Effect of beta-blockade on right ventricular performance in patients with and without right ventricular dysfunction due to coronary artery disease.

To assess the effects of beta-blockade on right ventricular performance in patients with and without right ventricular dysfunction due to coronary artery disease, we performed radionuclide ventriculography on eight patients with normal right ventricular ejection fraction (RVEF greater than or equal to 35%) and 14 patients with mild to moderate right ventricular dysfunction (RVEF less than 35%) at rest. All patients had chronic stable angina pectoris, and nine patients had prior myocardial infarction. Radionuclide ventriculography was performed on placebo and during clinical beta-blockade (heart rate, 50 to 60 beats per minute and less than or equal to 20% increase in heart rate over baseline during stage I treadmill exercise, Bruce protocol) with the oral, cardioselective beta-blocking agent, betaxolol. The resting RVEF (mean +/- 1 SD) was 33% +/- 7% on placebo and 34% +/- 7% during clinical beta-blockade. Mean exercise RVEF was 40% +/- 8% on placebo and 39% +/- 8% during clinical beta-blockade. These differences were not statistically significant. Resting left ventricular ejection fraction ranged from 22% to 60% (mean, 42% +/- 8%). On placebo, one of eight patients with a resting RVEF greater than or equal to 35% had a normal exercise RVEF response (greater than or equal to 5% increment) whereas nine of 14 patients with resting RVEF less than 35% had normal exercise response. The discordant relationship between baseline RVEF and exercise response on placebo became less marked during clinical beta-blockade. We conclude that beta-blockade does not produce significant deterioration of right ventricular systolic function or right ventricular reserve either in patients with normal or in those with mild to moderately impaired resting right ventricular systolic function.

Retention of [99mTc]-d,l-HM-PAO in rat brain: an autoradiographic study.

The regional cerebral distribution pattern of [99mTc]-d,l-HM-PAO in rat brain was studied by autoradiography. The regional cerebral uptake of this tracer is related to regional cerebral blood flow (rCBF); however, the ratio of retained radioactivity (determined by digital imaging techniques) in gray matter compared to white matter is lower than that reported for the blood flow ratio. Considerable inhomogeneity is observed in cortical gray matter for at least 60 min postinjection, demonstrating that minimal, if any, cerebral redistribution of this agent occurs.

Radiopharmaceuticals in clinical trials.

Several radiopharmaceuticals with a propensity to concentrate in painful metastatic bone cancer lesions are under development as a systemic radiation alternative to 32P. All are reactor produced and, when injected, have in all but 117mSn-DTPA decreased or eliminated the pain in more than three quarters of the patients, and all have caused transient myelotoxicity. Three of the four are under clinical evaluation and the generated data will be used for new drug applications for routine human use.

An unusual cause of apparent regional hyperperfusion on radionuclide cerebral angiography study: case report.

An unusual pattern of radioactivity in the venous phase was noted in the 99mTc-DTPA cerebral angiogram of a patient with persistent headaches. Initially the possibility of a small arteriovenous malformation with large draining veins was considered. However, contrast angiography revealed dilated cerebral veins with significant arteriovenous shunting. The differential diagnosis of regional hyperperfusion on the radioactivity study is discussed.

Glycopyrrolate in 99mTc-pertechnetate brain imaging.

Glycopyrrolate, a synthetic anticholinergic agent, was administered parenterally to two groups of patients referred for 99mTc-pertechnetate brain imaging to assess its ability to suppress pertechnetate uptake by the choroid plexus, oral mucosa, and salivary (parotid) glands. Pertechnetate activity was almost completely eliminated from the choroid plexus and mouth and appeared to be moderately reduced in the parotid gland. The drug can be given orally and may prove valuable in pertechnetate brain imaging.

The radionindium bone-marrow image in acute (malignant) myelofibrosis.

A patient with a rapidly fatal case of acute myelofibrosis had a radioindium bone-marrow image that unexpectedly showed a normal pattern of distribution, unlike the more typical forms of chronic myelofibrosis or agnogenic myeloid metaplasia. The rapid progression of the disease and the unique handling of radioindium by the reticuloendothelial system may explain the discordant findings.

Sensitivity of technetium-99m-d,1-HMPAO to radiolysis in aqueous solutions.

The sensitivity of technetium-99m- (99mTc) d,l-HMPAO to radiolytically induced dissociation in aqueous solutions was investigated. It was found that cobalt-60 (60Co) gamma irradiation of solutions containing 99mTc-d,l-HMPAO with only 1600 cGy reduced the lipophilic chelates' radiochemical purity (RCP) to 50%-60%. The radiolytic sensitivity of 99mTc-meso-HMPAO is significantly lower. The results indicate that radiolytically produced intermediates limit the in vitro stability of 99mTc-d,l-HMPAO.

Radiation dose calculations in persons receiving injection of samarium-153 EDTMP.

Samarium-153 EDTMP has been proposed as a radionuclide therapeutic agent to treat malignant bone tissue disorders. Data obtained from laboratory rats has been used to calculate the radiation dose for humans following the administration of [153Sm]EDTMP. The data reveals that the highest doses are present in the skeleton and the urinary bladder wall (bladder dose varies with frequency of voiding). Skeletal activity was used to estimate the bone marrow dose from the [153Sm]EDTMP beta radiation. Although this estimate indicates high marrow irradiation it is only an approximation since the beta radiation from inhomogeneously deposited bone activity surrounding the marrow produces variable radiation dose distributions.

Kinetic analysis of technetium-99m d,1-HM-PAO decomposition in aqueous media.

Technetium-99m-d,1-hexamethylpropyleneamine oxime [99mTc]d,1-HM-PAO) is a neutral-lipophilic chelate formed from a kit in high yield by stannous reduction of Na99mTcO4-. Of three methods used to analyze the purity of the 99mTc complexes, a single strip method using ether as the developing solvent was the most rapid and simple to perform. The lipophilic chelate converts to 99mTcO4- and other hydrophilic products with time and this limits the useful lifetime of the preparations. The rate of decomposition of [99mTc]d,1-HM-PAO increased in the presence of excess stannous ion and at pH greater than 9.

Enzymatic inhibition of diphosphonate: a proposed mechanism of tissue uptake.

Enzymes have been proposed as tissue receptors that bine 99mTc-stannous diphosphonate and its analogs. Incubation of diphosphonate with several enzymes demonstrated inhibition of acid and alkaline phosphatase activity but showed no effect on glutamic oxalacetic transaminase and lactate dehydrogenase activity. Complete reversal of the diphosphonate-induced inhibition of alkaline phosphatase activity occurred when calcium ion was added to the reaction. The specificity of calcium to induce reversal was dispelled when magnesium ion gave identical results. Diphosphonate-induced inhibition of acid phosphatase, however, was not reversed by calcium or magnesium.

Assay of 32P-sodium phosphate using a commercial dose calibrator.

Dose calibrators are not usually used to measure the activity of pure beta-emitting radionuclides. In this work, the activity of 32P-sodium phosphate was accurately measured with a Capintec CRC-2 dose calibrator. Using a calibration knob setting of 012 on the 1-mCi range, the 32P dose (in mCi) could be calculated directly simply by multiplying the instrument readout by 10. The dose calibrator response was found to be linear at this knob setting and moderate alterations in geometry produced no significant changes.

Skeletal localization of samarium-153 chelates: potential therapeutic bone agents.

A series of stable complexes of 153Sm has been produced using multidentate acetate and phosphonate ligands. Biodistribution studies in unanesthetized rats showed varying degrees of bone and soft-tissue uptake for these complexes. Of the complexes studied, [153Sm] ethylenediaminetetramethylenephosphonate (EDTMP) showed the best combination of high bone uptake, low nonosseous uptake, and rapid blood clearance which warranted its further investigation in rabbits. Rabbit studies confirmed the [153Sm]EDTMP results obtained in rats. Blood clearance in rabbits was found to be more rapid than [99mTc] methylene diphosphonate (MDP). Scintigraphic images were virtually indistinguishable from [99mTc]MDP images. Lesion/normal bone ratios were determined from digitized images obtained using a drill hole model and found to be approximately 17:1. Based on these excellent biodistribution characteristics, [153Sm] EDTMP could be therapeutically useful in treating metastatic bone cancer.

Samarium-153-EDTMP: pharmacokinetic, toxicity and pain response using an escalating dose schedule in treatment of metastatic bone cancer.

Samarium-153 emits medium-energy beta particles and an imageable gamma photon with a physical half-life of 46.3 hr. When chelated to ethylenediaminetetramethylenephosphonic acid (EDTMP), it is remarkably stable in vitro and in vivo. In this study, we administered escalating amounts of 153Sm-EDTMP, from 0.1 to 1.0 mCi/kg (3.7-37 MBq/kg), to 22 patients with painful metastatic bone cancer. A complete concordance was found when the scintigrams of 153Sm-EDTMP were compared qualitatively to 99mTc-HDP bone images. Moreover, the skeletal uptake of the 153Sm-EDTMP related to the number of metastatic sites (r = 0.65; p = 0.001) showed an inverse proportion to the plasma radioactivity at 30 min following injection (r = -0.79; p = 0.0001) and was unaffected by the administered (mCi/kg), (r = 0.33; p = 0.13). Myelotoxicity was observed in 10 of the 29 treatment courses and leukopenia occurred in two. Thrombocytopenia occurred in patients who had low pretreatment platelet counts, albeit within the normal range (p = 0.001), most suffered from prostate cancer (p = 0.007) and retained a higher percentage of the 153Sm-EDTMP in their skeleton (p = 0.057). In four patients an exacerbation of the pre-existing pain ("flare reaction") was recorded. Pain palliation occurred in 65% of the treated patients (mean: 3.8 mo, range: 1-11 mo). Retreatment in first time responder patients was quite effective. Our preliminary results indicate that 153Sm-EDTMP is a promising radiotherapeutic agent for palliative treatment of metastatic bone cancer pain, and further study is necessary to ascertain its optimal dose, efficacy and toxicity.

Radiographic and neuro-SPECT imaging in an immature third ventricle teratoma: case report.

We report a case of an immature teratoma of the third ventricle, which was preoperatively thought to be a choroid plexus papilloma. The diagnosis was made by biopsy since the radiographic (CT, MRI), angiographic and scintigraphic findings ([99mTc]pertechnetate, 99mTc-DTPA, 99mTc-HMPAO brain SPECT) were nonspecific. Disruption of the blood-brain barrier is the mechanism for radionuclidic and contrast tumoral uptake and is demonstrated by marked contrast enhancement on CT and focal concentration on [99mTc]pertechnetate and 99mTc-DTPA images. No suppression of [99mTc]pertechnetate tumor uptake was observed following the administration of potassium perchlorate. Increased concentration of tumor protein is suggested by the increased signal on the T1-weighted magnetic resonance images and high [99mTc]pertechnetate uptake. The tumor's detection on the 99mTc-HMPAO brain SPECT was due to its intraventricular location. A number of potential mechanisms for brain tumor localization of 99mTc-HMPAO are discussed.

Technetium-99m glucoheptonate imaging in lung cancer and benign lung disease: concise communication.

We prospectively studied technetium-99m glucoheptonate (Tc-GHA) uptake in 58 patients with newly diagnosed lung cancer and in 20 patients with pulmonary inflammatory disease or metastatic carcinoma. Fifty-three (91%) primary tumors accumulated Tc-GHA: squamous cell 20/22, adenocarcinoma 7/7, large cell 10/11, and small cell 16/18. Intensity of tumor uptake was greatest in small-cell cancer. Supraclavicular metastases were detected in two patients. Fourteen patients with mediastinal evaluation by Tc-GHA imaging and trispiral tomography underwent mediastinoscopy or thoracotomy. Five of ten patients with negative mediastinum by tomography and Tc-GHA imaging showed metastases by biopsy (false-negative Tc-GHA). Less intense accumulation of Tc-GHA was observed in 18/20 cases of pulmonary inflammatory disease or pulmonary metastases. Although Tc-GHA accumulates by an unknown mechanism in primary lung cancer, we cannot recommend its use in detecting mediastinal spread of lung cancer due to its unacceptably high false-negative rate.

Complexing of Tc-99m with cyclam: concise communication.

The macrocyclic amine, cyclam, has been found to be an efficient complexing agent for Tc-99m. Complexes can be formed in yields of higher than 95% at pH 11 in 10(-3) M cyclam using 5 x 10(-6) M SnC4H4O6 as a reducing agent. The complex is positively charged and is stable in air. It is not decomposed by dilution, by 0.05 M NaOH, or 0.05 M H2O2, but does show slight decomposition in 0.05 M HCl. In unanesthetized mice the complex is cleared rapidly from the blood by the kidneys and liver. Preliminary studies show that derivatives of cyclam also complex Tc-99m.

Dynamic SPECT of the brain using a lipophilic technetium-99m complex, PnAO.

The lipophilic 99mTc-labeled oxime propylene amine oxime (PnAO) should, according to recent reports behave like 133Xe in the human brain. This study compares SPECT images of the two tracers in six subjects: four stroke cases, one transitory ischemic attack case and one normal subject. Technetium-99m PnAO was injected i.v. as a bolus of 15 to 25 mCi. The distribution was followed over 10-sec intervals using a highly sensitive, rapidly rotating SPECT (Tomomatic 64) and compared to 133Xe flow maps. Upon arrival of the PnAO bolus to the brain, a high uptake was found in brain tissue with high cerebral blood flow followed by rapid washout. In the stroke cases, low flow areas were equally well visualized by both tracers. Two dissimilarities were seen in the initial pictures: PnAO visualized the cerebral veins and showed a lesser contrast of gray:white matter uptake. The results suggest that PnAO has a high yet incomplete brain extraction yielding a flow dominated initial distribution with limitations mentioned.

Human pharmacokinetics of samarium-153 EDTMP in metastatic cancer.

Samarium-153 ethylenediaminetetramethylene phosphonic acid ([153Sm]EDTMP) has been proposed to palliate pain resulting from osteoblastic metastatic bone cancer. Encouraging results in dogs with primary malignant bone cancer provided the catalysis for human biodistribution studies in five patients with metastatic skeletal carcinoma. The objective was to assess the preferential localization of [153Sm]EDTMP in bony lesions and compare it to the 99mTc-labeled phosphonates. Blood clearance of [153Sm]EDTMP was rapid with minimal accumulation in nonosseous tissues. Both radiopharmaceuticals showed identical lesion uptake in 23 paired lesions (p greater than 0.05). This indicates that the two radiopharmaceuticals concentrate in metastatic skeletal lesions by the same mechanism and since [153Sm]EDTMP emits beta radiation it may be therapeutically useful in ameliorating metastatic bony cancer pain.

Technetium-99m d,l-HM-PAO: a new radiopharmaceutical for SPECT imaging of regional cerebral blood perfusion.

Following investigation of a large number of new ligands based upon propylene amine oxime (PnAO) the d,l-diastereoisomer of hexamethyl propyleneamine oxime (HM-PAO) was selected as the preferred ligand for 99mTc as a tracer for cerebral perfusion imaging. The neutral, lipophilic 99mTc complex of d,l-HM-PAO was formed in high yield by stannous reduction of 99Mo/99mTc generator eluate using a kit formulation of the ligand. Two minutes following i.v. administration of this complex in rats, 2.25% of the injected dose appears in the brain. Little washout of the tracer is observed up to 24 hr postinjection. By qualitative autoradiographic comparison with iodoantipyrine this new radiopharmaceutical displays blood flow dependent brain uptake with little redistribution of the tracer over time. The lipophilic 99mTc complex converts slowly in vitro to a secondary complex. This conversion process may account for the ability of [99mTc]d,l-HM-PAO to be retained within the brain without redistribution.

Effect of beta blockade with betaxolol on left ventricular systolic function in chronic stable angina pectoris and left ventricular dysfunction.

To assess the effect of beta blockade on left ventricular (LV) performance in patients with LV dysfunction and stable angina pectoris, 18 subjects taking a placebo followed by incremental doses of the cardioselective beta-adrenergic blocking agent betaxolol (5, 10, 20, 40 and 80 mg/day) were studied. The study ended with the achievement of optimal clinical beta blockade (heart rate at rest 50 to 60 beats/min, a 20% or smaller increase in heart rate during stage 1 of symptom-limited treadmill exercise using the modified Bruce protocol). Optimal clinical beta blockade produced a decrease in mean frequency of angina, from 6.8 +/- 1.7 to 0.7 +/- 0.8 episodes per week (p less than 0.0005) and an increase in mean treadmill exercise capacity, from 3.1 +/- 1.7 to 7.7 +/- 2.8 minutes (p less than 0.0005). LV systolic function was assessed at rest and during symptom-limited exercise with radionuclide left ventriculography. Mean LV ejection fraction (EF) during therapy with placebo was 39 +/- 7% at rest and 40 +/- 8% at peak exercise. Mean LVEF during optimal clinical beta blockade was 43 +/- 11% at rest and 45 +/- 10% at peak exercise. Neither of these changes was statistically significant. No patient had clinical or radiographic signs of LV failure. The results suggest that optimal clinical beta blockade with betaxolol, in doses sufficient to significantly reduce the frequency of angina and improve exercise capacity in patients with stable angina pectoris and mild to moderate LV systolic dysfunction, does not cause significant deterioration of LV systolic function or produce LV failure.