The Experts below are selected from a list of 54 Experts worldwide ranked by ideXlab platform

Rachelle Buchbinder - One of the best experts on this subject based on the ideXlab platform.

  • The Cochrane Library - Muscle relaxants for pain management in rheumatoid arthritis
    Cochrane Database of Systematic Reviews, 2012
    Co-Authors: Bethan L Richards, Samuel L Whittle, Rachelle Buchbinder
    Abstract:

    Background Pain management is a high priority for patients with rheumatoid arthritis (RA). Muscle relaxants include drugs that reduce muscle spasm (for example benzodiazepines such as diazepam (Valium), alprazolam (Xanax), lorazepam (Ativan) and non-benzodiazepines such as metaxalone (Skelaxin) or a combination of paracetamol and orphenadrine (Muscol)) and drugs that prevent increased muscle tone (baclofen and dantrolene). Despite a paucity of evidence supporting their use, antispasmodic and antispasticity muscle relaxants have gained widespread clinical acceptance as adjuvants in the management of patients with chronic musculoskeletal pain. Objectives The aim of this review was to determine the efficacy and safety of muscle relaxants in pain management in patients with RA. The muscle relaxants that were included in this review are the antispasmodic benzodiazepines (alprazolam, bromazepam, chlordiazepoxide,cinolazepam, clonazepam, cloxazolam, clorazepate, diazepam, estazolam, flunitrazepam, flurazepam, flutoprazepam, halazepam, ketazolam, loprazolam, lorazepam, lormetazepam, medazepam, midazolam, nimetazepam, nitrazepam, nordazepam, oxazepam, Pinazepam, prazepam, quazepam, temazepam, tetrazepam, triazolam), antispasmodic non-benzodiazepines (cyclobenzaprine, carisoprodol, chlorzoxazone, meprobamate, methocarbamol, metaxalone, orphenadrine, tizanidine and zopiclone), and antispasticity drugs (baclofen and dantrolene sodium). Search methods We performed a search of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 4th quarter 2010), MEDLINE (1950 to week 1 November 2010), EMBASE (Week 44 2010), and PsycINFO (1806 to week 2 November 2010). We also searched the 2008 to 2009 American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) abstracts and performed a handsearch of reference lists of relevant articles. Selection criteria We included randomised controlled trials which compared a muscle relaxant to another therapy (active, including non-pharmacological therapies, or placebo) in adult patients with RA and that reported at least one clinically relevant outcome. Data collection and analysis Two blinded review authors independently extracted data and assessed the risk of bias in the trials. Meta-analyses were used to examine the efficacy of muscle relaxants on pain, depression, sleep and function, as well as their safety. Main results Six trials (126 participants) were included in this review. All trials were rated at high risk of bias. Five cross-over trials evaluated a benzodiazepine, four assessed diazepam (n = 71) and one assessed triazolam (n = 15). The sixth trial assessed zopiclone (a non-benzodiazepine) (n = 40) and was a parallel group study. No trial duration was longer than two weeks while three single dose trials assessed outcomes at 24 hours only. Overall the included trials failed to find evidence of a beneficial effect of muscle relaxants over placebo, alone (at 24 hrs, 1 or 2 weeks) or in addition to non-steroidal anti-inflammatory drugs (NSAIDs) (at 24 hrs), on pain intensity, function, or quality of life. Data from two trials of longer than 24 hours duration (n = 74) (diazepam and zopiclone) found that participants who received a muscle relaxant had significantly more adverse events compared with those who received placebo (number needed to harm (NNTH) 3, 95% CI 2 to 7). These were predominantly central nervous system side effects, including dizziness and drowsiness (NNTH 3, 95% CI 2 to 11).  Authors' conclusions Based upon the currently available evidence in patients with RA, benzodiazepines (diazepam and triazolam) do not appear to be beneficial in improving pain over 24 hours or one week. The non-benzodiazepine agent zopiclone also did not significantly reduce pain over two weeks. However, even short term muscle relaxant use (24 hours to 2 weeks) is associated with significant adverse events, predominantly drowsiness and dizziness.

  • Muscle relaxants for pain management in rheumatoid arthritis
    Cochrane database of systematic reviews (Online), 2012
    Co-Authors: Bethan L Richards, Samuel L Whittle, Rachelle Buchbinder
    Abstract:

    Pain management is a high priority for patients with rheumatoid arthritis (RA). Muscle relaxants include drugs that reduce muscle spasm (for example benzodiazepines such as diazepam (Valium), alprazolam (Xanax), lorazepam (Ativan) and non-benzodiazepines such as metaxalone (Skelaxin) or a combination of paracetamol and orphenadrine (Muscol)) and drugs that prevent increased muscle tone (baclofen and dantrolene). Despite a paucity of evidence supporting their use, antispasmodic and antispasticity muscle relaxants have gained widespread clinical acceptance as adjuvants in the management of patients with chronic musculoskeletal pain. The aim of this review was to determine the efficacy and safety of muscle relaxants in pain management in patients with RA. The muscle relaxants that were included in this review are the antispasmodic benzodiazepines (alprazolam, bromazepam, chlordiazepoxide,cinolazepam, clonazepam, cloxazolam, clorazepate, diazepam, estazolam, flunitrazepam, flurazepam, flutoprazepam, halazepam, ketazolam, loprazolam, lorazepam, lormetazepam, medazepam, midazolam, nimetazepam, nitrazepam, nordazepam, oxazepam, Pinazepam, prazepam, quazepam, temazepam, tetrazepam, triazolam), antispasmodic non-benzodiazepines (cyclobenzaprine, carisoprodol, chlorzoxazone, meprobamate, methocarbamol, metaxalone, orphenadrine, tizanidine and zopiclone), and antispasticity drugs (baclofen and dantrolene sodium). We performed a search of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 4th quarter 2010), MEDLINE (1950 to week 1 November 2010), EMBASE (Week 44 2010), and PsycINFO (1806 to week 2 November 2010). We also searched the 2008 to 2009 American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) abstracts and performed a handsearch of reference lists of relevant articles. We included randomised controlled trials which compared a muscle relaxant to another therapy (active, including non-pharmacological therapies, or placebo) in adult patients with RA and that reported at least one clinically relevant outcome. Two blinded review authors independently extracted data and assessed the risk of bias in the trials. Meta-analyses were used to examine the efficacy of muscle relaxants on pain, depression, sleep and function, as well as their safety. Six trials (126 participants) were included in this review. All trials were rated at high risk of bias. Five cross-over trials evaluated a benzodiazepine, four assessed diazepam (n = 71) and one assessed triazolam (n = 15). The sixth trial assessed zopiclone (a non-benzodiazepine) (n = 40) and was a parallel group study. No trial duration was longer than two weeks while three single dose trials assessed outcomes at 24 hours only. Overall the included trials failed to find evidence of a beneficial effect of muscle relaxants over placebo, alone (at 24 hrs, 1 or 2 weeks) or in addition to non-steroidal anti-inflammatory drugs (NSAIDs) (at 24 hrs), on pain intensity, function, or quality of life. Data from two trials of longer than 24 hours duration (n = 74) (diazepam and zopiclone) found that participants who received a muscle relaxant had significantly more adverse events compared with those who received placebo (number needed to harm (NNTH) 3, 95% CI 2 to 7). These were predominantly central nervous system side effects, including dizziness and drowsiness (NNTH 3, 95% CI 2 to 11). Based upon the currently available evidence in patients with RA, benzodiazepines (diazepam and triazolam) do not appear to be beneficial in improving pain over 24 hours or one week. The non-benzodiazepine agent zopiclone also did not significantly reduce pain over two weeks. However, even short term muscle relaxant use (24 hours to 2 weeks) is associated with significant adverse events, predominantly drowsiness and dizziness.

Bethan L Richards - One of the best experts on this subject based on the ideXlab platform.

  • The Cochrane Library - Muscle relaxants for pain management in rheumatoid arthritis
    Cochrane Database of Systematic Reviews, 2012
    Co-Authors: Bethan L Richards, Samuel L Whittle, Rachelle Buchbinder
    Abstract:

    Background Pain management is a high priority for patients with rheumatoid arthritis (RA). Muscle relaxants include drugs that reduce muscle spasm (for example benzodiazepines such as diazepam (Valium), alprazolam (Xanax), lorazepam (Ativan) and non-benzodiazepines such as metaxalone (Skelaxin) or a combination of paracetamol and orphenadrine (Muscol)) and drugs that prevent increased muscle tone (baclofen and dantrolene). Despite a paucity of evidence supporting their use, antispasmodic and antispasticity muscle relaxants have gained widespread clinical acceptance as adjuvants in the management of patients with chronic musculoskeletal pain. Objectives The aim of this review was to determine the efficacy and safety of muscle relaxants in pain management in patients with RA. The muscle relaxants that were included in this review are the antispasmodic benzodiazepines (alprazolam, bromazepam, chlordiazepoxide,cinolazepam, clonazepam, cloxazolam, clorazepate, diazepam, estazolam, flunitrazepam, flurazepam, flutoprazepam, halazepam, ketazolam, loprazolam, lorazepam, lormetazepam, medazepam, midazolam, nimetazepam, nitrazepam, nordazepam, oxazepam, Pinazepam, prazepam, quazepam, temazepam, tetrazepam, triazolam), antispasmodic non-benzodiazepines (cyclobenzaprine, carisoprodol, chlorzoxazone, meprobamate, methocarbamol, metaxalone, orphenadrine, tizanidine and zopiclone), and antispasticity drugs (baclofen and dantrolene sodium). Search methods We performed a search of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 4th quarter 2010), MEDLINE (1950 to week 1 November 2010), EMBASE (Week 44 2010), and PsycINFO (1806 to week 2 November 2010). We also searched the 2008 to 2009 American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) abstracts and performed a handsearch of reference lists of relevant articles. Selection criteria We included randomised controlled trials which compared a muscle relaxant to another therapy (active, including non-pharmacological therapies, or placebo) in adult patients with RA and that reported at least one clinically relevant outcome. Data collection and analysis Two blinded review authors independently extracted data and assessed the risk of bias in the trials. Meta-analyses were used to examine the efficacy of muscle relaxants on pain, depression, sleep and function, as well as their safety. Main results Six trials (126 participants) were included in this review. All trials were rated at high risk of bias. Five cross-over trials evaluated a benzodiazepine, four assessed diazepam (n = 71) and one assessed triazolam (n = 15). The sixth trial assessed zopiclone (a non-benzodiazepine) (n = 40) and was a parallel group study. No trial duration was longer than two weeks while three single dose trials assessed outcomes at 24 hours only. Overall the included trials failed to find evidence of a beneficial effect of muscle relaxants over placebo, alone (at 24 hrs, 1 or 2 weeks) or in addition to non-steroidal anti-inflammatory drugs (NSAIDs) (at 24 hrs), on pain intensity, function, or quality of life. Data from two trials of longer than 24 hours duration (n = 74) (diazepam and zopiclone) found that participants who received a muscle relaxant had significantly more adverse events compared with those who received placebo (number needed to harm (NNTH) 3, 95% CI 2 to 7). These were predominantly central nervous system side effects, including dizziness and drowsiness (NNTH 3, 95% CI 2 to 11).  Authors' conclusions Based upon the currently available evidence in patients with RA, benzodiazepines (diazepam and triazolam) do not appear to be beneficial in improving pain over 24 hours or one week. The non-benzodiazepine agent zopiclone also did not significantly reduce pain over two weeks. However, even short term muscle relaxant use (24 hours to 2 weeks) is associated with significant adverse events, predominantly drowsiness and dizziness.

  • Muscle relaxants for pain management in rheumatoid arthritis
    Cochrane database of systematic reviews (Online), 2012
    Co-Authors: Bethan L Richards, Samuel L Whittle, Rachelle Buchbinder
    Abstract:

    Pain management is a high priority for patients with rheumatoid arthritis (RA). Muscle relaxants include drugs that reduce muscle spasm (for example benzodiazepines such as diazepam (Valium), alprazolam (Xanax), lorazepam (Ativan) and non-benzodiazepines such as metaxalone (Skelaxin) or a combination of paracetamol and orphenadrine (Muscol)) and drugs that prevent increased muscle tone (baclofen and dantrolene). Despite a paucity of evidence supporting their use, antispasmodic and antispasticity muscle relaxants have gained widespread clinical acceptance as adjuvants in the management of patients with chronic musculoskeletal pain. The aim of this review was to determine the efficacy and safety of muscle relaxants in pain management in patients with RA. The muscle relaxants that were included in this review are the antispasmodic benzodiazepines (alprazolam, bromazepam, chlordiazepoxide,cinolazepam, clonazepam, cloxazolam, clorazepate, diazepam, estazolam, flunitrazepam, flurazepam, flutoprazepam, halazepam, ketazolam, loprazolam, lorazepam, lormetazepam, medazepam, midazolam, nimetazepam, nitrazepam, nordazepam, oxazepam, Pinazepam, prazepam, quazepam, temazepam, tetrazepam, triazolam), antispasmodic non-benzodiazepines (cyclobenzaprine, carisoprodol, chlorzoxazone, meprobamate, methocarbamol, metaxalone, orphenadrine, tizanidine and zopiclone), and antispasticity drugs (baclofen and dantrolene sodium). We performed a search of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 4th quarter 2010), MEDLINE (1950 to week 1 November 2010), EMBASE (Week 44 2010), and PsycINFO (1806 to week 2 November 2010). We also searched the 2008 to 2009 American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) abstracts and performed a handsearch of reference lists of relevant articles. We included randomised controlled trials which compared a muscle relaxant to another therapy (active, including non-pharmacological therapies, or placebo) in adult patients with RA and that reported at least one clinically relevant outcome. Two blinded review authors independently extracted data and assessed the risk of bias in the trials. Meta-analyses were used to examine the efficacy of muscle relaxants on pain, depression, sleep and function, as well as their safety. Six trials (126 participants) were included in this review. All trials were rated at high risk of bias. Five cross-over trials evaluated a benzodiazepine, four assessed diazepam (n = 71) and one assessed triazolam (n = 15). The sixth trial assessed zopiclone (a non-benzodiazepine) (n = 40) and was a parallel group study. No trial duration was longer than two weeks while three single dose trials assessed outcomes at 24 hours only. Overall the included trials failed to find evidence of a beneficial effect of muscle relaxants over placebo, alone (at 24 hrs, 1 or 2 weeks) or in addition to non-steroidal anti-inflammatory drugs (NSAIDs) (at 24 hrs), on pain intensity, function, or quality of life. Data from two trials of longer than 24 hours duration (n = 74) (diazepam and zopiclone) found that participants who received a muscle relaxant had significantly more adverse events compared with those who received placebo (number needed to harm (NNTH) 3, 95% CI 2 to 7). These were predominantly central nervous system side effects, including dizziness and drowsiness (NNTH 3, 95% CI 2 to 11). Based upon the currently available evidence in patients with RA, benzodiazepines (diazepam and triazolam) do not appear to be beneficial in improving pain over 24 hours or one week. The non-benzodiazepine agent zopiclone also did not significantly reduce pain over two weeks. However, even short term muscle relaxant use (24 hours to 2 weeks) is associated with significant adverse events, predominantly drowsiness and dizziness.

Samuel L Whittle - One of the best experts on this subject based on the ideXlab platform.

  • The Cochrane Library - Muscle relaxants for pain management in rheumatoid arthritis
    Cochrane Database of Systematic Reviews, 2012
    Co-Authors: Bethan L Richards, Samuel L Whittle, Rachelle Buchbinder
    Abstract:

    Background Pain management is a high priority for patients with rheumatoid arthritis (RA). Muscle relaxants include drugs that reduce muscle spasm (for example benzodiazepines such as diazepam (Valium), alprazolam (Xanax), lorazepam (Ativan) and non-benzodiazepines such as metaxalone (Skelaxin) or a combination of paracetamol and orphenadrine (Muscol)) and drugs that prevent increased muscle tone (baclofen and dantrolene). Despite a paucity of evidence supporting their use, antispasmodic and antispasticity muscle relaxants have gained widespread clinical acceptance as adjuvants in the management of patients with chronic musculoskeletal pain. Objectives The aim of this review was to determine the efficacy and safety of muscle relaxants in pain management in patients with RA. The muscle relaxants that were included in this review are the antispasmodic benzodiazepines (alprazolam, bromazepam, chlordiazepoxide,cinolazepam, clonazepam, cloxazolam, clorazepate, diazepam, estazolam, flunitrazepam, flurazepam, flutoprazepam, halazepam, ketazolam, loprazolam, lorazepam, lormetazepam, medazepam, midazolam, nimetazepam, nitrazepam, nordazepam, oxazepam, Pinazepam, prazepam, quazepam, temazepam, tetrazepam, triazolam), antispasmodic non-benzodiazepines (cyclobenzaprine, carisoprodol, chlorzoxazone, meprobamate, methocarbamol, metaxalone, orphenadrine, tizanidine and zopiclone), and antispasticity drugs (baclofen and dantrolene sodium). Search methods We performed a search of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 4th quarter 2010), MEDLINE (1950 to week 1 November 2010), EMBASE (Week 44 2010), and PsycINFO (1806 to week 2 November 2010). We also searched the 2008 to 2009 American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) abstracts and performed a handsearch of reference lists of relevant articles. Selection criteria We included randomised controlled trials which compared a muscle relaxant to another therapy (active, including non-pharmacological therapies, or placebo) in adult patients with RA and that reported at least one clinically relevant outcome. Data collection and analysis Two blinded review authors independently extracted data and assessed the risk of bias in the trials. Meta-analyses were used to examine the efficacy of muscle relaxants on pain, depression, sleep and function, as well as their safety. Main results Six trials (126 participants) were included in this review. All trials were rated at high risk of bias. Five cross-over trials evaluated a benzodiazepine, four assessed diazepam (n = 71) and one assessed triazolam (n = 15). The sixth trial assessed zopiclone (a non-benzodiazepine) (n = 40) and was a parallel group study. No trial duration was longer than two weeks while three single dose trials assessed outcomes at 24 hours only. Overall the included trials failed to find evidence of a beneficial effect of muscle relaxants over placebo, alone (at 24 hrs, 1 or 2 weeks) or in addition to non-steroidal anti-inflammatory drugs (NSAIDs) (at 24 hrs), on pain intensity, function, or quality of life. Data from two trials of longer than 24 hours duration (n = 74) (diazepam and zopiclone) found that participants who received a muscle relaxant had significantly more adverse events compared with those who received placebo (number needed to harm (NNTH) 3, 95% CI 2 to 7). These were predominantly central nervous system side effects, including dizziness and drowsiness (NNTH 3, 95% CI 2 to 11).  Authors' conclusions Based upon the currently available evidence in patients with RA, benzodiazepines (diazepam and triazolam) do not appear to be beneficial in improving pain over 24 hours or one week. The non-benzodiazepine agent zopiclone also did not significantly reduce pain over two weeks. However, even short term muscle relaxant use (24 hours to 2 weeks) is associated with significant adverse events, predominantly drowsiness and dizziness.

  • Muscle relaxants for pain management in rheumatoid arthritis
    Cochrane database of systematic reviews (Online), 2012
    Co-Authors: Bethan L Richards, Samuel L Whittle, Rachelle Buchbinder
    Abstract:

    Pain management is a high priority for patients with rheumatoid arthritis (RA). Muscle relaxants include drugs that reduce muscle spasm (for example benzodiazepines such as diazepam (Valium), alprazolam (Xanax), lorazepam (Ativan) and non-benzodiazepines such as metaxalone (Skelaxin) or a combination of paracetamol and orphenadrine (Muscol)) and drugs that prevent increased muscle tone (baclofen and dantrolene). Despite a paucity of evidence supporting their use, antispasmodic and antispasticity muscle relaxants have gained widespread clinical acceptance as adjuvants in the management of patients with chronic musculoskeletal pain. The aim of this review was to determine the efficacy and safety of muscle relaxants in pain management in patients with RA. The muscle relaxants that were included in this review are the antispasmodic benzodiazepines (alprazolam, bromazepam, chlordiazepoxide,cinolazepam, clonazepam, cloxazolam, clorazepate, diazepam, estazolam, flunitrazepam, flurazepam, flutoprazepam, halazepam, ketazolam, loprazolam, lorazepam, lormetazepam, medazepam, midazolam, nimetazepam, nitrazepam, nordazepam, oxazepam, Pinazepam, prazepam, quazepam, temazepam, tetrazepam, triazolam), antispasmodic non-benzodiazepines (cyclobenzaprine, carisoprodol, chlorzoxazone, meprobamate, methocarbamol, metaxalone, orphenadrine, tizanidine and zopiclone), and antispasticity drugs (baclofen and dantrolene sodium). We performed a search of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 4th quarter 2010), MEDLINE (1950 to week 1 November 2010), EMBASE (Week 44 2010), and PsycINFO (1806 to week 2 November 2010). We also searched the 2008 to 2009 American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) abstracts and performed a handsearch of reference lists of relevant articles. We included randomised controlled trials which compared a muscle relaxant to another therapy (active, including non-pharmacological therapies, or placebo) in adult patients with RA and that reported at least one clinically relevant outcome. Two blinded review authors independently extracted data and assessed the risk of bias in the trials. Meta-analyses were used to examine the efficacy of muscle relaxants on pain, depression, sleep and function, as well as their safety. Six trials (126 participants) were included in this review. All trials were rated at high risk of bias. Five cross-over trials evaluated a benzodiazepine, four assessed diazepam (n = 71) and one assessed triazolam (n = 15). The sixth trial assessed zopiclone (a non-benzodiazepine) (n = 40) and was a parallel group study. No trial duration was longer than two weeks while three single dose trials assessed outcomes at 24 hours only. Overall the included trials failed to find evidence of a beneficial effect of muscle relaxants over placebo, alone (at 24 hrs, 1 or 2 weeks) or in addition to non-steroidal anti-inflammatory drugs (NSAIDs) (at 24 hrs), on pain intensity, function, or quality of life. Data from two trials of longer than 24 hours duration (n = 74) (diazepam and zopiclone) found that participants who received a muscle relaxant had significantly more adverse events compared with those who received placebo (number needed to harm (NNTH) 3, 95% CI 2 to 7). These were predominantly central nervous system side effects, including dizziness and drowsiness (NNTH 3, 95% CI 2 to 11). Based upon the currently available evidence in patients with RA, benzodiazepines (diazepam and triazolam) do not appear to be beneficial in improving pain over 24 hours or one week. The non-benzodiazepine agent zopiclone also did not significantly reduce pain over two weeks. However, even short term muscle relaxant use (24 hours to 2 weeks) is associated with significant adverse events, predominantly drowsiness and dizziness.

A. De Sarro - One of the best experts on this subject based on the ideXlab platform.

  • Benzodiazepine receptor affinities, behavioral, and anticonvulsant activity of 2-aryl-2,5-dihydropyridazino[4,3-b]indol- 3(3H)-ones in mice.
    Pharmacology Biochemistry and Behavior, 2000
    Co-Authors: G.b. De Sarro, Ruth M. Mckernan, Pietro Giusti, M. Rizzo, Angelo Carotti, F. Campagna, Umberto Falconi, Fausta Palluotto, Cristina Rettore, A. De Sarro
    Abstract:

    DE SARRO, G., A. CAROTTI, F. CAMPAGNA, R. MCKERNAN, M. RIZZO, U. FALCONI, F. PALLUOTTO, P.GIUSTI, C. RETTORE AND A. DE SARRO. Benzodiazepine receptor affinities, behavioral, and anticonvulsant activity of 2-aryl-2,5-dihydropyridazino[4,3-b]indol-3(3H)-ones in mice. PHARMACOL BIOCHEM BEHAV 65(3) 475–487, 2000.—The anticonvulsant properties of 1,4-benzodiazepines (BDZs), pyrazoloquinolones (CGS), 2-aryl-2,5-dihydropyridazino[4,3-b]indol-3(3H)-ones (PIs) 1, and abecarnil were studied after intraperitoneal (IP) administration in mice. The anticonvulsant effects were evaluated on seizures evoked by means of auditory stimulation in DBA/2 mice or on seizures induced by administration of pentylenetetrazole (PTZ) in Swiss mice. In DBA/2 mice abecarnil was the most potent compound studied. The rank order of potency for anticonvulsant activity was abecarnil > flunitrazepam > 1i > diazepam > Pinazepam > 1d > quazepam > prazepam > halazepam > 1f > 1e > 1b > CGS 9896 > 1c > 1h, and 1a, the latter being inactive against audiogenic seizures. Some PIs 1 and abecarnil showed anticonvulsant properties against seizures induced by PTZ with a potency lower than that observed in audiogenic seizures. The pharmacological actions of 1d, 1f, and 1i were significantly reduced by a treatment with flumazenil (8.24 μmol/kg IP), suggesting a clear involvement of benzodiazepine mechanisms in the anticonvulsant activity of these compounds or their metabolites. The anticonvulsant activity of 1d, 1f, and 1i was also evaluated against seizures induced by two β-carbolines namely methyl-β-carboline-3-carboxylate (β-CCM) and methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM), in DBA/2 mice: they gave better protection against seizures induced by β-CCM than the ones by DMCM. The potency of various BDZs and PIs as inhibitors of specific [3H]flumazenil binding to neuronal membranes, was also evaluated. The radioligand binding study, carried out on stable cell lines expressing definite combinations of benzodiazepine receptor subunits, demonstrated that 1b, 1e, 1d, and 1h have preferential interaction with α1, β3, γ2, receptor subtypes.

  • Anticonvulsant Activity of Azirino[1,2-d] [1,4]Benzodiazepines and Related 1,4-Benzodiazepines in Mice
    Pharmacology Biochemistry and Behavior, 1997
    Co-Authors: G.b. De Sarro, Alba Chimirri, Ruth M. Mckernan, K Quirk, Pietro Giusti, A. De Sarro
    Abstract:

    Abstract DE SARRO, G. B., A. CHIMIRRI, R. MCKERNAN, K. QUIRK, P. GIUSTI AND A. DE SARRO. Anticonvulsant activity of azirino[1,2-d][1,4]benzodiazepines and related 1,4-benzodiazepines in mice. PHARMACOL BIOCHEM BEHAV 58 [1] 281–289, 1997.—The anticonvulsant properties of several 1,4-benzodiazepine and azirino[1,2-d][1,4]benzodiazepine (ABDZ) derivatives were studied after intraperitoneal (IP) administration in DBA/2 mice (a strain genetically susceptible to sound-induced seizures) and in Swiss mice. The anticonvulsant effects were evaluated on seizures evoked by means of auditory stimulation (109 dB, 12–16 kHz) in animals placed singly under a hemispheric Perspex dome or on seizures induced by administration of pentylenetetrazole. The 1,4-benzodiazepines were generally more potent than the related ABDZ derivatives. The rank order of potency for anticonvulsant activity was flunitrazepam > diazepam > Pinazepam > ABDZ5 > ABDZ4 > prazepam > halazepam > ABDZ1 > ABDZ3 > camazepam > ABDZ6 > ABDZ2. The impairment of locomotor performance following IP administration of these derivatives was also evaluated by means of the rotarod test. The rank order of potency for impairment of coordinated motor movements was Pinazepam > flunitrazepam > diazepam > ABDZ5 > prazepam > halazepam > ABDZ4 > ABDZ3 > ABDZ1 > camazepam > ABDZ2 = ABDZ6. The potency of various 1,4-benzodiazepines and ABDZs as inhibitors of specific [3H]flumazenil binding to membranes from cerebellum or cortex was evaluated. In general, ABDZs were active as anticonvulsants and inhibited [3H]flumazenil binding in the micromolar range. Radioligand binding studies carried out in stable cell lines demonstrated that none of the ABDZs tested showed a particular subtype specificity. The pharmacological actions of ABDZ4 and ABDZ5, which appeared to be the most potent ABDZs as anticonvulsants, were significantly reduced by treatment with flumazenil (8.24 μmol/kg IP), suggesting a clear involvement of benzodiazepine mechanisms in the anticonvulsant activity of these compounds or their metabolites. The anticonvulsant activity of ABDZ4 and ABDZ5 was also evaluated against seizures induced in DBA/2 mice by two β-carbolines: methyl-β-carboline-3-carboxylate (β-CCM) and methyl-6,6-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM). Both ABDZ4 and ABDZ5 give better protection against seizures induced by β-CCM than DMCM, suggesting a preferential action on the benzodiazepine receptor subtype BDZ1.

  • Azirino[1, 2-d][1, 4]benzodiazepine derivatives and related 1,4-benzodiazepines as anticonvulsant agents in DBA/2 mice
    General Pharmacology-the Vascular System, 1996
    Co-Authors: G.b. De Sarro, Alba Chimirri, Maria Zappalà, Piero Guisti, Maria Lipartiti, A. De Sarro
    Abstract:

    Abstract 1. 1. The behavioral and anticonvulsant effects of several 1,4-benzodiazepine (BDZ) and azirino[1,2- d ] [1, 4]benzodiazepine (ABDZ) derivatives were studied after intraperitoneal administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures. 2. 2. The anticonvulsant effects were evaluated on seizures evoked by means of auditory stimulation (109 dB, 12–16 kHz) in animals placed singly under a Perspex dome. 3. 3. The 1,4-benzodiazepines were generally more potent than the related azirino[1,2-d][1,4]benzodiazepine derivatives which, however, showed a remarkable anticonvulsant activity. The rank order of potency for anticonvulsant activity was flunitrazepam > diazepam > Pinazepam > ABDZ5 > ABDZ4 > prazepam > halazepam > ABDZ1 > ABDZ3 > camazepam > ABDZ6 > ABDZ2. 4. 4. The impairment of locomotor performance following intraperitoneal (IP) administration of the aforementioned derivatives was also evaluated by means of rotarod test. The rank order of potency for impairment of coordinated motor movements was Pinazepam > flunitrazepam > diazepam > ABDZ5 > prazepam > halazepam > ABDZ4 > ABDZ3 > ABDZ1 > camazepam > ABDZ2 = ABDZ6. 5. 5. A hypothermic activity was observed after the highest doses of the benzodiazepines studied. 6. 6. The potency of various 1,4-benzodiazepines and azirino[1,2-d][1,4]benzodiazepines as inhibitors of specific [ 3 H]flumazenil binding to membranes from cerebellum or cortex was evaluated. In general, they inhibited [ 3 H]flumazenil binding at the micromolar range. However, some ABDZ derivatives, although active as anticonvulsants, failed to displace [ 3 H]flumazenil. 7. 7. The azirino[1,2- d ] [1,4]benzodiazepine derivatives are more lipophilic than the related benzodiazepines, but the different degree of anticonvulsant activity and impairment of coordinated motor movements cannot be directly related to the lipophilicity of the compounds studied. 8. 8. The pharmacologic actions of ABDZ4 and ABDZ5, which appeared as the most potent anticonvulsants of the azirino[1,2- d ] [1,4]benzodiazepine derivatives, were significantly reduced by treatment with flumazenil (8.24μmol/kg IP) suggesting a clear involvement of benzodiazepine mechanisms in the anticonvulsant activity of these compounds or their metabolites. 9. 9. The anticonvulsant activity of ABDZ4 and ABDZ5 was also evaluated against seizures induced by the two β-carbolines, methylβ-carboline-3-carboxylate (β-CCM) and methyl6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM), in DBA/2 mice. Both ABDZ4 and ABDZ5 gave better protection against the seizures induced by β-CCM than DMCM, suggesting a preferential action on BDZ1 receptors.

  • 1,4-Benzodiazepine derivatives as anticonvulsant agents in DBA/2 mice
    General Pharmacology-the Vascular System, 1996
    Co-Authors: G.b. De Sarro, Rosaria Gitto, M. Rizzo, Mario Zappia, A. De Sarro
    Abstract:

    Abstract 1. 1. The behavioural and anticonvulsant effects of 10 1,4-benzodiazepine derivatives were studied after intraperitoneal administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures. 2. 2. The anticonvulsant effects were evaluated on seizures evoked by means of auditory stimulation (109 dB, 12–16 kHz) in animals placed singly under a perspex dome. The rank order of potency for anticonvulsant activity was alprazolam > clonazepam > flunitrazepam > diazepam > Pinazepam > desmethyldiazepam > oxazepam > prazepam > halazepam > camazepam. 3. 3. The impairment of locomotor performance following IP administration of the above reported derivatives was also evaluated by means of the rotarod test. 4. 4. Hypothermic activity was observed after the highest doses of the benzodiazepines studied. 5. 5. The potency of various 1,4-benzodiazepines as inhibitors of specific[ 3 H]flumazenil binding to membranes from cerebellum or cortex was evaluated. In general, 1,4-benzodiazepines were active as anticonvulsants at micromolar range and inhibited [ 3 h]flumazenil binding at nanomolar range. 6. 6. The different degree of anticonvulsant activity and impairment of coordinated motor movements cannot be directly related to the benzodiazepine binding affinity or to the lipophilicity of the compounds studied.

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  • Benzodiazepine receptor affinities, behavioral, and anticonvulsant activity of 2-aryl-2,5-dihydropyridazino[4,3-b]indol- 3(3H)-ones in mice.
    Pharmacology Biochemistry and Behavior, 2000
    Co-Authors: G.b. De Sarro, Ruth M. Mckernan, Pietro Giusti, M. Rizzo, Angelo Carotti, F. Campagna, Umberto Falconi, Fausta Palluotto, Cristina Rettore, A. De Sarro
    Abstract:

    DE SARRO, G., A. CAROTTI, F. CAMPAGNA, R. MCKERNAN, M. RIZZO, U. FALCONI, F. PALLUOTTO, P.GIUSTI, C. RETTORE AND A. DE SARRO. Benzodiazepine receptor affinities, behavioral, and anticonvulsant activity of 2-aryl-2,5-dihydropyridazino[4,3-b]indol-3(3H)-ones in mice. PHARMACOL BIOCHEM BEHAV 65(3) 475–487, 2000.—The anticonvulsant properties of 1,4-benzodiazepines (BDZs), pyrazoloquinolones (CGS), 2-aryl-2,5-dihydropyridazino[4,3-b]indol-3(3H)-ones (PIs) 1, and abecarnil were studied after intraperitoneal (IP) administration in mice. The anticonvulsant effects were evaluated on seizures evoked by means of auditory stimulation in DBA/2 mice or on seizures induced by administration of pentylenetetrazole (PTZ) in Swiss mice. In DBA/2 mice abecarnil was the most potent compound studied. The rank order of potency for anticonvulsant activity was abecarnil > flunitrazepam > 1i > diazepam > Pinazepam > 1d > quazepam > prazepam > halazepam > 1f > 1e > 1b > CGS 9896 > 1c > 1h, and 1a, the latter being inactive against audiogenic seizures. Some PIs 1 and abecarnil showed anticonvulsant properties against seizures induced by PTZ with a potency lower than that observed in audiogenic seizures. The pharmacological actions of 1d, 1f, and 1i were significantly reduced by a treatment with flumazenil (8.24 μmol/kg IP), suggesting a clear involvement of benzodiazepine mechanisms in the anticonvulsant activity of these compounds or their metabolites. The anticonvulsant activity of 1d, 1f, and 1i was also evaluated against seizures induced by two β-carbolines namely methyl-β-carboline-3-carboxylate (β-CCM) and methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM), in DBA/2 mice: they gave better protection against seizures induced by β-CCM than the ones by DMCM. The potency of various BDZs and PIs as inhibitors of specific [3H]flumazenil binding to neuronal membranes, was also evaluated. The radioligand binding study, carried out on stable cell lines expressing definite combinations of benzodiazepine receptor subunits, demonstrated that 1b, 1e, 1d, and 1h have preferential interaction with α1, β3, γ2, receptor subtypes.

  • Anticonvulsant Activity of Azirino[1,2-d] [1,4]Benzodiazepines and Related 1,4-Benzodiazepines in Mice
    Pharmacology Biochemistry and Behavior, 1997
    Co-Authors: G.b. De Sarro, Alba Chimirri, Ruth M. Mckernan, K Quirk, Pietro Giusti, A. De Sarro
    Abstract:

    Abstract DE SARRO, G. B., A. CHIMIRRI, R. MCKERNAN, K. QUIRK, P. GIUSTI AND A. DE SARRO. Anticonvulsant activity of azirino[1,2-d][1,4]benzodiazepines and related 1,4-benzodiazepines in mice. PHARMACOL BIOCHEM BEHAV 58 [1] 281–289, 1997.—The anticonvulsant properties of several 1,4-benzodiazepine and azirino[1,2-d][1,4]benzodiazepine (ABDZ) derivatives were studied after intraperitoneal (IP) administration in DBA/2 mice (a strain genetically susceptible to sound-induced seizures) and in Swiss mice. The anticonvulsant effects were evaluated on seizures evoked by means of auditory stimulation (109 dB, 12–16 kHz) in animals placed singly under a hemispheric Perspex dome or on seizures induced by administration of pentylenetetrazole. The 1,4-benzodiazepines were generally more potent than the related ABDZ derivatives. The rank order of potency for anticonvulsant activity was flunitrazepam > diazepam > Pinazepam > ABDZ5 > ABDZ4 > prazepam > halazepam > ABDZ1 > ABDZ3 > camazepam > ABDZ6 > ABDZ2. The impairment of locomotor performance following IP administration of these derivatives was also evaluated by means of the rotarod test. The rank order of potency for impairment of coordinated motor movements was Pinazepam > flunitrazepam > diazepam > ABDZ5 > prazepam > halazepam > ABDZ4 > ABDZ3 > ABDZ1 > camazepam > ABDZ2 = ABDZ6. The potency of various 1,4-benzodiazepines and ABDZs as inhibitors of specific [3H]flumazenil binding to membranes from cerebellum or cortex was evaluated. In general, ABDZs were active as anticonvulsants and inhibited [3H]flumazenil binding in the micromolar range. Radioligand binding studies carried out in stable cell lines demonstrated that none of the ABDZs tested showed a particular subtype specificity. The pharmacological actions of ABDZ4 and ABDZ5, which appeared to be the most potent ABDZs as anticonvulsants, were significantly reduced by treatment with flumazenil (8.24 μmol/kg IP), suggesting a clear involvement of benzodiazepine mechanisms in the anticonvulsant activity of these compounds or their metabolites. The anticonvulsant activity of ABDZ4 and ABDZ5 was also evaluated against seizures induced in DBA/2 mice by two β-carbolines: methyl-β-carboline-3-carboxylate (β-CCM) and methyl-6,6-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM). Both ABDZ4 and ABDZ5 give better protection against seizures induced by β-CCM than DMCM, suggesting a preferential action on the benzodiazepine receptor subtype BDZ1.

  • Azirino[1, 2-d][1, 4]benzodiazepine derivatives and related 1,4-benzodiazepines as anticonvulsant agents in DBA/2 mice
    General Pharmacology-the Vascular System, 1996
    Co-Authors: G.b. De Sarro, Alba Chimirri, Maria Zappalà, Piero Guisti, Maria Lipartiti, A. De Sarro
    Abstract:

    Abstract 1. 1. The behavioral and anticonvulsant effects of several 1,4-benzodiazepine (BDZ) and azirino[1,2- d ] [1, 4]benzodiazepine (ABDZ) derivatives were studied after intraperitoneal administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures. 2. 2. The anticonvulsant effects were evaluated on seizures evoked by means of auditory stimulation (109 dB, 12–16 kHz) in animals placed singly under a Perspex dome. 3. 3. The 1,4-benzodiazepines were generally more potent than the related azirino[1,2-d][1,4]benzodiazepine derivatives which, however, showed a remarkable anticonvulsant activity. The rank order of potency for anticonvulsant activity was flunitrazepam > diazepam > Pinazepam > ABDZ5 > ABDZ4 > prazepam > halazepam > ABDZ1 > ABDZ3 > camazepam > ABDZ6 > ABDZ2. 4. 4. The impairment of locomotor performance following intraperitoneal (IP) administration of the aforementioned derivatives was also evaluated by means of rotarod test. The rank order of potency for impairment of coordinated motor movements was Pinazepam > flunitrazepam > diazepam > ABDZ5 > prazepam > halazepam > ABDZ4 > ABDZ3 > ABDZ1 > camazepam > ABDZ2 = ABDZ6. 5. 5. A hypothermic activity was observed after the highest doses of the benzodiazepines studied. 6. 6. The potency of various 1,4-benzodiazepines and azirino[1,2-d][1,4]benzodiazepines as inhibitors of specific [ 3 H]flumazenil binding to membranes from cerebellum or cortex was evaluated. In general, they inhibited [ 3 H]flumazenil binding at the micromolar range. However, some ABDZ derivatives, although active as anticonvulsants, failed to displace [ 3 H]flumazenil. 7. 7. The azirino[1,2- d ] [1,4]benzodiazepine derivatives are more lipophilic than the related benzodiazepines, but the different degree of anticonvulsant activity and impairment of coordinated motor movements cannot be directly related to the lipophilicity of the compounds studied. 8. 8. The pharmacologic actions of ABDZ4 and ABDZ5, which appeared as the most potent anticonvulsants of the azirino[1,2- d ] [1,4]benzodiazepine derivatives, were significantly reduced by treatment with flumazenil (8.24μmol/kg IP) suggesting a clear involvement of benzodiazepine mechanisms in the anticonvulsant activity of these compounds or their metabolites. 9. 9. The anticonvulsant activity of ABDZ4 and ABDZ5 was also evaluated against seizures induced by the two β-carbolines, methylβ-carboline-3-carboxylate (β-CCM) and methyl6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM), in DBA/2 mice. Both ABDZ4 and ABDZ5 gave better protection against the seizures induced by β-CCM than DMCM, suggesting a preferential action on BDZ1 receptors.

  • 1,4-Benzodiazepine derivatives as anticonvulsant agents in DBA/2 mice
    General Pharmacology-the Vascular System, 1996
    Co-Authors: G.b. De Sarro, Rosaria Gitto, M. Rizzo, Mario Zappia, A. De Sarro
    Abstract:

    Abstract 1. 1. The behavioural and anticonvulsant effects of 10 1,4-benzodiazepine derivatives were studied after intraperitoneal administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures. 2. 2. The anticonvulsant effects were evaluated on seizures evoked by means of auditory stimulation (109 dB, 12–16 kHz) in animals placed singly under a perspex dome. The rank order of potency for anticonvulsant activity was alprazolam > clonazepam > flunitrazepam > diazepam > Pinazepam > desmethyldiazepam > oxazepam > prazepam > halazepam > camazepam. 3. 3. The impairment of locomotor performance following IP administration of the above reported derivatives was also evaluated by means of the rotarod test. 4. 4. Hypothermic activity was observed after the highest doses of the benzodiazepines studied. 5. 5. The potency of various 1,4-benzodiazepines as inhibitors of specific[ 3 H]flumazenil binding to membranes from cerebellum or cortex was evaluated. In general, 1,4-benzodiazepines were active as anticonvulsants at micromolar range and inhibited [ 3 h]flumazenil binding at nanomolar range. 6. 6. The different degree of anticonvulsant activity and impairment of coordinated motor movements cannot be directly related to the benzodiazepine binding affinity or to the lipophilicity of the compounds studied.