A randomized, dose-response, multicenter phase II study of radium-223 chloride for the palliation of painful bone metastases in patients with castration-resistant prostate cancer.

PURPOSE: To investigate the dose-response relationship and pain-relieving effect of radium-223, a highly bone-targeted alpha-pharmaceutical. METHODS: One hundred patients with castration-resistant prostate cancer (CRPC) and painful bone metastases were randomized to a single intravenous dose of 5, 25, 50 or 100 k Bq/kg radium-223. The primary end-point was pain index (visual analogue scale [VAS] and analgesic use), also used to classify patients as responders or non-responders. RESULTS: A significant dose response for pain index was seen at week 2 (P = .035). At week 8 there were 40%, 63%, 56% and 71% pain responders (reduced pain and stable analgesic consumption) in the 5, 25, 50 and 100 k Bq/kg groups, respectively. On the daily VAS, at week 8, pain decreased by a mean of -30, -31, -27 and -28 mm, respectively (P = .008, P = .0005, P = .002, and P < . 0001) in these responders (post-hoc analysis). There was also a significant improvement in the brief pain inventory functional index for all dose-groups (P = .04, .01, .002 and .02, Wilcoxon signed rank test). Furthermore, a decrease in bone alkaline phosphatase in the highest dose-group was demonstrated (P = .0067). All doses were safe and well tolerated. CONCLUSION: Pain response was seen in up to 71% of the patients with a dose response observed 2 weeks after administration. The highly tolerable side-effect profile of radium-223 previously reported was confirmed.

Contrast-enhanced power Doppler imaging of normal and decreased blood flow in canine prostates.

The purpose of this study was to investigate if Sonazoid, a new ultrasound (US) contrast agent, can improve the delineation of areas with normal and decreased blood flow in the prostate. Sonazoid was administered in the dose range of 0.00625-0.0375 microL microbubbles/kg into five anaesthetised mongrel adult male dogs. Transrectal power Doppler imaging of the prostate was performed in 2-D and 3-D with a C9-5 end-fire probe, using an HDI 3000 scanner. An area of decreased blood flow was created by inducing tissue ablation with a CL60 laser system, to mimic an avascular lesion. A subjective assessment of the intraprostatic vessels and the prostate vascular architecture was performed, with and without Sonazoid, before and after inducing the abnormal site. Visibility of the prostate blood flow improved following Sonazoid injection (p < 0.001). A symmetric, radial vascular pattern was identified in the normal prostate prior to tissue ablation, but only on the enhanced images. After tissue ablation, a disturbance of the normal vascular pattern and identification of areas with lack of blood flow was possible, following Sonazoid injection. Furthermore, the location and size of these areas were verified in all dogs by gross histology examination. Sonazoid enhances the visibility of the prostate vascular architecture and improves, thereby the delineation of areas with normal and decreased blood flow.

Enhanced visualisation of the normal prostate blood flow in young healthy volunteers using a new ultrasound contrast agent.

PURPOSE: To evaluate the sonographic appearance of normal prostate vascularity before and after injection of a new ultrasound contrast agent, Sonazoid (NC100100, Nycomed Amersham). MATERIAL AND METHODS: Five healthy male volunteers were given three injections of Sonazoid each. Transrectal B-mode, colour Doppler and colour Doppler energy (i.e. power Doppler) imaging was performed. The visibility of the vascular pattern and the vascular architecture of the prostate, including dynamics of contrast inflow and blood flow symmetry, were evaluated. RESULTS: The depiction of the vascularity was improved in all subjects after injection of Sonazoid for both Doppler modes. No improvement was seen for B-mode. Contrast dynamics within the prostate vessels were demonstrated with a mean time from injection of the ultrasound contrast agent to enhancement of the Doppler signals in the subcapsular arteries of 14+/-1 s (11--17 s), and the ultrasound contrast agent reached the central periurethral veins 4--7 s later. A symmetric, radial, spoke-like intraprostatic vascular pattern could be identified in all subjects using power Doppler imaging and ultrasound contrast agent. CONCLUSION: Sonazoid improved the detection of normal human prostate vascular anatomy for both colour and power Doppler imaging. Contrast dynamic studies revealed a radial spoke-like intraprostatic vascular pattern. This information might be useful in examination of patients with suspicion of prostate cancer, and needs to be further investigated.

Enhanced detection of blood flow in the normal canine prostate using an ultrasound contrast agent.

RATIONALE AND OBJECTIVES: To evaluate the sonographic appearance of normal prostate vascularity in dogs before and after injection of a new ultrasound contrast agent, NC100100. METHODS: Thirty-five intravenous injections of NC100100, in doses ranging from 0.00625 to 0.05 microL microbubbles/kg, were administered to seven anesthetized mongrel male dogs. Transrectal color Doppler imaging and power Doppler imaging were used to perform the assessment. The visibility of the vascular pattern of the prostate was assessed, including dynamics of contrast inflow, blood flow symmetry, and duration times. RESULTS: Before contrast administration, the vascular pattern was poorly visualized in all cases. After contrast injection, the visibility of the vascular architecture improved significantly for both modalities. Independent of the imaging method used, higher doses tended to be more effective than lower doses. Contrast kinetics in the prostate vessels was demonstrated with a mean time from injection of the ultrasound contrast agent to enhancement of the Doppler signals in the subcapsular arteries (+/-1 SD) of 13+/-3 seconds, and the ultrasound contrast agent reached the central periurethral veins 3 to 6 seconds later. A spokelike radial pattern of internal prostatic vessels observed with enhanced ultrasound could also be seen on silicone microfil x-ray images. The Doppler enhancement persisted for a mean time ( +/-1 SD) of 904 seconds (approximately 15 minutes) +/- 225 seconds and tended to increase with increasing dose. CONCLUSIONS: NC100100 significantly improves the detection of blood flow in the normal canine prostate and allows more accurate depiction of the vascular architecture of the prostate.

Exercise-induced overexpression of key regulatory proteins involved in glucose uptake and metabolism in tetraplegic persons: molecular mechanism for improved glucose homeostasis.

Complete spinal cord lesion leads to profound metabolic abnormalities and striking changes in muscle morphology. Here we assess the effects of electrically stimulated leg cycling (ESLC) on whole body insulin sensitivity, skeletal muscle glucose metabolism, and muscle fiber morphology in five tetraplegic subjects with complete C5-C7 lesions. Physical training (seven ESLC sessions/wk for 8 wk) increased whole body insulin-stimulated glucose uptake by 33+/-13%, concomitant with a 2.1-fold increase in insulin-stimulated (100 microU/ml) 3-O-methylglucose transport in isolated vastus lateralis muscle. Physical training led to a marked increase in protein expression of GLUT4 (378+/-85%), glycogen synthase (526+/-146%), and hexokinase II (204+/-47%) in vastus lateralis muscle, whereas phosphofructokinase expression (282+/-97%) was not significantly changed. Hexokinase II activity was significantly increased, whereas activity of phosphofructokinase, glycogen synthase, and citrate synthase was not changed after training. Muscle fiber type distribution and fiber area were markedly altered compared to able-bodied subjects before ESLC training, with no change noted in either parameter after ECSL training. In conclusion, muscle contraction improves insulin action on whole body and cellular glucose uptake in cervical cord-injured persons through a major increase in protein expression of key genes involved in the regulation of glucose metabolism. Furthermore, improvements in insulin action on glucose metabolism are independent of changes in muscle fiber type distribution.

Improved body composition after 8 wk of electrically stimulated leg cycling in tetraplegic patients.

The practical aspects of utilizing electrically stimulated leg cycling (ESLC) to counteract alterations in body composition were investigated in five tetraplegic subjects with long-standing complete spinal cord injuries (C5-C7). After a 2-wk adaptation period, the subjects performed seven ESLC sessions per week for 8 wk. No adverse reactions were noted in response to the ESLC program. The ESLC sessions were accompanied by higher lactate concentrations compared with arm exercise. Heart rate and blood pressure response revealed clear, but not serious, signs of autonomic dysreflexia in the beginning of the ESLC sessions. Body temperature increased moderately during the ESLC sessions. Peak oxygen uptake (Vo2) during an ESLC session increased by 70% (P < 0.05) after 8 wk of training. Body composition, evaluated by dual-energy X-ray absorptiometry (DEXA), demonstrated an increase in lean body mass (LBM) from 66.2 +/- 2.6 to 68.2 +/- 2.1% (P < 0.05), with a concomitant decrease in whole body fat (BF) content from 29.7 +/- 2.6 to 27.8 +/- 2.1% (P < 0.05) after training. The cross-sectional area of quadriceps, hamstrings, gluteus maximus, and gluteus medius muscles, measured by computer tomographic scans, increased from 267 +/- 27 to 324 +/- 27 cm2 (P < 0.05) after the training. In conclusion, daily ESLC sessions during a 2-mo period resulted in increased LBM, decreased BF content, and increased muscular endurance in tetraplegic subjects without any noticeable adverse effects.

Whole body and splanchnic metabolic and circulatory effects of glucose during beta-adrenergic receptor inhibition.

The aim of the study was to assess the possible contribution of adrenergic mechanisms to the thermogenic and circulatory effects of glucose ingestion. With the use of indirect calorimetry and arterial, pulmonary arterial, and hepatic venous catheterization, whole body and splanchnic oxygen uptake and blood flow were examined in nine propranolol-treated healthy male volunteers before and during 2 h after oral ingestion of 75 g of glucose. The glucose effects were compared with those in nine untreated controls. After propranolol, the glucose-induced rise in splanchnic blood flow was reduced by approximately 60%, and the hepatic venous glucose release to the systemic circulation was significantly delayed. Glucose-induced increments in pulmonary and splanchnic oxygen uptake and cardiac output were similar in the two groups. It is concluded that adrenergic mechanisms contribute to the glucose-induced rise in splanchnic blood flow and thereby probably to the time course for intestinal absorption of nutrients. It is suggested that the magnitude of glucose-induced thermogenesis is independent of adrenergic stimulation.

Intact glucose transport in morphologically altered denervated skeletal muscle from quadriplegic patients.

The present study was undertaken to investigate the nature of the whole body insulin resistance that characterizes patients with complete cervical spinal cord lesion. Nine patients with C5-C7 lesions and ten age-matched healthy individuals were studied. Whole body insulin-mediated glucose utilization was reduced by 43% in the quadriplegic patients compared with the controls (P < 0.001). In the quadriplegic patients, lean body mass corresponded to 66 +/- 3% of total body mass. Despite whole body insulin resistance, in isolated vastus lateralis muscle, basal and insulin-stimulated 3-O-methylglucose transport, as well as protein expression of the insulin or exercise-regulatable glucose transporter, GLUT-4, and glycogen content were comparable between the patients and controls. Strikingly, muscle fiber area was reduced by 44% (P < 0.05), percentage of type IIb fibers was increased (P < 0.01), and there was a complete loss of type I fibers in the patients. In conclusion, the dissociation between whole body insulin-mediated glucose uptake and skeletal muscle glucose transport in quadriplegic patients primarily reflects the decreased muscle mass. Furthermore, these findings demonstrate a remarkable capacity of skeletal muscle to maintain an intact glucose transport system despite severe morphological alterations.

Metabolic, thermal and circulatory effects of intravenous infusion of amino acids in tetraplegic patients.

Metabolic, circulatory and thermal effects of intravenously (i.v.) administered amino acids were studied in eight patients with complete cervical spinal cord injuries, and compared with the effects in eight healthy subjects. Using indirect calorimetry and catheter techniques, whole-body and splanchnic oxygen consumption, blood flow and blood temperatures were measured before and at timed intervals during 2.5 h of i.v. infusion of 600 kJ of a mixture of 19 amino acids. Pulmonary oxygen uptake increased from 209 +/- 11 to 267 +/- 13 ml min-1 in the patients and from 268 +/- 5 to 320 +/- 8 ml min-1 in the controls. The thermic effect of amino acids was 21 +/- 3% and 16 +/- 2% in patients and controls, respectively. In both groups the splanchnic tissues accounted for approximately half of the rise in whole-body oxygen consumption. Cardiac output rose by, on average, 0.5 +/- 0.1 and 0.8 +/- 0.2 1 min-1 in patients and controls, respectively, while the hepatic blood flow remained unchanged in both groups. Pulmonary arterial blood temperature increased by 0.647 +/- 0.100 degrees C in the patients and by 0.244 +/- 0.174 degrees C in the controls (P < 0.05). The whole-body specific heat was low in the patients, its calculated maximum value being approximately 20% below the normal level. During the amino acid infusion the arterial blood concentration of amino acids rose by approximately 170% and 112% of its basal levels in patients and controls, respectively, indicating a significantly reduced capacity for cellular uptake of amino acids in tetraplegic patients. It is concluded that, in tetraplegic patients, i.v. infused amino acids induce prompt thermogenesis of normal magnitude accompanied by supranormal temperatures and amino acid concentrations in the blood, and that low whole-body specific heat contributes to the well-known thermoregulatory instability in tetraplegia.

Glucose-induced thermogenesis in tetraplegic patients with low sympathoadrenal activity.

The influence of the sympathoadrenal system on the thermic effect of glucose was examined by studying six tetraplegic patients with complete lesions of the cervical spinal cord. Indirect calorimetry and catheter techniques were employed, and measurements were made before and during 2 h after oral ingestion of 75 g of glucose. The results were compared with previous findings from an identical study in healthy subjects and with those from a control group of five tetraplegic patients receiving water instead of glucose. In response to glucose, energy expenditure rose from 69 +/- 5 to 79 +/- 5 and from 88 +/- 3 to 98 +/- 4 W, (not significant) in the patients and healthy subjects, respectively. In both patients and the healthy subjects the postprandial oxygen consumption increased exclusively in extrasplanchnic tissues. Splanchnic blood flow, which in normals increased 34 +/- 1%, did not change in the patients after glucose. Blood temperatures were unchanged in normals after glucose but rose by approximately 0.5 degrees C in the patients. The patients' arterial plasma concentrations of norepinephrine were low in the basal state and did not rise significantly after glucose. The arterial blood glucose concentrations after glucose were significantly higher in the patients than in the healthy subjects. Insulin levels rose to 105 +/- 20 mU/l in the patients and to 59 +/- 7 mU/l in the controls (P < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary function and symptom-limited exercise stress testing in subjects with late sequelae of poliomyelitis.

Sixty-eight subjects, consecutively admitted to our rehabilitation hospital with a presumptive postpolio syndrome, were examined by pulmonary function and symptom-limited exercise stress testing. The purpose of this investigation was to study how many of these subjects could be classified as suffering from cardiorespiratory deconditioning. The subjects had moderately reduced lung function of restrictive type, and none of the subjects had forced expiratory volume for one second (FEV1) below 30% of predicted value, indicating that hypoventilation would probably not occur. A pronounced reduction in maximal oxygen uptake (max VO2) was seen, especially in women. The maximal heart rate (max HR) values were above 70% of predicted values in all but one subject, indicating that the subjects might benefit from endurance training. Fifteen subjects had a suspected pulmonary limitation due to the exercise, with the ratio ventilation/maximal voluntary ventilation (V/MVV) above 70%. However, max HR in these subjects did not differ from that in the subjects with the ratio V/MVV below 70%. Thirteen other subjects had a ratio V/MVV < 70% but did not achieve respiratory quotient (R) > 1.0 and/or capillary lactate concentration > 4 mmol/l during exercise, indicating that muscular factors limited the exercise. These results indicate that cardiorespiratory deconditioning was considerable in most of our subjects with postpolio syndrome.

Meal-induced rise in resting energy expenditure in patients with complete cervical spinal cord lesions.

Central activation of the sympathoadrenal system is generally considered to be an essential component of the mechanisms whereby food ingestion stimulates resting energy expenditure. The functional importance of such sympathoadrenal stimulation has been demonstrated primarily in animals. To the extent that central sympathoadrenal stimulation is required for normal human nutrient-induced thermogenesis, this process should be defective in patients with complete cervical spinal cord lesion and severed connection between the central nervous system and the peripheral sympathetic nerves. Consequently, respiratory gas exchange was measured by indirect calorimetry in 9 tetraplegic patients and in 6 healthy individuals. Measurements were performed before and 2 hours after ingestion of a standardised mixed meal (40% of basal 24 h energy requirements). The basal energy expenditure was 64 +/- 4 watts in the tetraplegic patients and 79 +/- 6 watts in the controls. After the meal, energy expenditure increased on average by 17 +/- 2 watts or 26 +/- 3% of the basal values in the patients and by 14 +/- 2 watts or 19 +/- 3% in the healthy controls (NS). The thermic effect of the meal, ie the rise in energy expenditure expressed in percent of the meal's energy content, was 5.5 +/- 0.7% in the patients and 3.8 +/- 0.6% in the controls (NS). Plasma concentrations of noradrenaline were low in the tetraplegic patients (0.3-0.4 nmol/l) compared to the healthy controls (1.1-1.4 nmol/l), p < 0.02. It is concluded that nutrient-induced thermogenesis in tetraplegic patients with low sympathoadrenal activity is not diminished compared to healthy controls. The findings indicate that efferent sympathoadrenal stimulation from the brain is not a causal necessity for nutrient-induced thermogenesis in man.

Lung volumes in tetraplegic patients according to cervical spinal cord injury level.

Fifty-six tetraplegic patients with motor complete lesions (Frankel A and B) underwent spirometric measurements more than 6 months after injury. The results were evaluated according to the level of transection of the cervical cord. A pronounced restrictive respiratory dysfunction was demonstrated in all patients. The expiratory reserve volume (ERV) was zero or markedly reduced in patients at all lesion levels. Systematic increases in both ERV and vital capacity (VC) were found with lower lesion level. The inspiratory capacity (IC) was reduced at all injury levels, but there were no systematic differences in IC between injury levels C4-C8. The total lung capacity (TLC) was reduced and the ratio residual volume/total lung capacity (RV/TLC) was increased in patients at all injury levels. The lung function of patients tested > 12 months after injury was not significantly different from the function in those tested 6-12 months after injury. A respiratory rehabilitation programme for tetraplegic patients should take into account the fact that the respiratory function, especially the forced expiration, is dependent upon injury level.