The effect of a benzodiazepine antagonist, RO15-1788, in diazepam dependent rats

A benzodiazepine antagonist, RO15-1788, was administered intragastrically to diazepam-dependent gastric fistula rats and a precipitated abstinence syndrome was observed. The intensity of the RO15-1788 precipitated abstinence syndrome, calculated by the Precipitated Abstinence Scale, increased in intensity in a log-dose manner over a dose range of 1.0 to 15.0 mg/kg of RO15-1788 and plateaued at the 15.0 mg/kg dose. The RO15-1788 precipitated diazepam abstinence syndrome differed both qualitatively and quantitatively from the diazepam withdrawal syndrome.     

Diazepam and pentobarbital dependence in the rat

Diazepam (100–133 mg/kg/day), administered chronically through a gastric fistula, and pentobarbital (ca 692 mg/kg/day), administered chronically in food, were studied for their dependence producing properties in Sprague-Dawley female rats. The diazepam abstinence syndrome was apparent 10 to 20 hours after withdrawal, persisted for over 60 hours and consisted of poker tail, explosive awakenings, digging in sawdust, jerks, tremors, wet dog shakes, hostility, decreased food and water consumption and weight loss. The pentobarbital abstinence syndrome came on rapidly peaking within 10 hours and was largely over by 16 hours. The pentobarbital abstinence syndrome differed from diazepam's by the presence of grand mal, clonic and atypical convulsions. Diazepam completely and in a dose related way suppressed the diazepam abstinence syndrome. Similarly pentobarbital suppressed the pentobarbital abstinence syndrome. The signs which could be suppressed in a dose related manner were different for the diazepam and pentobarbital abstinence syndromes. Diazepam only partially suppressed the pentobarbital abstinence syndrome and pentobarbital only partially suppressed the diazepam abstinence syndrome. These data indicate that diazepam and pentobarbital produce different types of dependencies in the rat and are not equivalent in suppressing signs of abstinence.     

Diversity of Channels Generated by Different Combinations of Epithelial Sodium Channel Subunits

The epithelial sodium channel is a multimeric protein formed by three homologous subunits: α, β, and γ; each subunit contains only two transmembrane domains. The level of expression of each of the subunits is markedly different in various Na⁺ absorbing epithelia raising the possibility that channels with different subunit composition can function in vivo. We have examined the functional properties of channels formed by the association of α with β and of α with γ in the Xenopus oocyte expression system using two-microelectrode voltage clamp and patch-clamp techniques. We found that αβ channels differ from αγ channels in the following functional properties: (a) αβ channels expressed larger Na⁺ than Li⁺ currents (I_Na+/I_Li+ 1.2) whereas αγ channels expressed smaller Na⁺ than Li⁺ currents (I_Na+/I_Li+ 0.55); (b) the Michaelis Menten constants (K _m) of activation of current by increasing concentrations of external Na⁺ and Li⁺ of αβ channels were larger (K _m > 180 mM) than those of αγ channels (K _m of 35 and 50 mM, respectively); (c) single channel conductances of αβ channels (5.1 pS for Na⁺ and 4.2 pS for Li⁺) were smaller than those of αγ channels (6.5 pS for Na⁺ and 10.8 pS for Li⁺); (d) the half-inhibition constant (K _i) of amiloride was 20-fold larger for αβ channels than for αγ channels whereas the K _i of guanidinium was equal for both αβ and αγ. To identify the domains in the channel subunits involved in amiloride binding, we constructed several chimeras that contained the amino terminus of the γ subunit and the carboxy terminus of the β subunit. A stretch of 15 amino acids, immediately before the second transmembrane domain of the β subunit, was identified as the domain conferring lower amiloride affinity to the αβ channels. We provide evidence for the existence of two distinct binding sites for the amiloride molecule: one for the guanidium moiety and another for the pyrazine ring. At least two subunits α with β or γ contribute to these binding sites. Finally, we show that the most likely stoichiometry of αβ and αγ channels is 1α:1β and 1α:1γ, respectively.     

Wildlife detector dogs and camera traps: a comparison of techniques for detecting feral cats

A major challenge in controlling overabundant wildlife is monitoring their populations, particularly as they decline to very low density. Camera traps and wildlife detector dogs are increasingly being used for this purpose. We compared the cost-effectiveness of these two approaches for detecting feral cats (Felis catus) on two pastoral properties in Hawke's Bay, North Island, New Zealand. One property was subject to intensive pest removal, while the other had no recent history of pest control. Camera traps and wildlife detector dogs detected cats at similar rates at both sites. The operating costs of each method were also comparable. We identify a number of advantages and disadvantages of each technique, and suggest priorities for further research.     

Intermittent hypoxia and activation of inflammatory molecular pathways in OSAS

Obstructive sleep apnoea syndrome (OSAS) represents a highly prevalent disease and is recognized as a risk factor for the development of various cardiovascular disorders. The pathogenesis of cardiovascular complications in OSAS is not completely understood, but the unique form of hypoxia with repetitive short cycles of desaturation followed by rapid reoxygenation termed intermittent hypoxia (IH) is likely to play a significant role. There is increasing evidence that IH leads to a preferential activation of inflammatory over adaptive pathways. This promotes activation of various inflammatory cells, particularly lymphocytes and monocytes, with the downstream consequence of expression of pro-inflammatory cytokines, chemokines and adhesion molecules that may contribute to endothelial dysfunction. This review provides a critical analysis of the current evidence of inflammatory mechanisms initiated by IH that may contribute to the cardiovascular pathogenesis in OSAS.     

The synthesis and structure-activity relationship of pyridazinones as glucan synthase inhibitors

A structure-activity relationship study of the lead 5-[4-(benzylsulfonyl)piperazin-1-yl]-4-morpholino-2-phenyl-pyridazin-3(2H)-one 1 has resulted in the identification of 2-(3,5-difluorophenyl)-4-(3-fluorocyclopentyloxy)-5-[4-(isopropylsulfonyl)piperazin-1-yl]-pyridazin-3(2H)-one 11c as a β-1,3-glucan synthase inhibitor. Compound 11c exhibited significant efficacy in an in vivo mouse model of Candida glabrata infection.