Biomedical subjects

F F Knapp

Publications and source records attributed to F F Knapp.

At least 37 records · Page 2Linked to original sources

PubMed2000

Preparation and biodistribution of rhenium-188 labeled albumin microspheres B 20: a promising new agent for radiotherapy.

Intra-arterial infusion of labeled particles is an effective method for endoradiotherapy of tumors. In this study, we radiolabeled biodegradable HSA microspheres (mean diameter = 25 microm) with the short-lived beta-emitter 188Re available from the aluminia-based 188W/188Re generator system. After 1 h 35-40% of the relative large amount of Sn(II) chloride required for effective reduction of Re(VII) for efficient attachment to the particles is precipitated as an amorphous coat of tin hydroxid colloid on the particle surface. The final 188Re bound to the particles was found to be stable in vitro. The radiolabelling yield was > 90%. The biological half-life was > 250 h and demonstrated sufficient in vivo stability after i.v. injection in Wistar rats. Because of the attractive properties of 188Re and the uniform particle size and stability, in vivo, this new agent is an attractive candidate for endoradiotherapy of tumors after selective catheterization.

Albumins↗

PubMed2000

Intratumoral injection with [(188)Re]rhenium sulfide suspension for treatment of transplanted human liver carcinoma in nude mice.

Hepatocellular carcinoma (HCC) is one of the most common malignancies in China. Direct intratumoral injection of nonremovable radioactive material has been widely studied because it could deliver high doses of radiation to target sites and minimize radiation leakage to non-target organs or tissues. Thirty nude mice bearing SMMC 7721 human liver carcinoma were used for the biodistribution study after intratumoral injection of [(188)Re]rhenium sulfide suspension or sodium [(188)Re]perrhenate solution. Another 30 tumor-bearing mice were divided into six groups, four groups of which were treated with a 0.1 ml [(188)Re]rhenium sulfide suspension at doses of 3.7, 7.4, 18.5, 29.6 MBq by a single intratumoral injection. For control studies, to study the tumor inhibiting ratio, the remaining two groups were injected with nonradioactive rhenium sulfide suspension and Hanks' balanced salt solution, respectively. The injections were repeated 6 days later. The retention percentages of radioactivity (%ID) in tumors injected with [(188)Re]rhenium sulfide suspension were 90.96+/-6.63%, 86.09+/-22.58% and 87.62+/-13.97% at 1, 24 and 48 h, respectively. Tumor inhibition ratios are as high as 89% when the outer space of tumor (0.5-0.6 cm from center) received about 507.6 Gy doses. Intratumoral injection of [(188)Re]rhenium sulfide suspension results in high tumor retention indicating this approach has strong potential for the treatment of hepatic carcinoma.

Animals↗

PubMed2000

A comprehensive study on the blockage of thyroid and gastric uptakes of 188Re-perrhenate in endovascular irradiation using liquid-filled balloon to prevent restenosis.

188Re-perrhenate has been reported effective in preventing restenosis after percutaneous transluminal coronary angioplasty. However, if the balloon ruptures, 188Re-perrhenate is released into the circulation, causing high radiation dosing to the thyroid and stomach. In this study, we evaluated the effects of perchlorate or iodide given at different times and in different ways for blocking the uptake of 188Re-perrhenate in the thyroid glands and the stomach to find the best method to apply clinically to reduce the radiation dose in case of balloon rupture. Sodium perchlorate, sodium iodide, or potassium iodide was given orally or intravenously to rats before, during, and after the injection of 188Re-perrhenate. The rats were sacrificed and we calculated the concentration of 188Re-perrhenate in various organs to evaluate the preblocking, mixed formula, and postblocking effects of perchlorate or iodide. Our data showed that the preblocking method effectively reduced the uptake of 188Re-perrhenate in both the thyroid and the stomach. The mixed formula method also demonstrated good blocking effect. The postblocking method showed obvious depression of thyroid uptake of perrhenate but its blocking effect on the stomach was not satisfactory.

Administration, Oral↗

PubMed2000

Rhenium-188-HEDP in the palliative treatment of bone metastases.

INTRODUCTION: Rhenium-188-HEDP (188Re-HEDP) is a new and attractive radiopharmaceutical for the treatment of bone pain due to metastases. As a product of a 188W/188Re generator it is convenient for clinical use. With a short physical half life of 16.9 hours and a maximal beta-energy of 2.1 MeV, it is suitable for therapy. METHODS: We investigated the influence of 188Re-HEDP on pain relief, analgesic intake and impairment of bone marrow function in 15 patients. All patients were interviewed using standardized questions before, and 1, 2, 3, 4, 8, and 12 weeks after therapy. Blood samples were drawn weekly for 12 weeks, and a blood count was performed. Patients underwent gamma camera imaging to determine the radionuclide accumulation 4, 20, and 28 hours after therapy. The patients were treated with 1600 to 3459 MBq of 188Re-HEDP. RESULTS: Patients showed an improvement of the Karnofsky performance index from 74 +/- 8% to 84 +/- 11% 12 weeks after therapy. This improvement was statistically significant (p = 0.001). Eighty percent of the patients described pain relief and reduction of analgesics. Twenty percent of the patients could discontinue their analgesics. Mean platelet count decreased from (284 +/- 84)*10(3)/microliter to (205 +/- 62)*10(3)/microliter, and mean leukocyte count from (7.5 +/- 1.5)*10(3)/microliter to (5.9 +/- 2.1)*10(3)/microliter after therapy. The maximal differences between the values of platelets and leukocytes before and after therapy were not statistically significant (p = 0.021 and p = 0.094). Prostate specific antigen decreased from 95 +/- 83 ng/ml to 41 +/- 21 ng/ml, the difference was not statistically significant (p = 0.443). The bone accumulation 4, 20, and 28 hours after therapy was 1.3 +/- 0.5%, 0.6 +/- 0.3%, and 0.45 +/- 0.2% of the injected dose of a single metastasis, and 57 +/- 17%, 15.5 +/- 2% and 11 +/- 3% in the whole body, respectively. The effective half-life of 188Re-HEDP was 15.3 +/- 3.0 hours in the bone metastases, and 11.4 +/- 2.8 hours in the whole body. This corresponds to a residence time of 0.22 +/- 0.25 hours in the bone metastases, and of 10.54 +/- 2.59 hours in the whole body. CONCLUSION: In a small patient population, 188Re-HEDP therapy for bone pain palliation was effective and was associated with minimal toxicity.

Aged↗

PubMed2000

In vivo biodistribution of 125IPIP and internal dosimetry of 123IPIP radioiodinated agents selective to the muscarinic acetylcholinergic receptor complex.

The development of new radioiodinated ligands for imaging the muscarinic acetylcholinergic complex (mAChR) using single photon emission computed tomography (SPECT) requires the evaluation of human organ doses prior to approval for human use. Animal biodistribution and excretion data were obtained and evaluated for IPIP, a new mAChR agent. Preliminary biodistribution studies were performed on four different stereoisomers of IPIP. A biokinetic model of the Z-(S)-IPIP stereoisomer was constructed for the rat and used to estimate the internal absorbed dose in humans based on an extrapolation of the rat model. The thyroid is the critical organ for this radiopharmaceutical, with an absorbed dose estimate of 2.4 mGy/MBq for both males and females, when labeled with 123I. Even when blocked, the thyroid is still the critical organ, yet with a 90% dose reduction. The heart and brain receive the next highest doses in both males and females. Effective dose estimates for the use of pure 123I-PIP in humans are 0.16 mSv/MBq for males and 0.14 mSv/MBq for females. The biodistribution studies of the Z-(S)-IPIP stereoisomer showed the most promise as a successful agent for imaging muscarinic receptor sites in the heart and brain. IPIP also demonstrated potential as a therapeutic radiopharmaceutical for some colon carcinomas where muscarinic receptor sites are expressed in the tumor cells. These results provide preliminary data for use of IPIP in clinical studies on humans.

Animals↗

PubMed2000

Monte Carlo modeling of radiation dose distributions in intravascular radiation therapy.

Radiation dose distributions are developed for balloon and wire sources of radioactivity within coronary arteries. The Monte Carlo codes MCNP 4B and EGS4 were used to calculate dose distributions for photons and electrons at discrete energies around such sources, with and without the presence of a high-density atherosclerotic plaque. An interactive computer program was developed which then calculates dose distributions for many radionuclides by applying the emission spectra to the discrete energy grids calculated by the Monte Carlo codes, weighting appropriately for electron energy and abundance. Results for Re-186 and Re-188 balloon sources are shown in comparison to an Ir-192 wire source. The program provides dose distributions as well as estimates of activity levels needed to deliver prescribed doses to the vessel wall at selected distances from the lumen in a selected time interval. In addition, dose calculations are presented in this paper for other organs in the body, from photon radiation as well as from possible loss of liquid activity into the bloodstream in the case of a balloon rupture. These results, especially the interactive computer program permitting easy comparison of various radionuclides and their physical characteristics, will greatly facilitate the comparison process and aid in the selection of the best candidate(s) for clinical use.

Biophysical Phenomena↗

PubMed2000

Simple new method for effective concentration of 188Re solutions from alumina-based 188W-188Re generator.

UNLABELLED: (188)Re is a useful generator-produced radioisotope currently under evaluation for a variety of therapeutic applications, including bone pain palliation and intravascular radiation therapy. Because the (188)W parent is available only in a relatively low specific activity (<0.15-0.19 GBq/mg) from reactor irradiation of enriched (186)W, relatively large volumes of 0.9% saline (>15 mL) are required for elution of the (188)Re daughter from traditional alumina-based (188)W-(188)Re generators. Because these large bolus volumes result in solutions with a relatively low specific volume activity of (188)Re (<1 GBq/mL for the 18.5-GBq generator), the availability of effective methods for eluent concentration is important. Our new approach is based on the use of 0.3 mol/L ammonium acetate as a representative salt of a weak acid instead of saline for generator elution. METHODS: After generator elution, the ammonium acetate generator eluent (15-20 mL) is passed through a tandem IC-H Plus cation (Dowex-H)-anion (QMA Light) column system. Exchange of ammonium cations with hydrogen ions on the cation column forms an acetic acid solution containing perrhenate anions from which the macroscopic levels of the acetate anion of the eluent have been effectively removed. Because perrhenic acid is fully dissociated at this pH, the QMA Light column specifically traps the (188)Re-perrhenate, which is subsequently eluted with a low volume (<1 mL) of saline. Concentration ratios greater than 20:1 are readily achieved with this method. RESULTS: A typical clinical-scale generator loaded with 19.2 GBq (188)W was used to validate the approach. Saline elution provided (188)Re in a 75%-80% yield. Although elution with 0.15 mol/L NH4OAc gave lower yields (55%-60%), use of 0.3 mol/L NH4OAc provided yields comparable with those of saline (70%-75%). (188)W parent breakthrough was not detected after passage of the bolus through the tandem concentration system. Bolus volumes of 15-20 mL, which initially contained as much as 11.1-14.8 GBq (188)Re, were readily concentrated to less than 1 mL saline using QMA Light cartridges. The generator was evaluated for more than 3 mo with no decrease in performance. CONCLUSION: This approach represents a simple, rapid, and effective method using inexpensive disposable components of concentrating solutions of (188)Re for preparation of therapeutic agents.

Aluminum Oxide↗

PubMed2000

99mTc(V)DMSA quantitatively predicts 188Re(V)DMSA distribution in patients with prostate cancer metastatic to bone.

Rhenium-188 dimercaptosuccinic acid complex [188Re(V)DMSA], a potential therapeutic analogue of the tumour imaging agent 99mTc(V)DMSA, is selectively taken up in bone metastases in patients with prostate cancer. It would be helpful in planning palliative radionuclide therapy if 99mTc(V)DMSA could be used to predict tumour and kidney retention of 188Re(V)DMSA. The aim of this study was to determine the correlation between tumour-to-normal tissue ratios and kidney-to-soft tissue ratios of 99mTc(V)DMSA and 188Re(V)DMSA. This would determine whether a scan with 99mTc(V) DMSA could be used to identify patients for whom 188Re(V)DMSA treatment would be contra-indicated, and enable prediction of relative kidney and tumour radiation absorbed dose in 188Re(V)DMSA treatment. Ten patients with prostate carcinoma were recruited following observation of disseminated bone metastases on a recent 99mTc-hydroxydiphosphonate bone scan. Whole-body planar scans were obtained at ca. 4 h and 24 h after hydration and injection of 600 MBq 99mTc(V)DMSA, and a week later, at similar times after hydration and injection of 370 MBq 188Re(V)DMSA. A triple-energy window (TEW) scatter correction was applied to the 188Re scans. Counts per pixel were determined in regions of interest drawn over metastatic sites, kidneys and normal soft tissue. Tumour-to-soft tissue ratios were significantly lower (by a factor of approximately 0.8 after the TEW was applied) on 188Re scans than on 99mTc scans, but the two were highly linearly correlated both in all individual patients and in tumours pooled from all patients together both at 4 h and at 24 h. Kidney-to-soft tissue ratios were similarly correlated and were lower for 188Re than for 99mTc by a similar factor. Both tumour- and kidney-to-soft tissue ratios increased between 4 and 24 h but the latter increased more. In conclusion, only minor differences were seen between 99mTc and 188Re scans, and kidney-to-background ratios on 188Re scans were not higher than on 99mTc scans. These differences are insufficient to infer that they are due to a real difference in biodistribution, and they may be due only to different physical imaging characteristics. Thus 99mTc(V)DMSA scans are predictive of 188Re(V)DMSA biodistribution and could be used to estimate tumour and renal dosimetry and assess suitability of patients for 188Re(V)DMSA treatment.

Aged↗

PubMed1999

Iodine-123 labelled Z-(R,R)-IQNP: a potential radioligand for visualization of M(1 )and M(2) muscarinic acetylcholine receptors in Alzheimer's disease.

Z-(R)-1-Azabicyclo[2.2.2]oct-3-yl (R)-alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)-alpha-phenylacetate (Z-IQNP) has high affinity to the M(1 )and M(2) muscarinic acetylcholine receptor (mAChR) subtypes according to previous in vitro and in vivo studies in rats. In the present study iodine-123 labelled Z-IQNP was prepared for in vivo single-photon emission tomography (SPET) studies in cynomolgus monkeys. SPET studies with Z-[(123)I]IQNP demonstrated high accumulation in monkey brain (>5% of injected dose at 70 min p.i.) and marked accumulation in brain regions such as the thalamus, the neocortex, the striatum and the cerebellum. Pretreatment with the non-selective mAChR antagonist scopolamine (0.2 mg/kg) inhibited Z-[(123)I]IQNP binding in all these regions. The percentage of unchanged Z-[(123)I]IQNP measured in plasma was less than 10% at 10 min after injection, which may be due to rapid hydrolysis, as has been demonstrated previously with the E-isomer of IQNP. Z-[(123)I]IQNP showed higher uptake in M(2)-rich regions, compared with previously obtained results with E-[(123)I]IQNP. In conclusion, the radioactivity distribution from Z-[(123)I]IQNP in monkey brain indicates that Z-[(123)I]IQNP binds to the M(1)- and M(2)-rich areas and provides a high signal for specific binding, and is thus a potential ligand for mAChR imaging with SPET.

Alzheimer Disease↗

PubMed1999

Improved radioiodination of 1,2-dipalmitoyl-3-IPPA via a tributyltin intermediate.

1,2-Palmitoyl-3-[15-(4-iodophenyl)pentadecan-3-oyl]-rac-glycerol (MIPAG) is a new agent for the clinical evaluation of pancreatic lipase activity and has demonstrated promise in preliminary clinical studies with patients affected with pancreatic insufficiency. Iodine-131-MIPAG was initially prepared via thallium-iodide displacement. Because of the need for a simple method which is amendable for the routine clinical use of MIPAG we have investigated the preparation and radioiodination of MIPAG utilizing the tributyltin precursor, 1,2-palmitoyl-3-[15-(4-tributylstannylphenyl)pentadecan-3-oy l]-rac-glycerol (TBT-MIPAG, 2). Compound 2 was prepared via the condensation of 1,2-palmitoyl-rac-glycerol with 15-(4-tributylstannylphenyl)pentadecanoic acid (TBT-PPA) prepared from 4-bromophenylacetylene. Electrophilic radioiodination using peracetic acid with sodium iodide-125 in ethanol at 80 degrees C for 60 min afforded I-125-MIPAG in 65.9% (+/- 11.5%) yield and radiochemical purity of 94% (+/- 3.0%) after C-18 Sep-Pak purification (n = 6). This improved method for radioiodination utilizing TBT-MIPAG now provides radioiodinated MIPAG for routine clinical evaluation.

Fatty Acids↗

PubMed1999

Effect of reaction conditions on preparations of rhenium-188 hydroxyethylidene diphosphonate complexes.

Rhenium-186 (Re-186) hydroxyethylidene diphosphonate (HEDP) has been shown to localize in metastatic foci within bone in a manner similar to Tc-99m bone-seeking agents. Usually, in the preparation of diagnostic Tc-99m radiopharmaceuticals, the concentration of Tc is at trace level (10(-8) M). However, large amounts of carrier are included in the preparation of Re-186 radiopharmaceuticals (10(-4) M), which may significantly affect the preparation of Re-HEDP. In this study, Re-188 was used as an Re tracer. The effects of pH and concentrations of Re carrier on the preparation of Re-HEDP were investigated. Re-188-Sn-HEDP was prepared by reconstitution of a kit of lyophilized HEDP mixture, and tin chloride with a radioactive solution of perrhenate in saline. The total concentration of Re present in this work ranged from 10(-8) to 10(-3) M. The results showed that high labeling efficiency was obtained for each preparation. Although the chemical behaviors of the Re-188 HEDP complexes, with and without carrier, were similar, the biodistribution patterns of carrier free Re-188 HEDP in rats were found to differ from the biodistribution patterns of carrier-added Re-188 HEDP.

Animals↗

PubMed1999

[188Re]Rhenium sulfide suspension: a potential radiopharmaceutical for tumor treatment following intra-tumor injection.

Intralesional therapy has been shown to be an effective treatment for tumors. In this study, the suitability of [188Re]rhenium sulfide suspension for tumor treatment following intra-tumor injection was evaluated. The [188Re]rhenium sulfide suspension was radiolabeled with 188Re with a radiochemical yield of more than 96%. In vitro stability studies revealed that more than 99% of the 188Re remained in sulfide form over a 3-day period. After ultrasonication for 5 or 10 min, the main particle size was 1-5 microm. Two [188Re]rhenium sulfide suspensions ultrasonicated for 5 and 10 min, respectively, were injected into separate group of tumor-bearing mice that were killed after specified times to compare the retention of 188Re in tumors and the leakage to different organs by periods and organs removed to gamma counting. The mean retention percentages of 188Re in tumors injected with suspension ultrasonicated for 5 (or 10) min were as follows: 1 h, 90.5 +/- 7.7% (83.1 +/- 13.7%); 24 h, 92.2 +/- 8.6% (83.9 +/- 9.8%); 48 h, 88.3 +/- 10.9% (80.2 +/- 3.8%); and 72 h, 91.5 +/- 7.6% (78.8 +/- 3.0%). Tumor-inhibiting ratio was 96.5%. These results demonstrated that [188Re]rhenium sulfide suspension is an effective radiopharmaceutical for tumor treatment by intralesional therapy.

Animals↗

PubMed1999

A rapid and simple Sep Pak method for purification of radioiodinated IQNP, a high affinity ligand for the muscarinic receptor.

A simplified procedure for the purification of 1-azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)-alpha-phenylacetate (IQNP) stereoisomers utilizing a silica Sep Pak (SSP) is described. Iodine-131-E- and iodine-125-Z-(R,R)-IQNP were isolated after SSP purification in 80% and 75% radiochemical yields, respectively. The biodistribution of iodine-131-E-/iodine-125-Z-(R,R)-IQNP, purified either by SSP or high performance liquid chromatography (HPLC), was evaluated in female rats and demonstrated no significant differences in the uptake in various organs and cerebral regions. The utilization of SSP thus affords a simple and rapid method for the purification of IQNP for use in a variety of animal studies.

Animals↗

PubMed1999

BMIPP-design and development.

In the early 1980s a major obstacle for myocardial SPECT using iodine-123-labeled fatty acids and imaging technology available at that time was the rapid metabolism and myocardial washout of activity. Development of the 15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP) fatty acid analogue was based on the established effects of methyl-branching in delineating the enzymatic aberration in Refum's disease and our early studies with the tellurium (Te)-substituted fatty acid analogues. Extensive animal studies with the Te-fatty acids demonstrated that this major structural alteration did not affect initial myocardial extraction, but could successfully inhibit subsequent metabolism and significantly delay washout. Tracer kinetic evaluation and metabolic studies on experimental animals and Langendorff-perfused rat hearts clearly demonstrated that introduction of methyl-branching is an effective approach which alters tracer kinetics by delaying myocardial washout of radioiodinated fatty acids by increasing myocardial retention. Although irreversible retention of iodine-123 BMIPP is not observed, subsequent extensive human studies have clearly substantiated the delayed myocardial washout of BMIPP in comparison with the p-IPPA straight chain analogue. Although contemporary SPECT capabilities allow much more rapid acquisition periods, the delayed washout is still a practical benefit in relation to the use of BMIPP. Most important, the unexpected mis-match which has been widely observed between perfusion tracer distribution and the regional BMIPP distribution (i.e. BMIPP < flow tracer) has been linked to the identification of jeopardized, but viable myocardial regions. In this paper the development of BMIPP is discussed and the results of recent studies focusing on evaluating the effects of the absolute configuration of the branched methyl group using the 3(R)-BMIPP and 3(S)-BMIPP are described.

Animals↗

PubMed1999

Metabolism of radioiodinated fatty acid analogs in ischemic and hypoxic canine myocardium.

UNLABELLED: Myocardial metabolism of 17-[123I]-iodoheptadecanoic acid (IHDA), 15-(p-[131I]-iodophenyl)pentadecanoic acid (pIPPA) and 15-(p-[125I]-iodophenyl)-3,3-dimethylpentadecanoic acid (DMIPP) was assessed during ischemia and hypoxia. The simultaneous investigation allowed us to evaluate differences in metabolic handling of these three fatty acids. METHODS: In 17 open-chest dogs, the left ascending coronary artery was cannulated and extracorporeal bypass (ECB) perfused. In 3 dogs, ECB flow was kept normal, and these control experiments showed that kinetics of the radioiodinated fatty acids were not affected by the ECB technique itself. In 9 dogs, ECB flow was reduced to one third (ischemia), and in 5 dogs, the ECB area was perfused with venous blood and was kept at control values (hypoxia). After simultaneous intravenous injection of IHDA, pIPPA and DMIPP, seven paired biopsy specimens from the native and ECB-perfused myocardium were taken over an assay period of 35 min. Total activity and the distribution in the aqueous phase and lipid fractions were determined, and time-activity curves were constructed. RESULTS: In ischemic (Is) but not in hypoxic (Hy) myocardium, peak total activity of IHDA, pIPPA and DMIPP decreased significantly versus normal (N) myocardium (IHDA: N = 700 +/- 267 versus Is = 335 +/- 158 dpm/mg/mCi; pIPPA: N = 988 +/- 318 versus Is = 438 +/- 180 dpm/mg/mCi; DMIPP: N = 352 +/- 146 versus Is = 179 +/- 82 dpm/mg/mCi; all P values < 0.001). The relative decrease was similar for IHDA, pIPPA or DMIPP. Half-time values of total activity were prolonged for IHDA and pIPPA but were shortened for DMIPP in ischemic and hypoxic myocardium (IHDA: N = 22, Is = 44 and Hy = 50 min; pIPPA: N = 24, Is = 95 and Hy = 169 min; DMIPP: N = 528, Is = 409 and Hy = 115 min). The aqueous phase activity for IHDA, pIPPA and DMIPP decreased significantly versus normal myocardium in both ischemic (IHDA: N = 71% +/- 9% versus Is = 36% +/- 9%, P < 0.001; pIPPA: N = 62% +/- 10% versus Is = 25% +/- 8%, P < 0.001; DMIPP: N = 26% +/- 11% versus Is = 18% +/- 3%, P < 0.05) and hypoxic (IHDA: N = 76% +/- 8% versus Hy = 62% +/- 8%, P < 0.05; pIPPA: N = 66% +/- 8% versus Hy = 46% +/- 10%, P < 0.05; DMIPP: N = 32% +/- 6% versus Hy = 24% +/- 4%, P < 0.05) myocardium. The relative decrease was significantly highest for pIPPA and lowest for DMIPP. Incorporation into triacylglycerols increased significantly for IHDA, pIPPA and DMIPP in both ischemic and hypoxic myocardium. In normal myocardium, DMIPP was already mainly incorporated into triacylglycerols. Activity of IHDA and pIPPA in acylcarnitine increased significantly in ischemic and hypoxic myocardium. CONCLUSION: Kinetics of the radioiodinated fatty acid analogs in myocardium are altered during oxygen deprivation in a similar fashion as documented in literature for natural fatty acids. However, the changes were different between IHDA, pIPPA and DMIPP, suggesting different metabolic handling and thus reflecting different aspects of myocardial fatty acid metabolism.

Animals↗

PubMed1999

Pharmacokinetics and metabolism of the methyl-branched fatty acid (BMIPP) in animals and humans.

UNLABELLED: The aim of this study was to further characterize the major metabolite of 15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP). METHODS: Radioactive components of 131I-BMIPP were evaluated in Langendorff-perfused rat hearts, as well as in blood samples from 20 patients after injection of 123I-BMIPP. Rat hearts were perfused with pH 7.4 Krebs-Henseleit buffer with or without 0.4 mmol/L bovine serum albumin (BSA) or 0.4 mmol/L palmitate. Lipids were Folch extracted and hydrolyzed from samples of the outflow, as well as from homogenized hearts. Radioactive components were determined by thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC) analyses. The major metabolite of BMIPP was then further characterized by electrospray mass spectrometry. RESULTS: The rat heart perfusate showed one major polar metabolite observed by TLC (Rf = 0.35; solvent = benzene-dioxane-acetic acid 80:18:2). The addition of BSA/palmitate to the perfusate buffer significantly increased backdiffusion of BMIPP (Rf = 0.55), as well as reduced BMIPP uptake and metabolism. The major metabolite was identified by mass spectral analysis as 2-(p-iodophenyl)acetic acid (IPC2). From TLC and HPLC analyses of the serum lipids obtained from patients, the same metabolite could be identified with levels increasing over time (0%, 5.2% and 11.8% of the injected dose; 3 min, 20 min and 3 h postinjection, respectively). In addition to the identification of unmetabolized BMIPP (53.9%), the rat heart lipid hydrolysate also contained alpha-methyl-14-(p-iodophenyl)tetradecanoic acid (20.8%), 12-(p-iodophenyl)-substituted-dodecanoic (17.1%), -hexanoic acid (5.2%) and IPC2 (1.1%). CONCLUSION: The animal results show the complexity of uptake, metabolism and release of BMIPP from which a part is metabolized through alpha- and subsequent beta-oxidation to the final IPC2 metabolite as confirmed by mass spectral analysis. The results from patient studies suggest that the slow myocardial washout observed in vivo after intravenous administration of BMIPP may represent a similar process, because both unmetabolized BMIPP and the final metabolite were also identified in serum samples.

Animals↗

PubMed1999

A new experimental determination of the dose calibrator setting for 188Re.

UNLABELLED: Accurate activity measurements of radionuclides using commercial dose calibrators requires that the correct dial setting (or calibration factor) be applied. The dose calibrator setting for the medical radionuclide 188Re (as 188ReO4-) has been determined experimentally using solution sources prepared and calibrated at the National Institute of Standards and Technology (NIST). METHODS: The specific activity of two sources (in units of MBq/g) in the standard 5-mL NIST ampoule and in a 5-mL SoloPak dose vial were calibrated using 4pibeta liquid scintillation counting with 3H-standard efficiency tracing and gamma-ray/bremmstrahlung counting in the NIST "4pi" gamma ionization chamber on gravimetrically related sources. RESULTS: The newly determined settings for the NIST Capintec CRC-12 dose calibrator are (631+/-4) x 10 and (621+/-3) x 10 for the respective ampoule and dose vial geometries with an expanded (at a presumed 95% confidence level) uncertainty of 0.4%-0.5% in the activity determination. The setting for the dose vial geometry was independently confirmed using a Capintec CRC-15R at Cedars-Sinai Medical Center using sources calibrated against a NIST standard. CONCLUSION: These new settings result in activity readings 28%-30% lower than those obtained using the previously recommended setting of 496 x 10. This discrepancy most likely results from underestimating the total radiation yield from 188Re decay when calculating the dose calibrator response. This study emphasizes the need for experimental determinations of dose calibrator settings in the geometry in which the measurements will be performed.

Calibration↗

PubMed1999

Dual-label studies with [125I]-3(R)/[131I]-3(S)-BMIPP show similar metabolism in rat tissues.

UNLABELLED: Biodistribution studies with the radioiodinated 3(R)- and 3(S)-isomers of 15-(p-iodophenyl)-3-methylpentadecanoic acid (BMIPP) in rats have shown that 3(R)-BMIPP has 20%-25% higher heart uptake than 3(S)-BMIPP (15-180 min). In contrast, the 3(S)-isomer has slightly higher liver uptake, and uptake in other tissues examined is similar. METHODS: To evaluate the possible differences in metabolic fate of the two isomers, a mixture of [125I]-3(R)/[131I]-3(S)-BMIPP was administered to fasted female Fisher rats. Groups of rats (3 per group) were killed 15, 60 and 180 min after administration. Urine and feces were collected from a fourth group (n = 3) over 7 d. Samples of blood, heart, liver, lungs, kidney and urine were Folch extracted. The distributions of 125I and 131I in the organic (lipid), aqueous and pellet samples were determined. The lipid samples as well as the organic fractions from base-hydrolyzed triglyceride (TG) fractions and acid-hydrolyzed urine samples were then analyzed by thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC). RESULTS: The relative distributions of 125I and 131I in the lipid, aqueous and pellet samples were similar for both isomers. Distribution of 125I and 131I in the various components of the lipid extracts observed by TLC (hexane:ether:HOAc, 70:30:1) was also similar, with principal incorporation into the free fatty acid (FFA) and TG pools. HPLC analyses (C18) of the FFA fraction showed similar 125I and 131I profiles, corresponding to BMIPP, and the alpha-methyl-C14 (14-(p-iodophenyl)-3-(R,S)-methyltetradecanoic acid) and C12, C10 and C6 carbon chain-length catabolites. By TLC, radioactive components of 125I and 131I in the urine had the same TLC mobility as hippuric acid. HPLC analyses (C18) of acid-hydrolyzed urine gave a single 125I/131I component with the same relative retention time as 2-(p-iodophenyl)acetic acid, which is the final alpha/beta-oxidative BMIPP catabolite. Unexpectedly, HPLC of lipids from base-hydrolyzed TG from the heart tissue showed 125I/131I components with the same retention times as shorter-chain fatty acids, similar to the FFA fraction, with only low levels of activity detected in BMIPP. CONCLUSION: These results show that 3(R)-BMIPP and 3(S)-BMIPP are metabolized similarly in rat tissues and that higher myocardial extraction observed for 3(R)-BMIPP may reflect differences in the relative membrane transport of the two isomers.

Animals↗