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1.
J Control Release ; 196: 344-54, 2014 Dec 28.
Article in English | MEDLINE | ID: mdl-25451545

ABSTRACT

Monoclonal antibodies (mAbs) are usually delivered systemically, but only a small proportion of the drug reaches the lung after intravenous injection. The inhalation route is an attractive alternative for the local delivery of mAbs to treat lung diseases, potentially improving tissue concentration and exposure to the drug while limiting passage into the bloodstream and adverse effects. Several studies have shown that the delivery of mAbs or mAb-derived biopharmaceuticals via the airways is feasible and efficient, but little is known about the fate of inhaled mAbs after the deposition of aerosolized particles in the respiratory system. We used cetuximab, an anti-EGFR antibody, as our study model and showed that, after its delivery via the airways, this mAb accumulated rapidly in normal and cancerous tissues in the lung, at concentrations twice those achieved after intravenous delivery, for early time points. The spatial distribution of cetuximab within the tumor was heterogeneous, as reported after i.v. injection. Pharmacokinetic (PK) analyses were carried out in both mice and macaques and showed aerosolized cetuximab bioavailability to be lower and elimination times shorter in macaques than in mice. Using transgenic mice, we showed that FcRn, a key receptor involved in mAb distribution and PK, was likely to make a greater contribution to cetuximab recycling than to the transcytosis of this mAb in the airways. Our results indicate that the inhalation route is potentially useful for the treatment of both acute and chronic lung diseases, to boost and ensure the sustained accumulation of mAbs within the lungs, while limiting their passage into the bloodstream.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/pharmacokinetics , Respiratory System/metabolism , Administration, Inhalation , Aerosols , Animals , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/pharmacokinetics , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Cetuximab , Drug Delivery Systems , Female , Histocompatibility Antigens Class I/genetics , Lung Neoplasms/drug therapy , Macaca fascicularis , Mice , Mice, Inbred BALB C , Mice, Knockout , Mice, Nude , Receptors, Fc/genetics
2.
Eur Respir J ; 23(5): 752-8, 2004 May.
Article in English | MEDLINE | ID: mdl-15176692

ABSTRACT

Inhibition of tumour necrosis factor-alpha (TNF-alpha), levels of which are increased in the blood of cirrhotic rats, prevents hyperdynamic circulatory state, mainly by decreasing the vascular overproduction of nitric oxide. Hepatopulmonary syndrome, which is characterised by intrapulmonary vascular dilatation and increased alveolar to arterial oxygen tension difference (PA-a,O2), is mainly related to pulmonary over-production of NO by macrophages accumulated in lung vessels. Since TNF-alpha is a potent activator of macrophagic inducible nitric oxide synthase (NOS), the aim of this study was to investigate whether TNF-alpha inhibition prevented hepatopulmonary syndrome and hyperdynamic circulatory state in rats with cirrhosis. TNF-alpha was inhibited by 5 weeks of pentoxifylline (10 mg x kg body weigh(-1) x day(-1)) in rats with cirrhosis induced by common bile duct ligation. Cardiac output, pulmonary and systemic vascular resistance, PA-a,O2 and cerebral uptake of intravenous technetium-99m-labelled albumin macroaggregates (which reflects intrapulmonary vascular dilatation) were similar in sham- and pentoxifylline-treated cirrhotic rats. Blood TNF-alpha concentrations and pulmonary intravascular macrophage sequestration, as assessed by morphometric analysis and radioactive colloid uptake, were decreased with pentoxifylline. Pentoxifylline also prevented increases in aorta and lung NOS activities and inducible NOS expression. Thus pentoxifylline prevents development of hyperdynamic circulatory state and hepatopulmonary syndrome, probably by inhibiting the effects of tumour necrosis factor-alpha on vascular nitric oxide synthase and intravascular macrophages. These results support an important role for tumour necrosis factor-alpha in the genesis of hepatopulmonary syndrome.


Subject(s)
Enzyme Inhibitors/pharmacology , Hepatopulmonary Syndrome/prevention & control , Liver Cirrhosis/physiopathology , Pentoxifylline/pharmacology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Animals , Aorta/enzymology , Bacterial Translocation/drug effects , Blood Cells/pathology , Blood Circulation/drug effects , Hemodynamics/drug effects , Liver Cirrhosis/blood , Liver Cirrhosis/metabolism , Liver Cirrhosis/microbiology , Lung/enzymology , Macrophages/pathology , Male , Nitric Oxide Synthase/antagonists & inhibitors , Nitric Oxide Synthase/metabolism , Phagocytosis , Pulmonary Circulation/drug effects , Rats , Rats, Wistar , Tumor Necrosis Factor-alpha/metabolism
3.
J Gene Med ; 5(7): 600-8, 2003 Jul.
Article in English | MEDLINE | ID: mdl-12825199

ABSTRACT

BACKGROUND: A multitude of cationic lipids have been synthesized since they were first proposed for use in gene therapy. Cationic lipids are able to efficiently transfect cells both in vitro and in vivo. Whereas most research groups have focused their investigations on the toxicity of these molecules, and on the location of expression of the DNA transferred by these vectors, little has been done to determine their biodistribution and elimination pathways. Our group has developed a family of cationic lipids termed phosphonolipids. Following a large in vitro screening experiment, we have selected several molecules for in vivo testing, with some of these phosphonolipids forming lipoplexes efficient in transfecting mouse lungs. It was thus of interest to study their fate after intravenous injection. METHODS: The respective biodistributions of both the GLB43 phosphonolipid and plasmid DNA were investigated and compared with DNA expression sites. Using the optimal conditions determined for phosphonolipids, we followed the gene transfer agent and plasmid DNA distributions versus time by radiolabeling them with (14)C and (32)P, respectively. Otherwise, we performed imaging by radiolabeling plasmid DNA with (99m)Tc. RESULTS: The lipoplexes appear to be directly located in the lung after administration. Secondly, the plasmid is released mainly into the lungs and the phosphonolipid vector is rapidly degraded. The hydrophilic moiety of the phosphonolipid is eliminated in the urine, as is the free plasmid. CONCLUSIONS: This study reveals that there are slight differences in the observed results depending on the technique used to label the DNA; secondly, results show that the residence time of phosphonolipids in the mouse body is related to the DNA binding time.


Subject(s)
Gene Transfer Techniques , Genetic Vectors , Lung/metabolism , Phospholipids , Animals , Biological Availability , Female , Gene Expression , Gene Targeting , Genetic Therapy , Injections, Intravenous , Liposomes , Luciferases/metabolism , Mice , Plasmids
4.
Dakar Med ; 48(2): 148-52, 2003.
Article in French | MEDLINE | ID: mdl-15770812

ABSTRACT

At time of pathological situations, a pulmonary fixation of labelled substances injected by intravenous way is observed. This fixation would result from a phagocytosis of these substances by abnormal cells whose presence was induced in the endothelium: Pulmonary Intravascular Macrophages (PIM's). After activation by phagocytosis, these cells are able to secrete powerful vasoactive mediators capable of inducing cardiopulmonary accidents. Hepatic cholestase was induced in Wistar rats by ligation and section of common bile duct. The recruitment of PIM's was followed in vivo by phagocytosis scintigraphic imaging after labelled colloid injection. During the 35 days of evolution of the pathology, we observe a pulmonary fixation of the colloid agents which progresses up to 70% as well as a concomitant decease in the hepatic activity. Histologic examination showed numerous cells related to pulmonary capillaries' endothelium belonging to mononuclear phagocytes line and expressing an activated phenotype of monocytes. The scintigraphic and histological tests carried out enabled us to validate the model of induction of PIM's in rat by ligation of the choledoque one. The study of the vasoactive response via certain mediators can from now be approached, a Doppler technique on the pig aorta is being in the course of evaluation.


Subject(s)
Macrophages, Alveolar/diagnostic imaging , Macrophages, Alveolar/physiology , Vasomotor System , Animals , Lung/physiology , Male , Radionuclide Imaging , Rats , Rats, Wistar , Reflex , Vasomotor System/physiology
6.
Rev Med Interne ; 23(9): 745-50, 2002 Sep.
Article in French | MEDLINE | ID: mdl-12378827

ABSTRACT

PURPOSE: To analyse the medical prescriptions reimbursed by the Languedoc-Roussillon health care to the patient above 65 years old and analyse potential drugs interactions. To deduct the presenting actual educational modalities and information needed to ameliorate the quality of prescriptions for the elderly. METHODS: The data from the second trimester 1999 were taken from the LR health care data base on pharmaceutical agents which records the prescriptions dispensed in the pharmacies by teletransmission of codes CIP (Club International Pharmaceutique). The drug interactions of the prescriptions for the elderly of 65 or above in January 1999 by the LR health care Gard region. RESULTS: The prescriptions differ according to the sex and age. The drugs of psychotrope family and veinotonics (10% more) laxatives and NSAID's (2 to 3% more) for women. The majority of prescribed drugs diminish after a pick at the age of 85. The antihyperlipidemic drugs are an exception because their prescription diminishes immediately after 70's. The analyse of medical interactions shows lots of problem: sulfonylureas with fibrates (533 prescriptions), oral anticoagulant and fibrates (23), between sulfomylureas (273), or NSAID's (174) and a lot of contraindicated drugs (Ozidia 37). CONCLUSIONS: Some medical treatments because of their large number of prescription need to be continually educated to the practitioners. Some drugs which are inadvisable because of their adverse effects have had an individual treatment. This database is a good way to analyse the drug iatrogeny and its prevention.


Subject(s)
Drug Interactions , Drug Prescriptions/statistics & numerical data , Aged , Aged, 80 and over , Database Management Systems , Drug Prescriptions/standards , Female , France , Humans , Male , Physicians, Family
7.
Gene Ther ; 9(11): 736-9, 2002 Jun.
Article in English | MEDLINE | ID: mdl-12032699

ABSTRACT

Gene transfer to the lung can be achieved via a systemic, that targets the endothelium, or local, that targets the epithelium, delivery route. In the present study, we followed the distribution of a plasmid after transfection using some of our phosphonolipids, which have previously shown their efficiency in transfecting mouse lungs. The plasmid was radiolabeled and varying combinations of plasmid/phosphonolipid were administered by intravenous injection, or by endotracheal spray. The distribution of radioactive labeling was observed over a time course using a gamma-camera. These images were then correlated with the results for luciferase expression levels in the lungs. In each case, lungs were well targeted. However, whereas an intravenous injection reaches all of the lung immediately, progressive diffusion occurs when the plasmid/phosphonolipid is administered via an aerosol. Elimination of the radioactivity associated with plasmid occurs via the urinary tract after intravenous injections, and via the feces using the aerosol delivery approach. The radioactivity detected in the lungs correlated strongly with transgene expression. Thus, such an imaging technique is a powerful strategy to predict the formulation that will generate the best transfection efficiency. This study reveals that scintigraphic imaging permits both validation of the administration method and the results obtained for each animal, thereby reducing the statistical variability of in vivo experiments.


Subject(s)
Genetic Therapy/methods , Lung , Transfection/methods , Aerosols , Animals , Biological Transport , Cystic Fibrosis/therapy , Gamma Cameras , Gene Expression , Genetic Markers , Injections, Intravenous , Luciferases/genetics , Mice , Plasmids , Transgenes
8.
Chest ; 120(3): 941-7, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11555533

ABSTRACT

STUDY OBJECTIVES: In regard to nuclear medicine literature reporting lung uptake of colloidal radiopharmaceuticals in patients with liver diseases, it has been hypothesized that liver abnormalities could trigger induction of pulmonary intravascular macrophages (PIMs) in humans normally lacking them. Recently, experimental induction of PIMs in rats in which they are not normally prevalent has been demonstrated to be at the origin of pulmonary hemodynamic alterations with an increased susceptibility to ARDS. If such induction may occur in humans, the risk of pulmonary hemodynamic alterations has to be considered and detected. This study demonstrates in a rodent model of biliary cirrhosis that scintigraphy of phagocytic function as commonly used for liver exploration is a suitable strategy for staging PIM development. DESIGN: Sixty rats were randomized as follows: bile duct section (n = 40), sham operation (n = 10), and no operation (n = 10). The rats were submitted to scintigraphy of phagocytic function every 5 days over 35 days for the assessment of radiocolloid uptake within lung and liver. At day 35, radioactivity of blood was counted and immunohistochemistry was performed on lung specimens. RESULTS: As disease progressed, radiopharmaceutical uptake decreased within the liver, while increasing considerably in the lung. At day 35, lung uptake averaged about 66% as compared to 3% before surgery. Lung histologic findings revealed numerous intravascular mononuclear cells closely related to the monocyte-macrophage lineage. CONCLUSION: Scintigraphy of phagocytic function commonly used for liver scanning could be a suitable strategy for the diagnosis of the induction of PIMs under pathologic situations.


Subject(s)
Liver Cirrhosis, Biliary/physiopathology , Lung/cytology , Macrophages, Alveolar/diagnostic imaging , Phagocytosis , Animals , Disease Models, Animal , Disease Progression , Immunohistochemistry , Liver/metabolism , Liver Cirrhosis, Biliary/diagnostic imaging , Liver Cirrhosis, Biliary/metabolism , Lung/metabolism , Male , Radionuclide Imaging , Radiopharmaceuticals , Random Allocation , Rats , Rats, Wistar , Technetium Tc 99m Sulfur Colloid
9.
J Aerosol Med ; 14(1): 107-14, 2001.
Article in English | MEDLINE | ID: mdl-11495481

ABSTRACT

The project for a European standard testing procedure to characterize nebulizers in terms of particle size distribution has been based on using the Andersen-Marple personal cascade impactor model 298 (A-MPCI) with a sodium fluoride reference solution. In the present study methods based on laser diffraction (Mastersizer-X) and time-of-flight (TOF)(APS) and another cascade impactor (GS1-CI) were compared with the A-MPCI. Two types of nebulizer (Pari LC+ and Microneb) were tested with all apparatuses, and a third type of nebulizer (NL9) was tested with the A-MPCI and Mastersizer-X. Nebulizers were charged with a solution of sodium fluoride in conditions reproducing the European Committee for Normalization (CEN) protocol. There was no difference between the Mastersizer-X and the A-MPCI or between the GS1-CI and the A-MPCI in terms of mass median aerodynamic diameter (MMAD). Comparison between the APS and the A-MPCI showed a significant difference with the Microneb. The geometric standard deviations (GSD) obtained with the A-MPCI were on average 10% greater than GSD obtained with the other apparatuses, but the differences were not statistically significant. We conclude that laser diffraction can be used for particle size distribution in the context of the European standard, and that the Mastersizer-X is particularly interesting for industrial practice in view of its simplicity and robustness.


Subject(s)
Guidelines as Topic , Lasers , Nebulizers and Vaporizers/standards , Equipment Design , Equipment Safety , Europe , Humans , Particle Size
10.
J Aerosol Med ; 14(1): 55-64, 2001.
Article in English | MEDLINE | ID: mdl-11495486

ABSTRACT

Anti-infectious agents such as pentamidine, antibiotics (mainly colistine and aminoglycosides), and amphotericin B can be administered by aerosol. Apart from pentamidine and Tobi, this route of administration is not officially approved and it constitutes an empirical approach, which has benefited from recent research summarized hereafter. The most fundamental question is related to the potentially deleterious effects of nebulization processes, especially ultrasound, on the anti-infectious properties of the drugs. Colimycin, which was chosen as a reference because its polypeptide structure makes it unstable a priori, proved to be resistant to high frequency ultrasound, which is encouraging for other molecules such as aminoglycosides or betalactamins. The nebulizer characteristics also have to be taken into account. An aerosol can be produced from an amphotericin B suspension and from colistine using both an ultrasonic nebulizer and a jet nebulizer. Differentiating between good and bad nebulizers is not dependent upon the physical process involved to nebulize the drug, but on the intrinsic characteristics of the device and its performance with a known drug. The inhaled mass of an aerosol in the respirable range must be high and dosimetric nebulizers represent significant progress. Finally, administration of anti-infectious aerosols requires a new pharmacological approach to monitor treatment, and urinary assays are promising for this purpose.


Subject(s)
Aerosols/administration & dosage , Anti-Infective Agents/administration & dosage , Respiratory Tract Infections/drug therapy , Administration, Inhalation , Anti-Infective Agents/therapeutic use , Humans , Nebulizers and Vaporizers , Particle Size , Respiratory Mechanics , Sensitivity and Specificity
11.
J Aerosol Med ; 14(1): 95-105, 2001.
Article in English | MEDLINE | ID: mdl-11495490

ABSTRACT

For cystic fibrosis (CF) gene therapy using an aerosolized adenovirus expressing the CFTR gene, optimization of the inhalation conditions is a prerequisite to obtain sufficient amount of CFTR protein expression in the target areas of the respiratory tract. For such a purpose, in vivo radioisotopic imaging of the radiolabeled virus is a unique strategy for a quantitative assessment of the actual deposition. In the present study, an adenovirus CFTR (AdCFTR) was labeled with 99m Technetium gamma emitting isotope in such conditions that its bioactivity was preserved. The 99mTc-AdCFTR aerosol was characterized using both laser diffraction and cascade impaction for sizing with further determination of nebulized and inhalable fractions. After administration to baboons, scintigraphic quantitation of the regional lung distribution was performed and the actual dose deposited in the target area was estimated and expressed as an equivalent viral titer. Since a virus scintigraphy is not realistic in a hospital setting, we have developed an approach using 99mTc-DTPA (diethylene triamino pentaacetic acid) that could be used to predict the virus deposition. Indeed, similarities observed between 99mTc-DTPA and 99mTc-adenovirus aerosol imaging patterns validates the use of the 99mTc-DTPA scintigraphy that we propose as a pretherapeutic test for each patient prior to gene transfer.


Subject(s)
Adenoviridae/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/administration & dosage , Cystic Fibrosis/therapy , Genetic Therapy/methods , Lung/diagnostic imaging , Administration, Inhalation , Aerosols/administration & dosage , Aerosols/pharmacokinetics , Animals , Biological Availability , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Disease Models, Animal , Female , Lung/metabolism , Papio , Radionuclide Imaging , Sensitivity and Specificity , Technetium/pharmacology
12.
Hum Gene Ther ; 12(1): 1-11, 2001 Jan 01.
Article in English | MEDLINE | ID: mdl-11177537

ABSTRACT

Cystic fibrosis is a common, heriditary disease resulting from mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Airway transfer of the CFTR gene is a potential strategy to treat or prevent the lung pathology that is the main cause of morbidity and mortality. Among the vectors used for gene therapy, adenoviruses have shown their ability to transfer the CFTR gene to respiratory epithelial cells, using either instillation or nebulization. Our objective was to characterize the lung deposition of aerosolized adenovirus by quantitative radioisotopic imaging, the only noninvasive technique allowing in vivo quantitation of inhaled drugs. We first labeled an adenovirus expressing human CFTR with the gamma-emitting radioisotope, technetium 99m (99mTc), and determined the best labeling conditions to allow preservation of virus bioactivity. We then administered the radioaerosol to baboons, determined lung regional deposition of 99mTc-labeled adenovirus, and compared the expression of CFTR transcripts 3 and 21 days after inhalation. The expression of vector-encoded mRNA ranged from 4 to 22% with respect to the endogenous CFTR mRNA depending on the lung segments. Moreover, we have developed a model using 99mTc-DTPA (diethylenetriamine pentaacetic acid), which can be used, as an alternative to adenovirus, to determine the profile of lung deposition of the vector. This study demonstrates that scintigraphy is a useful technique to achieve optimization of gene administration to the airways.


Subject(s)
Adenoviridae/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Cystic Fibrosis/diagnostic imaging , Cystic Fibrosis/therapy , Genetic Therapy , Lung/diagnostic imaging , Radiopharmaceuticals , Technetium Tc 99m Pentetate , Adenoviridae/growth & development , Administration, Inhalation , Animals , Cystic Fibrosis/genetics , DNA Primers/chemistry , DNA Probes , DNA, Viral/metabolism , Female , Gene Transfer Techniques , Genetic Vectors , Humans , Lung/virology , Papio , Polymerase Chain Reaction , RNA, Messenger/analysis , Radionuclide Imaging
13.
J Rheumatol ; 28(1): 35-40, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11196540

ABSTRACT

OBJECTIVE: Clinical assessment of rheumatoid arthritis (RA) based on pain and swelling and physical examination is limited by observer error and interpretation. We compared magnetic resonance imaging (MRI) and clinical examination to detect synovitis in RA. METHODS: Twelve patients with active RA were assessed according to Ritchie index, swollen joint count and score, swollen joint count of hands and wrists [2 wrists, 10 metacarpophalangeal (MCP), 10 proximal interphalangeal (PIP)], morning stiffness, pain intensity, Disease Activity Score (DAS), erythrocyte sedimentation rate, and C-reactive protein. MR images of hands and wrists were obtained with an adapted device, on T1 weighted (T1W) spin echo (SE) coronal images before and after gadolinium DTPA, TIW SE axial images with gadolinium DTPA, T2* gradient echo recall coronal and axial sequences, and assessed by 2 radiologists (O = no synovitis, 1 = synovitis). RESULTS: The swollen joint count on hands and wrists was 59 on clinical examination (mean 5.08 +/- 3.15 per patient; 20/24 wrists, 7/120 MCP, 32/120 PIP) and 162 on MRI (mean 13.50+/- 5.65; 22/24 wrists, 70/120 MCP, 70/120 PIP). Statistically significant correlations were found between MRI synovitis count and swollen joint count (p = 0.015) and score (p = 0.019), Ritchie Index (p = 0.035), DAS (p = 0.02) and morning stiffness (p = 0.07). MRI revealed synovitis significantly more often than clinical examination (162 vs 59; p = 0.00002) [2-fold in PIP (70/32) and 10-fold in MCP (70/7)]. Clinical examination and MRI were concordant for 157/264 joints (59.5%). The association of normal MRI with synovitis on clinical examination was observed in 2 cases, the opposite in 105. CONCLUSION: MRI is more sensitive than clinical examination to detect synovitis of hands and wrists in RA, especially for MCP and PIP joints, and is valuable for assessment of inflammation in hands and wrists in RA.


Subject(s)
Arthritis, Rheumatoid/diagnosis , Magnetic Resonance Imaging , Synovitis/diagnosis , Adult , Aged , Arthritis, Rheumatoid/blood , Arthritis, Rheumatoid/complications , Arthritis, Rheumatoid/physiopathology , Blood Sedimentation , C-Reactive Protein/analysis , Female , Finger Joint/pathology , Humans , Joints/pathology , Male , Middle Aged , Reproducibility of Results , Severity of Illness Index , Synovitis/blood , Synovitis/etiology , Wrist Joint/pathology
14.
Soc Sci Med ; 50(12): 1807-25, 2000 Jun.
Article in English | MEDLINE | ID: mdl-10798334

ABSTRACT

In this paper, the health of women aged 30 to 49 years is analyzed according to the family and work roles which they exercise, based on the 1991-1992 French national health survey. Households are classified based on the amount of their material resources, and a variety of measures of health and of health-related behaviors are considered. Looking at each role separately, the 'healthy married', 'healthy mother' and 'healthy worker' effects are very obvious for almost all health measures, and higher household income per unit of consumption is clearly associated with better health of women. The role patterns of women are not evenly distributed across income levels: housewives and lone mothers are more common at the bottom and middle of the income scale than at the top, while working women without children, married or not, are much more common at the top. In health terms, more heterogeneity is attached to role patterns in the middle of the income scale than at either extreme. In the middle stratum, two groups of women stand out as being clearly disadvantaged in comparison with that of married women with children and a job: (1) lone mothers, particularly in terms of mental health conditions, malaise symptoms and health-related behaviour, and (2) housewives, particularly in terms of physical health conditions. At the bottom of the income scale, no significant disadvantage is found for housewives compared to married working mothers, yet their overall health pattern is somewhat negative. At the top of the income scale, married working women without children, as well as single women do feel more often than married working mothers that they suffer from handicap or discomfort. The findings are discussed in terms of role enhancement and role strain, health selection, the nature of the health disadvantage associated with specific role patterns, and the importance of the structural context in the role framework.


Subject(s)
Family Relations , Role , Women's Health , Adult , Demography , Female , France/epidemiology , Health Services Research , Health Status Indicators , Humans , Middle Aged , Odds Ratio , Socioeconomic Factors , Spouses/statistics & numerical data
15.
Vet Microbiol ; 57(2-3): 171-80, 1997 Sep.
Article in English | MEDLINE | ID: mdl-9355252

ABSTRACT

We report the development and validation of a 99mTc-labelling technique of bacteria, applied to Salmonella abortusovis. The radioactive labelling is obtained using a pre-tinning step of the cells followed by direct incubation of S. abortusovis suspension with 99mTc-pertechnetate. Several procedures with different amounts of stannous tin (SnF2 or SnCl2) were evaluated. The selected method, respectful of bacterial viability, provided a 30% labelling yield. Viability of 99mTc-labelled bacteria was assessed by flow cytometry using rhodamine 123 and was demonstrated to be unchanged, turbidimetric measurements showing only a slight increase in the growth rate for radiolabelled cells. Incubation of 99mTc-labelled S. abortusovis with pronase, saponine and urea demonstrated labelling stability and suggested an intra-cellular localization for 99mTc. A preliminary study was also conducted in sheep to evaluate the value of the imaging of radiolabelled S. abortusovis. Spatial and temporal patterns of their in vivo dissemination in the lymphatic system after a sub-cutaneous injection were compared with control lymphoscintigraphic agents. These imaging data supported the assumption that the radioactivity detected in vivo was proportional to the number of 99mTc-labelled bacteria.


Subject(s)
Salmonella/isolation & purification , Sheep/microbiology , Sodium Pertechnetate Tc 99m , Animals , Flow Cytometry/methods , Fluorescent Dyes , Isotope Labeling/methods , Reproducibility of Results , Rhodamine 123 , Rhodamines , Salmonella/growth & development , Sodium Pertechnetate Tc 99m/pharmacokinetics
16.
Magn Reson Med ; 38(2): 179-82, 1997 Aug.
Article in English | MEDLINE | ID: mdl-9256094

ABSTRACT

A new method for absolute quantitation of MRS spectra is presented. This method is not based on a reference peak, derived from a real NMR signal, but rather on a synthesized NMR reference produced by an electronic device, transmitted by a broad-band antenna to avoid quality factor variations. This signal is therefore received at the same time as the sample signal. The reference line produced is stable in time (maximum variation lower than 2%) and allows precise and accurate measurement of absolute concentrations (mean error lower than 3%) in vitro and in vivo.


Subject(s)
Magnetic Resonance Spectroscopy/methods , Muscle, Skeletal/chemistry , Humans , Phantoms, Imaging , Reference Values
17.
Br J Rheumatol ; 36(7): 758-62, 1997 Jul.
Article in English | MEDLINE | ID: mdl-9255109

ABSTRACT

The potential of scintigraphy with technetium 99m-labelled J001 (99mTc-J001) to detect synovitis was studied in 15 rabbits with osteoarthritis (OA) of the right knee (section of cruciate ligaments), in five sham-operated rabbits and in four non-operated rabbits. J001 is a non-pyrogenic, acylated poly (1,3) galactoside isolated from the membrane of a non-pathogenic strain of Klebsiella pneumoniae which is able to bind selectively to macrophages via the binding to CD11b and CD14 molecules. The results of 99mTc-J001 scintigraphy were compared with those of scintigraphy with 99mTc-labelled methylene diphosphonate (99mTc-MDP) and GC-APG (a derivative of J001 unable to bind macrophages in vitro). The mean scintigraphic ratios (diseased healthy knee) of 99mTc-J001 were significantly higher in OA rabbits than in sham- and non-operated rabbits, from as early as day 18 until day 90. 99mTc-J001 scintigraphy demonstrated earlier increased uptake than 99mTc-MDP scintigraphy. The mean scintigraphic ratios of 99mTc-J001 were significantly higher than those of 99mTc-GC-APG (which remained normal) in OA rabbits. The normal scintigraphic ratios of 99mTc-J001 in sham-operated and non-operated rabbits, as well as of 99mTc-GC-APG in OA rabbits, suggested that the increased uptake demonstrated with 99mTc-J001 in OA rabbits, as early as day 18 corresponded to imaging of synovitis via elective macrophage targeting. These results showed that 99mTc-J001 scintigraphy should be a specific method of detecting synovitis in OA.


Subject(s)
Macrophages/diagnostic imaging , Osteoarthritis/diagnostic imaging , Synovitis/diagnostic imaging , Animals , Anterior Cruciate Ligament/physiopathology , Anterior Cruciate Ligament/surgery , CD11 Antigens/analysis , Lipopolysaccharide Receptors/analysis , Macrophages/chemistry , Macrophages/metabolism , Male , Osteoarthritis/metabolism , Osteoarthritis/pathology , Posterior Cruciate Ligament/physiopathology , Posterior Cruciate Ligament/surgery , Rabbits , Radionuclide Imaging , Sodium Pertechnetate Tc 99m/analysis , Sodium Pertechnetate Tc 99m/metabolism , Technetium Tc 99m Medronate/analysis , Technetium Tc 99m Medronate/metabolism
18.
Clin Exp Rheumatol ; 15(3): 269-74, 1997.
Article in English | MEDLINE | ID: mdl-9177921

ABSTRACT

BACKGROUND AND OBJECTIVE: J001 scintigraphy is a new approach, based on macrophage targeting, developed for tumor and inflammation imaging. J001, a non-pyrogenic acylated poly(1,3)galactoside purified from the membrane of a non-encapsulated strain of Klebsiella pneumoniae associates selectively with macrophages via binding to CD11b and CD14 molecules. Since macrophages play a primary role in inflammatory arthritis processes, J001 labeled with 99mTc appeared to be of interest for the scintigraphic imaging of inflammatory lesions. The purpose of this study was to assess the potential of J001 scintigraphy for imaging inflammatory arthritis in the model of ovalbumin-induced arthritis in rabbits. MATERIAL AND METHODS: Ovalbumin-induced arthritis was developed in 17 rabbits. 99mTc-J001 scintigraphy was performed 4 weeks after arthritis induction in 17 rabbits and was repeated at 6 and 8 weeks in 8 rabbits. 99mTc-J001 and 99mTc-MDP scintigraphy were performed before and 2.5 months after radionuclide synovectomy with the intra-articular injection of a high energy beta-emitting radionuclide (186Re) in 3 rabbits and 186Re (first subjected to a complete decrease of radioactivity) in 3 rabbits. RESULTS: 99mTc-J001 scintigraphy was able to image inflammatory arthritis 4 weeks after induction. J001 scintigraphy demonstrated an increased uptake earlier than MDP, which was maintained at week 8. After radionuclide synovectomy, a clear decrease in the J001 scintigraphy ratio occurred, whereas the MDP scintigraphy ratio was stable. After the intra-articular injection of inactive 186Re, no changes in MDP and J001 scintigraphy ratio appeared. CONCLUSION: 99mTc-J001 scintigraphy is able to image joint inflammation and to assess the response to anti-inflammatory treatment in an experimental model of arthritis.


Subject(s)
Arthritis/diagnostic imaging , Macrophages/diagnostic imaging , Organotechnetium Compounds , Animals , Arthritis/immunology , Injections, Intra-Articular , Knee Joint/diagnostic imaging , Knee Joint/drug effects , Male , Ovalbumin , Rabbits , Radioisotopes/pharmacology , Radionuclide Imaging , Rhenium/pharmacology , Synovial Membrane/drug effects , Technetium Tc 99m Medronate
19.
J Neurosci Methods ; 72(1): 5-14, 1997 Mar.
Article in English | MEDLINE | ID: mdl-9128162

ABSTRACT

The progress of myelination in the brain was evaluated by visualization of grey/white matter differentiation on magnetic resonance (MR) images and quantitative analysis of MR data. In vivo quantitative MR imaging was used to monitor the T2 transverse relaxation time changes associated with cerebral development and myelination. The progress of myelination was evaluated using two neonatal animal models, the monkey and the dog, known to mature at very different rates. Three beagles were studied from birth to 4 months of age and nine baboons from 1 to 30 months of age. The T2 values in the frontal, parietal and occipital white matter were calculated and the changes in these values with age were followed. Brain maturation in both species was found to correspond to decreasing T2 values in both grey and white matter. This decrease was observed both in the dog brain and, despite slower maturation, in the baboon brain, and appeared to fit with the myelination process in these models. Exploiting the physicochemical parameters of water in tissues via T2 determination is a convenient and reliable strategy for the documentation of brain development in both experimental approaches and clinical situations.


Subject(s)
Brain/growth & development , Brain/physiology , Magnetic Resonance Imaging/methods , Myelin Sheath/physiology , Age Factors , Animals , Animals, Newborn , Dogs , Papio , Time Factors
20.
Nucl Med Biol ; 23(8): 947-55, 1996 Nov.
Article in English | MEDLINE | ID: mdl-9004283

ABSTRACT

The potential of 99m-Tc-J001 for the investigation of inflammatory lesions via the targeting of recruited macrophages (M phi) has already been documented in several experimental models and in human diseases. To achieve a functional imaging of inflammation via M phi targeting, minimal labeled colloid content and high in vivo stability of 99mTc-J001 are essential. The actual specificity of such scintigraphy is closely dependent upon the radiolabeling of only the J001 molecules available for M phi targeting. To develop an appropriate radiopharmaceutical kit, optimization of the labeling conditions was achieved from a series of pilot formulations that were evaluated for radiolabeling efficiency and both in vitro and in vivo 99mTc-J001 stability. Colloids were characterized using autocorrelation spectroscopy and multiangle laser-light scattering, radioactive colloid content of the formulations being deduced from biodistribution studies. This work has made possible the definition of a formulation exhibiting a radiolabeling yield > 97.0%, associated with in vivo stability and minimal colloid formation, thus greatly enhancing the specificity of such macrophage scintigraphy.


Subject(s)
Glycolipids/chemical synthesis , Glycolipids/pharmacokinetics , Inflammation/diagnostic imaging , Inflammation/pathology , Macrophages/diagnostic imaging , Organotechnetium Compounds/chemical synthesis , Organotechnetium Compounds/pharmacokinetics , Radiopharmaceuticals/chemical synthesis , Radiopharmaceuticals/pharmacokinetics , Animals , Arthritis/diagnostic imaging , Chemical Phenomena , Chemistry, Physical , Drug Stability , Isotope Labeling/methods , Magnetic Resonance Spectroscopy/methods , Male , Phosphorus , Rabbits , Radionuclide Imaging , Rats , Rats, Wistar , Tissue Distribution
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