Lung Uptake Research Articles

Active Uptake of Ulifloxacin from Plasma to Lung That Controls Its Concentration in Epithelial Lining Fluid

Ulifloxacin is a new quinolone antibiotic and it is effective against pneumonia. We previously showed that it is highly distributed into the epithelial lining fluid (ELF) in rats, which might be resulting from certain active transport. The transport system has not been, however, clarified yet. In this study, we attempted to characterize the distribution mechanism of ulifloxacin into the rat ELF. We also aimed to elucidate the feature of ulifloxacin uptake in rat lung and human lung adenocarcinoma cells (Calu-3). In infusion studies, ulifloxacin concentrations in the ELF and lung were higher than that in the plasma, and decreased by co-administration of sparfloxacin or azithromycin to the level of plasma concentration. Integration plot analysis showed that active uptake of ulifloxacin from the plasma to lung was also inhibited by sparfloxacin and azithromycin. In in vitro studies, time and temperature-dependent uptake into Calu-3 was observed, and this uptake was inhibited by sparfloxacin and azithromycin as observed in the rat lung. Additionally sparfloxacin inhibited the active uptake of ulifloxacin into Calu-3 more strongly than levofloxacin as observed in the rat lung. These results suggest that active uptake of ulifloxacin from the plasma to lung controls the distribution of ulifloxacin from the plasma to ELF, and that the uptake of ulifloxacin into Calu-3 has partly similar characteristics to its uptake into the rat lung. We believe our study will contribute to much better understanding of antibiotic efficacy against pathogens which cause pneumonia.

Unsuspected Second Malignancy Detection by FDG PET Scan

A whole body F-18 FDG PET scan was done on a 45-year-old man with a small cell carcinoma of the left lung for a metastatic survey. Imaging showed intense uptake in the left lung (maximum standardized uptake value (SUVmax) of 8.32 corrected for body weight), at the site of the primary and in the hilar lymph nodes. Focal intense uptake was also seen in the rectum (SUVmax of 21.73 corrected for body weight). No anatomic imaging for the pelvis was done, as the patient had no bowel symptoms. Posttreatment PET scan done 9 months after the first scan showed significant reduction in the primary mass in the lung (SUVmax 4.45) but an increase in the rectal mass (SUVmax 83.22). He now complained of bleeding per rectum. Colonoscopy and CT scan of the abdomen showed a mass in the rectum, which on biopsy revealed invasive adenocarcinoma.

Aerosoltherapy in lung cancer

Introduction: Although airways route is an attractive alternative route to systemic administration, increasing concentration of the drug in the lungs while reducing whole-body toxicity, it is not often exploited in lung cancer treatment. After checking that cetuximab, an anti-cancer antibody binding to EGFR, resists the physical constraints of nebulization, we established an animal model of lung tumour sensitive to the antibody. Then, we used the animal model to evaluate cetuximab antitumor efficiency, biodistribution and pharmacokinetic following delivery through airways. Methods: Cetuximab was nebulized with the IA-1C MicroSprayer™ (PennCentury Inc., USA) connected to a FMJ-250 high pressure syringe, a device used to administrate, directly inside the trachea, aerosol in mice. The effect of nebulization on cetuximab was assessed in terms of its affinity for membrane EGFR (using flow cytometry), inhibition of cell growth and inhibition of EGFR phosphorylation. To ensure that airways delivery of cetuximab did not lead to additional toxicity, we compared tolerance to cetuximab delivered through systemic and pulmonary routes in mice without tumors. An animal model of lung cancer sensitive to cetuximab was established and consists in the instillation of human epidermoid carcinoma cells endotracheally in nude mice. The model was exploited to study cetuximab biodistribution and pharmacokinetic following delivery through systemic and pulmonary routes. Therapeutic efficiency of nebulized cetuximab was determined in tumor- bearing animals. Results: Firstly, our results showed that MicroSprayer™ did not alter cetuximab integrity, immunological and pharmacological properties. Secondly, airways administration of cetuximab in mice seemed to be well-tolerated and did not induced additional toxicity in lungs, kidney, colon, skin, liver or spleen. Finally, higher, more rapid and prolonged lung uptake was observed in animals receiving cetuximab through the pulmonary route. Antitumor efficiency of nebulized cetuximab is currently under investigation. Conclusion: These results highlight the potential of the pulmonary route for delivery of anticancer antibody in lung cancer.

Important parameters in the detection of left main trunk disease using stress myocardial perfusion imaging

We sought noninvasively to diagnose left main trunk (LMT) disease using myocardial perfusion imaging (MPI). Five hundred and eight patients with suspected coronary artery disease (CAD) underwent both stress MPI and coronary angiography. The extent and severity of perfusion abnormalities were assessed using a 20-segment model. In addition, perfusion defects in both left anterior descending and left circumflex arterial territories were defined as a left main (LM) pattern defect, and those in 3-coronary arterial territories as a 3-vessel pattern defect. In 42 patients with LMT disease, a summed stress score (19.4 ± 10.0 vs. 13.5 ± 10.0; p < 0.0001) and a summed rest score (12.1 ± 9.7 vs. 7.0 ± 7.8; p = 0.002) were greater than in 466 patients without LMT disease, while a summed difference score was similar (7.3 ± 7.7 vs. 6.5 ± 6.1; p = NS). The prevalence of an LM-pattern defect was low in both groups (12% vs. 8%; p = NS). However, a 3-vessel pattern defect (33% vs. 7%; p < 0.0001), lung uptake of radiotracers (38% vs. 11%; p < 0.0001), and transient ischemic dilation (31% vs. 13%; p = 0.003) were more frequently observed in patients with LMT disease than in those without. Logistic regression analysis showed that a 3-vessel pattern defect (OR=3.5, 95% CI = 1.4-8.8; p = 0.007), lung uptake of radiotracers (OR = 2.5, 95% CI = 1.1-5.7; p = 0.03), and previous myocardial infarction (MI) (OR = 2.4, 95% CI = 1.0-5.7; p = 0.05) were the most important parameters to detect LMT disease. After excluding 163 patients with previous MI, a repeat analysis revealed that lung uptake of radiotracers (OR = 8.2, 95% CI = 2.3-29.2; p = 0.001) and an LM-pattern defect (OR = 6.3, 95% CI = 1.4-27.2; p < 0.02) were independent predictors for LMT disease. In the identification of LMT disease, lung uptake of radiotracers was a single best parameter, which was independent of the presence or absence of previous MI.

Drug-induced pneumonitis detected earlier by 18F-FDG-PET than by high-resolution CT: a case report with non-Hodgkin’s lymphoma

Drug-induced pneumonitis is a serious and an unpredictable side effect of chemotherapy in patients with malignant lymphoma. We present the case of a 51-year-old man who developed drug-induced pneumonitis during chemotherapy for non-Hodgkin's lymphoma in which pneumonitis was detected earlier by 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) than by high-resolution computed tomography (HRCT). After five courses of chemotherapy, 18F-FDG-PET was performed for assessing residual lesions, and diffuse lung uptake was incidentally observed. No symptoms were present, and HRCT performed immediately following PET revealed no abnormalities. Mild dyspnea appeared 3 days after PET, and additional HRCT revealed patchy ground-glass opacities disseminated with the appearance of interlobular septum thickening. Drug-induced pneumonitis was finally diagnosed, and treatment was initiated. 18F-FDG-PET can be an imaging modality for detecting drug-induced pneumonitis at an extremely early stage in which HRCT is incapable of revealing any abnormal changes.

99mTc-MIBI imaging of AIDS-related Kaposi's sarcoma in the lungs

Pulmonary Kaposi's sarcoma (KS) occurs in more than 10% of patients with acquired immunodeficiency syndrome (AIDS) and has a high mortality rate. Prompt detection, diagnosis, and treatment reduce patient morbidity and mortality. The objective of this study was to determine the efficacy of 99mTc-hexakis-2-methoxy isobutyl isonitrile (99mTc-MIBI) imaging in detecting pulmonary AIDS-related KS. 99mTc-MIBI imaging was performed on 72 human immunodeficiency virus-seropositive patients with bronchoscopic diagnosis of pulmonary KS (36 patients), pneumonia (22), normal tracheo-bronchial tree (11), lymphoma (2), and bronchogenic carcinoma (1). Lung uptake and lymph node detection in KS were compared on planar and single photon emission computed tomography (SPECT) scans. The lung/myocardium ratios on the 1-h planar images were significantly higher in KS and normal lungs than opportunistic infection. Using the lung/myocardium ratio of 1 as cutoff, the sensitivity, specificity, and accuracy of the 1-h planar images for detecting pulmonary KS were 75, 57.58, and 66.67%, respectively. Abnormal lymph node uptake, pleural/pericardial effusions, and ascites were detected more readily on SPECT. Planar 99mTc-MIBI imaging has moderate sensitivity, specificity, and accuracy for detecting pulmonary KS. SPECT is more effective in detecting abnormal lymph nodes, pleural/pericardial effusions, and ascites. 99mTc-MIBI SPECT followed by planar imaging at 40-60 min can be useful in assessing pulmonary KS.

Reduced lung uptake of Iodine‐123 metaiodobenzylguanidine in high‐altitude pulmonary oedema

Iodine-123 metaiodobenzylguanidine ((123)I-MIBG) uptake in the lungs is a potentially suitable marker of pulmonary endothelial function because MIBG behaviour in the pulmonary circulation is quantitatively similar to that of norepinephrine. In addition, hypoxia reduces (123)I-MIBG transport in pulmonary endothelial cells in vitro. The present study was undertaken to evaluate (123)I-MIBG uptake in the lungs of patients with high-altitude pulmonary oedema (HAPE). (123)I-MIBG scintigraphy was performed in eight patients with HAPE. The findings were compared with those in 24 patients with congestive heart failure due to idiopathic dilated cardiomyopathy (DCM) and in 13 normal control subjects. In patients with HAPE, the (123)I-MIBG examination was performed 7-14 days after admission. Anterior planar images were acquired 15 min after injection of (123)I-MIBG and the total lung to upper mediastinum ratio (L/M ratio) was calculated for both lungs. The L/M ratio in patients with HAPE (1.39 +/- 0.15, mean +/- SD) was significantly lower than in those with congestive heart failure/DCM (1.66 +/- 0.16) or in normal controls (1.53 +/- 0.14). There were no significant differences among the groups in (123)I-MIBG accumulation in the heart. Although the mechanism of altered (123)I-MIBG kinetics in HAPE remains obscure, decreased (123)I-MIBG uptake in the lungs may potentially be a suitable technique for the assessment of pathological conditions associated with the pulmonary endothelium.

Assessment of 18F-labeled mitochondrial complex I inhibitors as PET myocardial perfusion imaging agents in rats, rabbits, and primates

Myocardial extractions of mitochondria complex I (MC-I) inhibitors were high and well correlated with flow. This study assessed the potential of MC-I inhibitors to be developed as myocardial perfusion imaging (MPI) agents. RP1003, RP1004, and RP1005 representing three classes of MC-I inhibitor were synthesized and radio-labeled with (18)F. These agents were evaluated for IC(50) values, tissue biodistribution, and cardiac PET imaging. (18)F-RP1004 was further examined for first-pass extraction and by imaging in non-human primates (NHP) and rats following coronary ligation. RP1003, RP1004, and RP1005 exhibited high MC-I inhibitory activity with IC(50) of 3.7, 16.7, and 14.4 nM. Heart uptakes in rats (percent injected dose per gram tissue) at 15 and 60 min after injection were 3.52 +/- 0.36 and 2.68 +/- 0.20 for (18)F-RP1003, 2.40 +/- 0.21 and 2.67 +/- 0.27 for (18)F-RP1004, and 2.28 +/- 0.12 and 1.81 +/- 0.17 for (18)F-RP1005. The heart to lung and liver uptake ratios were favorable for cardiac imaging with these agents. In isolated perfused rabbit hearts, the uptake of (18)F-RP1004 increased from 0.74 +/- 0.19 to 1.68 +/- 0.39 mL/min/g at flow rates of 1.66 to 5.06 mL/min/g. These values were higher than or similar to that of (99m)Tc-sestamibi. Cardiac imaging with these agents in rats and rabbits allowed visualization of the heart with minimal lung interference and rapid liver activity clearance. Imaging with (18)F-RP1004 also showed clear myocardium and marked liver activity washout in the NHP and clear detection of the perfusion-deficit area associated with left coronary artery ligation in the rat. MC-I inhibitors have the potential to be a new class of MPI agent.

FDG-PET in patients at risk for acute respiratory distress syndrome: a preliminary report

To compare the pattern of lung uptake of 18F-fluorodeoxyglucose (FDG) by positron emission tomography (PET) imaging in patients with lung contusion that developed or did not progress to acute respiratory distress syndrome (ARDS). Prospective, observational study. Trauma Center (academic urban hospital). Eight patients with blunt thoracic trauma and pulmonary contusion, confirmed by computed tomography (CT) on admission, underwent repeat CT and FDG-PET (on the same day) 24-72 h after admission. No subjects met the criteria for ARDS at the time of the PET and second CT. Four subjects subsequently developed ARDS 1-3 days after the PET scan; the other four did not develop the syndrome. Three of the four subjects who subsequently developed ARDS showed diffuse FDG uptake throughout the entire lungs, while those who did not develop ARDS showed significant FDG uptake only in areas of focal lung opacity (non or poorly aerated lung units) on CT. FDG uptake in normally aerated lung regions was higher for those who subsequently developed ARDS than those who did not, approaching statistical significance. The normally aerated tissue:liver ratio was significantly higher in subjects who developed ARDS than in those who did not (P = 0.029). In this small series of patients with thoracic trauma, diffuse lung uptake of FDG was detected by PET imaging 1-3 days prior to clinically determined ARDS.

Imaging of Fibrogenesis in Patients with Idiopathic Pulmonary Fibrosis with cis-4-[18F]-Fluoro-l-Proline PET

Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease for which no single diagnostic modality is able to evaluate the activity of the disease process. Cis-4-(18)F-fluoro-L: -proline ((18)F-proline) was shown in animal studies to be a reliable marker for fibrosis formation. We tested this candidate radioligand for imaging of fibrogenesis in patients with IPF. Five patients with IPF proven by lung biopsy and computed tomography were included. Furthermore, we also included one patient with non-specific interstitial pneumonia (NSIP) and scleroderma and one with NSIP and organising pneumonia. Positron emission tomography (PET) acquisition was performed 1, 2 and 3h after injection of 400MBq (18)F-proline. We scored (18)F-proline activity visually and quantitatively by calculating the activity in the regions of interest over lung, liver and mediastinum. We found low uptake of (18)F-proline in the lungs of all patients with IPF. The highest uptake was seen at 2h post-injection, with a decline at 3h past injection. The differences in lung uptake between patients were small, except for one patient with NSIP and organising pneumonia who had a slightly higher (18)F-proline uptake. No significant correlations between (18)F-proline uptake and clinical parameters were found. Due to the low pulmonary uptake of (18)F-proline in patients with IPF, (18)F-proline does not seem to be a suitable radioligand to evaluate the activity of fibrosis formation in patients with IPF. The low uptake in the lungs of patients with interstitial fibrosis may be explained by the slow nature of fibrogenesis or to the relatively low dose of proline that can be used.

Granulomatous disease: is it a nuisance or an asset during PET/computed tomography evaluation of lung cancers?

To evaluate combined PET-computed tomography (CT) criteria for differentiating between granulomatous disease (GD) and malignancy (CA) in oncologic PET-CT studies. Sixty-two patients who were referred for fluoro-2-deoxyglucose (FDG) PET-CT evaluation of pulmonary lesion(s) without a history of concurrent infection were studied. PET-CT was performed 1.5 h after intravenous administration of 555 MBq 18F-FDG in the fasting state with oral contrast. Combined PET-CT criteria including (i) calcifications (Ca2+) within lymph nodes, (ii) Ca2+ in lung nodules, (iii) liver and/or spleen Ca2+, (iv) locations of lung lesion(s), (v) hilar FDG uptake, (vi) comparison of lung versus maximum mediastinal FDG uptake, (vii) lymph node uptake not in the most probable lymphatic drainage pathway from a particular lung lesion, and (viii) extra pulmonary abnormal FDG uptake were each assigned a numerical score (0-3) with progressively higher score and sum of scores toward the increasing likelihood of GD. These patients either had pathological confirmation by biopsy/resection or were followed radiographically for a period of 2 years (CA=13; GD=49). Discriminant analysis was performed on all the above criteria with this gold standard. Simple t-test and box plot analysis were also performed on the summation of the scores (from 0 in CA to 13 in GD). When all eight criteria were entered into discriminant analysis, the combined PET-CT criteria classified correctly 71% of patients with a sensitivity of 65% and specificity of 92% for GD. The most significant discriminating criterion was FDG uptake in the lung lesion(s) less than maximum mediastinal uptake (P=0.01). The sum scores in GD and CA were significantly different (4.9+/-2.4 vs. 3.2+/-1.5, respectively, P=0.014). Box plots showed a clear separation at a cut-off value of around 3.5. Results show that the set of combined PET-CT criteria are highly specific for GD, which is not necessarily a nuisance during oncologic evaluation. Knowledge of these criteria may attribute some of the abnormal PET findings to GD, which is a useful asset for quick recognition and clinical interpretation.

Preparation and evaluation of [67Ga]-DTPA-β-1–24-corticotrophin in normal rats

β-1–24-corticotrophin was successively labeled with [67Ga]-gallium chloride after residulation with freshly prepared cyclic DTPA-dianhydride. The best results of the conjugation were obtained by the addition of 1 ml of a β-1–24-corticotrophin pharmaceutical solution (1 mg/mL, pH=6.5) to a glass tube pre-coated with DTPA-dianhydride (0.01 mg) at 25 °C with continuous mild stirring for 30 min. Radio-thin layer chromatography showed an overall radiochemical purity of &gt;90% at optimized conditions after labeling. HPLC showed a radiochemical purity more than 95% (specific activity =300–500 MBq/mg, labeling efficiency 77%). The stability of the radioconjugate was tested in presence of human serum at 37 °C. Preliminary in vivo studies in normal rats were performed to determine the biodistribution of the radioimmunoconjugate up to 30 min. Lungs showed to have the major tracer uptake which is consistent with the natural distribution of ACTH receptors in human body. Pretreatment of animals with cold peptide following labeled compound administration reduced lung uptake at least 10 and 3 times after 15 and 30 min, respectively, as well as significant decrease in adrenal uptake after 15 min. These data support the specific receptor binding of the radiolabeled compound. This tracer can be used in detection of ACTH receptor in lung and adrenal malignancies.

Risk Stratification Assessed by Combined Lung and Heart Iodine-123 Metaiodobenzylguanidine Uptake in Patients With Idiopathic Dilated Cardiomyopathy

Iodine-123 metaiodobenzylguanidine (123I-MIBG) has been used to assess myocardial sympathetic nervous activity and severity of heart failure. (123)I-MIBG is also used as a potential marker of pulmonary endothelial cell function and may be related to pulmonary hypertension. Thus, we hypothesized that combined assessment of lung and heart 123I-MIBG kinetics predicts future clinical outcome more accurately than myocardial evaluation alone in patients with chronic heart failure. To test this hypothesis, we examined 123I-MIBG scintigrams in 62 consecutive patients with idiopathic dilated cardiomyopathy. Anterior planar images were obtained 15 minutes and 3 hours after 123I-MIBG injection. Cardiac and pulmonary 123I-MIBG activities were quantified as heart-to-mediastinum activity ratio and lung-to-mediastinum activity ratio. We introduced lung-to-heart activity ratio as the new 123I-MIBG parameter including myocardial sympathetic nerve activity and pulmonary endothelial cell function. Delayed lung-to-heart ratio was correlated with pulmonary vascular resistance (r = 0.48, p <0.0001), disease duration (r = 0.49, p <0.0001), and number of heart failure episodes (r = 0.55, p <0.0001). During a mean follow-up of 25 months, 15 patients had a cardiac event. Area under receiver operating characteristic curves for prediction of the event was greatest in delayed lung-to-heart ratio (lung to heart 0.92, heart to mediastinum 0.83, lung to mediastinum 0.80). In multivariate analysis, the lung-to-heart ratio (hazard ratio 2.76/0.1 increase, p = 0.002) was selected as an independent predictor for a future cardiac event. In conclusion, the combined assessment of lung and heart 123I-MIBG uptake may help to predict future clinical outcome for patients with idiopathic dilated cardiomyopathy more accurately than myocardial evaluation alone.

Distribution of Free and Liposomal Doxorubicin After Isolated Lung Perfusion in a Sarcoma Model

Isolated lung perfusion (ILP) with free and a novel liposomal-encapsulated doxorubicin (Liporubicin, CT Sciences SA, Lausanne, Switzerland) was compared with respect to drug uptake and distribution in rat lungs bearing a sarcomatous tumor. A single sarcomatous tumor was generated in the left lung of 39 Fischer rats, followed 10 days later by left-sided ILP (n = 36) with free and equimolar-dosed liposomal doxorubicin at doses of 100 microg (n = 9) and 400 microg (n = 9) for each doxorubicin formulation. In each perfused lung, the drug concentration and distribution were assessed in the tumor and in three areas of normal lung parenchyma by high-performance liquid chromatography (n = 6) and fluorescence microscopy (n = 3). Histologic assessment and immunostaining with von Willebrand factor was performed in 3 animals with untreated tumors. The sarcomatous tumors in controls were well vascularized with fine branching capillaries present throughout the tumors. Isolated lung perfusion resulted in a heterogeneous drug distribution within the perfused lung and a consistently lower drug uptake in tumors than in lung parenchyma for both doxorubicin formulations and both drug doses applied. Isolated lung perfusion with free doxorubicin resulted in a significantly higher drug uptake than Liporubicin in both the tumor and lung tissue for both drug doses applied (p < 0.01). However, the tumor/normal tissue drug ratio was lower for free than for liposomal doxorubicin at a drug dose of 100 microg (0.27 +/- 0.1 vs 0.53 +/- 0.5; p = 0.225) and similar for both doxorubicin formulations at a drug dose of 400 microg (0.67 +/- 0.2 vs 0.54 +/- 0.2; p = 0.335). Both doxorubicin formulations resulted in fluorescence signaling emerging from all tissue compartments of normal lung parenchyma but only in weak and sporadic signaling from the tumors confined to the tumor periphery and vessels situated within the tumor for both drug doses assessed. Isolated lung perfusion with free and liposomal doxorubicin resulted in a heterogeneous drug distribution within the perfused lung and in a lower drug uptake in tumors than in lung tissue for both doxorubicin formulations and drug doses applied.

Metastatic Human Colonic Carcinoma: Molecular Imaging with Pretargeted SPECT and PET in a Mouse Model

To prospectively determine if a bispecific monoclonal antibody (MoAb) pretargeting method with a radiolabeled hapten peptide can depict small (<0.3 mm in diameter) microdisseminated human colon cancer colonies in the lungs of nude mice. Animal studies were approved in advance by animal care and use committees. Animals injected intravenously with a human colon cancer cell line to establish microdisseminated colonies in the lungs were pretargeted with TF2--a recombinant, humanized, anti-carcinoembryonic antigen (CEA) and anti-histamine-succinyl-glycine (HSG) bispecific MoAb; 21 hours later, a radiolabeled HSG peptide was given. Imaging and necropsy data for tumor-bearing animals given the anti-CEA bispecific MoAb (n = 38, all studies) were compared with those of animals given fluorine 18 ((18)F) fluorodeoxyglucose (FDG) (n = 15, all studies), peptide alone (n = 20, all studies), or an irrelevant anti-CD22 bispecific MoAb (n = 12, all studies). Uptake of these agents in the lungs of non-tumor-bearing animals enabled assessment of specificity (n = 15, 4, and 6 for TF2 pretarget, hapten peptide alone, and (18)F-FDG, respectively). TF2-pretargeting helped localize tumors in the lungs within 1.5 hours of the radiolabeled HSG peptide injection, while the peptide alone, irrelevant bispecific MoAb pretargeted peptide, and (18)F-FDG failed. Necropsy data indicated that the signal in tumor-bearing lungs was five times higher than in blood within 1.5 hours, increasing to 50 times higher by 24 hours. Peptide uptake in tumor-bearing lungs pretargeted with TF2 was nine times higher than in non-tumor-bearing lungs, while it was only 1.5-fold higher with (18)F-FDG or the peptide alone. Micro-positron emission tomographic (PET) images showed discrete uptake in individual metastatic tumor colonies; autoradiographic data demonstrated selective targeting within the lungs, including metastases less than 0.3 mm in diameter. Bispecific antibody pretargeting is highly specific for imaging micrometastatic disease and may thus provide a complementary method to (18)F-FDG at clinical examination.

Mannosylated gelatin nanoparticles bearing an anti-HIV drug didanosine for site-specific delivery

The present investigation was aimed at developing and exploring the use of mannosylated gelatin nanoparticles for the selective delivery of an anti-HIV drug, didanosine, to the target organs. The mannosylated gelatin nanoparticles (MN-G-NPs) were prepared using a two-step desolvation technique and coupled with mannose using the amino group of gelatin present on the surface of nanoparticles. The mannosylation was confirmed using infrared and nuclear magnetic resonance spectroscopy. MN-G-NPs were characterized for shape, particle size, zeta potential, and percentage drug entrapment. The size of nanoparticles was found to be in range of 248–325 nm, and maximum drug payload was found to be 40.2% to 48.5%. Average size was found to be more, but drug payload was less in the case of MN-G-NPs as compared with unconjugated nanoparticles (G-NPs). The results of the in vitro release profile demonstrated that G-NPs release a comparatively higher percentage of drug than MN-G-NPs. Cellular uptake by MN-G-NPs was 2.7 times more as compared with G-NPs. Fluorescence studies revealed the enhanced uptake of MN-G-NPs in the macrophage tissues when compared with unmodified G-NPs. Intravenous administration of free-drug solution resulted in a high concentration of drug in serum, whereas it was much less in the case of G-NPs. Coupling of the nanoparticles with mannose significantly enhanced the lung, liver, and lymph nodes uptake of drug, which is reflected in the recovery of a higher percentage of the dose from these organs following administration of MN-G-NPs in comparison to noncoupled G-NPs or free drug.

A place for TL,NO with TL,CO?

In 1915, Krogh 1 first measured the diffusion of carbon monoxide to demonstrate that oxygen passively diffused from the alveolus to pulmonary capillary blood. The history review by Hughes and Bates 2 discusses this excellently. Subsequently, in 1957, Roughton and Forster 3 demonstrated that CO diffusion measured by the diffusing capacity of the lung for CO ( D L,CO) reflected both alveolar capillary membrane diffusion and reaction with pulmonary capillary blood. The overall resistance is: 1/ D L,CO = 1/ D m +1/Θ V c (1) where D m is the membrane diffusing capacity, Θ the specific transfer conductance of the blood (measured by CO reaction with red cells using a rapid reaction apparatus) and V c the pulmonary capillary blood volume 3. In healthy young volunteers, D L,CO is 30 mL·min−1 torr−1, D m is 57 mL·min−1 torr−1 and V c is 80 mL. To acknowledge that the overall process involved more than just diffusion, J. Cotes coined the term transfer factor of the lung for CO ( T L,CO). In 1982, T. Higenbottam and I were studying lung uptake and toxicity of NO in cigarette smokers; A. Chamberlain (our then research assistant) suggested that we measure this as transfer factor of the lung for NO ( T L,NO). Quite independently, ∼10 yrs earlier, the late D. Bargeton and H. Guenard had speculated that if another gas could be found that reacted with haemoglobin, by inhaling it simultaneously with CO, the equation of Roughton and Forster 3 could be solved for D m and V c in a single breath rather than by measuring T L,CO at two or more oxygen concentrations and cardiac outputs. NO reacts, in effect, instantly with haemoglobin. The resulting single-breath studies from our respective two groups 4, 5 generated much interest, including an editorial …

Does Beta Blocker Therapy Affect the Diagnostic Accuracy of Adenosine Single-Photon-Emission Computed Tomographic Myocardial Perfusion Imaging?

We retrospectively evaluated perfusion defect presence, extent, and severity in 158 consecutive patients receiving beta blockers, who underwent adenosine single-photon-emission computed tomography (SPECT) myocardial perfusion imaging (MPI) and coronary angiography. Seventy-six patients (group 1) had their beta blockers withdrawn 48 hours prior to testing, and 82 patients (group 2) remained on the beta blocker regimen. Groups 1 and 2 were similar in gender, age, pretest symptoms, and history of coronary artery disease (CAD). Group 1 patients had higher resting heart rates (79 +/- 19/min versus 68 +/- 13/min; P < 0.001), peak heart rates (91 +/- 21/min versus 80 +/- 15/min; P < 0.001), resting diastolic blood pressures (82 +/- 14 mm Hg versus 74 +/- 13 mm Hg; P < 0.001), peak systolic blood pressures (139 +/- 23 mm Hg versus 124 +/- 23 mm Hg; P < 0.001), and peak diastolic blood pressures (72 +/- 12 mm Hg versus 68 +/- 11 mm Hg; P = 0.04) than group 2 patients. Group 1 also had a higher incidence of angina during the 48 hours off beta blockers than group 2 (10% versus 2%; P < 0.001). There was no significant difference between the two groups in symptoms and side effects during adenosine infusion, quantitated lung/heart ratio, visually assessed lung uptake, transient ischemic dilation, post-stress ejection fraction, summed stress score, summed rest score, and summed difference score. In conclusion, in patients with CAD, beta blocker therapy does not affect the extent, severity, and reversibility of perfusion defects on adenosine SPECT MPI.

In Vivo Imaging of64Cu-Labeled Polymer Nanoparticles Targeted to the Lung Endothelium

Nanoparticles (NPs) targeting the intercellular adhesion molecule 1 (ICAM-1) hold promise as a mean of delivering therapeutics to the pulmonary endothelium in patients with acute and chronic respiratory diseases. As these new materials become available, strategies are needed to understand their behavior in vivo. We have evaluated the use of (64)Cu and PET to noninvasively image the lung uptake and distribution of NPs coated with an anti-ICAM antibody. Model fluorescent NPs were coated with a mixture of an anti-ICAM antibody (or nonspecific IgG) and (64)Cu-DOTA-IgG (where DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). Biodistribution and small-animal PET and CT studies were performed in healthy mice and in mice pretreated with lipopolysaccharides (LPSs). Metabolism studies were also performed to evaluate the stability of (64)Cu-labeled NPs in lungs in vivo. The lungs of mice administered anti-ICAM NPs labeled with (64)Cu were clearly imaged by small-animal PET 1, 4, and 24 h after administration. Both biodistribution and small-animal imaging showed a 3- to 4-fold higher uptake in the lungs of mice injected with ICAM-targeted NPs relative to that of the control group. Lung uptake was further enhanced by pretreating the mice with LPS, presumably because of ICAM-1 upregulation. However, an approximately 2-fold decrease in lung signal was observed in each experimental group over 24 h. Metabolism studies in lung tissues harvested from mice injected with (64)Cu-labeled anti-ICAM NPs showed considerable release of a small (64)Cu-radiometabolite from the NPs beginning as early as 1 h after injection. A decrease in lung fluorescence was also observed, most likely reflecting partial release of NPs from the lungs in vivo. The use of small-animal PET to track (64)Cu-labeled nanostructures in vivo shows potential as a strategy for the preclinical screening of new NP drug delivery agents targeting the lung endothelium and other tissues. Future design optimization to prolong the stability of the radiolabel in vivo will further improve this promising approach.

Evaluation of portosystemic shunt caused by patent ductus venosus through sequential whole-body scanning using per-sigmoid colon 123I-IMP scintigraphy

The correct estimation of the portosystemic shunt (PSS) ratio prior to surgery for patent ductus venosus is important. Until now, formulas using the lung and liver uptake for per-rectal portal scintigraphy using 123I-iodoamphetamine (IMP) have been mainly used for calculating the PSS ratio. However, these methods did not take radioactivity in the brain or changes in organ radioactivity over time into consideration. Here, we performed sequential whole-body scanning by per-sigmoid colon 123I-IMP scintigraphy, and evaluated the changes in radioactivity in the liver, lungs, and brain over time. The patient was 7-year-old boy with a patent ductus venosus. A 10 Fr. catheter was inserted into the sigmoid colon under fluoroscopic guidance, through which about 55.5 MBq of 123I-IMP was administered. Following the administration, the patient was placed in the supine position and sequential whole-body scanning (from head to thigh) was performed for up to about 80 min. Four regions of interest (ROIs) were placed on the whole brain, lungs, liver, and mediastinum. The PSS ratios were calculated using both the traditional formula (PSS index: brain uptake is not considered) and our original formula (new index: brain uptake is considered). Prior to surgery, the radioactivity could be seen clearly in the brain and lungs just following the injection. The liver uptake was faint on the first and second scans (15 min/scan), and increased gradually over time. In contrast, almost no radioactivity was detected in the brain or lungs following surgery. The liver uptake could be seen clearly just following the injection. The new index was significantly higher than the PSS index. Both the new index and the PSS index showed changes over time especially prior to surgery. Distinct brain radioactivity was observed early following administration in a patient with PSS. The calculation of the PSS fraction should be performed taking the brain radioactivity into consideration. The timing of the scan should be fixed, but 30 min following administration may be too early to begin scanning.