Effects of methoxyflurane anesthesia on the pharmacokinetics of I-IAZA in sprague–dawley rats

Effects of methoxyflurane anesthesia on the pharmacokinetics of intravenous ¹²⁵I-IAZA in rats are reported. No significant differences in t_1/2, t_1/2β, V_ss, and Cl_TB for total radioactivity (¹²⁵I-IAZA and metabolites) were observed between the anesthetized (Group 1, n = 4) and nonanesthetized (Group 2, n = 3) animals. For ¹²⁵I-IAZA, Cl_TB increased from 646 ± 52 mL/h/kg to 2250 ± 351 mL/h/kg and t_1/2β decreased from 97.7 ± 17.5 min to 35.6 ± 5.4 min, for Groups 1 and 2, respectively. There were no differences in V_ss or t_1/2 between the two groups. These findings support literature reports of anesthetic effects on xenobiotic pharmacokinetics, and indicate a need for caution in the evaluation of preclinical imaging studies in which animals are immobilized with anesthetics.     

Clinical pharmacokinetics of 123I-IAZA in healthy volunteers.

123I-labelled iodoazomycin arabinoside (123I-IAZA) is an experimental radiopharmaceutical that has been shown to have clinical utility for imaging regional tissue hypoxia. We report the clinical pharmacokinetics of IAZA, the radiopharmacokinetics of 123I-IAZA and total radioactivity kinetics after injection of 123I-IAZA. Six healthy volunteers each received an intravenous bolus injection of 185 MBq of 123I-IAZA. Thirteen blood samples and a cumulative urine sample were collected over 28 h from each subject. A two-compartment open model best described the disposition characteristics of all three chemical components, with terminal phase half-lives of 179 +/- 24, 232 +/- 41 and 294 +/- 27 min for 123I-IAZA, IAZA and total radioactivity, respectively. 123I-IAZA had a steady-state volume of distribution (Vss) of 0.716 +/- 0.088 l.kg-1 and a systemic clearance (Cls) of 239 +/- 48 ml.min-1. Radioactive decay was responsible for about 37% of clearance; of the remaining radioactivity, about 92% was eliminated renally. Only about 12% of 123I-IAZA was eliminated unchanged in urine, indicating that renal excretion was the major route of elimination for the radioactive metabolites rather than for 123I-IAZA itself. The effective half-lives of 123I-IAZA and total radioactivity reported here are considerably shorter than previously estimated. Our results confirm that 123I-IAZA has appropriate pharmacokinetic and radiopharmacokinetic properties to support clinical hypoxia imaging.     

Glycosylated RGD-containing peptides: tracer for tumor targeting and angiogenesis imaging with improved biokinetics.

The alpha(v)beta3 integrin plays an important role in metastasis and tumor-induced angiogenesis. Targeting with radiolabeled ligands of the alpha(v)beta3 integrin may provide information about the receptor status and enable specific therapeutic planning. Previous studies from our group resulted in tracers that showed alpha(v)beta3-selective tumor uptake. However, these first-generation compounds predominantly revealed hepatobiliary excretion with high radioactivity found in the liver. In this report, the synthesis and biological evaluation of the first glycosylated RGD-containing peptide (RGD-peptide) for the noninvasive imaging of alpha(v)beta3 expression are described. METHODS: Peptides were assembled on a solid support using fluorenylmethoxycarbonyl-coupling protocols. The precursor cyclo(-Arg-Gly-Asp-D-Tyr-Lys(SAA)-) GP1 was synthesized by coupling 3-acetamido-2,6-anhydro-4,5,7-tri-O-benzyl-3-deoxy-beta-D-glycero-D-gulo-heptonic acid (SAA(Bn3)) with cyclo(-Arg(Mtr)-Gly-Asp(OtBu)-D-Tyr(tBu)-Lys-) and subsequent removal of the protection groups. Iodine labeling was performed by the Iodo-Gen method (radiochemical yield > 50%). The in vitro binding assays were performed using purified immobilized alpha(IIb)beta3, alpha(v)beta5, and alpha(v)beta3 integrins. For in vivo experiments, nude mice bearing xenotransplanted melanomas and mice with osteosarcomas were used. RESULTS: The glycosylated peptide 3-iodo-Tyr4-cyclo(-Arg-Gly-Asp-D-Tyr-Lys(SAA)-) GP2 showed high affinity and selectivity for alpha(v)beta3 in vitro (50% inhibitory concentration = 40 nmol/L). Pretreatment studies indicate specific binding of [125I]GP2 on alpha(v)beta3-expressing tumors in vivo. Comparison of the pharmacokinetics of [125I]GP2 and [125I]-3-iodo-Tyr4-cyclo(-Arg-Gly-Asp-D-Tyr-Val-) [125I]P2 revealed for [125I]GP2 an increased activity concentration in the blood (e.g., 3.59 +/- 0.35 percentage injected dose [%ID]/g vs. 1.72 +/- 0.44 %ID/g at 10 min postinjection) and a significantly reduced uptake in the liver (e.g., 2.59 +/- 0.24 %ID/g vs. 21.96 +/- 2.78 %ID/g at 10 min postinjection). Furthermore, a clearly increased activity accumulation in the tumor was found (e.g., 3.05 +/- 0.31 %ID/g vs. 0.92 +/- 0.16 %ID/g at 240 min postinjection), which remained almost constant between 60 and 240 min postinjection. This resulted in good tumor-to-organ ratios for the glycosylated tracer (e.g., 240-min postinjection osteosarcoma model: tumor-to-blood = 16; tumor-to-muscle = 7; tumor-to-liver = 2.5), which were confirmed by the first gamma-camera images of osteosarcoma-bearing mice at 240 min postinjection. CONCLUSION: This study demonstrates that the introduction of a sugar moiety improves the pharmakokinetic behavior of a hydrophobic peptide-based tracer. Additionally, this alpha(v)beta3-selective glycosylated radioiodinated second-generation tracer GP2 shows high tumor uptake and good tumor-to-organ ratios that allow noninvasive visualization of alpha(v)beta3-expressing tumors and monitoring therapy with alpha(v)beta3 antagonists. Finally, the favorable biokinetics make the glycosylated RGD-peptide a promising lead structure for tracers to quantify the alpha(v)beta3 expression using PET.     

Pharmacokinetics and biodistribution of a small radioiodine labeled nerve growth factor fragment

Nerve growth factor (NGF) exerts various actions on neuronal and non-neuronal tissues and has potential therapeutic utility, but difficulties in using the whole protein have stimulated interest in small NGF fragments. We radioiodinated a small cyclic peptide derived from NGF using the Bolton-Hunter method [125I-C(92-96)], and confirmed binding to high affinity NGF receptors by cross-linkage analysis. Pharmacokinetic characteristics in intravenously injected mice were T 1/2 alpha 5.2 min, T 1/2beta 121.3 min, clearance 11.8+/-0.5 ml/min, and volume of distribution 69.7+/-4.6 ml. Dose-proportionate increases in areas-under-curve and peak-concentrations indicated linear pharmacokinetics. Biodistribution data revealed that clinically relevant doses allowed C(92-96) accumulation sufficient to elicit biological responses in receptor expressing organs including the lungs, liver, spleen, and pancreas.     

Work capacity of permanent residents of high altitude

Tibetan and Andean natives at altitude have allegedly a greater work capacity and stand fatigue better than acclimatized lowlanders. The principal aim of the present review is to establish whether convincing experimental evidence supports this belief and, should this be the case, to analyze the possible underlying mechanisms. The superior work capacity of high altitude natives is not based on differences in maximum aerobic power (V(O2 peak)), mL kg(-1)min(-1)). In fact, average V (O2 peak) of both Tibetan and Andean natives at altitude is only slightly, although not significantly, higher than that of Asian or Caucasian lowlanders resident for more than 1 yr between 3400 and 4700 m (Tibetans, n = 152, vs. Chinese Hans, n = 116: 42.4 +/- 3.4 vs. 39.2 +/- 2.6 mL kg(-1)min(-1), mean +/- SE; Andeans, n = 116, vs. Caucasians, n = 70: 47.1 +/- 1.7 vs. 41.6 +/- 1.2 mL kg(-1)min(-1)). However, compared to acclimatized lowlanders, Tibetans appear to be characterized by a better economy of cycling, walking, and running on a treadmill. This is possibly due to metabolic adaptations, such as increased muscle myoglobin content and antioxidant defense. All together, the latter changes may enhance the efficiency of the muscle oxidative metabolic machinery, thereby supporting a better prolonged submaximal performance capacity compared to lowlanders, despite equal V(O2 peak). With regard to Andeans, data on exercise efficiency is scanty and controversial and, at present, no conclusion can be drawn as to the origin of their superior performance.     

Radiolabeled alpha(v)beta3 integrin antagonists: a new class of tracers for tumor targeting.

The alpha(v)beta3 integrins play an important role during tumor metastasis and tumor-induced angiogenesis. Targeting of this receptor may provide information about the receptor status of the tumor and enable specific therapeutic planning. Cyclo(-Arg-Gly-Asp-D-Phe-Val-) has been shown to be a selective alpha(v)beta3 integrin antagonist with high affinity. In this study we describe the synthesis and biological evaluation of [125I]-3-iodo-D-Tyr4-cyclo(-Arg-Gly-Asp-D-Tyr-Val-) ([125I]P2), [125I]-3-iodo-Tyr5-cyclo(-Arg-Gly-Asp-D-Phe-Tyr-) ([125I]P4) and the negative control peptide [1251]-3-iodo-D-Tyr4-cyclo(-Arg-D-Ala-Asp-Tyr-Val-) ([125I]P6). METHODS: Peptides were assembled on a solid support using fluorenylmethoxycarbonyl amino acid coupling protocols. Radioiodination was performed using the iodogen method. The in vitro binding assays were performed using isolated, immobilized alphaIIbeta3 and alpha(v)beta3 integrins. Expression of the alphaVbeta3 receptor on the different tumors was validated by immunohistochemical methods using alpha(v) and alpha(v)beta3 specific antibodies. For biodistribution studies, nude mice with melanoma M21 or mammary carcinoma MaCaF and BALB/c mice with osteosarcoma were used. RESULTS: The in vitro binding assays demonstrate that the introduction of tyrosine and subsequent iodination have no influence on the high affinity and selectivity for alpha(v)beta3. Immunohistochemical staining clearly indicates the presence of the alpha(v)beta3 integrins on the tumor tissue of the melanoma and the osteosarcoma. Pretreatment and displacement studies show specific binding of [125I]P2 on melanoma M21-bearing nude mice and osteosarcoma-bearing BALB/c mice but less specific binding on mammary carcinomas. [125I]P2 exhibits fast elimination kinetics. The accumulation in the tumor 10 min postinjection is 2.07 +/- 0.32 %ID/g for the melanoma M21 and 3.50 +/- 0.49 %ID/g for the osteosarcoma and decreases to 1.30 +/- 0.13 %ID/g and 2.03 +/- 0.49 %ID/g 60 min postinjection, respectively. [125I]P4 shows even faster elimination kinetics, resulting in a tumor accumulation of 0.40 +/- 0.10 %ID/g 60 min postinjection for the osteosarcoma-bearing BALB/c mice. Both peptides reveal predominately hepatobiliary excretion. For [1251]P2, this also is confirmed by autoradiography. The negative control peptide [125I]P6 shows no specific activity accumulation. CONCLUSION: [125I]P2 exhibits high affinity and selectivity for the alpha(v)beta3 integrin in vitro and in vivo and, thus, represents the first radiolabeled alpha(v)beta3 antagonist for the investigation of angiogenesis and metastasis in vivo.     

头低位（—20℃）限制活动7d对兔庆大霉素药代动力学的影响

目的 探讨模拟失重条件下以血流量改变为经代动力学变化。方法 选择庆大霉素作为模型药物,采用头低位（－２０℃（兔限制活动为模拟失重动物模型,观察模拟失重对兔庆大霉素药代动力学参数的影响。７只家兔在头低位７ｄ前后,分别静脉滴注了３ｍｇ／ｋｇ的庆大霉素,用ＴＤｘＦＬｘ测定了给药后４ｈ内的血药浓度。结果 庆大霉素的分布变慢,这表现在α值由头低位前的（０．１８３８±０．１０７６）ｍｉｎ＾－１降至头低位后的（     

Labeling of human clots in vitro with an active-site mutant of t-PA

Prompt detection of acute thrombosis and its response to treatment with thrombolytic agents generally require angiography. Scintigraphic approaches with labeled antibodies to or components of the coagulation and fibrinolytic systems have been disappointing because of prolonged circulating half-lives of tracers and relatively slow or limited binding to thrombi. Accordingly, we developed and characterized a thrombolytically inactive, active-site mutant (Ser-478----Thr) of tissue-type plasminogen activator (t-PA) designed to detect thrombi in vivo. Binding of iodine-125-(125I) labeled Ser----Thr t-PA to thrombi in vitro was time- and concentration-dependent, and specific judging from inhibition by pre-incubation with anti-t-PA IgG. Clearance of 125I-labeled mutant t-PA in rabbits was rapid and biexponential (alpha t1/2 = 1.9 +/- 0.4 min, beta t1/2 = 39.8 +/- 11.2 min). Thus, the amidolytically inactive mutant of t-PA designed binds rapidly and specifically to human thrombi in vitro and is cleared rapidly from the circulation in vivo--properties rendering it attractive as a potentially useful clot imaging agent.     

Human pharmacokinetics of iohexol. A new nonionic contrast medium

The pharmacokinetics of iohexol, a new nonionic, water-soluble contrast medium, have been determined after intravenous injection in 20 healthy volunteers, at four different dose levels (125-500 mg I/kg). The apparent volume of distribution was 0.27 1/kg, indicating distribution in the extracellular water. The biologic half-life was 121 minutes, comparable with that of other intravascular contrast media. Iohexol was excreted completely unmetabolized in the urine, with a 100% recovery 24 hours after injection. A comparison of iohexol and chromium-51 (51Cr)-EDTA clearances indicates that iohexol is mainly excreted by glomerular filtration. The 51Cr-EDTA clearance was the same when injected separately and concomitantly with iohexol, indicating that glomerular filtration rate is not affected by iohexol. No dose dependency was observed in the investigated parameters t1/2 alpha, t1/2 beta, Vd, ClT or ClR. Iohexol pharmacokinetics are in correspondence with previously reported data on intravascular contrast media.     

Cardiovascular responses to facial cooling are age and fitness dependent.

PURPOSE: Aging of the cardiovascular system may be altered by differences in physical fitness. We investigated the cardiovascular responses to brief periods of facial cooling (5 degrees C) in 20 healthy men differing in age and aerobic fitness (VO2max). METHODS: Facial cooling was administered at rest in the supine position during 60-s quiet breathing to 6 fit young (FY; VO2max = 75.8 +/- 18 mL x kg(-1) x min(-1); 29 +/- 7 yr), 6 sedentary young (SY; VO2max = 36.0 +/- 2.2 mL x kg(-1) x min(-1); 27 +/- 3 yr), 6 fit old (FO; VO2max = 56.1 +/- 4.0 mL x kg(-1) x min(-1); 54 +/- 5 yr), and 6 sedentary old (SO; VO2max = 29.6 +/- 5.0 mL x kg(-1) x min(-1); 62 +/- 2 yr) volunteers. The following were measured before and after facial cooling: heart rate (HR), mean arterial blood pressure (MAP), pressure-rate product (PRP), and M-mode echocardiographically determined left ventricular internal dimensions, peak circumferential shortening (peak V(CF)), and ejection fraction (EF). RESULTS: Facial cooling produced a statistically significant bradycardia in all groups except for the SO whereas MAP was increased in the young groups but unchanged in the older groups. Pressure-rate product was significantly reduced in the FY, unchanged in the SY and FO, and significantly increased in the SO group. None of the groups showed a change in left ventricular dimensions, whereas only the SO group showed an increase in peak V(CF) (P < 0.05). CONCLUSIONS: These data suggest that endurance training and fitness level do not significantly alter cardiovascular responses to facial cooling in young men or physically fit older men. However, in older subjects, a sedentary lifestyle appears to be associated with an absent facial cooling reflex bradycardia, an increased PRP, and contractility (peak V(CF)).     

<Superscript>68</Superscript>Ga-labeled multimeric RGD peptides for microPET imaging of integrin α<Subscript>v</Subscript>β<Subscript>3</Subscript> expression

PURPOSE: We and others have reported that (18)F- and (64)Cu-labeled arginine-glycine-aspartate (RGD) peptides allow positron emission tomography (PET) quantification of integrin alpha(v)beta(3) expression in vivo. However, clinical translation of these radiotracers is partially hindered by the necessity of cyclotron facility to produce the PET isotopes. Generator-based PET isotope (68)Ga, with a half-life of 68 min and 89% positron emission, deserves special attention because of its independence of an onsite cyclotron. The goal of this study was to investigate the feasibility of (68)Ga-labeled RGD peptides for tumor imaging. METHODS: Three cyclic RGD peptides, c(RGDyK) (RGD1), E[c(RGDyK)](2) (RGD2), and E{E[c(RGDyK)](2)}(2) (RGD4), were conjugated with macrocyclic chelator 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and labeled with (68)Ga. Integrin affinity and specificity of the peptide conjugates were assessed by cell-based receptor binding assay, and the tumor targeting efficacy of (68)Ga-labeled RGD peptides was evaluated in a subcutaneous U87MG glioblastoma xenograft model. RESULTS: U87MG cell-based receptor binding assay using (125)I-echistatin as radioligand showed that integrin affinity followed the order of NOTA-RGD4 > NOTA-RGD2 > NOTA-RGD1. All three NOTA conjugates allowed nearly quantitative (68)Ga-labeling within 10 min (12-17 MBq/nmol). Quantitative microPET imaging studies showed that (68)Ga-NOTA-RGD4 had the highest tumor uptake but also prominent activity accumulation in the kidneys. (68)Ga-NOTA-RGD2 had higher tumor uptake (e.g., 2.8 +/- 0.1%ID/g at 1 h postinjection) and similar pharmacokinetics (4.4 +/- 0.4 tumor/muscle ratio, 2.0 +/- 0.1 tumor/liver ratio, and 1.1 +/- 0.1 tumor/kidney ratio) compared with (68)Ga-NOTA-RGD1. CONCLUSIONS: The dimeric RGD peptide tracer (68)Ga-NOTA-RGD2 with good tumor uptake and favorable pharmacokinetics warrants further investigation for potential clinical translation to image integrin alpha(v)beta(3).     

Left ventricular remodeling after infarction: sequential MR imaging with oral nicorandil therapy in rat model

PURPOSE: To use magnetic resonance (MR) imaging in quantification of the short- and long-term effects of therapy with orally administered nicorandil on left ventricular (LV) geometry and function independent of infarction size. MATERIALS AND METHODS: Forty-six rats were subjected to reperfused infarction and randomly divided into two groups. Group 1 rats (n = 21) were treated with nicorandil (3 mg/kg/day in drinking water) for 4 days before infarction and 8 weeks after infarction (hereafter, the nicorandil group). Group 2 rats (n = 25) received tap water for the same period and served as the control group. Mesoporphyrin- (as a necrosis-specific agent) enhanced MR imaging was used to define necrotic myocardium on day 2 after infarction in all 46 animals. Contrast material-enhanced MR images showed large but identical infarction size in 11 control and 11 nicorandil rats. Only these 22 rats underwent repeat MR imaging at 8 weeks after infarction. The following variables were measured: LV volumes, ejection fraction, mass, wall thickness, and infarction size. Student t test and analysis of variance for repeated measurements were used for statistical analysis. RESULTS: The size of the necrotic region on mesoporphyrin-enhanced MR images was 39% +/- 3 of the size of the left ventricle in the control group and 41% +/- 2 in the nicorandil group (difference not significant, unpaired Student t test). Pretreatment with nicorandil for 6 days before imaging did not reduce LV dilation or improve function compared with those in control animals with identical infarction size. Eight weeks after infarction, control animals showed deterioration in LV function, wall thinning, and gradient in regional dysfunction (analysis of variance test). Nicorandil produced significant salutary effects on LV ejection fraction (37% +/- 3 in the nicorandil group vs 24% +/- 3 in the control group), end-diastolic volume (0.53 mL +/- 0.03 vs 0.65 mL +/- 0.04), end-systolic volume (0.36 mL +/- 0.03 vs 0.49 mL +/- 0.05), LV wall thickening in remote noninfarcted myocardium (28% +/- 2 vs 19% +/- 1), and a rim of infarction (16% +/- 2 vs 8% +/- 1) (P <.05 for all parameters). The increase in LV mass was reduced in the nicorandil group (0.73 g +/- 0.03) compared with that in the control group (0.89 g +/- 0.04) (P <.05). CONCLUSION: In animals studied longitudinally, MR imaging demonstrated the deleterious changes in LV geometry and function in the period after infarction and the salutary effects of medical therapy.     

Measurements of hyperpolarized gas properties in the lung. Part III: (3)He T(1).

Hyperpolarized (3)He spin-lattice relaxation was investigated in the guinea pig lung using spectroscopy and imaging techniques with a repetitive RF pulse series. T(1) was dominated by interactions with oxygen and was used to measure the alveolar O(2) partial pressure. In animals ventilated with a mixture of 79% (3)He and 21% O(2), T(1) dropped from 19.6 sec in vivo to 14.6 sec after cardiac arrest, reflecting the termination of the intrapulmonary gas exchange. The initial difference in oxygen concentration between inspired and alveolar air, and the temporal decay during apnea were related to functional parameters. Estimates of oxygen uptake were 29 +/- 11 mL min(-1) kg(-1) under normoxic conditions, and 9.0 +/- 2.0 mL min(-1) kg(-1) under hypoxic conditions. Cardiac output was estimated to be 400 +/- 160 mL min(-1) kg(-1). The functional residual capacity derived from spirometric magnetic resonance experiments varied with body mass between 5.4 +/- 0.3 mL and 10.7 +/- 1.1 mL. Magn Reson Med 45:421-430, 2001.     

Quantitative analysis of (-)-N-(11)C-propyl-norapomorphine in vivo binding in nonhuman primates.

(-)-N-(11)C-propyl-norapomorphine ((11)C-NPA) is a new dopamine agonist PET radiotracer that holds potential for imaging the high-affinity states of dopamine D(2)-like receptors in the living brain. The goal of this study was to develop and evaluate analytic strategies to derive in vivo (11)C-NPA binding parameters. METHODS: Two baboons were scanned 4 times after (11)C-NPA injections. The metabolite-corrected arterial input functions were measured. Regional brain time-activity curves were analyzed with kinetic and graphical analyses, using the arterial time-activity curve as the input function. Data were also analyzed with the simplified reference-tissue model (SRTM) and graphical analysis with reference-region input. RESULTS: (11)C-NPA exhibited moderately fast metabolism, with 31% +/- 5% of arterial plasma concentration corresponding to the parent compound at 40 min after injection. Plasma clearance was 29 +/- 1 L/h, and plasma free fraction (f(1)) was 5% +/- 1%. For kinetic analysis, a 1-tissue compartment model (1TCM) provided a good fit to the data and more robust derivations of the tissue distribution volumes (V(T), in mL/g) than a 2-tissue compartment model (2TCM). Using 1TCM, V(T)s in the cerebellum and striatum were 3.4 +/- 0.4 and 7.5 +/- 2 mL/g, respectively, which led to estimates of striatal binding potential (BP) of 4.0 +/- 1.1 mL/g and striatal equilibrium specific-to-nonspecific partition coefficient (V(3)") of 1.2 +/- 0.2. V(T) values derived with graphical analysis were well correlated with but slightly lower than V(T) values derived with kinetic analysis. V(3)" values derived with SRTM were well correlated with but slightly higher than V(3)" values derived with kinetic analysis. Using any method, a significant difference was detected in BP and V(3)" values between the 2 animals. It was determined that 30 min of scanning data were sufficient to derive V(3)" values using kinetic, graphical (arterial input and reference-region input), and SRTM analyses. CONCLUSION: This study indicates that (11)C-NPA is a suitable PET tracer to quantify the agonist high-affinity sites of D(2)-like receptors.     

Effect of high-volume and -intensity endurance training in heart transplant recipients

BACKGROUND: A recommended component of heart transplant recipients (HTR) is endurance-oriented exercise therapy. However, the trainability of HTR after transplantation is vague. We examined the effect of high-volume and -intensity exercise training on exercise performance in HTR, compared with HTR undergoing regular rehabilitation training, and sedentary healthy subjects (SHS). METHODS: We studied four groups of individuals; of those, three groups were HTR. Subjects were a regularly trained HTR group of denervated (HTR-D; N = 15), reinnervated (HTR-R; N = 26) hearts, a high-volume and -intensity endurance-training group (training time 7-20 h.wk(-1); HTR-ET; N = 12), and a group of sedentary healthy subjects (SHS; N = 21). All participants performed cardiopulmonary exercise testing. RESULTS: The HTR-ET achieved a significantly higher performance (255 +/- 47 W, VO(2max) of 45.2 +/- 6.9 mL.kg(-1).min(-1)) in contrast to all other groups (HTR-D: 119 +/- 17 W, VO(2max) of 17.4 +/- 4.5 mL.kg(-1).min(-1); HTR-R: 119 +/- 17 W, VO(2max) of 16.9 +/- 3.7 mL.kg(-1).min(-1); SHS: 184 +/- 19 W, VO(2max) of 35.0 +/- 6.9 mL.kg(-1).min(-1)). The HR at maximal power output in the HTR-ET was 169 +/- 17 bpm and similar to SHS (164 +/- 17 bpm), but significantly higher than HTR-D (125 +/- 16) and HTR-R (142 +/- 10). Maximal lactate concentration (LAmax) of HTR-ET was 9.9 +/- 2.2 mmol.L(-1), comparable to SHS (9.2 +/- 2.1 mmol.L(-1)), and significantly higher than HTR-D (5.5 +/- 1.5 mmol.L(-1)) and HTR-R (5.1 +/- 1.0 mmol.L(-1)). CONCLUSIONS: Data suggest that HTR can perform high-volume and -intensity exercise training, reaching exercise performance comparable to or even exceeding values of sedentary or moderately trained healthy subjects.     

Oxygen-uptake efficiency slope as a determinant of fitness in overweight adolescents

PURPOSE: Peak oxygen uptake (VO2peak) is frequently difficult to assess in overweight individuals; therefore, submaximal measures that predict VO2peak are proposed as substitutes. Oxygen uptake efficiency slope (OUES) has been suggested as a submaximal measurement of cardiorespiratory fitness that is independent of exercise intensity. There are few data examining its value as a predictor of V O2peak in severely overweight adolescents. METHODS: One hundred seven severely overweight (BMI Z 2.50 +/- 0.34) and 43 nonoverweight (BMI Z 0.13 +/- 0.84) adolescents, performed a maximal cycle ergometer test with respiratory gas-exchange measurements. OUES was calculated through three exercise intensities: lactate inflection point (OUES LI), 150% of lactate inflection point (OUES 150), and VO2peak (OUES PEAK). RESULTS: When adjusted for lean body mass, VO2peak and OUES at all exercise intensities were lower in overweight subjects (VO2peak: 35.3 +/- 6.4 vs 46.8 +/- 7.9 mL.kg(-1) LBM.min(-1), P < 0.001; OUES LI: 37.9 +/- 10.0 vs 43.7 +/- 9.2 mL.kg(-1) LBM.min(-1).logL(-1) P < 0.001; OUES 150: 41.6 +/- 9.0 vs 49.8 +/- 11.1 mL.kg(-1) LBM.min(-1).logL(-1) P < 0.001; and OUES PEAK: 45.1 +/- 8.7 vs 52.8 +/- 9.6 mL.kg(-1) LBM.min(-1).logL(-1) P < 0.001). There was a significant increase in OUES with increasing exercise intensity in both groups (P < 0.001). OUES at all exercise intensities was a significant predictor of VO2peak for both groups (r2 = 0.35-0.83, P < 0.0001). However, limits of agreement for predicted VO2peak relative to actual VO2peak were wide (+/- 478 to +/- 670 mL.min(-1)). CONCLUSIONS: OUES differs significantly in overweight and nonoverweight adolescents. The wide interindividual variation and the exercise intensity dependence of OUES preclude its use in clinical practice as a predictor of VO2peak.     

Biodistribution and planar gamma camera imaging of (123)I- and (131)I-labeled F(ab')(2) and Fab fragments of monoclonal antibody 14C5 in nude mice bearing an A549 lung tumor

Detection of antigen 14C5, involved in substrate adhesion and highly expressed on the membrane of many carcinomas, including lung cancer, provides important diagnostic information that can influence patient management. The aim of this study was to evaluate the biodistribution and planar gamma camera imaging characteristics of radioiodinated F(ab')(2) and Fab fragments of monoclonal antibody (mAb) 14C5 in tumor-bearing mice. METHODS: F(ab')(2) and Fab 14C5 fragments were radioiodinated using the Iodo-Gen method. In vitro stability, binding specificity and affinity of (125)I-labeled 14C5 fragments were studied in A549 lung carcinoma cells. Biodistribution, blood clearance and tumor-targeting characteristics of (131)I-labeled 14C5 fragments and intact mAb 14C5 were studied in Swiss nu/nu mice bearing A549 lung carcinoma tumors. Planar gamma imaging illustrated the potential use of these (123)I-labeled 14C5 fragments for radioimmunodetection (RID). RESULTS: Saturation binding experiments showed highest affinity for (125)I-labeled F(ab')(2) fragments (K(d)=0.37+/-0.10 nmol/L) and lowest affinity for (125)I-labeled Fab fragments (K(d)=2.25+/-0.44 nmol/L). Blood clearance studies showed that the alpha half-life (t(1/2)alpha) value for Fab, F(ab')(2) and mAb 14C5 was 14.9, 21 and 118 min, respectively. The beta half-life t(1/2)beta value for Fab, F(ab')(2) and mAb 14C5 was 439, 627 and 4067 min, respectively. (131)I-Fab fragments showed highest tumor uptake 3 h after injection (2.4+/-0.8 %ID/g), (131)I-labeled F(ab')(2) showed highest tumor uptake 6 h after injection (4.7+/-0.7 %ID/g) and for (131)I-labeled mAb highest tumor uptake was observed at 24 h (10.7+/-2.3 %ID/g). In planar gamma imaging, both labeled fragments gave better tumor-to-background contrast than (123)I-mAb 14C5. CONCLUSION: Fab and F(ab')(2) fragments derived from intact mAb 14C5 have significant potential for diagnostic and therapeutic applications and may provide new tools in mAb-based radiopharmaceuticals for targeting non-small cell lung cancer.     

Effects of increased lipid concentration and hyperemic blood flow on the intrinsic myocardial washout kinetics of (99m)TcN-NOET.

Bis(N-ethoxy,N-ethyldithiocarbamato)nitrido technetium (V) ((99m)Tc) ((99m)TcN-NOET) is a myocardial perfusion imaging agent demonstrating significant redistribution and currently in phase III clinical trials. Previous studies have suggested that (99m)TcN-NOET is bound intravascularly. Therefore, we sought to determine whether modifications in the vascular compartment would provide further insights into the mechanisms of (99m)TcN-NOET myocardial washout and redistribution. METHODS:(99m)TcN-NOET cardiac washout was studied ex vivo in 15 isolated perfused rat hearts after bolus injection (1.5 MBq) in the absence (n = 6) or presence of bovine serum albumin ([BSA] 0.03%) with (n = 5) or without (n = 4) bound lipids. The intrinsic myocardial washout of the tracer was also studied in vivo in 6 dogs after intracoronary bolus injection of the tracer (0.75 MBq) before and after hyperlipidemia induced by intravenous administration of 300 mL of 20% intralipids (n = 3) or hyperemia induced by intravenous infusion of the adenosine A(2A) receptor agonist ATL-146e (0.3 micro g/kg/min; n = 6). RESULTS: On isolated hearts, there was no significant myocardial washout of (99m)TcN-NOET with Krebs-Henseleit buffer. Addition of BSA without bound lipids resulted in a significant cardiac washout of the tracer (P < 0.001 by repeated measures ANOVA). The presence of lipids bound to BSA further accelerated the washout rate of (99m)TcN-NOET (half-life [t(1/2)], 431.5 +/- 23.2 min vs. 242.9 +/- 63.2 min; P < 0.05). In vivo in dogs, intralipid administration significantly increased the intrinsic washout rate of (99m)TcN-NOET (t(1/2), 108.0 +/- 23.9 min vs. 51.8 +/- 11.8 min; P < 0.05). In addition, vasodilatation with ATL-146e resulted in a 4.9-fold increase in coronary flow (P < 0.05 vs. baseline) and a significantly faster intrinsic (99m)TcN-NOET myocardial washout (t(1/2), 81.1 +/- 12.1 min vs. 40.7 +/- 7.3 min; P < 0.05). CONCLUSION: The myocardial washout kinetics of (99m)TcN-NOET are affected by a variety of intravascular factors, supporting the hypothesis that the tracer is most likely localized on the vascular endothelium. The potential impact of variations in circulating lipid levels among patients on clinical imaging with (99m)TcN-NOET requires further investigation.     

Pharmacokinetics of 1M gadobutrol in patients with chronic renal failure

RATIONALE AND OBJECTIVES: To investigate the pharmacokinetics of 1M gadobutrol as a new neutral MR contrast agent in patients with impaired renal function. METHODS: Twenty-one patients with impaired renal function and any indication for a contrast-enhanced MRI were enrolled into this prospective study and classified in two subgroups according to their creatinine clearance (group 1, 30-80 mL/ min; group 2, 30 mL/min or less, not requiring dialysis). Eleven patients were assigned to the lower dose of 0.1 mmol Gd/kg and 10 patients to the higher dose of 0.3 mmol Gd/kg. To calculate pharmacokinetic parameters, urine and venous blood samples were drawn at baseline and up to 72 hours for group 1 and 120 hours for group 2 after administration of gadobutrol. RESULTS: The predominant extracellular distribution of gadobutrol at steady state did not change according to the degree of renal impairment. The mean elimination half-life of gadobutrol increased to 7.4 +/- 2.6 hours (0.1 mmol/kg) and 5.4 +/- 1.5 hour (0.3 mmol/kg) in group 1 and to 17.9 +/- 6.2 hours (0.1 mmol/kg) and 20.4 +/- 16.9 hours (0.3 mmol/kg) in group 2, compared with 1.5 hours in healthy volunteers. The relation between serum (tbeta) and urine (t(elim)) elimination half-lives, as well as total serum and renal clearance, indicated renal elimination as the main pathway of elimination. The recovery of gadobutrol in the urine of group 1 was complete within 72 hours for both dosage levels. Patients with severe renal impairment showed a mean recovery of 80.1% (0.1 mmol/kg) and 85.3% (0.3 mmol/kg) within the observation period of 120 hours. CONCLUSIONS: The half-life of gadobutrol is prolonged in patients with impaired renal function, but elimination by means of the kidneys is the predominant route.     

Remote control production of an aqueous solution of no-carrier-added 34mCl- via the 32S(alpha,pn) nuclear reaction.

A remote system was established for the production of a biologically important radionuclide, chlorine-34m (32.0min, beta(+) 53%, IT 47%). The (32)S(alpha,pn)(34m)Cl reaction on elemental sulfur of natural isotopic composition was adopted for the production method. The target sulfur was melted by heating in the target chamber and then irradiated with 65MeV alpha particles (58.2MeV on target) at 3 microA for 30min. Generated (34m)Cl was extracted remotely with hot water from the molten sulfur in the target chamber. Within 20min, [(34m)Cl]chloride was obtained as a 10+/-3mL aqueous solution at a yield of 450 +/- 90 MBq, which corresponds to a recovery efficiency of 79 +/- 17% (n = 5). Both radionuclidic and radiochemical purities were more than 99% with a specific activity of 1.1GBq/ micromol. Non-radioactive impurities in the solution were identified as F(-), Cl(-), NO(3)(-), SO(4)(2-); other unknown ions were also present.