Guanidines
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Publication
Journal: Drugs
December/8/1999
Abstract
Zanamivir is a novel inhibitor of the enzyme neuraminidase, a surface glycoprotein essential for the replication of type A and B influenza viruses. Statistically significant reductions in median time to alleviation of major symptoms of influenza were reported in phase II and III studies of zanamivir. Benefit was seen with early treatment (within 30 or 36 hours of onset of illness) in phase II trials. Median times to alleviation of major (or 'clinically significant') symptoms were reduced by 1 to 2.5 days after treatment with zanamivir 10 mg twice daily by oral inhalation for 5 days in 3 phase III studies. Benefit of zanamivir treatment in terms of time to return to normal activities and reductions in consumption of paracetamol (acetaminophen), and reductions in the level of interference of influenza with sleep, work, leisure and recreational activities, were reported. Reductions relative to placebo of 2.5 to 3.25 days were observed in median time to alleviation of major symptoms in high-risk patients. Available data also indicate potential of zanamivir in the prophylaxis of influenza. A statistically significant reduction in the incidence of influenza A was reported with zanamivir 10 mg by oral inhalation once daily for 4 weeks in a double-blind study in 1107 persons in 2 university communities. Prophylactic benefit of zanamivir in influenza A and B outbreaks has also been suggested by data from a nursing home community. Adverse event profiles in patients receiving zanamivir therapeutically or prophylactically appear similar to those in patients receiving placebo. The most commonly reported adverse events in therapeutic trials have been nasal signs and symptoms, diarrhoea, nausea, headache, bronchitis and cough.
CONCLUSIONS
Prompt treatment with zanamivir in patients with naturally acquired influenza is associated with significant reductions in duration of symptomatic illness, accelerated return to normal levels of activity and reduced consumption of antibiotics for influenza-related complications. While vaccination in selected populations remains the seasonal intervention of choice for prophylaxis, the efficacy, good tolerability and lack of resistance seen with zanamivir are likely to make the drug a valuable treatment option, particularly in individuals not covered or inadequately protected by vaccination, and in those at high risk of influenza-related complications. Confirmation of the prophylactic efficacy of zanamivir would indicate a major potential role for the drug in this setting, especially in persons for whom vaccination is not suitable or fully effective, in closed communities (e.g. nursing homes) and in individuals at high risk.
Publication
Journal: Journal of Immunology
December/29/1976
Abstract
Mature circulating guinea pig basophils, purified to comprise 25% or more of leukocytes, have been successfully maintained in short-term tissue culture for up to 72 hr. These cells were found to retain the ability to synthesize histamine, as assayed by a new isotopic-thin layer chromatographic assay which can reliably detect as little as 0.5 pg of 3H-histamine. Cell-associated, newly synthesized histamine was detectable as early as 1 hr of culture, was substantially increased at 6 hr, and reached maximal levels at 24 hr, when it accounted for approximately 6.5% of total cell histamine. Newly synthesized histamine was still detectable at 48 and 72 hr of culture. Histamine synthesis was decreased by lwoering the concentration of histidine in the culture medium, and was markedly reduced by all the specific histidine dedarboxylase (HDC)3 inhibitors tested, but not by alpha-methyl-DOPA, pyrilamine maleate, or metiamide. Increasing the concentration of pyridoxal phosphate, the HDC coenzyme, above that normally present in culture medium resulted in only an equivocal increase in the amount of newly synthesized histamine, whereas aminoguanidine, an inhibitor of histaminase, had no detectable effect. Uptake of exogenous histamine by cultured basophils was trivial compared to histamine synthesis. Both newly synthesized and previously manufactured, nonisotopic, histamine seemed to be stored in the same pool, as the same proportion of both was released by concanavalin A (Con A). Cellular histamine was largely conserved, with little or no spontaneous release into the medium of detectable isotopic or nonisotopic histamine. These techniques provide a model for studying granulocyte metabolic processes in vitro, and should assist in the direct investigation of a variety of their physiologic functions.
Publication
Journal: European Journal of Pharmacology
September/27/1993
Abstract
Repeated treatment with imipramine (10 mg/kg intraperitoneally (i.p.), once daily for 14 days) caused a decrease in the Bmax, without affecting the Kd, of [3H]DTG (1,3-di-o-tolylguanidine) binding to the haloperidol-sensitive sigma sites in the striatum, hippocampus and cerebral cortex of the rat. A similar reduction was observed after chronic administration of a selective serotonin uptake inhibitor, fluoxetine (10 mg/kg i.p., twice daily for 14 days), but not of a selective norepinephrine uptake inhibitor, desipramine (10 mg/kg i.p., once daily for 14 days). Neither a single injection of imipramine (10 mg/kg i.p.) nor addition of imipramine or fluoxetine into the binding assay medium mimicked the changes in the maximal binding of brain sigma sites induced by chronic treatment with these drugs. Finally, depletion of brain serotonin by means of repeated administration of p-chlorophenylalanine, which produces inhibition of the amine synthesis, blocked the ability of repeated imipramine treatment to reduce the maximal number of [3H]DTG binding sites in the striatum and hippocampus. The present results suggest that cerebral serotonergic transmission may play a role in the regulation of cerebral sigma binding sites in the rat.