

1994 ◽  
Vol 142 (1) ◽  
pp. 145-152
Author(s):  
N Sato ◽  
X Wang ◽  
M A Greer
Keyword(s):  
Hormone Secretion ◽  
Wave Exposure ◽  
Rate Of Change ◽  
Second Phase ◽  
Tissue Fluid ◽  
Dependent Manner ◽  
Thyrotrophin Releasing Hormone ◽  
Releasing Hormone ◽  
Square Wave ◽  
Dose Dependent

Abstract The standard method of studying hormone secretion in vitro is to make instantaneous changes in the concentration of stimulators in the medium. However, in vivo the extracellular concentration of such substances changes more gradually; secretion does not occur in square-wave bursts and agonists or antagonists transmitted through the bloodstream are diluted and diffused by plasma or tissue fluid to further decelerate the rate of change in concentration at the cell surface. We have therefore compared in GH4C1 cells the dynamics of changes in cytosolic Ca2+ concentration ([Ca2+]i) and prolactin (PRL) secretion in response to two very different secretagogues, thyrotrophin-releasing hormone (TRH) and depolarizing K+, using a square-wave or ramp exposure for 5 min. The dynamics of hormone secretion were analysed by column perifusion (2 × 106 cells/column). Ca2+ dynamics were monitored by dual excitation microfluorimetry from 20–30 optically isolated cells using the Ca2+ indicator, fura-2. With square-wave exposure, both TRH (0·1–100 nm) and K+ (10–50 mm) induced dose-dependent increases in [Ca2+]i and PRL secretion. Concentrations of TRH >1 nm caused a two-phase increase in [Ca2+]i with an initial high-amplitude first phase and a low-amplitude second phase. Depolarizing K+ induced a sharp increase in [Ca2+]i which peaked within 15 seconds, then declined gradually on a sloping plateau. Both TRH and K+ induced an acute dose-dependent PRL secretory burst peaking within 2·5 min with a subsequent rapid decline. With ramp exposure, high doses of TRH (final concentration 10–100 nm) triggered an acute rise in [Ca2+]i; however, the peaks were clearly lower than those induced by the maximum concentration reached given as a square-wave. TRH (0·1–100 nm) induced PRL secretion in a dose-dependent manner. Ramp depolarizing K+ induced dose-dependent parallel 'ramp' increases in [Ca2+]i concentration and PRL secretion without a 'burst' rise in either. These data suggest that a rise in [Ca2+]i plays a more critical role in K+-induced than in TRH-induced PRL secretion; intracellular transduction systems which do not involve [Ca2+]i appear more important for the latter. Journal of Endocrinology (1994) 142, 145–152

Expression of B1 kinin receptors mediating paw edema and Formalin-induced nociception. Modulation by glucocorticoids

1995 ◽  
Vol 73 (7) ◽  
pp. 812-819 ◽  
Author(s):  
Maria M. Campos ◽  
Luciana V. Mata ◽  
João B. Callxto
Keyword(s):  
Formalin Test ◽  
Systemic Treatment ◽  
Second Phase ◽  
Paw Edema ◽  
Systemic Injection ◽  
Kinin Receptors ◽  
Rat Paw Edema ◽  
Inflammatory Processes ◽  
Second Phases ◽  
Rat Paw

Bradykinin (BK) and Tyr8-BK induced graded rat paw edema with EC50 values of 1.9 and 1.1 nmol/paw, while des-Arg9-BK (DABK, up to 300 nmol/paw) was marginally effective. Tyr8-BK, but not DABK, also caused a dose-related increase in mouse paw edema, with an EC50 of 1.3 nmol/paw. The response to Tyr8-BK (10 nmol/paw) in rat paw edema was antagonized by B2 receptor antagonists (HOE-140 or NPC 17731, 30 nmol/paw) but not by the B1 antagonist des-Arg9[Leu8]BK (DALBK, 100 nmol/paw). Daily intraplantar injections of Tyr8-BK (10 nmol/paw) for 7 days caused progressive desensitization (D) of edema in sham-operated and adrenalectomized Wistar rats. DABK (100 nmol/paw) caused marked paw edema in D paws from both groups, which was inhibited by DALBK (100 nmol/paw) and by dexamethasone (0.5 mg/kg, s.c). Systemic injection of lipopolysaccharide (10 μg/mouse, 24 h prior) potentiated the first and second phases of Formalin-induced pain but had no effect on paw edema. Coinjection of DABK (2–22 nmol/paw) with low doses of Formalin in lipopolysaccharide-treated mice, which had no effect on naive animals, dose dependently potentiated both phases of Formalin-induced pain but did not modify paw edema. These effects were antagonized by DALBK with ID50 values of 21.9 (first phase) and 64.1 (second phase) nmol/paw. Thus, both progressive desensitization of B2 receptors and systemic treatment with lipopolysaccharide induce a glucocorticoid-sensitive upregulation of B1 receptors mediating paw edema in the rat and Formalin-induced nociception in mice. These results suggest that induction of upregulation of B1 receptors may play important roles in controlling inflammatory processes and hyperalgesia.Key words: paw edema, rat, mouse, pain, Formalin test, bradykinin, B1 and B2 agonists and antagonists, lipopolysaccharide, dexamethasone.

scholarly journals O6B.7 Aristolochic acid and the risk of cancers in patients with diabetes

2019 ◽  
Vol 76 (Suppl 1) ◽  
pp. A55.1-A55
Author(s):  
Chi-Jen Chen ◽  
Wei-Che Chiu ◽  
Yao-Hsien Tseng ◽  
Yao-Hsu Yang ◽  
Chien-Mu Lin ◽  
...  
Keyword(s):  
Herbal Medicine ◽  
Aristolochic Acid ◽  
Population Based ◽  
Diabetic Patients ◽  
Research Database ◽  
Dependent Manner ◽  
Kidney Pelvis ◽  
Patients With Diabetes ◽  
Incident Cases ◽  
Dose Dependent

BackgroundThe purpose of this study was to investigate the association between the use of herbal medicine containing aristolochic acid (AA) and the risk of cancers among patients with diabetes.MethodsWe conducted a population-based cohort study on patients older than 18 years who had a diagnosis of diabetes (ICD-9 codes 250) between January 1, 1997 and December 31, 2010. To ensure comparability, we included only patients with diabetes who had visited traditional Chinese medicine clinics between January 1, 1997 and one year before the diagnosis of cancer or the censor dates. The use of herbal medicine containing AA was identified from January 1, 1997 to October 31, 2003 (the ban of herbs containing AA in November 2003). Each patient was individually tracked to identify incident cases of cancer (140–208) between January 1, 1999 and December 31, 2013.FindingsA total of 4 30 377 male and 4 31 956 female patients with diabetes were identified by using the National Health Insurance Research Database in Taiwan. There were 37 554 and 31 535 cancers during the follow-up period. AA use increased the risks of incident liver (155.0), kidney (189.0), pelvis and ureter (189.1, 189.2), and bladder (188) cancer in male patients with diabetes in a dose-dependent relationship. Similarly, there were increased risks of incident liver, pelvis and ureter, and bladder cancer in female diabetic patients in a dose-dependent manner.InterpretationOur study suggests that AA exposure plays an important role in the carcinogenesis of liver, kidney, pelvis, ureter, and bladder cancers in patients with diabetes.

Synergistic interaction in bovine pituitary cultures between growth hormone-releasing factor and other hypophysiotrophic factors

1986 ◽  
Vol 109 (1) ◽  
pp. 67-74 ◽  
Author(s):  
C. D. Ingram ◽  
R. J. Bicknell
Keyword(s):  
Growth Hormone ◽  
Synergistic Interaction ◽  
Pituitary Cells ◽  
Prolactin Release ◽  
Thyrotrophin Releasing Hormone ◽  
Growth Hormone Releasing Factor ◽  
Gh Secretion ◽  
Similar Dose ◽  
Effective Doses ◽  
Dose Dependent

ABSTRACT Synthetic human pancreatic GH-releasing factor (1–44)NH2 (GRF) and acetylcholine (ACh) were shown to evoke a dose-related release of GH from cultured bovine pituitary cells with half-maximal effective doses of 0·3 and 500 nmol/l respectively. Concentrations of ACh (10 μmol/l) and GRF (25 nmol/l) which were shown to give near maximal responses when presented alone, produced highly synergistic responses when tested in combination. This synergism was related to the ACh concentration employed, and both the ACh-induced release and ACh-induced synergism were abolished by the muscarinic antagonist, atropine. A synergistic interaction was also demonstrated between GRF and concentrations of thyrotrophin-releasing hormone (TRH) and bombesin which, in the absence of GRF, failed to elicit significant GH release. Acetylcholine stimulated a similar dose-dependent release of prolactin, but GRF was ineffectual in either directly stimulating prolactin release or affecting the response to ACh or TRH. No synergistic interaction could be detected between combinations of ACh and TRH or between ACh and bombesin. The data suggest that, in the somatotroph, GRF acts through a different second messenger pathway to ACh, TRH and bombesin and that these two pathways can be activated to produce a potentiated response. Growth hormone-releasing factor is, therefore, not only a specific GH secretagogue, but may act in concert with other hypophysiotrophic factors to regulate GH secretion from the bovine anterior pituitary. J. Endocr. (1986) 109, 67–74

scholarly journals Pseudomonas aeruginosa prioritizes detoxification of hydrogen peroxide over nitric oxide

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Darshan M. Sivaloganathan ◽  
Mark P. Brynildsen
Keyword(s):  
Nitric Oxide ◽  
Escherichia Coli ◽  
Hydrogen Peroxide ◽  
Pseudomonas Aeruginosa ◽  
Computational Modelling ◽  
Second Phase ◽  
Dependent Manner ◽  
Nitric Oxide Detoxification ◽  
Dose Dependent

Abstract Objective Bacteria are exposed to multiple concurrent antimicrobial stressors within phagosomes. Among the antimicrobials produced, hydrogen peroxide and nitric oxide are two of the most deleterious products. In a previous study, we discovered that when faced with both stressors simultaneously, Escherichia coli prioritized detoxification of hydrogen peroxide over nitric oxide. In this study, we investigated whether such a process was conserved in another bacterium, Pseudomonas aeruginosa. Results P. aeruginosa prioritized hydrogen peroxide detoxification in a dose-dependent manner. Specifically, hydrogen peroxide detoxification was unperturbed by the presence of nitric oxide, whereas larger doses of hydrogen peroxide produced longer delays in nitric oxide detoxification. Computational modelling revealed that the rate of nitric oxide consumption in co-treated cultures was biphasic, with cells entering the second phase of detoxification only after hydrogen peroxide was eliminated from the culture.

Antioxidant, Anti-inflammatory, and Analgesic Activities of Citrus reticulata Blanco Leaves Extracts: An In Vivo and In Vitro Study

2018 ◽  
Vol 16 (S1) ◽  
pp. S130-S142
Author(s):  
M. Nasri ◽  
F. Bedjou ◽  
D. Porras ◽  
S. Martínez-Flórez
Keyword(s):  
Second Phase ◽  
Citrus Reticulata ◽  
Dependent Manner ◽  
Dpph Radical ◽  
Huh7 Cells ◽  
Anti Inflammatory ◽  
Response Expression ◽  
Dose Dependent

Citrus species are cultivated and consumed widely. Citrus have been investigated for their pharmacological activity and human health. Their beneficial effects include antibacterial, analgesic, anti-inflammatory, and antitumoral effects. This studywas designed to evaluate the analgesic effect and the antioxidant and anti-inflammatory activities of Citrus reticulata Blanco leaves extracts (ECR) in cell and animal models. Antioxidant, anti-inflammatory, and antinociceptive activities were evaluated in mice using 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical inhibition, xylene-induced ear edema, formalin assay and acetic acid-writhing response. Expression of antiinflammatory genes was measured in lipopolysaccharide (LPS)-treated Huh7 cells. ECR showed a significant DPPH radical scavenging activity. No behavioral changes or deaths were observed in mice at doses less than 2,000 mg/kg body weight. Different concentrations of methanolic and aqueous extracts (100–500 mg/kg body wt.) reduced the duration of linking behavior in the second phase of the formalin chemical nociception assay and decreased the number of acetic acidinduced writhing responses in mice, indicating significant analgesic activity. ECR also diminished xylene-induced ear swelling in mice, suggesting an In Vivo anti-inflammatory action. No toxicity of ECR in the range of 0.1–10 μg/ml was observed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. Cell treatment with LPS-induced oxidative/ nitrosative stress as assessed by flow cytometry as the fluorescence of 2′,7′-dichlorofluorescein. This effect was significantly inhibited in a dose-dependent manner by ECR. Administration of ECR caused a dose-dependent inhibition of cytochrome P450 2E1, inducible nitric oxide synthase, tumor necrosis factor α, and interleukin-6 expression in LPS-treated cells. The present study demonstrates that extracts of Citrus reticulata leaves are safe, having antioxidant, anti-inflammatory, and analgesic effects both In Vivo and In Vitro.

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