We studied the combination effect of rimantadine hydrochloride and oseltamivir phosphate on mice infected with influenza A/Aichi/2/68 (H3N2) virus. Compounds were simultaneously administered in a 5-day-treatment course, starting 4 h before intranasal infection with 10 or 20 viral 50% mouse lethal doses. Initially, we tested combinations of oseltamivir (0.05, 0.1 and 0.2 mg/kg/day) and rimantadine (2.5, 5.0 and 7.5 mg/kg/day). Significant differences were recorded between combinationtreated groups, and groups with separately applied compounds and the placebo group, such as: protection index of oseltamivir with 5.0 or 7.5 mg/kg rimantadine varied between 34-41% and 43-87%, respectively, whereas the individual effects of oseltamivir, 5 mg/kg of rimantadine and 7.5 mg/kg of rimantadine were 0-10%, 0% and 18.7-29.6%, respectively; mean survival time in combination-treated groups was lengthened by 3.1-6.9 days, in oseltamivir groups by 0-1.9 days, and in rimantadine groups by 0.8-1.3 days at 5 mg/kg and 2.6-3.2 days at 7.5 mg/kg. The threedimensional method of Prichard and Shipman characterized the combination effect as synergistic. Further, we studied the activity of 0.05 mg/kg/day of oseltamivir combined with 5 mg/kg of rimantadine. Lung virus titre in Madin Darby canine kidney cells, lung index and consolidation score proved the high effectiveness of the combination. When compared with the placebo group, a 2.8 log 10 lower titre of 50% cell culture infectious dose (CCID 50 ) was recorded in the combinationtreated group at 48-60 h post-infection (the peak of lung virus growth). This is in contrast to the 0.1-1.0 log 10 and 1.1-1.4 log 10 reduction in CCID 50 titre observed in the oseltamivir and rimantadine groups, respectively. These data emphasize the high anti-influenza A potential of the combination.
Further studies of insulin secretion from isolated pancreatic islets of the NZO strain of obese hyperglycemic mouse have shown markedly impaired insulin secretory responses to D-glucose in islets from fasted or fed mice. NZO islets at a low glucose concentration (3.3 mM) showed a significant insulin secretory response to 0.5 mM 3-isobutyl-1-methylxanthine (IBMX), a phosphodiesterase inhibitor, but in the presence of this agent showed no significant additional response to increased glucose concentration. This contrasted with the situation in islets from an arbitrarily chosen control strain of mouse (C57Bl) which showed a small or insignificant response to 0.5 mM IBMX at a low glucose concentration, but a greatly enhanced response to glucose in the presence of IBMX. In contrast to the relative refractoriness of the NZO islets to glucose, they showed a large response to D,L-glyceraldehyde, at least equal to that found in the control islets. Glucose utilization was studied by measuring the conversion of D-[5-3H]glucose to [3H]H2O. In islets from both fasted and fed NZO mice, glucose utilization, when calculated on the basis of islet DNA content, was markedly reduced at high glucose concentrations compared to that in islets from the control strain. It is concluded that the relative unresponsiveness of NZO islets to glucose is associated with, and perhaps due to, a decreased rate of glucose utilization. The preserved responsiveness to glyceraldehyde suggests that the reduced glucose utilization may be due to a partial metabolic block before the triose phosphate step in the islet glycolytic pathway.
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