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Carla Uslenghi - One of the best experts on this subject based on the ideXlab platform.
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DOI 10.1007/s10194-009-0151-1 ORIGINAL
2013Co-Authors: Carla Ghelardini, E Vivoli, Æ Irene Grazioli, Æ Carla Uslenghi, N. Galeotti, I. Grazioli, Carla UslenghiAbstract:The central analgesia induced by antimigraine drugs is independent from Gi proteins: superiority of a fixed combination of indomethacin, Prochlorperazine and caffeine, compared to sumatriptan, in an in vivo mode
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the central analgesia induced by antimigraine drugs is independent from gi proteins superiority of a fixed combination of indomethacin Prochlorperazine and caffeine compared to sumatriptan in an in vivo model
Journal of Headache and Pain, 2009Co-Authors: Carla Ghelardini, Nicoletta Galeotti, E Vivoli, Irene Grazioli, Carla UslenghiAbstract:A hypofunctionality of Gi proteins has been found in migraine patients. The fixed combination of indomethacin, Prochlorperazine and caffeine (Indoprocaf) is a drug of well-established use in the acute treatment of migraine and tension-type headache. The aim of this study was to investigate if Indoprocaf was able to exert its central antinociceptive action when Gi proteins activity is abolished by pertussis toxin (PTX), compared to its single active ingredients and to sumatriptan. The mice model of abdominal constriction test induced by an i.p. injection of a 0.6% solution of acetic acid was used. The study showed that Indoprocaf (a fixed combination of indomethacin 1 mg/kg, Prochlorperazine 1 mg/kg and caffeine 3 mg/kg, s.c.) and sumatriptan (20 mg/kg, s.c.) exert their central antinociceptive action independently from the Gi proteins. In addition, the antinociceptive efficacy of Indoprocaf in this study was statistically superior to that of sumatriptan. This study also showed that the single active ingredients of Indoprocaf, indomethacin (1 mg/kg, s.c.), Prochlorperazine (1 mg/kg, s.c.) and caffeine (3 mg/kg, s.c.), were able to exert their central antinociceptive action independently from the Gi proteins. However, Indoprocaf at analgesic doses was able to abolish almost completely the abdominal constrictions, with a statistically higher efficacy compared to the single active ingredients, showing an important synergic effect of Indoprocaf. This synergic effect was evident not only when Gi proteins activity was abolished by PTX, but also under control condition, when Gi proteins were active. This study suggests that the central antinociceptive action induced by antimigraine drugs is independent from Gi proteins.
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Prochlorperazine induces central antinociception mediated by the muscarinic system
Pharmacological Research, 2004Co-Authors: Carla Ghelardini, Nicoletta Galeotti, Irene Grazioli, Carla Uslenghi, Alessandro BartoliniAbstract:Abstract The antinociceptive effect of the D 2 antagonist Prochlorperazine was examined in the mouse hot-plate and abdominal constriction tests. Prochlorperazine (1–2 mg kg −1 s.c./i.p.) produced an increase of the pain threshold in the mouse hot-plate test. The antinociception produced by Prochlorperazine was prevented by the D 2 selective agonist quinpirole, the unselective muscarinic antagonist atropine, the M 1 selective antagonist pirenzepine, and by the choline uptake inhibitor hemicholinium-3 hydrobromide (HC-3). Moreover, Prochlorperazine antinociception was abolished by pretreatment with an aODN against the M 1 receptor subtype, administered at the dose of 2 nmol per single i.c.v. injection. By contrast the analgesic effect of Prochlorperazine was not prevented by the opioid antagonist naloxone and the GABA B antagonist CGP-35348. Prochlorperazine also elicited a dose-dependent increase in ACh release from rat cerebral cortex. In the antinociceptive dose-range, Prochlorperazine did not impair mouse performance evaluated by the rota-rod and hole-board tests. On the basis of the above data, it can be postulated that Prochlorperazine exerted an antinociceptive effect mediated by a central cholinergic mechanism.
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efficacy of a fixed combination of indomethacin Prochlorperazine and caffeine versus sumatriptan in acute treatment of multiple migraine attacks a multicenter randomized crossover trial
Headache, 2003Co-Authors: Vincenzo Monda, Irene Grazioli, Carla Uslenghi, Maria Nicolodi, A Aloisio, Pierluigi Del Bianco, Marco Fonzari, Leonardo Vecchiet, F SicuteriAbstract:Objective.—To compare the efficacy of a fixed combination of indomethacin, Prochlorperazine, and caffeine suppositories with sumatriptan suppositories in the treatment of 2 consecutive migraine attacks of moderate or severe intensity in a multicenter, randomized, crossover study. Background.—A fixed combination of indomethacin, Prochlorperazine, and caffeine is the most commonly used drug for the acute treatment of migraine in Italy. No studies have been published comparing the efficacy of this combination with sumatriptan, the most widely prescribed of the triptans. Methods.—One hundred twelve patients with migraine with or without aura according to the diagnostic criteria of the International Headache Society were randomized to treat 2 migraine attacks with a fixed combination of indomethacin, Prochlorperazine, and caffeine and 2 migraine attacks with sumatriptan. Both drugs were rectally administered in a single dose for each attack. Patients were asked to take study medication as soon as possible at the onset of a headache. Results.—Of the 112 patients, 88 were compliant to the protocol. More attacks became pain-free at 2 hours postdose (primary end point) on the combination than on sumatriptan (49% versus 34%; P < .01), while there was no difference in the relief of headache at 2 hours postdose (71% versus 65%). The combination was statistically superior to sumatriptan in the time to a pain-free response (a higher percentage of attacks became pain-free from 0.5 hours postdose to 5 hours postdose), in alleviation of nausea, and in a sustained pain-free response (pain-free at 2 hours postdose with no use of rescue medication or relapses within 48 hours). Moreover, a significant consistent response was achieved for the combination compared with sumatriptan across (higher percentage of patients pain-free at 2 hours postdose in the first, second, third, and fourth treated attack) and within patients (pain-free in 2 of 2 treated attacks in 35% of patients taking the combination and 20% of patients on sumatriptan). Both drugs were well-tolerated. Conclusions.—This study, analyzed according to the more recent guidelines for controlled trials in migraine, showed that a fixed combination of indomethacin, Prochlorperazine, and caffeine is significantly more effective than sumatriptan in the acute treatment of migraine attacks. It is notable that the combination is less expensive than sumatriptan per unit dose.
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indomethacin caffeine and Prochlorperazine alone and combined revert hyperalgesia in in vivo models of migraine
Pharmacological Research, 2002Co-Authors: Nicoletta Galeotti, Carla Ghelardini, Irene Grazioli, Carla UslenghiAbstract:The combination of indomethacin, caffeine, and Prochlorperazine (hereinafter IndoProCaf) represents an effective antimigraine drug available on the Italian market. The aim of this study was to test the efficacy of the three active principles alone and in combination in reverting hyperalgesia. Hyperalgesia was induced by morphine withdrawal in mice treated with morphine for 15 days and then made hyperalgic by morphine substitution with water. This study showed that indomethacin 0.3 mg kg(-1), i.p.; caffeine 0.1 and 0.3 mg kg(-1), i.p.; and Prochlorperazine 0.1 mg kg(-1), i.p.; as well as the combination of the three active principles, were able to revert morphine withdrawal induced hyperalgesia, causing a statistically significant increase of pain threshold in hyperalgic mice. In a second model, hyperalgesia was induced by the i.p. injection of a 0.3% solution of acetic acid in mice and was evaluated counting the number of abdominal constrictions. Indomethacin (0.1 mg kg(-1), i.p.), caffeine (0.3 mg kg(-1), i.p.), and Prochlorperazine (0.1 mg kg(-1), i.p.) reduced the number of abdominal constrictions, while the combination of the three active principles was able to abolish almost completely the abdominal constrictions, with a significantly higher efficacy compared to the single active principles. In both models, indomethacin, caffeine, and Prochlorperazine reverted hyperalgesia at dosages 10 times lower than the corresponding analgesic ones. These data provide the pharmacologic evidence of the efficacy of IndoProCaf in reverting hyperalgesia, a condition of reduction of pain threshold similar to that occurring in migraine.
James Cassella - One of the best experts on this subject based on the ideXlab platform.
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the pharmacokinetics and bioavailability of Prochlorperazine delivered as a thermally generated aerosol in a single breath to volunteers
Clinical Pharmacology & Therapeutics, 2009Co-Authors: Michael J Avram, Daniel A Spyker, Thomas K Henthorn, James CassellaAbstract:A thermally generated aerosol (TGA) system can effect reliable delivery of excipient-free drug to alveoli, resulting in rapid systemic drug absorption. We developed a pharmacokinetic model of Prochlorperazine, administered by inhalation and as a rapid intravenous infusion, and we determined absolute TGA bioavailability in eight healthy volunteers in this institutional review board-approved, two-period crossover study. After the drug was administered as either a 5-s intravenous infusion or a TGA single-breath inhalation, blood was collected at various times for up to 24 h. Plasma Prochlorperazine concentrations were measured using liquid chromatography-tandem mass spectrometry. Inhalation and rapid intravenous administration produced similar plasma Prochlorperazine concentration profiles. Intravenous and inhalation pharmacokinetics were well characterized by a simultaneous two-compartment model with multiple absorption delays. Prochlorperazine pharmacokinetic parameters were similar to those reported for single intravenous doses. The geometric mean bioavailability after TGA delivery was 1.10. The administration of Prochlorperazine by inhalation resulted in pharmacokinetics similar to that seen after intravenous administration, in terms of speed, extent, and consistency of absorption.
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recirculatory pharmacokinetic model of the uptake distribution and bioavailability of Prochlorperazine administered as a thermally generated aerosol in a single breath to dogs
Drug Metabolism and Disposition, 2007Co-Authors: Michael J Avram, Daniel A Spyker, Thomas K Henthorn, James Cassella, Tom C Krejcie, Peter M Lloyd, Joshua D RabinowitzAbstract:A thermal aerosol generation process is capable of delivering pure drug reliably to the alveoli where it is absorbed systemically. Although deep lung absorption of drugs administered as an aerosol has been shown to be rapid, detailed characterization of their absorption and distribution has not been reported. The present study describes the pharmacokinetics of Prochlorperazine from the moment of administration as either a rapid intravenous infusion or a thermally generated aerosol and determines the bioavailability of the aerosol by two independent methods. Prochlorperazine disposition was determined in four anesthetized dogs after a 5-s intravenous infusion and after thermally generated aerosol administration in one breath. Venous blood samples were collected frequently from the time of drug administration to 24 h and left ventricular blood samples were drawn more often until 10 min after drug administration. Prochlorperazine disposition after intravenous and aerosol administration was characterized by fitting a recirculatory model to left ventricular and venous drug concentration data simultaneously. Prochlorperazine aerosol administration produced plasma drug concentrations similar to those after rapid intravenous administration of the same nominal dose, with peak left ventricular concentrations achieved in less than 30 s. Plasma concentration profiles of Prochlorperazine administered by both routes were well described by the recirculatory model. Bioavailability of the thermally generated aerosol was consistent and averaged more than 80% of emitted dose. Pulmonary administration of a thermally generated drug aerosol in one breath may be a viable alternative to rapid intravenous administration of drugs requiring rapid and predictable production of effective plasma concentrations.
Irene Grazioli - One of the best experts on this subject based on the ideXlab platform.
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the central analgesia induced by antimigraine drugs is independent from gi proteins superiority of a fixed combination of indomethacin Prochlorperazine and caffeine compared to sumatriptan in an in vivo model
Journal of Headache and Pain, 2009Co-Authors: Carla Ghelardini, Nicoletta Galeotti, E Vivoli, Irene Grazioli, Carla UslenghiAbstract:A hypofunctionality of Gi proteins has been found in migraine patients. The fixed combination of indomethacin, Prochlorperazine and caffeine (Indoprocaf) is a drug of well-established use in the acute treatment of migraine and tension-type headache. The aim of this study was to investigate if Indoprocaf was able to exert its central antinociceptive action when Gi proteins activity is abolished by pertussis toxin (PTX), compared to its single active ingredients and to sumatriptan. The mice model of abdominal constriction test induced by an i.p. injection of a 0.6% solution of acetic acid was used. The study showed that Indoprocaf (a fixed combination of indomethacin 1 mg/kg, Prochlorperazine 1 mg/kg and caffeine 3 mg/kg, s.c.) and sumatriptan (20 mg/kg, s.c.) exert their central antinociceptive action independently from the Gi proteins. In addition, the antinociceptive efficacy of Indoprocaf in this study was statistically superior to that of sumatriptan. This study also showed that the single active ingredients of Indoprocaf, indomethacin (1 mg/kg, s.c.), Prochlorperazine (1 mg/kg, s.c.) and caffeine (3 mg/kg, s.c.), were able to exert their central antinociceptive action independently from the Gi proteins. However, Indoprocaf at analgesic doses was able to abolish almost completely the abdominal constrictions, with a statistically higher efficacy compared to the single active ingredients, showing an important synergic effect of Indoprocaf. This synergic effect was evident not only when Gi proteins activity was abolished by PTX, but also under control condition, when Gi proteins were active. This study suggests that the central antinociceptive action induced by antimigraine drugs is independent from Gi proteins.
-
Prochlorperazine induces central antinociception mediated by the muscarinic system
Pharmacological Research, 2004Co-Authors: Carla Ghelardini, Nicoletta Galeotti, Irene Grazioli, Carla Uslenghi, Alessandro BartoliniAbstract:Abstract The antinociceptive effect of the D 2 antagonist Prochlorperazine was examined in the mouse hot-plate and abdominal constriction tests. Prochlorperazine (1–2 mg kg −1 s.c./i.p.) produced an increase of the pain threshold in the mouse hot-plate test. The antinociception produced by Prochlorperazine was prevented by the D 2 selective agonist quinpirole, the unselective muscarinic antagonist atropine, the M 1 selective antagonist pirenzepine, and by the choline uptake inhibitor hemicholinium-3 hydrobromide (HC-3). Moreover, Prochlorperazine antinociception was abolished by pretreatment with an aODN against the M 1 receptor subtype, administered at the dose of 2 nmol per single i.c.v. injection. By contrast the analgesic effect of Prochlorperazine was not prevented by the opioid antagonist naloxone and the GABA B antagonist CGP-35348. Prochlorperazine also elicited a dose-dependent increase in ACh release from rat cerebral cortex. In the antinociceptive dose-range, Prochlorperazine did not impair mouse performance evaluated by the rota-rod and hole-board tests. On the basis of the above data, it can be postulated that Prochlorperazine exerted an antinociceptive effect mediated by a central cholinergic mechanism.
-
efficacy of a fixed combination of indomethacin Prochlorperazine and caffeine versus sumatriptan in acute treatment of multiple migraine attacks a multicenter randomized crossover trial
Headache, 2003Co-Authors: Vincenzo Monda, Irene Grazioli, Carla Uslenghi, Maria Nicolodi, A Aloisio, Pierluigi Del Bianco, Marco Fonzari, Leonardo Vecchiet, F SicuteriAbstract:Objective.—To compare the efficacy of a fixed combination of indomethacin, Prochlorperazine, and caffeine suppositories with sumatriptan suppositories in the treatment of 2 consecutive migraine attacks of moderate or severe intensity in a multicenter, randomized, crossover study. Background.—A fixed combination of indomethacin, Prochlorperazine, and caffeine is the most commonly used drug for the acute treatment of migraine in Italy. No studies have been published comparing the efficacy of this combination with sumatriptan, the most widely prescribed of the triptans. Methods.—One hundred twelve patients with migraine with or without aura according to the diagnostic criteria of the International Headache Society were randomized to treat 2 migraine attacks with a fixed combination of indomethacin, Prochlorperazine, and caffeine and 2 migraine attacks with sumatriptan. Both drugs were rectally administered in a single dose for each attack. Patients were asked to take study medication as soon as possible at the onset of a headache. Results.—Of the 112 patients, 88 were compliant to the protocol. More attacks became pain-free at 2 hours postdose (primary end point) on the combination than on sumatriptan (49% versus 34%; P < .01), while there was no difference in the relief of headache at 2 hours postdose (71% versus 65%). The combination was statistically superior to sumatriptan in the time to a pain-free response (a higher percentage of attacks became pain-free from 0.5 hours postdose to 5 hours postdose), in alleviation of nausea, and in a sustained pain-free response (pain-free at 2 hours postdose with no use of rescue medication or relapses within 48 hours). Moreover, a significant consistent response was achieved for the combination compared with sumatriptan across (higher percentage of patients pain-free at 2 hours postdose in the first, second, third, and fourth treated attack) and within patients (pain-free in 2 of 2 treated attacks in 35% of patients taking the combination and 20% of patients on sumatriptan). Both drugs were well-tolerated. Conclusions.—This study, analyzed according to the more recent guidelines for controlled trials in migraine, showed that a fixed combination of indomethacin, Prochlorperazine, and caffeine is significantly more effective than sumatriptan in the acute treatment of migraine attacks. It is notable that the combination is less expensive than sumatriptan per unit dose.
-
indomethacin caffeine and Prochlorperazine alone and combined revert hyperalgesia in in vivo models of migraine
Pharmacological Research, 2002Co-Authors: Nicoletta Galeotti, Carla Ghelardini, Irene Grazioli, Carla UslenghiAbstract:The combination of indomethacin, caffeine, and Prochlorperazine (hereinafter IndoProCaf) represents an effective antimigraine drug available on the Italian market. The aim of this study was to test the efficacy of the three active principles alone and in combination in reverting hyperalgesia. Hyperalgesia was induced by morphine withdrawal in mice treated with morphine for 15 days and then made hyperalgic by morphine substitution with water. This study showed that indomethacin 0.3 mg kg(-1), i.p.; caffeine 0.1 and 0.3 mg kg(-1), i.p.; and Prochlorperazine 0.1 mg kg(-1), i.p.; as well as the combination of the three active principles, were able to revert morphine withdrawal induced hyperalgesia, causing a statistically significant increase of pain threshold in hyperalgic mice. In a second model, hyperalgesia was induced by the i.p. injection of a 0.3% solution of acetic acid in mice and was evaluated counting the number of abdominal constrictions. Indomethacin (0.1 mg kg(-1), i.p.), caffeine (0.3 mg kg(-1), i.p.), and Prochlorperazine (0.1 mg kg(-1), i.p.) reduced the number of abdominal constrictions, while the combination of the three active principles was able to abolish almost completely the abdominal constrictions, with a significantly higher efficacy compared to the single active principles. In both models, indomethacin, caffeine, and Prochlorperazine reverted hyperalgesia at dosages 10 times lower than the corresponding analgesic ones. These data provide the pharmacologic evidence of the efficacy of IndoProCaf in reverting hyperalgesia, a condition of reduction of pain threshold similar to that occurring in migraine.
Michael J Avram - One of the best experts on this subject based on the ideXlab platform.
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the pharmacokinetics and bioavailability of Prochlorperazine delivered as a thermally generated aerosol in a single breath to volunteers
Clinical Pharmacology & Therapeutics, 2009Co-Authors: Michael J Avram, Daniel A Spyker, Thomas K Henthorn, James CassellaAbstract:A thermally generated aerosol (TGA) system can effect reliable delivery of excipient-free drug to alveoli, resulting in rapid systemic drug absorption. We developed a pharmacokinetic model of Prochlorperazine, administered by inhalation and as a rapid intravenous infusion, and we determined absolute TGA bioavailability in eight healthy volunteers in this institutional review board-approved, two-period crossover study. After the drug was administered as either a 5-s intravenous infusion or a TGA single-breath inhalation, blood was collected at various times for up to 24 h. Plasma Prochlorperazine concentrations were measured using liquid chromatography-tandem mass spectrometry. Inhalation and rapid intravenous administration produced similar plasma Prochlorperazine concentration profiles. Intravenous and inhalation pharmacokinetics were well characterized by a simultaneous two-compartment model with multiple absorption delays. Prochlorperazine pharmacokinetic parameters were similar to those reported for single intravenous doses. The geometric mean bioavailability after TGA delivery was 1.10. The administration of Prochlorperazine by inhalation resulted in pharmacokinetics similar to that seen after intravenous administration, in terms of speed, extent, and consistency of absorption.
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recirculatory pharmacokinetic model of the uptake distribution and bioavailability of Prochlorperazine administered as a thermally generated aerosol in a single breath to dogs
Drug Metabolism and Disposition, 2007Co-Authors: Michael J Avram, Daniel A Spyker, Thomas K Henthorn, James Cassella, Tom C Krejcie, Peter M Lloyd, Joshua D RabinowitzAbstract:A thermal aerosol generation process is capable of delivering pure drug reliably to the alveoli where it is absorbed systemically. Although deep lung absorption of drugs administered as an aerosol has been shown to be rapid, detailed characterization of their absorption and distribution has not been reported. The present study describes the pharmacokinetics of Prochlorperazine from the moment of administration as either a rapid intravenous infusion or a thermally generated aerosol and determines the bioavailability of the aerosol by two independent methods. Prochlorperazine disposition was determined in four anesthetized dogs after a 5-s intravenous infusion and after thermally generated aerosol administration in one breath. Venous blood samples were collected frequently from the time of drug administration to 24 h and left ventricular blood samples were drawn more often until 10 min after drug administration. Prochlorperazine disposition after intravenous and aerosol administration was characterized by fitting a recirculatory model to left ventricular and venous drug concentration data simultaneously. Prochlorperazine aerosol administration produced plasma drug concentrations similar to those after rapid intravenous administration of the same nominal dose, with peak left ventricular concentrations achieved in less than 30 s. Plasma concentration profiles of Prochlorperazine administered by both routes were well described by the recirculatory model. Bioavailability of the thermally generated aerosol was consistent and averaged more than 80% of emitted dose. Pulmonary administration of a thermally generated drug aerosol in one breath may be a viable alternative to rapid intravenous administration of drugs requiring rapid and predictable production of effective plasma concentrations.
Carla Ghelardini - One of the best experts on this subject based on the ideXlab platform.
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DOI 10.1007/s10194-009-0151-1 ORIGINAL
2013Co-Authors: Carla Ghelardini, E Vivoli, Æ Irene Grazioli, Æ Carla Uslenghi, N. Galeotti, I. Grazioli, Carla UslenghiAbstract:The central analgesia induced by antimigraine drugs is independent from Gi proteins: superiority of a fixed combination of indomethacin, Prochlorperazine and caffeine, compared to sumatriptan, in an in vivo mode
-
the central analgesia induced by antimigraine drugs is independent from gi proteins superiority of a fixed combination of indomethacin Prochlorperazine and caffeine compared to sumatriptan in an in vivo model
Journal of Headache and Pain, 2009Co-Authors: Carla Ghelardini, Nicoletta Galeotti, E Vivoli, Irene Grazioli, Carla UslenghiAbstract:A hypofunctionality of Gi proteins has been found in migraine patients. The fixed combination of indomethacin, Prochlorperazine and caffeine (Indoprocaf) is a drug of well-established use in the acute treatment of migraine and tension-type headache. The aim of this study was to investigate if Indoprocaf was able to exert its central antinociceptive action when Gi proteins activity is abolished by pertussis toxin (PTX), compared to its single active ingredients and to sumatriptan. The mice model of abdominal constriction test induced by an i.p. injection of a 0.6% solution of acetic acid was used. The study showed that Indoprocaf (a fixed combination of indomethacin 1 mg/kg, Prochlorperazine 1 mg/kg and caffeine 3 mg/kg, s.c.) and sumatriptan (20 mg/kg, s.c.) exert their central antinociceptive action independently from the Gi proteins. In addition, the antinociceptive efficacy of Indoprocaf in this study was statistically superior to that of sumatriptan. This study also showed that the single active ingredients of Indoprocaf, indomethacin (1 mg/kg, s.c.), Prochlorperazine (1 mg/kg, s.c.) and caffeine (3 mg/kg, s.c.), were able to exert their central antinociceptive action independently from the Gi proteins. However, Indoprocaf at analgesic doses was able to abolish almost completely the abdominal constrictions, with a statistically higher efficacy compared to the single active ingredients, showing an important synergic effect of Indoprocaf. This synergic effect was evident not only when Gi proteins activity was abolished by PTX, but also under control condition, when Gi proteins were active. This study suggests that the central antinociceptive action induced by antimigraine drugs is independent from Gi proteins.
-
Prochlorperazine induces central antinociception mediated by the muscarinic system
Pharmacological Research, 2004Co-Authors: Carla Ghelardini, Nicoletta Galeotti, Irene Grazioli, Carla Uslenghi, Alessandro BartoliniAbstract:Abstract The antinociceptive effect of the D 2 antagonist Prochlorperazine was examined in the mouse hot-plate and abdominal constriction tests. Prochlorperazine (1–2 mg kg −1 s.c./i.p.) produced an increase of the pain threshold in the mouse hot-plate test. The antinociception produced by Prochlorperazine was prevented by the D 2 selective agonist quinpirole, the unselective muscarinic antagonist atropine, the M 1 selective antagonist pirenzepine, and by the choline uptake inhibitor hemicholinium-3 hydrobromide (HC-3). Moreover, Prochlorperazine antinociception was abolished by pretreatment with an aODN against the M 1 receptor subtype, administered at the dose of 2 nmol per single i.c.v. injection. By contrast the analgesic effect of Prochlorperazine was not prevented by the opioid antagonist naloxone and the GABA B antagonist CGP-35348. Prochlorperazine also elicited a dose-dependent increase in ACh release from rat cerebral cortex. In the antinociceptive dose-range, Prochlorperazine did not impair mouse performance evaluated by the rota-rod and hole-board tests. On the basis of the above data, it can be postulated that Prochlorperazine exerted an antinociceptive effect mediated by a central cholinergic mechanism.
-
indomethacin caffeine and Prochlorperazine alone and combined revert hyperalgesia in in vivo models of migraine
Pharmacological Research, 2002Co-Authors: Nicoletta Galeotti, Carla Ghelardini, Irene Grazioli, Carla UslenghiAbstract:The combination of indomethacin, caffeine, and Prochlorperazine (hereinafter IndoProCaf) represents an effective antimigraine drug available on the Italian market. The aim of this study was to test the efficacy of the three active principles alone and in combination in reverting hyperalgesia. Hyperalgesia was induced by morphine withdrawal in mice treated with morphine for 15 days and then made hyperalgic by morphine substitution with water. This study showed that indomethacin 0.3 mg kg(-1), i.p.; caffeine 0.1 and 0.3 mg kg(-1), i.p.; and Prochlorperazine 0.1 mg kg(-1), i.p.; as well as the combination of the three active principles, were able to revert morphine withdrawal induced hyperalgesia, causing a statistically significant increase of pain threshold in hyperalgic mice. In a second model, hyperalgesia was induced by the i.p. injection of a 0.3% solution of acetic acid in mice and was evaluated counting the number of abdominal constrictions. Indomethacin (0.1 mg kg(-1), i.p.), caffeine (0.3 mg kg(-1), i.p.), and Prochlorperazine (0.1 mg kg(-1), i.p.) reduced the number of abdominal constrictions, while the combination of the three active principles was able to abolish almost completely the abdominal constrictions, with a significantly higher efficacy compared to the single active principles. In both models, indomethacin, caffeine, and Prochlorperazine reverted hyperalgesia at dosages 10 times lower than the corresponding analgesic ones. These data provide the pharmacologic evidence of the efficacy of IndoProCaf in reverting hyperalgesia, a condition of reduction of pain threshold similar to that occurring in migraine.