Carbon Monoxide Poisoning: The Great Imitator.

Carbon Monoxide (CO) is one of the leading causes of poison deaths in the United States. Signs and symptoms are clinically variable secondary to inconsistent targeting of highly metabolic tissues by the gas. We report a case of a man in his early to mid-30's presenting to the emergency department with mental status changes, fatigue, headache, and flu-like symptoms for three days. The patient had been working on his motor vehicles in the garage during this time, using a portable diesel powered space heater to keep warm. Subsequent neurology and cardiology workup demonstrated bilateral globus pallidus (GP) lesions on brain imaging, increased non-myocardial infarction troponin levels, carboxyhemoglobin (COHb) level of 3.8%, elevated liver enzymes, and acute kidney failure. In this setting of his delayed presentation as a smoker with carbon monoxide poisoning, carboxyhemoglobin levels alone become less reliable. This report investigates the use of bilateral GP lesions, the most frequently affected structure, as well as damage preference to highly metabolic tissues to assist in diagnosis and prognosis for CO poisoning. Our observations can be used for further study of the relationship between bilateral GP necrosis and initial presentation and outcome of patients experiencing CO poisoning leading to earlier recognition, treatment, and decreased morbidity/mortality.

The clinical safety, biodistribution and internal radiation dosimetry of flutemetamol (¹8F) injection in healthy Japanese adult volunteers.

OBJECTIVES: The Phase I safety, biodistribution and internal radiation dosimetry study in adult healthy Japanese males of flutemetamol ((18)F) injection, an in vivo ß-amyloid imaging agent, is reported and compared with previously obtained Caucasian data. METHODS: Whole-body PET scans of 6 healthy volunteers (age 51.8-61.7 years) were acquired approximately 4 h post-injection (administered activity 102-160 MBq). Venous blood sampling determined (18)F activity concentrations in whole blood and plasma and high-performance liquid chromatography (HPLC) established the percentages of parent [(18)F]flutemetamol and its metabolites. Voided urine activity was recorded. The decay-corrected and normalised (18)F activity of 14 source organ regions as a function of time was entered into the OLINDA/EXM software to calculate the internal radiation dosimetry and effective dose of each subject following the MIRD schema. The pharmacokinetics, biodistribution and dosimetry profiles were compared to data obtained from a cohort of healthy Caucasian adult volunteers from a previous Phase I study of [(18)F]flutemetamol. RESULTS: Flutemetamol ((18)F) injection was well tolerated. The highest mean initial uptakes were measured in the liver (15.2%), lungs (10.2%) and brain (6.6%). The highest mean radiation absorbed doses were received by the gallbladder wall (366 µGy/MBq), upper large intestine (138 µGy/MBq) and small intestine (121 µGy/MBq). The mean effective dose was 34.9 µSv/MBq. HPLC analysis demonstrated that at 5-min post-injection about 75% of plasma (18)F radioactivity was in the form of parent [(18)F]flutemetamol, reducing to 8 and 2% at 25 and 90 min, respectively, giving rise to less lipophilic (18)F-labelled metabolites. Comparisons with the Caucasian cohort showed no differences that could be regarded as clinically significant. CONCLUSION: The clinical safety of [(18)F]flutemetamol demonstrated no differences of clinical significance in the pharmacokinetics, biodistribution and internal radiation dosimetry profiles between Caucasian and Japanese adults.

An exploratory efficacy study of the amyloid imaging agent [(18)F]flutemetamol in Japanese Subjects.

AIM: The aim of the study presented was to investigate the brain uptake properties of the amyloid PET agent [(18)F]flutemetamol in Japanese healthy controls and clinically probable Alzheimer's disease (AD) patients, and to make a comparison with the results of a previously performed study on Caucasian subjects. [(18)F]flutemetamol was recently approved by the American Food and Drug Administration and the European Medicines Agency for visualization of amyloid in vivo. Since the first clinical study of [(18)F]flutemetamol-an (18)F derivative of the PET tracer 11C-Pittsburgh Compound B targeting ß-amyloid--took place, several clinical studies have been performed, but few focusing on a Japanese population. METHODS: In the Step A, three elderly healthy volunteers and three AD subjects underwent dynamic PET scanning 0-30 and 60-150 min after injection of 185 MBq [(18)F]flutemetamol. The brain volume of distribution (VT) was quantified using Logan's linear graphical analysis and as standardized uptake value ratios (SUVR) with a cerebellar reference. The optimal acquisition window was determined from brain time activity curves for Step B. In the Step B, 5 AD and 5 elderly healthy volunteers were scanned from 80 to 140 min after intravenous injection of [(18)F]flutemetamol. The data from the two parts were pooled for estimation of overall efficacy. RESULTS: [(18)F]Flutemetamol injection was shown to be safe-no serious adverse events were reported during this study. A simplified SUVR estimate of the uptake of [(18)F]flutemetamol using a time window of 85-115 min post injection successfully discriminated AD cases from healthy volunteers. AD subjects showed an elevated tracer uptake in prefrontal cortex, the lateral temporal cortex and precuneus amongst other regions. No significant [(18)F]flutemetamol PET differences could be seen between the Japanese AD cases in this study and those from an earlier Caucasian study, or between control subjects in Japanese and Caucasian studies. CONCLUSIONS: This study supports the use of [(18)F]flutemetamol PET in Japanese population as a marker of the presence of fibrillar ß-amyloid. The lack of differences between the Japanese cohort and those from a previous Caucasian cohort supports the extrapolation of results from other Caucasian [(18)F]flutemetamol PET studies to the Japanese population.

The clinical safety, biodistribution and internal radiation dosimetry of [¹8F]fluciclovine in healthy adult volunteers.

PURPOSE: We report on the biodistribution and internal radiation dosimetry in humans of [(18)F]fluciclovine, a synthetic L-leucine analogue being investigated as a potential diagnostic biomarker for neoplasia. METHODS: Whole-body positron emission tomography (PET) scans of 6 healthy volunteers were acquired at up to 16 time points up to about 5 h after a bolus administration of [(18)F]fluciclovine (153.8 ± 2.2 MBq). Venous blood samples were taken up to about 4 h post-injection from which (18)F activity concentrations in whole blood and plasma were measured. Urine was collected as voided up to 4 h post-injection, from which the excreted (18)F activity was measured. Absolute values of the (18)F activity contained in up to 11 source regions (brain, salivary glands, lung, heart, pancreas, spleen, liver, red bone marrow, kidneys, uterus and urinary bladder contents) were determined directly from quantitative analysis of the images. For each source region, the (18)F activity decay-corrected and normalised to that injected, as a function of time, was fit by an analytical function which was subsequently integrated to yield the cumulated activity normalised to the injected activity. These normalised cumulated activities were then used as input to the Organ Level INternal Dose Assessment/EXponential Modelling (OLINDA/EXM) package to calculate the internal radiation dosimetry of each subject following the Medical Internal Radiation Dose (MIRD) schema. An effective dose was then estimated for each subject. RESULTS: [(18)F]Fluciclovine was clinically well tolerated in this study. Very little (18)F was excreted with only a mean value of 3.3% present in the urine at about 4 h post-injection; no activity within the intestinal contents was noted. The highest mean initial uptakes were measured in the liver (13.8%), red bone marrow (11.1%) and lung (7.1%). The highest mean radiation absorbed doses per unit administered activity were received by the pancreas (102.2 µGy/MBq), the cardiac wall (51.7 µGy/MBq) and the uterine wall (44.6 µGy/MBq). The mean effective dose per unit administered activity was 22.1 µSv/MBq. CONCLUSION: The internal radiation dosimetry of [(18)F]fluciclovine appears acceptable for PET imaging.

An open-label, multicenter, phase 2a study to assess the feasibility of imaging metastases in late-stage cancer patients with the alpha v beta 3-selective angiogenesis imaging agent 99mTc-NC100692.

BACKGROUND: The alpha(v)beta(3) integrin is one of the angiogenesis-related membrane proteins highly expressed on the neovasculature of breast cancer and lung carcinomas. Labeling of the alpha(v)beta(3) integrin with (99m)Tc-NC100692 provides a potential tool for imaging angiogenesis and hence the presence of malignant lesions. PURPOSE: To determine the feasibility of detecting metastatic lesions in liver, lung, bone, and brain with scintigraphy using the alpha(v)beta(3)-avid imaging agent (99m)Tc-NC100692 in patients with breast or lung cancer, and to assess its safety profile. MATERIAL AND METHODS: Twenty-five patients--15 with lung cancer and 10 with breast cancer--were recruited at 10 centers. Metastases were newly diagnosed by computed tomography, magnetic resonance imaging, or bone scintigraphy, i.e., the reference standard. Patients underwent whole-body scans of approximately 10-15 min duration beginning at 45 min post-injection and a SPECT acquisition of approximately 30 min beginning at 75 min after injection of up to 1100 MBq (99m)Tc-NC100692. In case of liver metastases, dynamic acquisitions of 15 min were performed starting immediately post-injection. Safety measurements were performed up to 2.5 hours after injection and included hematology, serum biochemistry, coagulation, urine analysis, vital signs, oximetry, 12-lead ECG assessments, and a physical examination. RESULTS: In patients with breast cancer, (99m)Tc-NC100692 scintigraphy detected 1 of 7 liver, 4 of 5 lung, 8 of 17 bone, and 1 of 1 brain metastases. The corresponding numbers for lung cancer patients were 0 of 2, 17 of 18, 2 of 2, and 7 of 9. There was overall stability through the follow-up period for all investigated safety parameters. CONCLUSION: Scintigraphy with (99m)Tc-NC100692 is feasible for detection of lung and brain metastases from breast and lung cancer, while the detection of liver and bone lesions is poor. The use of (99m)Tc-NC100692 is safe and well tolerated.

The biodistribution and radiation dosimetry of the Arg-Gly-Asp peptide 18F-AH111585 in healthy volunteers.

UNLABELLED: We report the safety, biodistribution, and internal radiation dosimetry of a new PET tracer, (18)F-AH111585, a peptide with a high affinity for the alpha(v)beta(3) integrin receptor involved in angiogenesis. METHODS: PET scans of 8 healthy volunteers were acquired at time points up to 4 h after a bolus injection of (18)F-AH111585. (18)F activity in whole blood and plasma and excreted urine were measured up to 4 h after injection. In vivo (18)F activities in up to 12 source regions were determined from quantitative analysis of the images. The cumulated activities subsequently calculated were then used to determine the internal radiation dosimetry, including the effective dose. RESULTS: Injection of (18)F-AH111585 was well tolerated in all subjects, with no serious or drug-related adverse events reported. The main route of (18)F excretion was renal (37%), and the 3 highest initial uptakes were by liver (15%); combined walls of the small, upper large, and lower large intestines (11%); and kidneys (9%). The 3 highest absorbed doses were received by the urinary bladder wall (124 microGy/MBq), kidneys (102 microGy/MBq), and cardiac wall (59 microGy/MBq). The effective dose was 26 microGy/MBq. CONCLUSION: (18)F-AH111585 is a safe PET tracer with a dosimetry profile comparable to other common (18)F PET tracers.

Phase I trial of the positron-emitting Arg-Gly-Asp (RGD) peptide radioligand 18F-AH111585 in breast cancer patients.

UNLABELLED: The integrin alpha v beta3 receptor is upregulated on tumor cells and endothelium and plays important roles in angiogenesis and metastasis. Arg-Gly-Asp (RGD) peptide ligands have high affinity for these integrins and can be radiolabeled for PET imaging of angiogenesis or tumor development. We have assessed the safety, stability, and tumor distribution kinetics of a novel radiolabeled RGD-based integrin peptide-polymer conjugate, 18F-AH111585, and its feasibility to detect tumors in metastatic breast cancer patients using PET. METHODS: The biodistribution of 18F-AH111585 was assessed in 18 tumor lesions from 7 patients with metastatic breast cancer by PET, and the PET data were compared with CT results. The metabolic stability of 18F-AH111585 was assessed by chromatography of plasma samples. Regions of interest (ROIs) defined over tumor and normal tissues of the PET images were used to determine the kinetics of radioligand binding in tissues. RESULTS: The radiopharmaceutical and PET procedures were well tolerated in all patients. All 18 tumors detected by CT were visible on the 18F-AH111585 PET images, either as distinct increases in uptake compared with the surrounding normal tissue or, in the case of liver metastases, as regions of deficit uptake because of the high background activity in normal liver tissue. 18F-AH111585 was either homogeneously distributed in the tumors or appeared within the tumor rim, consistent with the pattern of viable peripheral tumor and central necrosis often seen in association with angiogenesis. Increased uptake compared with background (P = 0.002) was demonstrated in metastases in lung, pleura, bone, lymph node, and primary tumor. CONCLUSION: 18F-AH111585 designed to bind the alpha v beta3 integrin is safe, metabolically stable, and retained in tumor tissues and detects breast cancer lesions by PET in most anatomic sites.