Molecular imaging of the human pulmonary vascular endothelium in pulmonary hypertension: a phase II safety and proof of principle trial.

PURPOSE: The adrenomedullin receptor is densely expressed in the pulmonary vascular endothelium. PulmoBind, an adrenomedullin receptor ligand, was developed for molecular diagnosis of pulmonary vascular disease. We evaluated the safety of PulmoBind SPECT imaging and its capacity to detect pulmonary vascular disease associated with pulmonary hypertension (PH) in a human phase II study. METHODS: Thirty patients with pulmonary arterial hypertension (PAH, n = 23) or chronic thromboembolic PH (CTEPH, n = 7) in WHO functional class II (n = 26) or III (n = 4) were compared to 15 healthy controls. Lung SPECT was performed after injection of 15 mCi 99mTc-PulmoBind in supine position. Qualitative and semi-quantitative analyses of lung uptake were performed. Reproducibility of repeated testing was evaluated in controls after 1 month. RESULTS: PulmoBind injection was well tolerated without any serious adverse event. Imaging was markedly abnormal in PH with ∼50% of subjects showing moderate to severe heterogeneity of moderate to severe extent. The abnormalities were unevenly distributed between the right and left lungs as well as within each lung. Segmental defects compatible with pulmonary embolism were present in 7/7 subjects with CTEPH and in 2/23 subjects with PAH. There were no segmental defects in controls. The PulmoBind activity distribution index, a parameter indicative of heterogeneity, was elevated in PH (65% ± 28%) vs. controls (41% ± 13%, p = 0.0003). In the only subject with vasodilator-responsive idiopathic PAH, PulmoBind lung SPECT was completely normal. Repeated testing 1 month later in healthy controls was well tolerated and showed no significant variability of PulmoBind distribution. CONCLUSIONS: In this phase II study, molecular SPECT imaging of the pulmonary vascular endothelium using 99mTc-PulmoBind was safe. PulmoBind showed potential to detect both pulmonary embolism and abnormalities indicative of pulmonary vascular disease in PAH. Phase III studies with this novel tracer and direct comparisons to lung perfusion agents such as labeled macro-aggregates of albumin are needed. CLINICAL TRIAL: ClinicalTrials.gov, NCT02216279.

Molecular Imaging of the Human Pulmonary Vascular Endothelium Using an Adrenomedullin Receptor Ligand.

This phase I study (NCT01539889) evaluated the safety, efficacy, and dosing of PulmoBind for molecular imaging of pulmonary circulation. PulmoBind is a ligand of the adrenomedullin receptor abundantly distributed in lung capillaries. Labeled with 99mTc, it allows single-photon emission computed tomographic (SPECT) imaging of lung perfusion. In preclinical studies, PulmoBind scans enabled detection of lung perfusion defects and quantification of microcirculatory occlusion caused by pulmonary hypertension. Healthy humans ( N = 20) were included into escalating groups of 5 mCi ( n = 5), 10 mCi ( n = 5), or 15 mCi ( n = 10) 99mTc-PulmoBind. SPECT imaging was serially performed, and 99mTc-PulmoBind dosimetric analysis was accomplished. The radiochemical purity of 99mTc-PulmoBind was greater than 95%. There were no safety concerns at the three dosages studied. Imaging revealed predominant and prolonged lung uptake with a mean peak extraction of 58% ± 7%. PulmoBind was well tolerated, with no clinically significant adverse event related to the study drug. The highest dose of 15 mCi provided a favorable dosimetric profile and excellent imaging. The postural lung perfusion gradient was detectable. 99mTc-PulmoBind is safe and provides good quality lung perfusion imaging. The safety/efficacy of this agent can be tested in disorders of pulmonary circulation such as pulmonary arterial hypertension.

Molecular imaging of the human pulmonary vascular endothelium using an adrenomedullin receptor ligand.

This phase I study (NCT01539889) evaluated the safety, efficacy, and dosing of PulmoBind for molecular imaging of pulmonary circulation. PulmoBind is a ligand of the adrenomedullin receptor abundantly distributed in lung capillaries. Labeled with 99mTc, it allows single-photon emission computed tomographic (SPECT) imaging of lung perfusion. In preclinical studies, PulmoBind scans enabled detection of lung perfusion defects and quantification of microcirculatory occlusion caused by pulmonary hypertension. Healthy humans (N  =  20) were included into escalating groups of 5 mCi (n  =  5), 10 mCi (n  =  5), or 15 mCi (n  =  10) 99mTc-PulmoBind. SPECT imaging was serially performed, and 99mTc-PulmoBind dosimetric analysis was accomplished. The radiochemical purity of 99mTc-PulmoBind was greater than 95%. There were no safety concerns at the three dosages studied. Imaging revealed predominant and prolonged lung uptake with a mean peak extraction of 58% ± 7%. PulmoBind was well tolerated, with no clinically significant adverse event related to the study drug. The highest dose of 15 mCi provided a favorable dosimetric profile and excellent imaging. The postural lung perfusion gradient was detectable. 99mTc-PulmoBind is safe and provides good quality lung perfusion imaging. The safety/efficacy of this agent can be tested in disorders of pulmonary circulation such as pulmonary arterial hypertension.

Decreased CYP3A expression and activity in guinea pig models of diet-induced metabolic syndrome: is fatty liver infiltration involved?

BACKGROUND: In humans, CYP3A drug-metabolizing enzyme subfamily is the most important. Numerous pathophysiological factors, such as diabetes and obesity, were shown to affect CYP3A activity. Often considered a precursor state for type II diabetes, metabolic syndrome exerts a modulating role on CYP3A, in our hypothesis. OBJECTIVE: To evaluate the effect of metabolic syndrome on CYP3A drug-metabolizing activity/expression in guinea pigs. METHODS: Hepatic microsomes were prepared from male Hartley guinea pigs fed with a control, a high-fat high sucrose (HFHS) or a high-fat high fructose diet (HFHF). Domperidone was selected as a probe substrate of CYP3A and formation of four of its metabolites was evaluated using high-performance liquid chromatography. CYP3A protein and mRNA expression were assessed by Western blot and reverse-transcription quantitative polymerase chain reaction, respectively. Hepatic fatty infiltration was evaluated using standard Oil Red O staining. Triglyceride and free fatty acid liver content were also quantified. RESULTS: Microsomal CYP3A activity was significantly decreased in both HFHS and HFHF diet groups versus the control diet group. Significant decreases of CYP3A mRNA and protein expression were observed in both HFHS and HFHF diet groups. Oil Red O staining showed a massive liver fatty infiltration in the HFHS and HFHF diet groups, which was not observed in the control diet group. Both triglyceride and free fatty acid liver content were significantly increased in the HFHS and HFHF diet groups. CONCLUSION: Diet-induced metabolic syndrome decreases CYP3A expression/activity in guinea pigs. This may ultimately lead to variability in drug response, ranging from lack of effect to life-threatening toxicity.

Metabolic syndrome potentiates the cardiac action potential-prolonging action of drugs: a possible 'anti-proarrhythmic' role for amlodipine.

Type II diabetes was shown to prolong the QT interval on the ECG and to promote cardiac arrhythmias. This is not so clear for metabolic syndrome, a precursor state of type II diabetes. The objectives of the present study were to generate a guinea pig model of metabolic syndrome by long-term exposure to diabetogenic diets, and to evaluate the monophasic action potential duration (MAPD)-modulating effects of drugs in these animals. Male Hartley guinea pigs were fed with either the control, the High Fat High Sucrose (HFHS) or the High Fat High Fructose (HFHF) diet for 150 days. Evolution of weight, blood cholesterol, triglycerides, urea and glucose tolerance were regularly monitored. Histopathological evolution was also evaluated in target organs such as pancreas, heart, liver and kidneys. Ex vivo experiments using the Langendorff retroperfusion technique, isolated hearts from guinea pigs either fed with the control, the HFHS or the HFHF diet were exposed to dofetilide 20 nM (D), chromanol 293B 10 µM (C) and amlodipine 100 nM (A) in different drug combinations and monophasic action potential duration was measured at 90% repolarization (MAPD90). Our data show that it is possible to generate a guinea pig model of metabolic syndrome by chronic exposure to diabetogenic diets. Minor histopathological abnormalities were observed, mainly in the pancreas and the liver. Metabolic syndrome potentiates the MAPD-prolonging actions of I(Kr)-blocking (dofetilide) and I(Ks)-blocking (chromanol 293B) drugs, an effect that is reversible upon administration of the calcium channel blocker amlodipine.

Evaluation of pulmonary perfusion by SPECT imaging using an endothelial cell tracer in supine humans and dogs.

BACKGROUND: Pulmonary perfusion is not spatially homogeneously distributed, and its variations could be of diagnostic value in lung vascular disease. PulmoBind is a ligand of the adrenomedullin receptor densely expressed in endothelial cells of lung capillaries. The aim of this study was to evaluate spatial distribution of human lung perfusion by using this novel molecular tracer of the pulmonary vascular endothelium. METHODS: Normal humans (n = 19) enrolled into the PulmoBind phase I trial were studied (Clinicaltrials.gov. NCT01539889 ). They were injected with (99m)Tc-PulmoBind for SPECT imaging. Results were compared with (99m)Tc-PulmoBind in quadruped mammals (dogs, n = 5). Imaging was performed in the supine position and distribution of activity was determined as a function of cumulative voxels along the different anatomical planes. RESULTS: PulmoBind uptake in humans was 58 ± 1 % (mean ± SEM) of the injected dose. Dorsal activity was 18.1 ± 2.1 % greater than ventral, and caudal activity was 25.7 ± 1.6 % greater than cranial. Lateral activity was only mildly higher than medial by 7.0 ± 1.0 %. In supine dogs, similar but higher PulmoBind gradients were present: dorsal 28.6 ± 2.5 %, caudal 34.1 ± 5.0 % and lateral 18.1 ± 2.0 %. CONCLUSIONS: The perfused pulmonary circulation of supine humans, assessed by an adrenomedullin receptor ligand, is not homogeneously distributed with more prominent distribution in dorsal and caudal regions. It is qualitatively similar to a supine quadruped mammal confirming the presence of a microcirculatory gravitational perfusion gradient detectable with this tracer. Future studies are needed to determine if this novel endothelial cell tracer could be used to detect physiologic and pathologic variations of lung perfusion such as in pulmonary hypertension. CLINICAL TRIAL: ClinicalTrial.gov, NCT01539889.