Inhalation of [123I]alpha1-protease inhibitor: toward a new therapeutic concept of alpha1-protease inhibitor deficiency?

UNLABELLED: The alpha1-protease inhibitor (alpha1-Pi) is separated from human serum and is therefore extremely expensive. Because only 2%-3% concentrates in the lung after intravenous administration, inhalational therapy for alpha1-Pi deficiency would seem likely to be better. The aims of this study were therefore to determine the pattern of deposition of inhaled alpha1-Pi labeled with 123I and measure the amount deposited in the lungs. METHODS: Eighteen patients with congenital severe alpha1-Pi deficiency were enrolled in the study. The low-specific-activity 123I-labeled alpha1-Pi aerosol (median particle size +/- SD, 3.9 +/- 2.5 microm) was generated by an air pressure-driven nebulizer. The patients inhaled for an average of 23.6 +/- 8.9 min. Static scintigrams in two projections were acquired immediately after (T1) and 1 (T2), 4 (T3), and 24 h (T4) after inhalation. The patients were divided into the following three groups according to their forced expiratory volume in 1 s (FEV1): group I, < or =40% of predicted normal (n = 8); group II, 40% < FEV1 < or = 60% of predicted normal (n = 4); group III, >60% of predicted normal (n = 6). RESULTS: The absolute percentage uptake values of alpha1-Pi in group I were 12.4 for T1, 7.3 for T2, 4.6 for T3, and 1.2 for T4; in group II the values were 13.0, 9.6, 6.2, and 2.0, respectively; and in group III, 14.6, 11.4, 6.5, and 3.6, respectively. Differences between the groups were generally statistically significant. Between T1 and T2, the probability value was <0.05 for group I versus group II, <0.006 for group I versus group III, and <0.39 for group II versus group III. Between T1 and T3, the probability value was <0.29 for group I versus group II, <0.22 for group I versus group III, and <0.94 for group II versus group III. Retention (between T1 and T4) was also dependent on the grade of the disease: P < 0.2 for group I versus group II, P < 0.001 for group I versus group III, and P < 0.02 for group II versus group III. Grading of the uptake pattern by three independent experienced investigators (87% agreement) revealed a peripheral deposition that was group dependent. We found that greater peripheral deposition corresponded with lower lung functional impairment: P < 0.5 for group I versus group II, P < 0.01 for group I versus group III, and P < 0.08 for group II versus group III. Degradation also corresponded with functional impairment: P < 0.05 for group I versus group II, P < 0.006 for group I versus group III, and P < 0.3 for group II versus group III. CONCLUSION: The results of this study show that sufficient amounts of alpha1-Pi can be deposited in the periphery of the lung by inhalation at least in patients with low-grade disease. Inhalation of alpha1-Pi may thus represent a new and more convenient route of drug administration.

Synthesis, characterization, and crystal structure of alpha-[Ru(azpy)2(NO3)2] (azpy = 2-(phenylazo)pyridine) and the products of its reactions with guanine derivatives.

The synthesis and characterization of alpha-[Ru(azpy)2(NO3)2], 1, are reported (azpy is 2-(phenylazo)pyridine; alpha indicates the isomer in which the coordinating pairs ONO2, N(py), and N(azo) are cis, trans, and cis, respectively). The solid-state structure of 1 has been determined by X-ray crystallography. Crystal data: orthorhombic a = 15.423(5) A, b = 14.034(5) A, c = 10.970(5) A, V = 2374(2) A3, space group P2(1)2(1)2(1) (No. 19), Z = 4, Dcalc = 1.655 g cm-3. The structure refinement converged at R1 = 0.042 and wR2 = 0.118 for 3615 unique reflections and 337 parameters. The octahedral complex shows monodentate coordination of the two nitrate ligands. The Ru-N(azo) bond distances (2.014(4) and 1.960(4) A), slightly shorter than the Ru-N(py) bonds (2.031(4) and 2.059(4) A), agree well with the pi-back-bonding ability of the azo groups. The binding of the DNA-model bases 9-ethylguanine (9egua) and guanosine (guo) to 1 has been studied and compared with previously obtained results for the binding of model bases to the bis(bipyridyl)ruthenium(II) complex. The ligands 9egua and guo appear to form monofunctional adducts, which have been isolated as alpha-[Ru(azpy)2(9egua)Cl]PF6, 2, alpha-[Ru(azpy)2(9egua)(H2O)]-(PF6)2, 3, alpha-[Ru(azpy)2(guo)(H2O)](PF6)2, 4, and alpha-[Ru(azpy)2(guo)Cl]Cl, 5. The orientations of 9egua and guo in these complexes have been determined in detail with the use of 2D NOESY NMR spectroscopy. In 2 and 5, H8 is directly pointed toward the coordinated Cl, whereas, in 3 and 4, H8 is wedged between the pyridine and phenyl rings. The guanine derivatives in the azpy complexes can have more orientations than found for related cis-[Ru(bpy)2Cl2] species. This fluxionality is considered to be important in the binding of the alpha-bis(2-(phenylazo)pyridine)ruthenium(II) complex to DNA. In complex 1, ruthenium is the chiral center and in the binding to guanosine, two diastereoisomers each of adducts 4 and 5 have been clearly identified by NMR spectroscopy.

Tuning the rotational behavior of lopsided heterocyclic nitrogen ligands (L) in octahedral cis-[Ru(bpy)2(L)2](PF6)2 complexes. A variable-temperature 1H NMR study.

In this paper are presented the syntheses, characterizations, and dynamic solution behaviors of three cis-[Ru(bpy)2(L)2] (bpy = 2,2'-bipyridine) complexes, 1-3, in which L represents the monodentate ligands 1-methylimidazole (MeIm), 1,2-dimethylimidazole (Me2Im), and 1-methylbenzimidazole (MeBim), respectively. Because of their different steric properties, these three monodentate ligands yield complexes that show quite different fluxional behaviors in solution. These behaviors are studied with several 1H NMR techniques at various temperatures between -95 and degrees C. The 1H NMR spectra of 1, which has the smallest monodentate ligand of the three used, indicate the complex to be in fast exchange (i.e., the imidazoles rotate around their Ru-N axes) at all recording temperatures. The sterically more demanding ligands, Me2Im and MeBim, in 2 and 3, respectively, are in fast exchange at 55 degrees C and in slow exchange at low temperatures, showing three different atropisomers: two head-to-tail (HT) isomers and one head-to-head (HH) isomer. The newly synthesized bidentate ligand 1,2-bis-(1-methyl-2-benzimidazolyl)ethane (mdbz) forms the complex cis-[Ru(bpy)2(mdbz)](PF6)2 (4), in which the two benzimidazole moieties are constrained and relatively fixed. The two tethered benzimidazoles in 4 cannot rotate around their Ru-N axes, and therefore 4 is a good model for the main HT isomer of 3.

[123I]IBZM SPECT for imaging of striatal D2 dopamine receptors in 56 schizophrenic patients taking various neuroleptics.

OBJECTIVE: The purpose of this study was to compare the binding of various typical and atypical neuroleptics to striatal D2 dopamine receptors in schizophrenic patients. METHOD: Fifty-six inpatients with schizophrenia, including 14 with schizoaffective disorder and one with schizophreniform disorder, were evaluated. Fourteen patients were neuroleptic free. Single photon emission computed tomography (SPECT) was performed 90 minutes after intravenous injection of [123I]benzamide ([123I]IBZM). Subsequent semiquantitative analysis of D2 receptor binding was done with the use of the basal ganglia (striatum)/frontal cortex (BG/FC) ratio of activity. Clinical symptoms were rated with the Positive and Negative Syndrome Scale and the Hamilton Depression Rating Scale. RESULTS: The BG/FC ratios in patients taking typical neuroleptics were significantly lower than those in the neuroleptic-free subjects but not lower than those in the patients taking atypical neuroleptics (clozapine, remoxipride). For atypical antipsychotics, a dose-dependent relationship with striatal D2 receptor binding could not be demonstrated. BG/FC ratios were not significantly correlated with clinical symptoms or with duration of illness. CONCLUSIONS: The results indicate that [123I]IBZM SPECT is useful for semiquantitative imaging of striatal D2 dopamine receptors and for estimating their blockade by neuroleptics. Thus, it may improve drug monitoring in psychiatric patients. Furthermore, the findings suggest a complex relationship between the antipsychotic effect of atypical neuroleptics and D2 receptor blockade.

Are serum neopterin concentrations superior to other parameters in the differential diagnosis and prognostic assessment of Graves' disease?

There is a lack (1.) of a single criterion for the definitive differentiation between immunogenic (IH) and non-immunogenic hyperthyroidism (NIH), and (2.) also a lack of an unequivocal prognostic predictor for the individual course of patients with immunogenic hyperthyroidism. In 152 patients scheduled for iodine-131 therapy, serum neopterin concentrations were measured using a commercially available RIA, and the neopterin concentrations of IH (n = 84) and NIH (n = 42) patients were compared. Of these patients, 83 and 26 per cent respectively were treated with antithyroid drugs which did not have a significant impact on neopterin levels. In patients with IH and NIH, the concentrations [mean +/- SD] of neopterin were 1.89 +/- 0.79 milligrams and 1.98 +/- 0.9 milligrams, respectively (p = 0.4). After therapy with iodine-131, 28% of the IH-patients were euthyroid, 32% hyperthyroid, and 40% hypothyroid. In finally euthyroid patients, pretherapeutic neopterin concentrations were higher (3.1 +/- 2.8 milligrams) than in finally hyperthyroid (1.8 +/- 0.7 milligrams), or hypothyroid (1.6 +/- 0.7 milligrams) patients. These results argue against a relevant clinical role of neopterin concentrations for the differential diagnosis of IH versus NIH in these patients. However, a prognostic significance of neopterin concentrations in patients with IH is suggested.

Vascularisation of ocular coralline hydroxyapatite implants.

Vascularisation of coralline hydroxyapatite used to replace the enucleated bulb is of critical importance for the uncomplicated implantation of a motility peg connecting the implant with the cosmetic prosthesis. Technetium-99m diphosphopropanedicarboxylic acid (DPD) single-photon emission tomography (SPET) was used to evaluate the rate of vascularisation as well as the time required for completion of vascularisation. Twenty-four patients were enrolled in the study, which was designed to evaluate vascularisation 10 days, 2 months and 4 months after implantation of a coralline implant. Nineteen patients completed the study and the visual impression of the completion of the vascularisation was scored from 0 (no vascularisation) to + (complete vascularisation) for each patient. No tracer accumulation was detected in any patient at the 10-day examination. Increasing vascularisation was demonstrated with time, and full vascularisation of the coralline implant was seen in all but one case by 4 months after implantation. We conclude that vascularisation of ocular coralline hydroxyapatite implants occurs early and is completed by 4 months after implantation in most cases, but should be confirmed at this time by 99mTc-DPD SPET.

[Changes in the blood picture after radioiodine therapy of thyroid cancer]. / Blutbildveränderungen nach Radiojodtherapie bei Schilddrüsenkarzinomen.

AIM: In this study the effect of radioiodine which was administered because of thyroid carcinoma on blood count and various other parameters was examined. PATIENTS AND METHODS: In 567 patients who had been treated because of a thyroid carcinoma between 1980 and 1990 with radioiodine, changes of hemoglobin, RBC, WBC, platelets, potassium, uric acid, gamma GT, GOT, GPT and AP were measured in correlation with the totally administered dose. RESULT: In low doses (< 18.5 GBq [500 mCi]), which are sufficient in most cases with clinical course without complications, relevant changes of blood count (hemoglobin: < or = 9.0/10.5 g/dl, RBC: < or = 3.1/3.5 10(12)/l (female/male), WBC: < or = 2.5 10(9)/l, platelets: < or = 0.5 10(11)/l) were observed in only 5 out of 469 cases. After moderate doses (> or = 18.5 GBq [500 mCi] and < 37 GBq [1000 mCi]) we found in only 1 out of 77 cases relevant changes. After very high doses (> or = 37 GBq [1000 mCi]), which are used to treat metastases and/or recurrences, thrombopoesis is most sensitive to the radiation exposure of the bone marrow. Relevant decrease of RBC and WBC were observed in 2 out of 21 patients. Pancytopenia (hemoglobin: < or = 12.0/13.5 g/dl, RBC: < or = 3.9/4.3 10(12)/l [female/male], WBC: < or = 3.5 10(9)/l, platelets: < or = 1.4 10(11)/l) occurred in 4 cases. CONCLUSION: In high-dose therapy with radioiodine frequent (monthly, but in any cases before each therapy) controls of blood count are necessary. In patients without metastases or recurrence no relevant changes can be expected in most cases.

Disseminated bone marrow metastases from primary breast cancer: detection and follow-up by radioimmune bone marrow scintigraphy.

Bone scintigraphy of a 40-yr-old patient suffering from primary breast cancer suggested the possibility of diffuse metastases. Bone marrow scintigraphy using 99mTc-labeled monoclonal antibodies (BW 250/183) demonstrated diffuse destruction of bone marrow due to metastatic disease and consecutive bone marrow extension. Bone marrow scintigraphy was highly sensitive in detecting progression of disease in this asymptomatic patient.

Cerebral blood flow in Sneddon syndrome.

Sneddon syndrome is defined as a clinical entity consisting of livedo racemosa generalisata (LRG) and cerebrovascular lesions, which often lead to physical and mental handicaps. Four patients with LRG and the suspected diagnosis of Sneddon syndrome had HMPAO-SPECT studies. The patients underwent CT and/or MR brain imaging and three patients had Duplex sonography of the cerebral arteries (TCD). Brain SPECT was abnormal in all patients, whereas CT/MRI revealed a cerebral lesion in only one patient and all TCD studies were normal. HMPAO-SPECT is valuable in detecting disturbed regional cerebral blood flow before irreversible ischemic insults occur, thus allowing the diagnosis of Sneddon syndrome at an early stage.

[Brain SPECT with 123I-labelled iodobenzamide (IBZM): aspects of semiquantitative evaluation]. / Hirn-SPECT mit 123J-markiertem Iodobenzamid (IBZM): Aspekte der semiquantitativen Auswertung.

The striatal dopamine-D2-receptor uptake of 123I-IBZM in 32 patients (18 without and 14 under therapy with typical neuroleptics) was measured semiquantitatively using different ROI techniques. The aim of the study was to evaluate the influence of these techniques on the different ratios (striatum/cortex) found by various examiners. Using the same SPECT system no major differences were found between rectangular and manually drawn ROIs of the same size. All ROI techniques could differentiate between patients with and without therapy on a highly significant level. Therefore, the resulting ratio is mainly dependent on the spatial resolution of the camera system and only to a relatively minor extent on the ROI technique. Ratios obtained by different observers are not comparable quantitatively.

Planar and SPECT imaging with technetium-99m labeled antigranulocyte antibodies in bone and soft tissue infection.

Scintigraphy with technetium-99m labeled antigranulocyte antibodies including planar and SPECT imaging demonstrated areas of inflammation in bone and soft tissue of the thigh of a 38-year-old man who had a fracture of the femur 20 years earlier. The clinical potential of this imaging modality in the diagnostic assessment of inflammatory diseases is discussed.

Tc-99m labeled monoclonal antibodies against granulocytes (BW 250/183) in the detection of appendicitis.

Scintigraphy with Tc-99m labeled antigranulocyte antibodies (BW 250/183 MoABs) was performed in 32 patients with suspected appendicitis. Abdominal imaging (planar/SPECT) was performed 2 hours after injection of the tracer. All patients also had surgery and a histologic examination of the resected tissue. Of the patients, 17 suffered from "acute appendicitis" and 12 had right positive scans (sensitivity = 70.6%). In 15 patients, acute appendicitis could have been ruled out, and in 11 of these cases the scan was true negative (specificity = 73.3%). The overall accuracy was 71.8% (23/32 cases). The use of Tc-99m antigranulocyte MoABs may overcome the problems associated with the Tc-99m HMPAO granulocyte and In-111 oxine approaches, which include nonspecific intestinal activity or the lack of timeliness. The use of Tc-99m labeled antigranulocyte antibodies is suitable as an emergency procedure and may play a role in the management of patients with suspected appendicitis.

Inhalation scintigraphy with an ultrafine aerosol in infants with functional bronchial stenoses.

Evaporation of Tc-99m pertechnetate at about 2500 degrees C on a carbon surface generates an ultrafine aerosol of Tc-99m-labeled carbon clusters (Technegas). The small particle size of about 100 nm enables the aerosol to behave similarly to a gas in its ability to penetrate. After inhalation, the radioactive particles adhere to the walls of the respiratory bronchioles and alveoli, or to the greater bronchial tubes if the airflow is not laminar. The high concentration of radioactivity in the argon carrier gas makes it possible to perform inhalation scintigraphy after only a few breaths. The authors investigated 24 infants with multiple events of bronchitis, most of whom had pneumonia. Seventeen patients had inhalation scintigraphy and bronchoscopy. Of these, 11 had scans diagnostic of bronchial stenosis and 6 had normal scans. Except for two pathologic scans, all scintigraphic findings matched well with the results of bronchoscopy. Seven patients had scintigraphy only, of which four were normal. Inhalation scintigraphy with Technegas is a reliable, nonhazardous procedure to preselect young patients for directed bronchoscopy.

Analogous effects of serum lipids from patients with nonthyroidal illness and normal subjects on the uptake of thyroxine and its conversion to triiodothyronine by rat hepatocytes in culture.

The low level of triiodothyronine (T3) in nonthyroidal illnesses (NTI) has been attributed to the decreased peripheral conversion of thyroxine (T4) to T3; patient's serum lipids decreased the conversion in a cell-free system. The objective of our study was to determine whether patients' serum lipids, whose content was elevated 2.5-fold above the reference serum value, and oleic acid affected the uptake of T4 and its conversion to T3 by rat hepatocytes in culture, thereby providing information on the cell's response to these processes. Serum ether extracts and oleic acid (0.1 mumol/l) were incubated with cells followed by assessment of T4 uptake and conversion of T4 to T3. The mean T4 uptake in the presence of ether extracts of NTI patients' or normals' sera were similar (112 +/- 15% and 110 +/- 24%, respectively). There was no difference in the T4 to T3 conversion between the patient and normal groups (90 +/- 14%); oleic acid also did not influence the conversion (96.7 +/- 1.6%). Uptake and conversion in the absence of either extracts and oleic acid were controls. These results suggest that serum lipids from NTI patients and normal subjects exercise qualitatively and quantitatively almost similar influences on T4 uptake and its conversion to T3; oleic acid is not an inhibitor of T4 uptake and T4 to T3 conversion in the rat hepatocyte. Since hepatocytes actively process fatty acids, their influence on intracellular conversion of T4 is not equitable with T4 conversion using the cell-free system. Our results do not support the hypothesis that abnormal lipid metabolism in NTI impairs hepatic T4 to T3 conversion.

[Current aspects of the pathology, diagnosis and therapy of C-cell carcinoma. A symposium held in Bonn, July 1991]. / Aktuelles zur Pathologie, Diagnostik und Therapie des C-Zell-Karzinoms. Symposium in Bonn im Juli 1991.

An essential element in the histological differentiation of medullary thyroid cancer (MTC) from other thyroid tumors is the use of immunohistochemical methods. The detection of calcitonin in the tumor cells is decisive. Factors which impair the prognosis of MTC are age (> 40 y), male sex, elevated DNA-content and mitotic activity of the tumor cells, immunoreactivity against dopa decarboxylase, histaminase and Leu-M1-antigen. Family screening is based mainly on calcitonin-stimulation tests (using pentagastrin or calcium) as a genetic marker for routine screening is not available yet. Scintigraphic methods using 99mTc-(V)-DMSA, 201Tl-chloride or 99mTc-anti-CEA antibodies become more important, especially in the detection of recurrent disease. Selective venous blood sampling is another sensitive method for localizing recurrent disease. Surgical treatment plays the dominant role in the management of MTC. Complete thyroidectomy in conjunction with systematic lymphadenectomy is now the primary treatment of choice.

Urinary extravasation from the kidney of recurrent renal cell carcinoma.

A man presented with recurrent renal cell carcinoma, complicated with acute pyelonephritis, 3 months status post partial nephrectomy. He underwent cystourethroscopy and a bilateral retrograde pyelogram, then was referred for a Tc-99m DTPA renal study; the images showed an initial photon-deficient area of the right kidney being gradually filled-in by radiotracer with further extension laterally, indicating urinary extravasation. 16 days later this area was aspirated, yielding 5 ml of yellowish fluid with clots consistent with necrotic tumor and pus.

The role of nuclear medicine in oncology.

Nuclear Medicine offers screening methods for oncology such as bone and bone marrow scintigraphy. During the last two decades, special procedures have gained widespread application. This paper is centered around the "tumor-specific" radiopharmaceuticals. In patients with thyroid cancer, I-131 still plays a significant role. Ga-67 still has its indications in lymphoma, while in other diseases Tl-201 chloride is now the agent of choice. Especially in thyroid cancer, Tl-201 has proved to be a reliable tumor imaging radiopharmaceutical. More recently, Tc-99m MIBI was introduced for tumor imaging. Tc-99m HMPAO may also be used for tumor scintigraphy, especially in brain lesions. In addition, I-123 IMP has successfully been used for imaging malignant melanoma. Another promising field of tumor diagnosis is receptor imaging. In neuroblastoma and malignant pheochromocytoma, I-131/123 mIBG is the radiopharmaceutical of choice and may be considered as a receptor imaging agent also. First clinical results with In-111 octreotide show potentials as somatostatin-receptor radiopharmaceutical in insulinoma, islet cell carcinoma, medullary and lung cancer, while I-123 estradiol needs some improvement until it may be recommended as diagnostic tool in breast cancer. Since 1978, radiolabeled poly- or monoclonal tumor antibodies and their fragments have gained widespread application. Especially the Tc-99m 225.28S melanoma antibody, I-131 or Tc-99m CEA and In-111/I-131 labeled OC-125 antibodies have proven to be of clinical significance in melanoma, colorectal and ovarian cancer.

Technetium-99m-labeled anti-granulocyte antibodies in suspected bone infections.

The introduction of 99mTc-labeled anti-granulocyte antibodies seemed to provide advantages in comparison with formerly used in vitro methods to label autologous white blood cells for inflammation imaging. For this reason, we have undertaken a study to evaluate the clinical significance of this method. Thirty unselected patients with suspected bone infections were studied prospectively using the monoclonal 99mTc-labeled anti-granulocyte antibody. Twenty patients were referred with suspected infections of the peripheral bones (Group I), as well as 10 patients with suspected infections of the spine (Group II). Planar whole-body scans were performed 4 hr and 20 to 24 hr after administration of 500 MBq of the labeled antibody. Scans were considered positive for a bacterial (septic) infection when a focally increased antibody accumulation occurred. All scans were evaluated in blinded fashion by two experienced readers. Of the 20 studies from Group I patients, four false-positive scintigraphic findings were observed, and one false-negative, resulting in a specificity of only 64% and a sensitivity of 89%. In Group II (10 studies), five scans were true-negative, and five false-negative. For both groups, the specificity of the scintigraphic method was quite low (75%), and the sensitivity was also relatively low (57%). The results of this study demonstrate that in an unselected patient population in whom the diagnosis is not known, scintigraphy with 99mTc-anti-granulocyte antibodies is not a reliable method for detecting septic inflammatory lesions: In addition, use of this method excludes septic lesions with only a moderate likelihood (83% negative predictive value).