Assessment of four methodologies (microparticle enzyme immunoassay, chemiluminescent enzyme immunoassay, affinity column-mediated immunoassay, and flow injection assay-tandem mass spectrometry) for measuring tacrolimus blood concentration in Japanese liver transplant recipients.

Therapeutic drug monitoring (TDM) and subsequent dosage adjustment for individual patients in the treatment with tacrolimus are required after liver transplantation to prevent rejection and over-immunosuppression, which leads to severe infection and adverse reactions including nephrotoxicity. The purpose of this study was to evaluate the analytical performance among commercially available immunoassay methods, which were microparticle enzyme immunoassay (MEIA), chemiluminescent enzyme immunoassay (CLIA), and affinity column-mediated immunoassay (ACMIA), compared with an assay using liquid chromatography-tandem mass spectrometry (LC-MS/MS). In addition, the flow injection assay (FIA-MS/MS) was also evaluated to determine whether it could be available as a new method of analysis in tacrolimus therapy. The blood tacrolimus concentrations in samples from liver transplant recipients (n = 102) were measured using MEIA, CLIA, ACMIA, and LC-MS/MS. Additional blood samples from liver transplant recipients (n = 54) were analyzed using both FIA-MS/MS and LC-MS/MS. Because the assay performance and characteristics of MEIA, CLIA, ACMIA, and FIA-MS/MS are relatively different, the measured data should be carefully considered depending on the methodology.

Physicochemical speciation of molybdenum in rain water.

A combination of a sensitive catalytic determination method with filtration and ultrafiltration has been used for the physicochemical speciation of molybdenum in natural and synthetic rain water samples. The concentration (CL) of labile molybdenum was evaluated by a direct catalytic determination. The total concentration (CT ) of molybdenum was determined after the acid decomposition of the sample to calculate the non-labile concentration (CT-CL). From the speciation results, molybdenum species in the successive rainfall sample were found in a fraction with smaller molecular weights < 10(3) Da and characterized as labile forms, i.e. simple molybdate ions. Non-labile molybdenum existed in particulate matter (> or = 0.45 microm in particle size) and distributed predominantly in the initial rainfall sample. The coprecipitation with Fe(III) hydroxide contributed to the formation of the non-labile molybdenum. In the initial rainfall sample, a small part of molybdenum was labile in the particle fraction (> or = 0.45 microm). This type of molybdenum was associated with the formation of humic iron aggregates.

Time course of the effects of temocapril on cardiovascular structure and function in patients with essential hypertension.

To investigate the time course of cardiovascular structural changes in patients with essential hypertension after angiotensin-converting enzyme (ACE) inhibition, we determined left ventricular structure, minimal vascular resistance in the forearm as an index of resistance vessel structure and stiffness beta of carotid artery in 15 essential hypertensive subjects during a placebo period and after 2, 6, and 12 months of temocapril treatment. Blood pressure decreased within 2 weeks, and the antihypertensive effects were noted throughout the 12-month administration period. Left ventricular mass index decreased significantly after 2 months (120+/-12 to 106+/-9 g/m2; p < 0.01) and was normalized after 12 months (88+/-6 g/m2). Postischemic minimal vascular resistance in the forearm decreased gradually from 2.1+/-0.5 to 1.6+/-0.4 PRU at month 12 of temocapril treatment. In contrast, increased stiffness index beta of carotid artery was not altered during a 1-year treatment period (11.4+/-4.9 to 11.6+/-3.8 at month 12 of treatment). These data indicated that the regression of structural changes of left ventricle and arterioles occurred gradually and progressively for 1-year treatment with ACE inhibition, but large arteries were not affected.

The effects of long-term treatment on left ventricular hypertrophy in patients with essential hypertension: relation to changes in neurohumoral factors.

This study compared the effects of 1 year of monotherapy with a calcium-channel antagonist (nilvadipine; NIL), an angiotensin-converting enzyme (ACE) inhibitor (temocapril; TEM), or a new vasodilator (cadralazine; CAD) on left ventricular (LV) hypertrophy in essential hypertension. Furthermore, to elucidate the mechanism responsible for regression of LV hypertrophy after treatment, LV mass index (LVMI) by echocardiography, plasma renin activity (PRA), aldosterone (PAC), norepinephrine, and atrial natriuretic peptide (ANP) concentration were measured before and after treatment. Thirty-six patients were randomly assigned to the NIL, TEM, or CAD groups. Blood pressure (BP) before treatment was 174 +/- 10/104 +/- 7, 173 +/- 18/103 +/- 8, and 171 +/- 16/103 +/- 7 mm Hg (mean +/- SD) in NIL, TEM, and CAD groups, respectively. BP was lower after treatment with each of the three test drugs than after the placebo period, and there were no differences in BP reduction among three groups. LVMI, in NIL and TEM, was reduced from 129 +/- 48 to 115 +/- 39 g/m2 and from 117 +/- 39 to 88 +/- 20 g/m2 (p < 0.05 and p < 0.01, respectively), whereas, in the CAD group, it was increased (110 +/- 30 to 138 +/- 27 g/m2; p < 0.01). In the CAD group, PAC decreased and ANP increased significantly. The change in LVMI correlated with that in BP for TEM and with that in ANP in all patients. These data indicated that LV volume overload as well as LV pressure overload may contribute to LV hypertrophy and that monotherapy with CAD is not desirable from the point of view of LV mass reduction in essential hypertension.

Time course of regression of vascular structural changes and its relation to cytosolic free calcium in hypertensives after nilvadipine treatment.

The objective of this study was to assess the regression of vascular structural changes seen in essential hypertension after long-term monotherapy with a calcium antagonist and to clarify the relations to cytosolic free calcium and neurohumoral factors. Blood pressure, minimal vascular resistance (MVR) by strain-gauge plethysmography, cytosolic free calcium in platelets ([Ca2+]i) by Quin 2 method, plasma renin activity (PRA) and plasma aldosterone concentration (PAC), plasma noradrenaline (PNA) and parathyroid hormone (PTH) were measured in 14 essential hypertensives during a placebo period and 2 and 6 months after anti-hypertensive treatment with nilvadipine. Blood pressure decreased from 174 +/- 10/104 +/- 8 mm Hg during the placebo period to 154 +/- 13/93 +/- 14 mm Hg 2 weeks after nilvadipine, and the hypotensive effects were found throughout the 6-month period. Although increased MVR seen in hypertensives did not change after 2 months (from 2.1 +/- 0.7 to 1.9 +/- 0.6 mm Hg/ml/min per 100 ml tissue (PRU), NS), MVR decreased significantly at 6 months (1.6 +/- 0.4, PRU, P < 0.05). Elevated [Ca2+]i seen in hypertensives during the placebo period decreased significantly 2 months after nilvadipine treatment (156 +/- 26 and 140 +/- 27 nM, P < 0.01). The changes in MVR were associated with those in [Ca2+]i 6 months after nilvadipine (r = 0.56, P < 0.05). However, the changes in MVR did not correlate with those in PRA, PAC, PNA or PTH.(ABSTRACT TRUNCATED AT 250 WORDS)

Diagnostic value of captopril test in hypertensive patients with renal artery stenosis.

To examine the utility of the single-dose captopril test in detecting renovascular hypertension (RVHT), the authors measured peripheral plasma renin activity (PRA), before and thirty and sixty minutes after an oral dose of captopril (25 mg), in 28 patients with RVHT and 22 patients with high-renin essential hypertension (EHT) without renal artery stenosis who were consuming 8 grams of sodium chloride per day. There was considerable overlap of individual values in basal PRA between the two groups. Sixty minutes after captopril, PRA was higher in RVHT than in EHT patients (74.8 +/- 63.9 versus 15.1 +/- 11.9 ng/mL/hr, P < 0.01). With the cutoff point set at 16 ng/mL/hr, RVHT was detected with a sensitivity of 96% and a specificity of 77%. The discriminating power was also superior to that based on blood pressure response to angiotensin II analogue under sodium depletion, rapid-sequence intravenous pyelography, or renography. These results show that captopril-stimulated peripheral PRA is an adequate screening tool for detecting RVHT in a population with high-renin hypertension.

Effects of erythropoietin treatment on thyroid dysfunction in hemodialysis patients with renal anemia.

The thyroid function was evaluated before and after 6 months of recombinant human erythropoietin (rhEPO) treatment (1,500-9,000 U/week) in 22 hemodialysis patients with hematocrit levels < 25%. Based upon the changes in hematocrit following rhEPO treatment, the patients were divided into two groups: 11 patients with an increase of the hematocrit level > 5% (group I) and 11 patients with an increase < 5% (group II). Before rhEPO administration, the levels of thyroid hormones, especially free thyroxine (T4) and free triiodothyronine (T3), were below the normal range despite normal thyrotropin values in most of the patients (low T4:7 cases in group I and 9 in group II; low T3:10 cases in group I and 10 in group II). RhEPO treatment significantly increased both total amount and free fractions of thyroid hormones in group I, whereas it did not affect these values in group II. Consequently, the pretreatment low T4 or low T3 status was resolved in a substantial number of the patients in group I (low T4:5 cases, low T3:4 cases). In addition, there was a significant correlation between the increases in hematocrit and free T3 in all studied subjects (r = 0.603; p < 0.05). These results suggest that anemia may participate to some extent in the pathogenesis of thyroid dysfunction in hemodialysis patients with renal anemia.

Regression of vascular structural changes and calcium metabolism in patients with essential hypertension after long-term monotherapy with enalapril.

We investigated the effect of one year of enalapril monotherapy on vascular structural changes and calcium metabolism in ten patients with essential hypertension. BP decreased from 169-10/103 +/- 10 mmHg during the placebo period to 138-12/82 +/- 10 mmHg after enalapril therapy. Minimal vascular resistance assessed by the venous occlusion technique with strain-gauge plethysmography was higher in the hypertensive patients than in the normotensive subjects (2.7 +/- 1.2 vs. 1.2 +/- 0.3 mmHg/ml/min per 100 ml tissue, P < 0.01). Although the elevated minimal vascular resistance seen in essential hypertensives decreased to 1.7 +/- 0.5 mmHg/ml/min per 100 ml tissue after enalapril (P < 0.01), it remained higher than that of normotensives (P < 0.05). Cytosolic free calcium ([Ca2+]i) in platelets measured by a Qiun-2 fluorescent indicator was higher in essential hypertensives than in normotensives (189 +/- 38 nM and 138 +/- 14 nM, respectively; P < 0.01). [Ca2+]i of essential hypertensives was reduced to 138 +/- 19 nM after treatment. Plasma renin activity was significantly increased after enalapril. Although plasma ionized calcium concentration did not change, parathyroid hormone was significantly increased after enalapril (from 0.36 +/- 0.22 to 0.58-0.32 ng/ml, P < 0.05). During the placebo period, minimal vascular resistance was correlated with [Ca2+]i (r = 0.62, P < 0.01). There was a close relationship between the changes in minimal vascular resistance and [Ca2+]i (r = 0.78, P < 0.01); however the change in minimal vascular resistance was not associated with changes in BP, catecholamine or parathyroid hormone.(ABSTRACT TRUNCATED AT 250 WORDS)

Altered renal response to enhanced endogenous 5-hydroxytryptamine after tryptophan administration in essential hypertension.

1. To examine the pathophysiological significance of 5-hydroxytryptamine (serotonin) in essential hypertension, we compared the renal response to intrarenally formed 5-hydroxytryptamine by oral dosing with its precursor, L-tryptophan (2 g), in nine patients with essential hypertension and in six subjects with normotension. 2. Before tryptophan administration, urinary excretion of 5-hydroxytryptamine was significantly higher in the hypertensive group than in the normotensive group (66 +/- 8 versus 36 +/- 6 ng/min, P less than 0.05), whereas renal plasma flow and glomerular filtration rate did not differ between the two groups. After dosing with tryptophan, urinary excretion of 5-hydroxytryptamine significantly increased to the same plateau level in both groups (366 +/- 55 ng/min in the hypertensive group and 365 +/- 64 ng/min in the normotensive group). Significant and equivalent decreases in renal plasma flow were observed in the early phase after tryptophan administration in both groups (-8.5 +/- 3.4% in the hypertensive group and -8.2 +/- 1.7% in the normotensive group). Thereafter, renal plasma flow increased to above the baseline value in normotensive subjects, whereas this late vasodilatation was absent in the hypertensive group. Glomerular filtration rate significantly decreased at the time of the fall in renal plasma flow in the normotensive group (106.8 +/- 7.8 to 92.7 +/- 8.5 ml min-1 1.73 m-2, P less than 0.05), whereas it remained unchanged in the hypertensive group (108.2 +/- 6.2 to 110.4 +/- 6.3 ml min-1 1.73 m-2, not significant).(ABSTRACT TRUNCATED AT 250 WORDS)

Cytosolic free calcium concentration in platelets in patients with renovascular hypertension and primary aldosteronism.

To investigate the role of cytosolic free calcium, [Ca2+]i, in secondary hypertension, the levels in platelets from 14 secondary hypertensives (7 renovascular hypertension, 7 primary aldosteronism) were compared with those from 21 essential hypertensives and 15 normotensives by means of the fluorescent indicator, quin-2. The mean BP was significantly higher in both the secondary hypertensives and essential hypertensives (122 +/- 8 and 124 +/- 12 mmHg) than in the normotensives (89 +/- 10 mmHg). Cytosolic free calcium in platelets was significantly higher in the essential hypertensives, but not in the secondary hypertensives, compared with the normotensives (182 +/- 34, 141 +/- 17, 138 +/- 15 nM respectively). There was no significant difference in platelet [Ca2+]i between renovascular hypertension and aldosteronism (142 +/- 19 versus 139 +/- 16 nM). There was no correlation between platelet [Ca2+]i and plasma renin activity, plasma aldosterone concentration or plasma noradrenaline concentration in the three groups. Thus, the increase in platelet [Ca2+]i seen in essential hypertension was not found in patients with secondary hypertension. Our results suggest that the cytosolic calcium handling of secondary hypertensive patients with renal artery stenosis or primary aldosteronism differs from that of essential hypertensives.