Interferon-induced changes in pharmacokinetics and tumor uptake of 111In-labeled antimelanoma antibody 96.5 in melanoma patients.

The type I interferons [both partially purified human leukocyte interferon (HuIFN-alpha) and recombinant alpha interferon] and the type II interferons have been shown to increase the expression of tumor-associated antigens in vitro. To determine whether HuIFN-alpha could increase tumor acquisition of the antimelanoma antibody 96.5 in vivo, five patients with metastatic malignant melanoma were treated with HuIFN-alpha at a dose of 3 X 10(6) units daily by im administration. Twenty-four hours after the first dose of HuIFN-alpha, 1 mg of antibody 96.5 labeled with 5 mCi of 111In was coadministered with 19 mg of unlabeled 96.5. Five patients matched for metastatic site and lesion size who had not received HuIFN-alpha were also given a dose of 5 mCi of radiolabeled 96.5 at the same total antibody dose (20 mg). In patients treated with HuIFN-alpha, there was a statistically significant increase in the plasma half-life of the 111In label (39.7 +/- 3.3 hr) compared to the untreated control group (29.8 +/- 3.2 hr). In addition, there was an increase in the apparent volume of distribution of the antibody in the HuIFN-alpha group (5.56 +/- 0.67 L) compared to controls (3.15 +/- 0.5 L) suggesting both an increased immediate extravascular distribution of radiolabeled antibody and a decrease in the subsequent rate of clearance of antibody from plasma. These two phenomena result in a 28% decrease in the area under the concentration curve in the HuIFN-alpha-treated group compared to controls. Computer analysis of whole-body scans from patients showed a threefold increase in radiolabeled antibody distributed to tumor relative to blood pool but no change in organ:blood ratios for liver, spleen, bone, or kidney compared to controls. This pilot study suggests that treatment of patients with HuIFN-alpha results in an improved distribution of radiolabeled antibody to tumor target without a concomitant increase of label in normal nontarget tissues. In addition, this change in whole-body distribution of antibody is manifested by changes in the pharmacokinetic parameters measured for monoclonal antibody.

Clinical pharmacology, metabolism, and tissue distribution of 90Y-labeled monoclonal antibody B72.3 after intraperitoneal administration.

B72.3 is a murine monoclonal antibody that recognizes a high-molecular-weight tumor-associated glycoprotein (TAG-72). Nine patients with TAG-72-positive ovarian carcinoma or papillary serous carcinoma of the peritoneum received an intraperitoneal infusion of 2, 4, or 10 mg B72.3 labeled with 0.5-1.2 (mean, 0.8) mCi 90Y. All patients had laparotomy, with multiple tissue and tumor samples removed 3-7 days later. The concentration of the total 90Y label in peritoneal fluid cleared with an extrapolated half-life of 68.6 +/- 4.5 hours. A low-molecular-weight 90Y-labeled species of metabolite was identified by high-performance liquid chromatography. The concentration of this low-molecular-weight species initially increased in the peritoneal fluid, with a half-life of 0.9 hour, and was rapidly cleared from the peritoneal cavity, with a half-life of 23.1 hours. Both the 90Y-labeled metabolite and the 90Y-labeled B72.3 were absorbed into the plasma, with half-lives of 16 +/- 2.2 hours and 25 +/- 5 hours, respectively. The clearance half-lives for these agents in plasma were 25 +/- 3 hours for the metabolite and 42 +/- 17 hours for B72.3. Approximately 8%-11% of the total injected 90Y label appeared in urine over 72 hours. Most of the label (about 70%) was present as the 90Y-labeled metabolite, but about 30% of the 90Y label in urine appeared identical to the authentic 90Y-labeled B72.3 standard when assayed by chromatography. Tissue distribution studies showed that normal tumor tissue and omentum contained the highest content of 90Y (about 0.017% of the injected dose per gram), followed in descending order by liver, normal lymph nodes, peritoneum, bone, and fascia. The lowest concentrations of 90Y were found in rectus abdominis muscle, bone marrow, and fat. There was substantial heterogeneity in the uptake of the 90Y label into tumor sites among patients and among different sites within the same patient. No correlation could be demonstrated between the TAG-72 content and the amount of 90Y label found in tumor sites. Preliminary radiation dosimetry estimates suggest that the tumor sites received about 82.8 cGy for each millicurie of 90Y administered. Thus, if an adequate total radiation dose can be achieved, 90Y-labeled B72.3 should be therapeutically useful for treating diffuse intraperitoneal disease.

Immunospecific saturable clearance mechanisms for indium-111-labeled anti-melanoma monoclonal antibody 96.5 in humans.

Liver uptake of 111In-labeled monoclonal antibodies (MoAb) remains a significant problem in radioimaging studies to date. To determine if the observed liver uptake of an 111In-labeled anti-melanoma antibody 96.5 (111In-96.5) was dependent on the presence of hepatic antigen or on recognition of circulating murine antibody, escalating doses of an unlabeled nonimmunoreactive MoAb (NIR-MoAb) were administered to 18 patients with metastatic malignant melanoma either 1 or 24 h prior to an infusion of 1 mg of 111In-96.5. The number of metastases imaged, pharmacokinetics, and the ratio of radioactivity (expressed as average counts/pixel) in liver (L), spleen (S), bone (B), and kidney (K) compared to blood pool (heart = H) were examined. Results were prospectively compared with data from six patients who received immunoreactive unlabeled 96.5 prior to 111In-96.5. Increasing dose or changes in the preinfusion time of NIR-MoAb had no significant effect on the biodistribution of 111In-96.5. In contrast, patients who received unlabeled, immunoreactive 96.5 prior to 111In-96.5 infusion demonstrated a significant drop [P less than 0.001] in the liver/heart ratio of radioactivity [2.81 +/- 0.35 (SEM)] compared to patients receiving the identical dose of NIR-MoAb [10.35 +/- 1.33]. Significant decreases in spleen/heart and bone/heart ratios were also observed. Pharmacokinetic studies showed that the volume of distribution (Vd) and the plasma t1/2 both decreased when 96.5 was administered compared to NIR-MoAb. In addition, a 4-fold increase in concentration X time was obtained after 96.5 antibody was administered compared to NIR-MoAb. More metastases were imaged in patients receiving preinfusions of 96.5 (23 of 28) than in patients receiving NIR-MoAb (10 of 18; P less than 0.05). Although tissue distribution of 111In-labeled antibody can be ascribed to nonspecific organ clearance of murine antibodies, a substantial component of tissue disposition of antibody 96.5 was shown to be a consequence of specific clearance of immunoreactive antibody which may cross-react with tissue antigens.

Radioimaging of melanoma using 99mTc-labeled Fab fragment reactive with a high molecular weight melanoma antigen.

Twenty patients with metastatic malignant melanoma were studied with 99mTc-labeled monoclonal antibody (MoAb) Fab fragment (NR-Ml-05) reactive with a high molecular weight (Mr 240,000) melanoma associated antigen. Patients received 40 mg unlabeled irrelevant MoAb (NR-2AD-IgG) and 7.5 mg unlabeled NR-Ml-05 (whole IgG) prior to infusion of 10 mg 99mTc-labeled (10-25 mCi) NR-Ml-05 Fab. Unlabeled MoAb were given to block nonspecific and specific binding sites. Gamma camera scans and single photon emission computed tomography were performed at 8 and 24 h postadministration. Of 172 preexisting lesions, 136 were imaged for a sensitivity of detection of 79%. Imaging was site and size dependent with the greatest sensitivity for liver lesions (100%) and the least for bowel (0%). Six sites (2 skin, 1 lung, 3 liver) were detected by single photon emission computed tomography that were missed on routine planar images. Forty-one additional unconfirmed sites were seen. Of these, 7 (17%) have been confirmed as tumor after a median follow-up time of 6 months. False positive scans included scar tissue, areas of chronic inflammation, an infected femoral aneurysm, and septic emboli. Nonspecific uptake of radioactivity occurred in kidney, gallbladder, bowel, thyroid, and myocardium. Human anti-mouse antibodies were detected in up to 69% of patients. In summary, radioimaging with 99mTc-NR-Ml-05 is a sensitive test, especially for detecting liver lesions. It is safe, simple to administer, and convenient for the patient. Biodistribution and imaging sensitivity differ significantly from studies in which 111In-labeled anti-melanoma MoAb have been used.

Radioimmunoimaging in malignant melanoma with 111In-labeled monoclonal antibody 96.5.

A radiolabeled monoclonal antibody (96.5) reactive with an Mr 97,000 antigen found on over 80% of melanoma cell lines and tissue extracts was examined for its ability to detect malignant melanoma metastases in vivo. For imaging purposes, it was conjugated with diethyltriaminepentaacetic acid and subsequently labeled with 111In by chelation. Thirty-one patients with metastatic melanoma received single injections of monoclonal antibody 96.5 at concentrations ranging from 0.5 to 20 mg and at specific activities of 111In ranging from 0.125 to 4 mCi/mg. Total-body scans were performed at various time intervals following administration. No serious side effects were observed. Of a total of 100 previously documented metastatic sites, 50 imaged for a specificity of 50%. The number of sites imaged increased significantly as the amount of antibody administered increased relative to the average radiation dose. Considerable background uptake of isotope was observed in blood pool and other organs with gradual acquisition of label in tumor sites by 48 to 72 h. Hence, tumor imaging of melanoma using 111In-labeled monoclonal antibody 96.5 appeared feasible, especially at antibody doses above 2 mg.

Improved tumor localization with increasing dose of indium-111-labeled anti-carcinoembryonic antigen monoclonal antibody ZCE-025 in metastatic colorectal cancer.

Monoclonal antibodies (MoAbs) against carcinoembryonic antigen (CEA) react with human colorectal cancer cells, and when labeled with a gamma-emitting radioisotope, may help to localize known and occult metastatic disease. We tested ZCE-025 (Hybritech, Inc, San Diego), a high-affinity immune gamma globulin1 (IgG1) MoAb anti-CEA that does not react with normal granulocyte glycoproteins in a phase I/II trial to determine the reagent's toxicity and its maximum efficacy in detecting metastatic colorectal cancer. Increasing doses of unlabeled ZCE-025 were mixed with 1 mg of Indium-111 (111In)-radiolabeled MoAb and administered intravenously (IV) to 34 patients who had metastatic colorectal cancer. Planar nuclear or single photon emission computed tomographic (SPECT) scans were performed 48 to 72 and 120 to 144 hours later. Total dose of MoAb and scanning sensitivity (number of imaged lesions/number of known lesions) were correlated up to 80 mg. At doses of 2.5 to 20 mg, a mean of 22% of the lesions were imaged; at 40 mg, 77% were imaged (P less than .01). Liver metastases were detected as areas of increased activity ("hot") at the 40 mg dose but showed decreased MoAb uptake at lower doses. At the 40 mg dose normal liver parenchymal uptake of the labeled MoAb was lower with respect to blood pool compared with the other doses. At 80 mg, however, sensitivity of detection declined to 21%. One milligram of 111In-labeled ZCE-025 antibody coinfused with 39 mg of unlabeled antibody appeared optimal for detecting metastatic colorectal cancer, particularly in the liver. Although the exact mechanism(s) for this dose effect is currently unknown, a partial "blocking" effect of unlabeled antibody with a change in MoAb biodistribution may be occurring.

Imaging with indium111-labeled anticarcinoembryonic antigen monoclonal antibody ZCE-025 of recurrent colorectal or carcinoembryonic antigen-producing cancer in patients with rising serum carcinoembryonic antigen levels and occult metastases.

We tested whether nuclear imaging with indium111 (111In)-labeled murine monoclonal (MoAb) anticarcinoembryonic antigen (anti-CEA) ZCE-025 antibody could detect recurrent disease in patients with a rising serum CEA level but negative findings for computed tomographic (CT) scans of the abdomen and pelvis, chest radiograph, and colonoscopy or barium enema. Twenty patients with a history of completely resected CEA-producing adenocarcinoma (18 with colon cancer, one with breast cancer, and one with Hodgkin's disease) and a rising serum CEA level were given an intravenous infusion of 2 mg of 111In-labeled ZCE-025 mixed with 38 mg of unlabeled ZCE-025. Planar and single-photon emission CT (SPECT) scans were acquired at 72 and 144 hours, and in 19 of the 20 patients these were positive. Of those 19, 13 underwent exploratory surgery, and cancer was found in 10, and two had a diagnostic biopsy, which confirmed cancer. Three patients who had negative laparotomies and all four patients who did not undergo surgery or biopsy were followed radiologically. In all seven, cancer was subsequently detected at the sites suggested by the ZCE-025 scan. Thus, tumor was confirmed in all 19 patients with positive scans. Five of 13 patients who were explored benefited from the study and the exploratory laparotomy, as disease was entirely resected in four or was subjected to definitive radiation therapy to the pelvis in the fifth. In two additional patients who were not explored, MoAb imaging resulted in definitive therapy to regionally confined recurrent disease. 111In-labeled anti-CEA MoAb ZCE-025 scanning in patients with rising CEA successfully imaged metastatic colorectal cancer that eluded detection by other methods and affected the care given to some. These results suggest an important role for 111In-labeled ZCE-025 scanning among patients with rising CEA and otherwise occult metastatic cancer.

Phase I trial of liposomal muramyl tripeptide phosphatidylethanolamine in cancer patients.

Twenty-eight evaluable patients with metastatic cancer refractory to standard therapy received escalating doses of muramyl tripeptide phosphatidylethanolamine (MTP-PE) (.05 to 12 mg/m2) in phosphatidylserine (PC):phosphatidylcholine (PS) liposomes (lipid:MTP-PE) ratio 250:1). Liposomal MTP-PE (L-MTP-PE) was infused over 1 hour twice weekly; doses were escalated within individual patients every 3 weeks as tolerated for a total treatment duration of 9 weeks. Routine clinical laboratory parameters, acute phase reactants and various immunologic tests were monitored at various time points during treatment. Toxicity was moderate (less than or equal to grade II) in 24 patients with chief side effects being chills (80% of patients), fever (70%), malaise (60%), and nausea (55%). In four patients L-MTP-PE treatment was deescalated due to severe malaise and recurrent fever higher than 38.8 degrees C. The maximum-tolerated dose (MTD) was 6 mg/m2. Significant (P less than .05) increases in WBC count, absolute granulocyte count, ceruloplasmin, beta 2-microglobulin, c-reactive protein, monocyte tumoricidal activity, and serum IL-1 beta were found. Significant decreases in serum cholesterol were also observed. Clearance of intravenously (iv)-infused technetium-99 (99mTc)-labeled liposomes containing MTP-PE in four patients was biphasic; gamma camera scans revealed uptake of radiolabel in liver, spleen, lung, nasopharynx, thyroid gland, and tumor (two patients). No objective tumor regression was seen. In view of its definite immunobiologic activity and lack of major toxicity, additional phase II and adjuvant trials of L-MTP-PE are warranted.

Reduction by morphine of human postprandial insulin release is secondary to inhibition of gastrointestinal motility.

The effect of morphine (0.1 mg/kg) on insulin secretion stimulated by oral, intraduodenal, or intravenous administration of glucose was studied in seven healthy volunteers. When glucose was given intravenously, morphine had no effect on plasma glucose, insulin, glucose-dependent insulinotropic polypeptide (GIP), or pancreatic glucagon. Following oral glucose, morphine slowed gastric emptying and reduced plasma concentrations of glucose, insulin, and GIP. During intraduodenal infusion of glucose, insulin concentrations in plasma were also decreased by morphine, an effect best explained by decreased small intestinal transit with delayed absorption of glucose and delayed release of GIP. We conclude that clinically relevant doses of morphine have no direct effect on insulin secretion and that the changes observed were secondary to slowed gastric emptying and small intestinal transit.

Should hypertension be treated after acute stroke? A randomized controlled trial using single photon emission computed tomography.

OBJECTIVE: To determine if previously hypertensive patients with acute ischemic stroke should be treated with antihypertensive medication in the immediate poststroke period. DESIGN: Randomized double-blind, placebo-controlled trial. SETTING: Sixteen consecutive hypertensive patients (four men and 12 women; mean age, 66 years [age range, 46 to 83 years]) with middle cerebral artery infarction within 72 hours of onset and blood pressure between 170 and 220 mm Hg(systolic) and 95 and 120 mm Hg (diastolic). INTERVENTION: Placebo (n = 6), nicardipine hydrochloride (20 mg [n = 5]), captopril (12.5 mg [n = 3]), or clonidine hydrochloride (0.1 mg [n = 2]) given every 8 hours for 3 days. MAIN OUTCOME MEASURES: Decline in blood pressure, change in cerebral blood flow as measured by single photon emission computed tomography, and clinical change as determined by the National Institutes of Health Stroke Scale. RESULTS: Blood pressure fell significantly in both the drug-treated group as a whole and in those patients receiving placebo (P < .001). There was no difference in blood pressure levels between these two groups throughout the study period. Patients receiving nicardipine had a consistently lower pressure than the other groups. A significant negative relationship was noted between the maximum blood pressure fall and improvement in cerebral blood flow. There were four patients whose blood pressure dropped by more than 16% of the baseline value on any 24 hours in the first 3 days. All either failed to increase or actually decreased their cerebral blood flow to the affected area. Three of these patients were treated with nicardipine. There was no significant difference in clinical course between the placebo-and drug-treated groups as a whole. CONCLUSIONS: Hypertensive ischemic stroke patients with a moderate elevation of blood pressure in the first few days may not require antihypertensive therapy. Nicardipine and possibly other calcium channel blockers may cause an excessive fall in blood pressure and impair cerebral blood flow in these patients and should therefore be used with caution.

Demonstration of dose-dependent global and regional cocaine-induced reductions in brain blood flow using a novel approach to quantitative single photon emission computerized tomography.

Ischemic stroke is a common cause of morbidity and mortality in cocaine addicts. Because the previous semiquantitative single photon emission computerized tomography (SPECT) method for measuring brain blood flow does not quantify blood flow, the magnitude and specificity of cocaine's effects during drug taking has not been well established. Here, using a novel quantitative approach to SPECT, we established that intravenous cocaine administration to nine recently abstinent cocaine-dependent subjects was associated with significant decreases in global and regional brain blood flow to dopamine-rich areas such as the prefrontal, frontal temporal, and subcortical gray matter. Establishing the utility of this relatively new quantitative SPECT technique provides an important tool for the management of vascular disorders of the brain. Additionally, identifying the site-specific effects of cocaine provides targets for the development of putative therapeutic medications to attenuate or minimize ischemic stroke in cocaine addicts.

A study of gastrointestinal opiate receptors: the role of the Mu receptor on gastric emptying: concise communication.

Animal and in vitro experiments suggest that opiates exert their actions by interaction with possibly five different subtypes of opiate receptors, identified as mu, kappa, sigma, delta, and epsilon. As yet there is no conclusive evidence for their existence in man. Our experiments on morphine and the enkephalin analog DAMME have suggested at least two types of opiate receptors involved in gastric secretion. In this study we have used the very powerful and nonselective opiate agonist etorphine to stimulate as many of the different opiate receptors as possible. We have then attempted to block selectively the mu receptor by administering a small dose of naloxone. Etorphine delayed gastric emptying whereas naloxone alone had no effect. In combination, the inhibitory effect of etorphine on gastric emptying was incompletely prevented while the subjective effects of etorphine were completely abolished. These results may indicate that mu receptors are important in the regulation of gastric emptying, but that other (non-mu) receptors are also involved. The radionuclide study of gastric emptying, as used here, is a potentially powerful tool in physiological research on the gastrointestinal tract.

Scintigraphic manifestations of "sternal cupping".

Sternal abnormalities in sickle-cell disease have been documented by bone scintigraphy and radiography in patients with homozygous sickle-cell anemia, but not in patients with sickle-thalassemia. We present here two unusual cases of sternal abnormalities in complicated sickle-cell disease. One is an infant with radiographic findings of "sternal cupping" and transient hypo-ossification of the sternum and sickle-thalassemia. The other patient is also a male infant with unusual, persistent under-ossification of bone, in association with radiographic findings of "sternal cupping." The second patient also had a 4P-chromosomal defect (Wolf-Hirschhorn syndrome) in which sternal hypo-ossification was described.

Localization of indium-111 leukocytes in noninfected neoplasms.

Indium-111-labeled autologous leukocyte studies in general carry a high sensitivity, specificity, and accuracy for the investigation of infections and abscesses. However, past studies have described sporadic cases in which 111In leukocytes localized in tumors. Our experience using 111In leukocytes for the investigation of fever of unknown origin in cancer patients, however, indicates a relatively high incidence of 111In leukocyte localization in noninfected neoplasms. Out of the 61 patients studied for fever of unknown origin, 21 patients (34%) manifested abnormal localization of 111In leukocytes in neoplasms without clinical evidence of infection. These included patients with abnormal localization in: (a) lymph nodes, (b) soft-tissue tumors, and (c) bone neoplasms. The tumors included both primary and secondary lesions, and hematologic as well as solid tumors. The mechanism of 111In leukocyte localization in tumors is still not completely explained. Interpretations of 111In leukocyte studies in cancer patients with fever should take into consideration the possibility that localization may occur in neoplastic tissue per se and does not always indicate the presence of infection.

Indium-111-labeled B72.3 monoclonal antibody in the detection and staging of breast cancer: a phase I study.

Sixteen patients with primary breast cancer were studied with a pancarcinoma monoclonal antibody B72.3, an IgG1 molecule directed against tumor-associated glycoprotein (TAG-72) present in several tumors. Five millicuries of 111In was used to label 0.2 mg (six patients), or 2 mg (six patients), or 20 mg using the site-directed bifunctional DTPA method (at carbohydrate moiety). Digital, planar, and SPECT images were obtained at 2, 48, 72 and 96 hr when possible. HAMA levels were obtained before the Mab infusion and at 1, 3, and 6 wk postinfusion. Fourteen of 14 known primary breast lesions were detected by imaging (100% sensitivity). Two fibrocystic lesions were negative. Seven of 14 patients had lymph node metastases by histologic methods, but all were missed by radioimmunoscintigraphy. Tumor uptake of Mab ranged 0.00054%-0.0038% of the ID/g. The tumor-to-normal breast tissue ratio was 4.3 +/- 0.91 (mean +/- s.e.m.). Lymph nodes localization of 111In-B72.3 by tissue analysis was similar for tumor-bearing and normal nodes (0.0039 +/- 0.0023 versus 0.0025 +/- 0.0019). Pharmacokinetics revealed mean plasma half-life of 33.3-41.2 hr for the different doses. There was no statistical difference between any of the pharmacokinetic parameters of different doses. HAMA was positive only in 17% of the patients. The study suggests that this antibody has 100% sensitivity for primary breast cancers, but very poor detection rate of metastatic lesions in axillary lymph nodes; thus making it of questionable value in the initial staging process of this disease.

Clinical parameters related to optimal tumor localization of indium-111-labeled mouse antimelanoma monoclonal antibody ZME-018.

Radioimmunolocalization of an 111In-labeled mouse antimelanoma monoclonal antibody (MoAb), ZME-018, was examined in 21 patients with metastatic malignant melanoma. Each patient received a single. i.v. infusion of MoAb at concentrations ranging from 1 mg to 20 mg, coupled to 5 mCi 111In by the chelating agent DPTA. No toxicity was observed in any patient. Total-body and regions of interest scans performed at 4, 24, and 72 hr following MoAb administration revealed uptake in 63 out of 105 previously diagnosed metastases for an overall sensitivity of 60%. Uptake was consistently observed in liver/spleen, and less frequently in bowel, testes, axillae and bone. Sensitivity of detection increased significantly at doses of MoAb above 2.5 mg, with 74% of lesions imaging at 20 mg/5 mCi compared with 29% at 2.5 mg/5 mCi (p less than 0.005). A significant correlation was observed between tumor uptake of 111In-MoAb conjugate and increasing tumor size. Soft-tissue lesions such as skin and lymph node metastases were imaged to a greater extent (76%) than visceral metastases (19%). In five of six patients, biopsies obtained from 3 days to 14 days after MoAb administration showed antibody present on tumor cells as demonstrated by flow cytometry and/or radioimmunoassay. Human anti-murine immunoglobulin responses were observed in seven of 17 patients studied. Mean plasma clearance of ZME-018 was prolonged with a T1/2 of 24.7 hr and increased slightly with increasing MoAb dose. Urinary excretion of 111In averaged 12.4% of the injected dose over 48 hours. Radioimmunolocalization of melanoma with 111In-labeled ZME-018 appears feasible. The sensitivity of the technique was related to dose, tumor size, and disease site.

Radioimmunoscintigraphy of prostate cancer.

The development of hybridoma technology has increased research efforts and clinical applications in the area of radioimmunodetection. Despite the many investigative antibodies directed against prostatic tissue or prostate cancer cell lines, only two have been tested in clinical trials. A 111In-labeled antibody directed against prostate-specific antigen, the best available serum tumor marker for prostate cancer, has shown poor sensitivity in limited clinical radioimmunoimaging trials. Monoclonal antibodies against prostatic acid phosphatase have shown better imaging results, particularly at higher antibody doses (greater than or equal to 40 mg). The limitations of this antibody include the poor results in detecting soft tissue lesions, including the primary lesion; the development of human antimouse antibodies in 50% of the patients at doses greater than or equal to 40 mg; the expense of the antibody; and the fact that better results are currently attainable by other less expensive imaging modalities. If and when a more suitable antibody or fragment is developed, the prospect of improved staging and new treatments using immunologic conjugates carrying therapeutic agents may become realities. Until such time, prostatic cancer will be staged with other currently available imaging modalities and conventional therapies with their limitations will remain state of the art.

Isradipine prevents global and regional cocaine-induced changes in brain blood flow: a preliminary study.

The L-type calcium channel antagonist, isradipine, reduces brain ischemia in animal models of ischemic stroke. These effects of isradipine appear more pronounced in dopamine (DA) rich brain regions. These same DA-rich brain regions have also been shown to be the areas most affected by cocaine-induced ischemic changes. Using a novel quantified approach to single photon emission computerized tomography, we demonstrated that isradipine pre-treatment prevented cocaine-induced ischemic changes, especially in these DA-rich brain regions. This is the first demonstration that any medication, including isradipine, can prevent the ischemic effects of cocaine on brain blood flow. Isradipine may, therefore, be a useful therapeutic agent for the prevention of brain ischemia in cocaine addicts.

Rapid diagnostic imaging of acute, nonclassic appendicitis by leukoscintigraphy with sulesomab, a technetium 99m-labeled antigranulocyte antibody Fab' fragment. LeukoScan Appendicitis Clinical Trial Group.

BACKGROUND: The purpose of this study was to evaluate the safety and efficacy of a technetium 99m-labeled antigranulocyte antibody Fab' fragment (sulesomab) as a diagnostic imaging agent in patients with suspected acute, nonclassic appendicitis. METHODS: This prospective multicenter trial involved 141 children and adults with suspected acute, nonclassic appendicitis. The investigators interpreted planar images acquired 15 to 30 minutes and 1, 2, and 4 hours after injection and also by single-photon emission computed tomography (SPECT). The imaging results were confirmed surgically, whereas nonsurgical patients were considered as not having appendicitis (intent to treat). RESULTS: Sulesomab had a sensitivity of 91% (29/32 patients) and a negative predictive rate of 97% for acute appendicitis. It detected additional abnormalities in 7 of 9 patients with other inflammatory abdominal disease and had a specificity of 92% (91/99 patients) and a positive predictive value of 80% for surgically confirmed right-lower-quadrant disease. In positive studies, 26% were identified by planar imaging at 15 to 30 minutes, 46% by 1 hour, 63% by 2 hours, and 71% by 4 hours; 29% required SPECT to detect the abnormality. Scanning time was 5 to 10 minutes per planar image and about 45 minutes for a SPECT study. Investigators found that sulesomab would have changed clinical management or reduced additional diagnostic studies in 64% of the patients. Adverse events were infrequent, minor, and self-limiting (9/141 patients, 6%). No human antimurine antibody response occurred in 48 evaluable patients. CONCLUSIONS: Sulesomab is safe, well-tolerated, and with no apparent immunogenicity. Focal inflammation or infection in the setting of suspected atypical appendicitis is rapidly and accurately detected. Management decisions incorporating sulesomab imaging potentially provide clear patient benefits, especially by correctly predicting surgery to be unnecessary in 97% of patients without acute appendicitis.

Comparative clinical pharmacology of [111In]-labeled murine monoclonal antibodies.

Patients with metastatic melanoma received either the murine antimelanoma antibody ZME-018 (20 patients) or antibody 96.5 (26 patients) at doses ranging from 1 to 20 mg and coupled to 2.5 or 5 mCi of [111In]. The pharmacokinetics and tissue disposition of these antibodies were measured at various times after infusion of the radiolabel. The clearance of the [111In]label from plasma closely fit (r2 greater than 0.90) an open, one-compartment mathematical model after administration of antibody 96.5. Clearance of [111In] from plasma after administration of ZME-018 fit a one-compartment model in some patients and a two-compartment model in others. The terminal phase half-lives of 96.5 and ZME-018 antibodies at the 20-mg dose were almost identical (27 +/- 2 h and 29 +/- 5 h, respectively). The half-lives calculated for 96.5 were not dependent upon the total antibody dose; however, with increasing doses of ZME-018 there was a dose-dependent increase in t 1/2 (from 17.8 +/- 2 h at the 2.5-mg dose to 29 +/- 5 h at the 20-mg dose). For 96.5 antibody, the apparent volume of distribution (Vd) approximated the total blood volume (7.8 +/- 0.71) at the 1-mg dose and decreased significantly at the 20-mg dose, suggesting saturation of extravascular antigen sites. In contrast, the Vd calculated for ZME-018 did not appear to be dependent upon the administered dose. Improved imaging occurred with increasing doses of unlabeled 96.5 above 2 mg, a finding not observed with ZME-018. The cumulative urine excretion of [111In] after administration of 96.5 or ZME-018 was 10%-14% of the total dose. These studies show that murine monoclonal antibodies of the same subtype but recognizing different surface antigens can exhibit markedly different in vivo pharmacokinetic behavior, which may partially explain differences in imaging noted with increasing doses of monoclonal antibody.