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  • 1
    Electronic Resource
    Electronic Resource
    BAY 38–7271: A Novel Highly Selective and Highly Potent Cannabinoid Receptor Agonist for the Treatment of Traumatic Brain Injury (2003)
    Oxford, UK : Blackwell Publishing Ltd
    CNS drug reviews 9 (2003), S. 0 
    Details
    ISSN: 1527-3458
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Traumatic brain injury (TBI) is the most common cause of mortality and morbidity in adults under 40 years of age in industrialized countries. Worldwide the incidence is increasing, about 9.5 million people are hospitalized per year due to TBI, and the death rate is estimated to be more than one million people per year. Recently BAY 38–7271 has been characterized as a structurally novel, selective and highly potent cannabinoid CB1/CB2 receptor agonist in vitro and in vivo with pronounced neuroprotective efficacy in a rat traumatic brain injury model, showing a therapeutic window of at least 5 h. Furthermore, neuroprotective efficacy was also found in models of transient and permanent occlusion of the middle cerebral artery and brain edema models as well. In this article we review the in vitro and in vivo pharmacology of BAY 38–7271, the results from acute and subacute toxicity studies, pharmacokinetics and drug metabolism in animals and healthy male volunteers. In phase I studies BAY 38–7271 was safe and well tolerated when administered by i.v. infusion for either 1 or 24 h.As the doses of BAY 38–7271 in animals needed for maximal neuroprotective efficacy were significantly lower than those inducing typical cannabinoid-like side effects, it is to be expected that the compound will offer a novel therapeutic approach with a favorable therapeutic window for the treatment of TBI or cerebral ischemia.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1527-3458.2003.tb00259.x
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  • 2
    Electronic Resource
    Electronic Resource
    Selective intermediate-/small-conductance calcium-activated potassium channel (KCNN4) blockers are potent and effective therapeutics in experimental brain oedema and traumatic brain injury caused by acute subdural haematoma (2004)
    Oxford, UK : Blackwell Science Ltd
    European journal of neuroscience 20 (2004), S. 0 
    Details
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Early deterioration and death after brain injury is often the result of oedema in the injured and peri-lesional tissue. So far, no pharmacotherapy is available that exhibits significant brain oedema-reducing efficacy in patients. We selected two low molecular weight compounds from different chemical classes, a triazole (1-[(2-chlorophenyl)diphenylmethyl]-1,2,3-triazole) and a cyclohexadiene (methyl 4-[4-chloro-3-(trifluoromethyl)phenyl]-6-methyl-3-oxo-1,4,7-tetrahydroisobenzofuran-5-carboxylate) to characterize their pharmacological properties on KCNN4 channels (intermediate/small conductance calcium-activated potassium channel, subfamily N, member 4) in vitro as well as in vivo. In vitro we replaced potassium by rubidium (Rb+) and determined Rb+ fluxes evoked by 10 µm of the calcium ionophore A23187 on C6BU1 rat glioma cells. Compared with known KCNN4 blockers, such as clotrimazole (IC50 = 360 ± 12 nm) and charybdotoxin (IC50 = 3.3 ± 1.9 nm), the triazole and cyclohexadiene were considerably more potent than clotrimazole and displayed similar potencies (IC50 = 12.1 ± 8.8 and 13.3 ± 4.7 nm, respectively). In the rat acute subdural haematoma model, both the triazole and cyclohexadiene displayed reduction of brain water content (−26% at 0.3 mg/kg and −24% at 0.01 mg/kg) and reduction of the intracranial pressure (−46% at 0.1 mg/kg and −60% at 0.003 mg/kg) after 24 h when administered as a 4-h infusion immediately after brain injury. When infarct volumes were determined after 7 days, the triazole as well as the cyclohexadiene displayed strong neuroprotective efficacy (−52% infarct volume reduction at 1.2 mg/kg and −43% at 0.04 mg/kg, respectively). It is concluded that blockade of KCNN4 channels is a new pharmacological approach to attenuate acute brain damage caused by traumatic brain injury.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1460-9568.2004.03615.x
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  • 3
    Electronic Resource
    Electronic Resource
    Tetanus toxin: Biochemical and pharmacological comparison between its protoxin and some isotoxins obtained by limited proteolysis (1988)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 338 (1988), S. 99-106 
    Details
    ISSN: 1432-1912
    Keywords: Tetanus toxin ; Protoxin ; Isotoxins ; Hydrophobicity ; Neurotransmitter release
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Single-chain tetanus toxin (toxin S) was prepared from short-term cultures by lysis under protection with protease inhibitors, precipitation with 40% ammonium sulfate, gel filtration, and chromatography on DEAE ion exchanger. Its limited proteolysis by trypsin, post-arginine cleaving enzyme from mouse submaxillary gland and clostripain led to bichainal derivatives (BT, BA, BCl) consisting of a heavy chain and a larger version of the light chain. The latter was then converted by trypsin into a small version which comigrated with the light chain of bichainal extracellular toxin (BE). The light chain produced by chymotrypsin (BC) and elastase (BEI) was of intermediate size. The nick region serves as substrate for all esteroproteases investigated and comprises between one and two kDa. Limited proteolysis increased the hydrophilicity (BT 〉 BE 〉 S) in hydrophobic interaction HPLC, and anionic behaviour (BC 〉 BE 〉 BT 〉 S) in DEAE ion exchanger HPLC. The bichainal toxins assessed (BC, BE or BT) were about two times more toxic than toxin S (LD50, mouse s. c. 2 ng/kg vs. 4 ng/kg). They were five to twelve times more potent than toxin S in three in vitro assays measuring the prevention of neurotransmitter release, i. c. on the phrenic nerve-hemidiaphragm preparation of the mouse (acetylcholine, with toxin BE and BT), on primary brain cell cultures from the mouse ([3H]noradrenaline, with toxin BE and BT), and on brain homogenate from rats ([3H]noradrenaline, with toxin BA, BC, BE and BT). Thus single-chain toxin is a less potent precursor of, or protoxin for, various bichainal isotoxins. The term tetanus toxin covers a family of agents that differ by their posttranslational processing.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00174855
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