Evaluation of the bubble point test of a 0.22-μm membrane filter used for the sterilizing filtration of PET radiopharmaceuticals

Objective

We developed a bubble point test kit and investigated the bubble point test of a 0.22-μm membrane filter used for the sterilizing filtration of [¹⁸F]FDG, [¹¹C]MET and [¹¹C]PIB. The bubble point test of the Millex-GS vented filter was often difficult due to air leakage from the vented portion of this filter. Therefore, to close the vented portion of this filter simply and reliably, we investigated the use of various materials.

Methods

The bubble point test of the Millex-GS vented filter was performed by closing the vented portion of this filter with various materials, such as vinyl tape, plastic paraffin film (parafilm), urethane elastomer adhesive mat and polyethylene foam cushion tape. Gradually, the plunger inside a syringe filled with air was pushed down to increase the pressure on the pressure gauge and the bubble point test kit. Simultaneously, the pressure when a continuous stream of air bubbles that appeared out of the 0.22-μm membrane filter was measured as the product-wetted bubble point value. Then, the plunger inside a syringe filled with 10 mL of water was pushed down to wash the 0.22-μm membrane filter. As in the case in the above-mentioned method of measuring the product-wetted bubble point, the water-wetted bubble point value was measured.

Results

The use of the polyethylene foam cushion tape and a double clip could easily and reliably prevent air leakage from the vented portion of the Millex-GS vented filter. In the bubble point test of [¹⁸F]FDG, [¹¹C]MET and [¹¹C]PIB, the product-wetted bubble point values were 382.7 ± 6.9 kPa, 385.4 ± 6.2 kPa and 351.6 ± 7.6 kPa, respectively. The bubble point ratio was used to determine the minimum product-wetted bubble point value. All results of the product-wetted bubble point test were beyond the minimum product-wetted bubble point value (334.4 kPa ([¹⁸F]FDG), 334.4 kPa ([¹¹C]MET) and 310.3 kPa ([¹¹C]PIB)). Then, the water-wetted bubble point values were 396.5 ± 8.3 kPa, 395.8 ± 8.3 kPa and 390.3 ± 7.6 kPa, respectively. All results of the water-wetted bubble point test were beyond the filter manufacturer’s minimum bubble point specification (344.8 kPa).

Conclusions

The bubble point test technique using the bubble point test kit was practical for routine quality control tests of PET radiopharmaceuticals.     

Interaction of some sterilizing filter materials with some technetium-99m radiopharmaceuticals

The retention of a variety of ^99mTc radiopharmaceuticals on four different sterilizing filter membranes has been evaluated. It was demonstrated that some ^99mTc radiopharmaceuticals show significant retention on certain types of sterilizing filters, presumably due to interactions between the radiopharmaceutical and the filter material.     

Canine SPECT studies for cerebral amino acid transport by means of123I-3-iodo-α-methyl-L-tyrosine and preliminary kinetic analysis

We have already reported that¹²³I-3-iodo-α-methyl-L-tyrosine (¹²³I-L-AMT) is superior as a singlephoton emitter labeled radiopharmaceutical reflecting cerebral amino acid transport. In this study, we investigated the distribution of¹²³I-L-AMT in the canine head by means of SPECT and kinetically analyzed the data in the brain. As a result, clear SPECT images of the canine brain were obtained. Kinetic analysis with a 2-compartment model, including or expressing membrane transport of the amino acid, was performed with time-activity curves in the arterial blood and in the cerebral region. The results of the analysis coincided closely with the experimental data and the relevance of the model was strongly suggested. Therefore¹²³I-L-AMT is considered to be useful as a single photon radiopharmaceutical which enables us to measure the cerebral amino acid transport rate.     

Charged particle penetration in gas targets designed for accelerator production of radionuclides used in nuclear medicine

Experimental methods for quantification of density reduction in gas targets bombarded by charged particle beams are presented and evaluated. One simple method requires only the measurement of target gas pressures. Parameters affecting density reduction were studied using theoretical and experimental techniques. Data for proton and deuteron penetration in neon and nitrogen are given for various beam energies, beam currents, gas pressures, and target lengths. In the case of ²⁰Ne(d, α)¹⁸F, these are correlated with [¹⁸F]F₂ activity recovered from a target which is used for routine production of ¹⁸F-F₂ for 2-deoxy-2[¹⁸F] fluoro-D-glucose. The mechanism of density reduction is discussed and its importance is evaluated in relation to other considerations necessary for optimizing gas target performance in radiopharmaceutical production applications.     

Computed chest tomography in an animal model for decompression sickness: radiologic, physiologic, and pathologic findings

This study was conducted to investigate the early pulmonary effects of acute decompression in an animal model for human decompression sickness by CT and light microscopy. Ten test pigs were exposed to severe decompression stress in a chamber dive. Three pigs were kept at ambient pressure to serve as controls. Decompression stress was monitored by measurement of pulmonary artery pressure and arterial and venous Doppler recording of bubbles of inert gas. Chest CT was performed pre- and postdive and in addition the inflated lungs were examined after resection. Each lung was investigated by light microscopy. Hemodynamic data and bubble recordings reflected severe decompression stress in the ten test pigs. Computed tomography revealed large quantities of ectopic gas, predominantly intravascular, in three of ten pigs. These findings corresponded to maximum bubble counts in the Doppler study. The remaining test pigs showed lower bubble grades and no ectopic gas by CT. Sporadic interstitial edema was demonstrated in all animals – both test and control pigs – by CT of resected lungs and on histologic examination. A severe compression–decompression schedule can liberate large volumes of inert gas which are detectable by CT. Despite this severe decompression stress, which led to venous microembolism, CT and light microscopy did not demonstrate changes in lung structure related to the experimental dive. Increased extravascular lung water found in all animals may be due to infusion therapy. Received: 7 December 1998; Revision received: 2 June 1999; Accepted: 9 June 1999     

Stannous ion quantitation in 99mTc-radiopharmaceutical kits

A simple and inexpensive method for the estimation of stannous ion, Sn (II), in radiopharmaceutical kits is described. The method used is a potentiometric titration of Sn (II) in 1 N HCl medium, using potassium iodate as the oxidizing agent in an atmosphere of nitrogen. The apparatus includes a pH meter, a platinum electrode, and a simple titration cell. Several commonly used radiopharmaceutical kits were analyzed for their Sn (II) content using this method. These studies indicate that the procedure can be used, as a routine quantitative test for the Sn (II) content of various ^99mTc-labeled radiopharmaceuticals.     

Automated striatal uptake analysis of <Superscript>18</Superscript>F-FDOPA PET images applied to Parkinson’s disease patients

Objective  

6-[¹⁸F]Fluoro-l-DOPA (FDOPA) is a radiopharmaceutical valuable for assessing the presynaptic dopaminergic function when used with positron emission tomography (PET). More specifically, the striatal-to-occipital ratio (SOR) of FDOPA uptake images has been extensively used as a quantitative parameter in these PET studies. Our aim was to develop an easy, automated method capable of performing objective analysis of SOR in FDOPA PET images of Parkinson’s disease (PD) patients.     

Ion chromatographic analysis of high specific activity 18FDG preparations and detection of the chemical impurity 2-deoxy-2-chloro-d-glucose

Because of the widespread use of 2-deoxy-2-[¹⁸F]fluoro-d-glucose (FDG) prepared by the “Julich” method or its variants it was decided necessary to determine the major chemical impurities present in the final product. An analytical system for quantifying FDG was developed using pulsed amperometry after separation by high-performance anion exchange chromatography. With this system a heretofore unidentified impurity, 2-deoxy-2-chloro-d-glucose (ClDG, ca 20–2000 μg; typically < 100 μg), was found in our preparation and in those from other laboratories using the “Julich” method. ClDG arises from Cl⁻ ion displacement during the labeling procedure where Cl⁻ ion comes from several sources, and Cl⁻ ion displacement from the HCl used in the hydrolysis step. FDG mass was present in the same preparations at a level of ca 1–40 μg. Other major chemical constituents were glucose (ca 1–6 mg) and mannose (ca 10–18 μg). Glycerol, arising from sterilizing filters, was also detected in most preparations.Although ClDG is a chemical impurity which has not been detected previously in nca FDG preparations, its biochemical and pharmacological properties are similar to FDG and 2-deoxy-d-glucose. Thus it is unlikely that the presence of small quantities of ClDG found in typical FDG preparations (ca 100 μg) would have adverse pharmacological or toxicological consequences that would limit continued application of this radiopharmaceutical in basic and clinical studies.     

Influence of whole-body vibration on biodistribution of the radiopharmaceutical [99mTc]methylene diphosphonate in Wistar rats

Abstract

Purpose: The radionuclide bone scan is the basis of skeletal nuclear medicine imaging. Bone scintigraphy is a highly sensitive method for indicating disease in bone. Mechanical stimulation in the manner of whole-body vibration (WBV) appears beneficial to the maintenance and/or enhancement of skeletal mass in individuals. The aim of this work was to evaluate the effect of WBV on the biodistribution of the radiopharmaceutical [^99mTc]methylene diphosphonate (^99mTc-MDP ) in Wistar rats.

Materials and methods: In the biodistribution analysis, animals were anesthetized with sodium thiopental, the radiopharmaceutical ^99mTc-MDP was administered via ocular plexus and after 10 min the animals were submitted to vibration of 20 Hz (1 min) in an oscillatory platform. Following, the animals were sacrificed, the organs were isolated, the radioactivity determined in a well counter, and the percentages of radioactivity per gram (%ATI/g) in the organs were calculated. An unpaired t-test following Welch test (p < 0.05) was done for statistical analysis of the results.

Results: The biodistribution was significantly (p < 0.05) decreased in kidney, bone, lung, stomach, prostate and bowel.

Conclusion: The analysis of the results indicates that the vibration could produce metabolic alterations with influence in the uptake of the radiopharmaceutical ^99mTc-MDP in bone, stomach, bowel, prostate, kidney and bladder.     

Hypoxia-induced redox alterations and their correlation with 99mTc-MIBI and 99mTc-HL-91 uptake in colon cancer cells

Colorectal cancer is one of the most common malignancies in the Western world and is an example of a solid tumour in which hypoxia is a common feature and develops because of the inability of the vascular system to supply adequate amounts of oxygen to growing tumours. Hypoxia effects on tumour cell biology can be detected and characterized using different methods. The use of imaging with γ-emitting radionuclides to detect hypoxic tissue was first suggested by Chapman in 1979 [N Engl J Med 301 (1979) 1429–1432]. ^99mTc-4,9-diaza-3,3,10,10-tetramethyldodecan-2,11-dione dioxime, also known as ^99mTc-HL-91, has been among the most studied hypoxia markers.The objective of this study was to correlate the uptake of ^99mTc-HL-91 and ^99mTc-MIBI in colon cancer cells under normoxic and hypoxic conditions and to compare this information with some parameters such as oxidative stress and mitochondrial dysfunction of the cells analyzed by flow cytometry.Our results show that the in vitro ^99mTc-HL-91 uptake is higher in hypoxic conditions, which is confirmed by the decreased uptake of ^99mTc-MIBI. Flow cytometry results demonstrate that hypoxic conditions used are not enough to induce cellular death, but are responsible for the alterations in the intracellular redox environment, namely, increase of ROS production, proteic pimonidazol-derived adduct formation and alteration in the mitochondrial membrane permeability. Therefore, these results confirm that ^99mTc-HL-91 is a radiopharmaceutical with favourable characteristics for detecting hypoxia.     

A single-step kit formulation for the (99m)Tc-labeling of HYNIC-Duramycin

Introduction^99mTc-Duramycin is a unique radiopharmaceutical that binds specifically to phosphatidylethanolamine (PE). The current effort is to develop a single-step kit formulation for the ^99mTc labeling of HYNIC-Duramycin.MethodsA titration series of Tricine/TPPTS coligand systems were tested for an optimal formulation to produce ^99mTc-Duramycin with high radiochemical purity and specific activity. The radiopharmaceutical prepared using the kit formulation was tested for PE binding specificity using polystyrene microbeads coated with different phospholipid species. Radiochemical performance of the kits was assessed after storage at ? 20 °C, room temperature and 37 °C. Biodistribution profile of kit-prepared ^99mTc-Duramycin was characterized in healthy rats at 3, 10, 20, 60 and 180 min after intravenous injection. Binding studies were performed using the rat aortic arch and a rat model of myocardial ischemia/reperfusion, which represent scenarios of physiological and pathological PE externalization.ResultsA Tricine/TPPTS ratio of 10:1 led to a consistent production of ^99mTc-Duramycin with high radiochemical purity (> 90%), whereas a higher ratio at 40:1 produced radiopharmaceuticals with incomplete substitution of Tricine coligand. ^99mTc-Duramycin prepared using the single-step kit formulation retained PE-binding specificity. The kits are stable over long-term storage. The biodistribution profile of kit-prepared ^99mTc-Duramycin is consistent with HPLC purified radiopharmaceutical from prior studies. Binding studies on a tissue level indicate that the radiopharmaceutical is suitable for studying biological processes that involve PE distribution and redistribution in various physiological and pathological conditions.ConclusionA single-step kit formulation is developed for ^99mTc-labeling of HYNIC-Duramycin. The radiopharmaceutical has high radiochemical purity and specific activity, retained PE binding activities, amiable to long-term storage, and is injection-ready for in vivo applications.     

Effects of heterogeneous structure and diffusion permeability of body tissues on decompression gas bubble dynamics

To gain insight into the special nature of gas bubbles that may form in astronauts, aviators and divers, we developed a mathematical model which describes the following: 1) the dynamics of extravascular bubbles formed in intercellular cavities of a hypothetical tissue undergoing decompression; and 2) the dynamics of nitrogen tension in a thin layer of intercellular fluid and in a thick layer of cells surrounding the bubbles. This model is based on the assumption that, due to limited cellular membrane permeability for gas, a value of effective nitrogen diffusivity in the massive layer of cells in the radial direction is essentially lower compared to conventionally accepted values of nitrogen diffusivity in water and body tissues. Due to rather high nitrogen diffusivity in intercellular fluid, a bubble formed just at completion of fast one-stage reduction of ambient pressure almost instantly grows to the size determined by the initial volume of the intercellular cavity, surface tension of the fluid, the initial nitrogen tension in the tissue, and the level of final pressure. The rate of further bubble growth and maximum bubble size depend on comparatively low effective nitrogen diffusivity in the cell layer, the tissue perfusion rate, the initial nitrogen tension in the tissue, and the final ambient pressure. The tissue deformation pressure performs its conservative action on bubble dynamics only in a limited volume of tissue (at a high density of formed bubbles). Our model is completely consistent with the available data concerning the random latency times to the onset of decompression sickness (DCS) symptoms associated with hypobaric decompressions simulating extravehicular activity. We believe that this model could be used as a theoretical basis for development of more adequate methods for the DCS risk prediction.     

Measurement of gas transport kinetics in high-frequency oscillatory ventilation (HFOV) of the lung using hyperpolarized (3)He magnetic resonance imaging

Purpose

To protect the patient with acute respiratory distress syndrome from ventilator associated lung injury (VALI) high‐frequency oscillatory ventilation (HFOV) is used. Clinical experience has proven that HFOV is an efficient therapy when conventional artificial ventilation is insufficient. However, the optimal settings of HFOV parameters, eg, tidal volumes, pressure amplitudes and frequency for maximal lung protection, and efficient gas exchange are not established unambiguously.

Methods

In this work magnetic resonance imaging (MRI) with hyperpolarized ³He was employed to visualize the redistribution of gas within the cadaver pig lung during HFOV. The saturated slice method was used to characterize fast gas kinetics.

Results

The strong differences in kinetics were observed for HFOV‐driven gas exchange in comparison with diffusive gas transport (apnea). The significant regional and HFOV frequency dependence was detected for washout and gas exchange within the lungs. Gas redistribution was much faster in posterior than in anterior parts of the lungs during HFOV, in contrast to minor differences with an opposite trend observed in apnea.

Conclusion

The method shows significant potential for visualization and quantification of gas redistribution under HFOV and may help in optimization of the parameters to improve the clinical effect of HFOV for patients. J. Magn. Reson. Imaging 2010;32:887–894. © 2010 Wiley‐Liss, Inc.     

Radiation doses to the eye lens from ocular tumour seeking radiopharmaceuticals

In view of the increasing interest in nuclear ophthalmology, the radiation doses of 13 radiopharmaceuticals to the human eye were estimated. The radiation dose to the lens, the most radiosensitive part of the eye, was not negligible. However, in the choice of radiopharmaceutical for the non-invasive detection of an ocular tumour the classical consideration of ‘critical organs’ should be decisive. From this point of view, the ³²P-test should be discontinued, while ¹²³I-labelled radiopharmaceuticals that show the lowest radiation risks to the patient should be encouraged.     

传染病员救护车负压净化系统研究

目的：研制具备负压净化功能的救护车，用于运送非典型肺炎一类的急性传染病员。方法：救护车病室自成一区，采用负压净化系统对周围环境进行防护，负压范围为-30～-80Pa，负压净化系统由负压净化装置和监测报警装置组成。通过以CO2气体为模拟污染源，对救护车病室内气溶胶颗粒的流向与分布进行测量。结果：CO2为替代污染气体的扩散范围以病室中部区域为主，在病室前部和后部得到了有效的抑制。结论：传染病员救护车负压净化系统能够有效抑制急性传染病员在运送途中对沿途周围环境的污染与病毒的传播。     

Quality control of colloid and particulate 99mTc-labeled radiopharmaceuticals

A procedure for the radiochemical purity control of colloid and particulate ^99mTc-labeled radiopharmaceuticals is described. The proposed technique is based on the use of two chromatograms, using in both, 15% H₃PO₄ as solvent and impregnated glass fiber media (Gelman ITLC type SG) as stationary phase. A pretreatment of the radiopharmaceutical with 6 N NaOH is involved prior to one chromatographic run. The procedure is fast and the different species (free pertechnetate, ^99mTc-Sn-colloid and labeled ^99mTc) in a ^99mTc-labeled radiopharmaceutical can be determined accurately and with reliability.     

Improved synthesis and low-temperature autoradiographic evaluation of 18F-n-fluoropropane as a myelin tracer for positron emission tomography

An improved synthesis of the lipophile ¹⁸F-fluoropropane, yielding 30–45 mCi ¹⁸F-labelled radiopharmaceutical, is described. The radiochemical yield was 55%–66% determined at the end of a 1-h synthesis. Radiochemical and chemical purity of ¹⁸F-fluoropropane was 99% as determined by gas chromatography. Low-temperature autoradiography was used to investigate the lipophile ¹⁸F-n-fluoropropane as a myelin tracer for use with positron emission tomography. The white to grey matter ratio based on autoradiograms 12 min after administration of the radiotracer was 2:1, the highest reported to date.The results described in this paper were reported at the 30th Annual Meeting of the Nuclear Medicine Society, St. Louis Mo., J Nucl Med (1983) 24:p 119     

Renal gammagraphy with 99mTc-phosphomycin

^99mTc-Phosphomycin, a new radiopharmaceutical for kidney visualization, was used for animal experiments and tests of 171 patients. The results confirmed the usefulness of this product. The ease and yield of the labelling procedure, the low cost of the product, the excellent quality of the images and the functional information obtained showed that the use of ^99mTc-phosphomycin as a radiopharmaceutical for kidney visualization has many advantages.     

The status of Tsukuba BNCT trial: BPA-based boron neutron capture therapy combined with X-ray irradiation

The phase II trial has been prepared to assess the effectiveness of BPA (250 mg/kg)-based NCT combined with X-ray irradiation and temozolomide (75 mg/m²) for the treatment of newly diagnosed GBM. BPA uptake is determined by ¹⁸F-BPA-PET and/or ¹¹C-MET-PET, and a tumor with the lesion to normal ratio of 2 or more is indicated for BNCT. The maximum normal brain point dose prescribed was limited to 13.0 Gy or less. Primary end point is overall survival.     

HPLC analysis of indium-111 diethylenetriaminepentaacetic acid (111In-DTPA) radiopharmaceutical

Indium-111 diethylenetriaminepentaacetic acid (¹¹¹In-DTPA) was analyzed by reversed-phase HPLC. On-line u.v. (220 mm) and radioactivity (NaI) detectors allowed simultaneous detection and quantitation of ¹¹¹In-DTPA radiopharmaceutical and free DTPA. The optimum HPLC conditions were derived from systematic study of the effect of various mobile phase parameters on retention characteristics of ¹¹¹In-DTPA and DTPA. The method was applied in stability study and routine quality control of ¹¹¹In-DTPA radiopharmaceutical.