The contribution of hematocrit (Ht) changes on cerebral blood flow (CBF) and brain oxygenation in ischemic cerebrovascular disease is still controversial. In the present study, effects of Ht variations of CBF and oxygen delivery were investigated in patients with ischemic cerebrovascular disease. CBF was measured by the Xe-133 intracarotid injection method in 27 patients, whose diagnoses included completed stroke, reversible ischemic neurological deficit, and transient ischemic attack. Ht values in the patients ranged from 31 to 53%. There was a significant inverse correlation between CBF and Ht in these Ht ranges. Oxygen delivery, i.e., the product of arterial oxygen content and CBF, increased with Ht elevation and reached the maximum level in the Ht range of 40-45% and then declined. The CBF-Ht and oxygen transport-Ht relations observed in our study were similar to those in the glass-tube model studies by other workers rather than to those in intact animal experiments. From these results, it is conceivable that in ischemic cerebrovascular disease, the vasomotor adjustment was impaired in such a manner that the relations among Ht, CBF, and oxygen delivery were different from those in healthy subjects. Further, an "optimal hematocrit" for brain oxygenation was also discussed.
The effect of small, deep ischemic lesions on the ipsilateral cortical circulation was investigated in 10 patients with persistent mild or moderate neurological deficits due to infarcts in the internal capsule. rCBF studies by the 133Xe intracarotid injection method were performed 14-180 days after the onset of the infarction. The rCBF functional image was made up from the data of 133Xe dynamic images measured by an Anger-type gamma camera and the rCBF values were calculated by the initial slope method. The average value of mean rCBFs (mCBF) in 10 patients was 44.9 +/- 7.1 ml/100g/min (average PaCO2; 39.9 +/- 4.3 mm Hg). In the rCBF functional images, a focal hypoperfusion area was observed in all cases and localized around the central sulcus, especially in the precentral and central areas. Significant decreases of mCBF and the tendency to decrease of the rCBFs in the hypoperfusion focus were noted in the patients with the larger infarcts in comparison with those with the smaller ones. These results suggest that a small, deep ischemic lesion such as a capsular infarct may have remote effects on the ipsilateral cortical circulation, due probably to the damage of a number of fibers passing through the lesion.
IntroductionDapagliflozin is an orally administered selective sodium-glucose cotransporter 2 (SGLT2) inhibitor under development for the treatment of type 2 diabetes mellitus (T2DM). Dapagliflozin lowers blood glucose through a reduction in renal glucose reabsorption. This study was performed to assess the effect of the oral antidiabetic agent voglibose [0.2 mg thrice daily (t.i.d.)] at steady-state, on the pharmacokinetics, safety and tolerability of dapagliflozin administered as a single oral dose (10 mg) to Japanese patients with T2DM.MethodsThis was an open-label, multi-center, drug–drug interaction study. A single oral dose of dapagliflozin (10 mg) was administered to 22 Japanese patients with T2DM in the presence and absence of voglibose (0.2 mg t.i.d.). Serial blood samples were collected before and at regular prespecified intervals after each dapagliflozin dose to determine dapagliflozin plasma concentrations and to evaluate pharmacokinetic parameters. Based on a mixed effect analysis of variance model, including the dosing condition as a fixed effect and patients as a random effect, the ratios of geometric means of area under curve from time 0 to infinity (AUC0-inf) and maximum observed plasma concentration (Cmax) with and without voglibose were estimated along with two-sided 90% confidence intervals (CIs).ResultsIn Japanese patients with T2DM, the exposure to dapagliflozin following a single oral dose of dapagliflozin 10 mg was not influenced by the concomitant administration of voglibose (0.2 mg t.i.d.). The geometric ratio (90% CI) for dapagliflozin AUC0-inf with/without voglibose was 1.009 (0.954, 1.067), and for Cmax 1.040 (0.899, 1.204). The median time to Cmax (tmax) and plasma clearance of dapagliflozin were also similar between treatments. The mean half-life (t½) for dapagliflozin was slightly higher when administered in combination with voglibose. Dapagliflozin 10 mg was well tolerated when administered alone and in combination with voglibose in Japanese patients with T2DM.ConclusionThe results presented here support the co-administration of dapagliflozin and voglibose without dose adjustment of either agent.
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