The effect of inhibition of renin-angiotensin system by valsartan during hypovolemic shock and low flow sigmoideal ischaemia in pigs

The aim of this experiment was to study the effect of Renin-Angiotensin System (RAS) blockade by means of valsartan on the colonic and systemic circulation in pigs during low flow sigmoideal ischemia in combination with hypovolemic shock. This condition resembles the situation that occurs in patients suffering from a ruptured aneurysm and a compromised colonic circulation. An experimental study in pigs was performed : 6 pigs with low flow sigmoideal ischemia and hypovolemic shock were treated with valsartan and a control group of 5 pigs with low flow sigmoideal ischemia and hypovolemic shock without medical treatment.Valsartan, 3 mg/kg, was administered intravenously. The operation was performed via left sided lumbotomy. The distal aorta was partially occluded to a flow reduction of 30% of the initial value. Hypovolemic shock was induced by withdrawing 20 ml/kg blood in 45 min. Resuscitation with 30 ml/kg haemaccel was iniated after 2 h of shock. The following parameters were measured: blood pressure, cardiac output; hemoglobin, lactate, angiotensin II in mixed venous blood (obtained from pulmonary artery) and in splanchnic blood (obtained from caudal mesenteric vein); and endoluminal pulse oximetry of the sigmoideal mucosa.Statistical analysis was performed by ANOVA and Wilcoxon signed rank test.There was a significant increase of lactate levels both in systemic and splanchnic circulation (P<0.05) in both groups. In the control group, the mean angiotensin II concentrations in the systemic circulation increased, after induction of ischaemia and shock. In the experimental group, the increase in angiotensin concentrations after resuscitation was significantly more prominent. In the colonic circulation, in both groups, there was a significant increase in angiotensin II levels in the splanchnic circulation following ischaemia and reperfusion (P<0.05), but there was no significant difference between the groups. There were no detectable mucosal signals measured by pulse oximetry after induction of shock throughout the experiment, whereas in the experimental group, median mucosal oxygen saturations of 81, 74.5 and 85% were achieved after resuscitation and declamping (P<0.01).In conclusion, angiotensin II inhibition during hypovolemic shock improves the colonic circulation, measured by pulse oximetry. However, other parameters of tissue ischaemia did not improve.     

An evaluation of the drug interaction potential of pazopanib, an oral vascular endothelial growth factor receptor tyrosine kinase inhibitor, using a modified Cooperstown 5+1 cocktail in patients with advanced solid tumors

Pazopanib, an oral inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-kit kinases, inhibits multiple cytochrome P450 (CYP450) enzymes in vitro. This study in patients with advanced cancer evaluated the effect of pazopanib on CYP450 function by comparing the pharmacokinetics of CYP-specific probe drugs in the presence and absence of pazopanib. The probes used included midazolam (CYP3A specific), warfarin (CYP2C9 specific), omeprazole (CYP2C19 specific), caffeine (CYP1A2 specific), and dextromethorphan (CYP2D6 specific). The estimated ratios of the geometric means (90% confidence interval (CI)) for the area under the curve to the last measurable point (AUC(0-t)) for these probe drugs with/without pazopanib were as follows: midazolam, 1.35 (1.18-1.54); omeprazole, 0.81 (0.59-1.12); caffeine, 1.00 (0.77-1.30); and S-warfarin, 0.93 (0.84-1.03). The geometric least-squares (LS) mean ratio of urine dextromethorphan:dextrorphan ranged from 1.33 (0-4-h interval) to 1.64 (4-8-h interval). The data suggest that pazopanib is a weak inhibitor of CYP3A4 and CYP2D6 and has no effect on CYP1A2, CYP2C9, and CYP2C19 in patients with advanced cancer.     

The role of luminance contrast in the detection of global structure in static and dynamic, same- and opposite-polarity, Glass patterns

Perception of global structure conveyed in static Glass patterns is difficult, though not impossible, when the constituent dipoles are formed by partnering opposite polarity dots. We investigate whether the addition of motion signals to opposite-polarity Glass patterns can act to restore the perception of global structure. The stimuli were concentric Glass patterns consisting of 200 dipoles concentrically orientated, or oriented at random orientations, placed on a grey background. For each dipole, one luminance-increment dot (Weber contrast of 1) was paired with another dot set to a contrast ranging between luminance increment and luminance decrement (i.e., a Weber contrast range of approximately -1 to 1). Dipoles were either stationary (Experiment 1), or randomly re-positioned at 17Hz (Experiment 2), on each frame transition. A two-interval forced-choice paradigm, in conjunction with an adaptive staircase, was used to obtain Glass-pattern detection thresholds. The task required observers to identify the interval that contained concentric Glass structure; the other interval contained randomly orientated dipoles. Generally, lower global form thresholds were observed for dynamic and same-polarity Glass patterns than for static and opposite-polarity Glass patterns. In particular, for dynamic presentations improvement in sensitivity was more evident for opposite-polarity than for same-polarity Glass patterns. These findings suggest that motion plays an important role in the detection of global structure in dynamic Glass patterns.     

The determinants of traditional Chinese medicine and acupuncture utilization for cancer patients with simultaneous conventional treatment

This paper investigates the determinants of traditional Chinese medicine (TCM) and acupuncture utilization for cancer patients who are simultaneously having conventional Western medical treatments. This study used five leading cancers in Taiwan, namely cervical, breast, lung, liver and colorectal cancers. A total of 2499 cancer patients were interviewed, of which 2034 had full information and were analysed. Logistic regressions were used for both TCM and acupuncture. The results showed that type of cancer and cancer duration determine the utilization for alternative treatments. While socio-economic factors also affect choice of alternative medicine, the magnitude differs by types of alternative treatment and cancer. Compared with men and older patients, women and younger patients tend to prefer alternative medicine, and patients from south have higher preference for alternative medicine, which could be a reflection of local culture. Our results are useful for the government to determine higher users of TCM and acupuncture among cancer patients, and make policies to suit these patients' needs.     

ANOMALOUS BINDING CHARACTERISTICS OF HUMAN THYROXINE BINDING GLOBULIN DUE TO A DILUTION-DEPENDENT SEPARATION ARTEFACT

Contrary to the accepted view, a recent study using Sephadex column separation suggested that thyroxine binding globulin (TBG) binds T4 and T3 with similar affinity, but with a much larger capacity for T4 than T3. We have evaluated this finding by comparing this separation method with equilibrium dialysis, taking account of the effect of serum dilution with each method. Estimates of free T4 fraction by equilibrium dialysis (with magnesium chloride precipitation) were valid over a wide range of serum dilutions. In contrast, Sephadex column separation gave a major overestimate of free hormone (underestimate of binding) in less diluted serum, indicating that this method cannot be used to establish a value for T4 affinity independent of serum dilution. Such a systematic error will result in a greater underestimate of affinity for the ligand with higher affinity when two ligands are compared at a single serum dilution. By equilibrium dialysis at 37 degrees C, the affinity of T4 for TBG was approximately 13-fold higher than that of T3, while the capacity of TBG for both T4 and T3 was close to the concentration of immunoreactive TBG. The previous report of similar T4 and T3 affinities appears to be due to a dilution-dependent underestimate of T4 affinity inherent in Sephadex column separation. Direct comparison of binding kinetics of various ligands requires a separation method that is valid over a wide range of binding protein concentrations.     

Bioavailability of Recombinant Human Growth Hormone in Different Concentrations and Formulations

Abstract: Whether the bioavailability of growth hormone depends on the concentration or formulation of the preparation was evaluated in 18 growth hormone-deficient patients. The design was a single-blinded, randomized cross-over study, where the patients were given a single, fixed dose subcutaneous injection of growth homrone (3 IU/m²) of 3 different preparations: (1) 4 IU/ml in a bicarbonate buffer dissolved in 0.9% benzyl alcohol (～1.37 mg/ml), (2) 5.9 IU/ml in a phosphate buffer dissolved in 1.5% benzyl alcohol (～2 mg/ml) and (3) 11.7 IU/ml in a phosphate buffer dissolved in 1.5% benzyl alcohol (～4 mg/ml). Conventional growth hormone-therapy was withdrawn 2 days before each study period. Blood samples were drawn over a 24-hr period and assessed for growth hormone, serum insulin-like growth factor I (IGF-I), insulin and glucose. The geometric mean values (～geometric S.D.) of the relative absorption fractions were F_{5.9 IU/4 IU}= AUC_{5.9 IU}/AUC_{4 IU}=(～1.139) (P=0.66), F_{11.7 IU}/AUC_{4 IU}=AUC_{11.7 IU}/AUC_{4 IU} (1.14±1.21) (P=0.009) and F_{11.7 IU/5.9 IU}=AUC_{11.7 IU}/AUC_{5.9 IU}=1.12 (～1.17) (P=0.005), respectively. The 90% confidence intervals were contained within the limits of 0.80-1.25 accepted for bioequivalence. Geometric mean values (～geometric S.D.) of the relative observed maximum concentration, C_max was for C_{max 5.9 IU}/C_{max 4 IU} = 1.04 (～1.19) (P=0.32), C_{max 11.7 IU}/C_{max 4 IU}=1.24 (～1.21) (P=0.0002) and C_{max 11.7 IU}/C_{max 5.9 IU}=1.19 (～1.29) (P=0.012). The median and the range values for the observed time to reach C_max was t_{max 5.9 IU}/t_{max 4 IU}=0.63 (0.04-1.00), t_{max 11.7 IU}/t_{max 4 IU}=0.59 (0.06-1.0) and t_{max 11.7 IU}/t_{max 5.9 IU}=0.90 (0.51-18.00). There were no significant differences in IGF-I, glucose and insulin profiles. Based on the upper limits of the 90% confidence intervals for relative AUC's the conclusion is that the three different preparations were bioequivalent.     

Infant hearing screening with an automated auditory brainstem response screener and the auditory brainstem response

From 1653 babies hospitalized in the Veterans General Hospital—Taipei from 1993 to 1995, 260 infants at risk of hearing impairment were selected. The risk criteria of hearing impairment for neonates were based on the recommendation of the US Joint Committee on Infant Hearing, 1990 Position Statement. All these infants were screened with the Algo-1 Plus, an automated auditory brainstem response (ABR) screener at a mean postconceptional age of 40.7 ± 4.5 weeks. Thirty-nine cases (39/260, 15%) involving 57 ears (57/520, 11%), failed the screening. Except for one infant who died, the babies had an ABR test for both air- and bone-conducted stimuli and an otological examination. The case-specific incidence of conductive hearing deficit at the initial ABR test was 5.4%. The prevalence of sensorineural hearing deficits was between 2.3% confirmed and 3.1% including infants who did not have follow-up tests. The n-value that indicated agreement between the Algo-1 and ABR results was 0.64, and the overall efficiency of using Algo-1 to correctly identify pass or failure of the ABR was 83%.