High prevalence of decreased cortisol reserve in brain-dead potential organ donors

OBJECTIVE: To investigate the adrenocortical function in brain-dead patients, potential organ donors. DESIGN: Prospective study. SETTING: Intensive care units in two teaching hospitals. PATIENTS: A total of 37 patients (28 men, nine women) with severe brain injury, having a mean age of 42 +/- 18 yrs, were included in the study. Group A consisted of 20 brain-injured patients who did not deteriorate to brain death. Group B included 17 brain-injured patients who were brain dead; of these, ten patients developed brain death during ICU stay and seven patients were admitted to the ICU after clinical brain death. INTERVENTIONS: In all patients (group A and group B), a morning blood sample was obtained at admission to the ICU to determine baseline plasma cortisol. Subsequently, 1 microg of corticotropin (adrenocorticotropic hormone, Synacthen) was administered intravenously, and a blood sample was taken 30 mins after the injection. In group B patients who became brain dead while being treated in the ICU (n = 10), the same procedure was repeated the morning after the confirmation of brain death. Patients having a cortisol level of at least 18 microg/dL after the administration of adrenocorticotropic hormone were defined as responders. MEASUREMENTS AND MAIN RESULTS: After the occurrence of brain death, group B patients had significantly lower values for baseline (8.5 +/- 6.2 vs. 17.0 +/- 6.6 microg/dL, p <.001) and stimulated (16.9 +/- 6.3 vs. 23.9 +/- 5.7 microg/dL, p =.001) plasma cortisol compared with group A patients. Thirteen group B patients (76%) and two group A patients (10%) were nonresponders to adrenocorticotropic hormone (p <.001). In group B patients, baseline and stimulated cortisol concentrations were significantly related (r =.71, p =.001), whereas there was no correlation between baseline cortisol and the increment in cortisol (r = -.37, p =.15). Mean hormonal data of the ten brain-dead patients studied at admission in the ICU and after the occurrence of brain death were the following: baseline plasma cortisol (23.5 +/- 11.4 vs. 6.8 +/- 4.2 microg/dL, p =.003) and stimulated serum cortisol (28.8 +/- 9.9 vs. 16.3 +/- 4.3 microg/dL, p =.008). CONCLUSIONS: Adrenal cortisol secretion after dynamic stimulation is deficient in a substantial proportion of brain-dead potential organ donors.     

Bombesin receptor antagonists may be preferable to agonists for tumor targeting.

Two bombesin analogs, Demobesin 4 and Demobesin 1, were characterized in vitro as gastrin-releasing peptide (GRP) receptor agonist and antagonist, respectively, and were compared as (99m)Tc-labeled ligands for their in vitro and in vivo tumor-targeting properties. METHODS: N(4)-[Pro(1),Tyr(4),Nle(14)]Bombesin (Demobesin 4) and N(4)-[d-Phe(6),Leu-NHEt(13),des-Met(14)]bombesin(6-14) (Demobesin 1) were characterized in vitro for their binding properties with GRP receptor autoradiography using GRP receptor-transfected HEK293 cells, PC3 cells, and human prostate cancer specimens. Their ability to modulate calcium mobilization in PC3 and transfected HEK293 cells was analyzed as well as their ability to trigger internalization of the GRP receptor in transfected HEK293 cells, as determined qualitatively by immunofluorescence microscopy and quantitatively by enzyme-linked immunosorbent assay (ELISA). Further, their internalization properties as (99m)Tc-labeled radioligands were tested in vitro in both cell lines. Finally, their biodistribution was analyzed in PC3 tumor-bearing mice. RESULTS: A comparable binding affinity with the 50% inhibitory concentration (IC(50)) in the nanomolar range was measured for Demobesin 4 and Demobesin 1 in all tested tissues. Demobesin 4 behaved as an agonist by strongly stimulating calcium mobilization and by triggering GRP receptor internalization. Demobesin 1 was ineffective in stimulating calcium mobilization and in triggering GRP receptor internalization. However, in these assays, it behaved as a competitive antagonist as it reversed completely the agonist-induced effects in both systems. (99m)Tc-Labeled Demobesin 1 was only weakly taken up by PC3 cells or GRP receptor-transfected HEK293 cells (10% and 5%, respectively, of total added radioactivity) compared with (99m)Tc-labeled Demobesin 4 (45% of total added radioactivity in both cell lines). Remarkably, the biodistribution study revealed a much more pronounced uptake at 1, 4, and 24 h after injection of (99m)Tc-labeled Demobesin 1 in vivo into PC3 tumors than (99m)Tc-labeled Demobesin 4. In vivo competition experiments demonstrated a specific uptake in PC3 tumors and in physiologic GRP receptor-expressing tissues. The tumor-to-kidney ratios were 0.7 for Demobesin 4 and 5.2 for Demobesin 1 at 4 h. CONCLUSION: This comparative in vitro/in vivo study with Demobesin 1 and Demobesin 4 indicates that GRP receptor antagonists may be superior targeting agents to GRP receptor agonists, suggesting a change of paradigm in the field of bombesin radiopharmaceuticals.     

Weekly Gemcitabine for the Treatment of Biliary Tract and Gallbladder Cancer

Objectives: To evaluate the efficacy and safety of weekly administration of gemcitabine treatment in chemotherapy-naïve patients with advanced biliary tract and gallbladder cancer. Patients and methods: Gemcitabine at a dose of 800?mg/m² was administered weekly as a 30-min infusion to patients with previously operated, histologically confirmed, metastatic, or unresectable locally advanced cholangiocarcinoma. Treatment was continued until unacceptable toxicity or disease progression. Results: A total of 30 patients (median age 66 years; range 54–72 years) were included in the study. A median of 14 (range, 4–33) weekly doses was administered. Out of 30 patients evaluable for response, nine partial responses were observed (30.0%), while a further 11 patients demonstrated stable disease (36.7%). The median time to disease progression was 7 months (range, 5–34). Overall response rate was superior in patients with cancer of the gallbladder (ORR=35.7%) compared with those patients with biliary duct cancer (ORR=27.3%). This correlated to a significantly longer time to progression of 6.4 months (95% confidence interval (CI), 5.6–7.1 months) versus 3.6 months (95% CI, 2.9–4.3 months; p=0.03) and a significantly better overall survival of 17.1 months (95% CI, 15.8–18.5 months) versus 11.4 months (95% CI, 10.2–12.6 months, p=0.021). Toxicities were generally mild with only one case of grade 3 neutropenia. There were no cases of febrile neutropenia and no treatment-related deaths. Conclusions: Weekly administration of gemcitabine provides a safe, well-tolerated, and effective treatment for chemotherapy naïve patients with advanced cholangiocarcinoma, particularly with a gallbladder origin.     

Comparison of Spirapril, Isradipine, or Combination in Hypertensive Patients With Left Ventricular Hypertrophy: Effects on LVH Regression and Arrhythmogenic Propensity

This study was designed to evaluate in 45 hypertensive patients with left ventricular hypertrophy (LVH) the effects of a 6-month course with one of three different antihypertensive regimens (the calcium channel blocker isradipine, the angiotensin converting enzyme inhibitor spirapril in monotherapy, or a combination of the two drugs, n = 15 per group) on blood pressure, LVH regression, and various functional correlates of LVH. All three treatment modalities decreased significantly LV mass index by an average of 10%, although the combination had the greatest blood pressure-lowering effect and spirapril had the least, as assessed by office resting pressures, ambulatory monitoring, and isometric grip testing. There was no correlation between magnitude of blood pressure lowering and degree of LVH regression. The effects of treatment on pressor hormone profiles differed among groups, as spirapril tended to suppress angiotensin II and norepinephrine, whereas isradipine had opposite effects. Exercise tolerance was prolonged by all three regimens, but significantly more by the combination. All three regimens decreased significantly the double product by 10% to 15%. Indices of electrophysiologic stability calculated from analysis of ambulatory electrocardiogram exhibited significant improvement in several parameters such as QRS duration, presence of late potentials, and measures of heart rate variability, resulting in fewer episodes of simple or complex ventricular arrhythmia. We conclude that all three regimens produce significant LVH regression associated with improved functional capacity and electrical stability. These results reflect the sum of the differential hemodynamic and hormonal effects exerted by each treatment modality.     

Ondansetron Versus Metoclopramide as Antiemetic Treatment During Cisplatin-based Chemotherapy: A prospective study with special regard to electrolyte imbalance

Cancer patients selected for cisplatin-based chemotherapy were randomly divided into two groups (42 patients in each) which received either metoclopramide or ondansetron as antiemetics. Metoclopramide was given i.v. with 5 doses of 2 mg/kg starting 30 min before the cisplatin infusion and continued with one dose every 3 h. Ondansetron was given with a first injection of 8 mg i.v. 30 min before the cisplatin infusion; the patients were given 8 mg orally 5 and 10 h after the cisplatin infusion followed by 8 mg × 3 during the next two days. In the present study ondansetron was superior to metoclopramide concerning antiemetic efficacy and gave also less side-effects as diarrhea, dizziness, extrapyramidal symptoms and electrolyte imbalance (sodium, potassium, magnesum, phosphorous) during the first 24 h following the cisplatin infusion.     

The effect of acutely induced hepatic failure on remifentanil and fentanyl blood levels in a pig model

BACKGROUND AND OBJECTIVE: Opioids and especially fentanyl are widely used during the intensive care unit management of intracranial pressure in fulminant hepatic failure patients as well as during and after liver transplantation. The newer synthetic opioid remifentanil is also increasingly being used in critical care patients. Due to a lack of data relating to the influence of acute hepatic failure on remifentanil and fentanyl pharmacokinetics, this study was designed in order to determine the impact of this condition on the blood levels of these opioids using a pig model. METHODS: Twenty pigs were randomly assigned to one of two groups: A group with surgically induced acute hepatic failure by hepatic devascularization (acute hepatic failure, n=10) and a control group (SHAM, n=10), subjected to a SHAM operation. Postoperatively, five animals in each group were administered remifentanil (1 microg kg-1 min-1) or fentanyl (0.2 microg kg-1 min-1) by continuous intravenous infusion. Blood samples for determination of drug concentrations were withdrawn at 0 h and 0.5, 1, 5, 7, 9 h after initiation of dosing. RESULTS: Significantly higher blood concentrations were found in animals with acute hepatic failure compared to SHAM-operated animals receiving remifentanil at 5 h (P=0.003), 7 h (P=0.007) and 9 h (P=0.004) and fentanyl at 7 h (P<0.0005) and 9 h (P=0.05). The small number and the great variability in drug concentrations did not allow a detailed kinetic analysis to be performed. Approximate clearance values were found to be greater for the SHAM compared with the acute hepatic failure animals for both fentanyl and remifentanil. CONCLUSIONS: Hepatic devascularization in our porcine acute hepatic failure model, appears to have significantly altered the disposition of fentanyl and unexpectedly remifentanil. These changes were thought to be brought about by severe disruption of blood flow and biotransformation in the liver, as well as by haemodynamic changes in the acute hepatic failure animals.     

Preclinical and first clinical experience with the gastrin-releasing peptide receptor-antagonist [<Superscript>68</Superscript>Ga]SB3 and PET/CT

Purpose

Gastrin-releasing peptide receptors (GRPR) represent attractive targets for tumor diagnosis and therapy because of their overexpression in major human cancers. Internalizing GRPR agonists were initially proposed for prolonged lesion retention, but a shift of paradigm to GRPR antagonists has recently been made. Surprisingly, radioantagonists, such as [^99mTc]DB1 (^99mTc-N₄′-DPhe⁶,Leu-NHEt¹³]BBN(6–13)), displayed better pharmacokinetics than radioagonists, in addition to their higher inherent biosafety. We introduce here [⁶⁸Ga]SB3, a [^99mTc]DB1 mimic-carrying, instead of the ^99mTc-binding tetraamine, the chelator DOTA for labeling with the PET radiometal ⁶⁸Ga.

Methods

Competition binding assays of SB3 and [^natGa]SB3 were conducted against [¹²⁵I-Tyr⁴]BBN in PC-3 cell membranes. Blood samples collected 5 min postinjection (pi) of the [⁶⁷Ga]SB3 surrogate in mice were analyzed using high-performance liquid chromatography (HPLC) for degradation products. Likewise, biodistribution was performed after injection of [⁶⁷Ga]SB3 (37 kBq, 100 μL, 10 pmol peptide) in severe combined immunodeficiency (SCID) mice bearing PC-3 xenografts. Eventually, [⁶⁸Ga]SB3 (283?±?91 MBq, 23?±?7 nmol) was injected into 17 patients with breast (8) and prostate (9) cancer. All patients had disseminated disease and had received previous therapies. PET/CT fusion images were acquired 60–115 min pi.

Results

SB3 and [^natGa]SB3 bound to the human GRPR with high affinity (IC₅₀: 4.6?±?0.5 nM and 1.5?±?0.3 nM, respectively). [⁶⁷Ga]SB3 displayed good in vivo stability (>85 % intact at 5 min pi). [⁶⁷Ga]SB3 showed high, GRPR-specific and prolonged retention in PC-3 xenografts (33.1?±?3.9%ID/g at 1 h pi – 27.0?±?0.9%ID/g at 24 h pi), but much faster clearance from the GRPR-rich pancreas (≈160%ID/g at 1 h pi to <17%ID/g at 24 h pi) in mice. In patients, [⁶⁸Ga]SB3 elicited no adverse effects and clearly visualized cancer lesions. Thus, 4 out of 8 (50 %) breast cancer and 5 out of 9 (55 %) prostate cancer patients showed pathological uptake on PET/CT with [⁶⁸Ga]SB3.

Conclusion

[⁶⁷Ga]SB3 showed excellent pharmacokinetics in PC-3 tumor-bearing mice, while [⁶⁸Ga]SB3 PET/CT visualized lesions in about 50 % of patients with advanced and metastasized prostate and breast cancer. We expect imaging with [⁶⁸Ga]SB3 to be superior in patients with primary breast or prostate cancer.