Biomedical subjects
Publications and source records attributed to J C Reynolds.
Prokinetic agents are medications that promote gastrointestinal motility. This article reflects the current state of our understanding of their mechanisms of action and their clinical utility in treating disorders of gastrointestinal motility, including gastroesophageal reflux, gastroparesis, small-intestinal dysmotility, and constipation.
Direct intralymphatic administration of radiolabeled monoclonal antibody in targeting antigen-bearing lymphoma cells in regional lymph nodes of patients with cutaneous T-cell lymphoma was evaluated. Seven consecutive patients undergoing staging lymphangiography received intralymphatic infusions of 111In-T101 to evaluate lymph node involvement. This procedure was accomplished without significant complication. The 111In-T101 rapidly distributed throughout the regional lymphatic compartment and passed into the systemic circulation. Tumor-bearing sites in the inguinal-femoral lymph nodes retained from 0.42 to 4.8% of the injected dose of radiolabeled antibody. Three patients were upstaged to Stage IVA based on tumor involvement found after radiolymphoscintigraphy-directed biopsy of groin lymph nodes, selected because of intense radioactivity by gamma camera imaging. Compared with previously reported s.c. antibody administration, there was a marked reduction in the radioactive exposure of normal tissues at the injection sites in the lower extremities. Direct intralymphatic delivery of 111In-T101 appears to be a feasible, efficient method for delivering therapeutic doses of radiolabeled antibody.
We studied the mechanism of gastric emptying of a pH-sensitive radiotelemetry capsule with respect to phases of the interdigestive migrating motor complex (IMMC) in fasting normal volunteers and the effect of the Heidelberg capsule (HC) on the duration or timing of the IMMC phases. A manometric catheter with eight mounted solid-state strain gauges was passed transnasally and positioned fluoroscopically in the duodenum and jejunum in four normal, fasted male volunteers, in their right lateral position. The HC was administered orally following the establishment of one complete IMMC cycle (defined by the recording time between the end of two subsequent phase III activity fronts) and during the beginning of Phase I of the next cycle. The gastric residence time (GRT) of the HC was measured as the time of a gastric pH rise of greater than or equal to 3.0 units. In three subjects, GRT of the HC lasted to within 5 min of the onset of the next duodenal phase III of the IMMC, while in the fourth subject, the HC passed during the second phase III activity front. There were no significant differences in the duration of each phase of duodenal IMMC in the presence or absence of the HC (Phase I, 54 +/- 9.3 vs 31.6 +/- 10.1; Phase II, 22 +/- 8.1 vs 58.9 +/- 32; Phase III, 5.3 +/- 0.7 vs 4.2 +/- 0.7 min; mean +/- SE; P greater than 0.1 in all phases). In addition, the HC had no effect on motility index or patterns of contractions.(ABSTRACT TRUNCATED AT 250 WORDS)
The specific role of late fetal and early neonatal gonadotropins and/or sex steroids on genital development, linear growth, and bone mass accretion remains unclear. To investigate this, we attempted to selectively suppress pituitary-testicular activation from midgestation through early infancy with a long-acting LHRH agonist (LHRHA), D-Trp6,Pro9-NEt-LHRH, in microspheres. The agonist was injected sc on days 72-81 in utero, on day 1 of life, and 3 months postnatally in male cynomolgus monkeys. Control animals were treated with placebo. We then examined the consequences of such an intervention in the first 6 months of life. In the LHRHA-treated animals, marked suppression of plasma testosterone and gonadotropin levels were evident in the first 3 months of life compared to control values. The mean testicular volumes of the LHRHA group were significantly lower at birth and in the first 2 months of life than those of the placebo group (P less than 0.05). However, by 4 months of age, the mean testicular volumes of the two groups were comparable. Similarly, the mean stretched phallic lengths of the LHRH approximately A group were significantly lower than those of the placebo group throughout the first 6 months of life (P less than 0.05). By contrast, LHRHA treatment had no effect on somatic growth, as mean body weights, total body lengths, and trunk lengths of the two groups were similar over the first 6 months of life. Mean bone widths and densities of the distal third of the left radius and the left midfemur were similar in the two groups at 1 and 6 months of life. We conclude that pituitary-testicular axis suppression with a long-acting LHRHA in utero and during early infancy results in markedly stunted penile and testicular growth without affecting general somatic growth and bone density of appendicular cortical bone in the cynomolgus monkey in the first 6 months of life. Thus, an intact fetal and neonatal pituitary-testicular axis is critical for normal genital growth. However, the sex steroid requirement for maintenance of bone mineral content of appendicular cortical bone may be lower than that necessary for normal genital development.
Using a newly available model for determining estimates of radiation absorbed dose of radioisotopes administered intraperitoneally, we have calculated absorbed dose to tumor and normal tissues based on a surgically controlled study of radiolabeled antibody distribution. Ten patients with peritoneal carcinomatosis received intraperitoneal injections of the murine monoclonal antibody B72.3 radiolabeled with 131I. Biodistribution studies were performed using nuclear medicine methods until laparotomy at 4-14 days after injection. Surgical biopsies of normal tissues and tumor were obtained. The marrow was predicted to be the critical organ, with maximum tolerated dose [200 rad (2 Gy) to marrow] expected at about 200 mCi (7.4 GBq). In patients with large intraperitoneal tumor deposits, the tumor itself is an important source tissue for radiation exposure to normal tissues. Local "hot-spots" for tumor-absorbed dose were observed, with maximum tumor-absorbed dose calculated at 11,000 rad (11 Gy) per 100 mCi (3.7 GBq) administered intraperitoneal; however, tumor rad dose varied considerably. This may pose serious problems for curative therapy, especially in patients with large tumor burdens.
Although in vitro studies suggest that cholinergic induced contractions and spontaneous tone are mediated by two different cellular pathways, this has not been shown in vivo. The purpose of this study was to distinguish these types of contractions in the feline lower esophageal sphincter (LES) through use of i.v. selective pharmacologic antagonists. Continuous infusion of the calcium channel antagonist verapamil (16-128 micrograms/kg/min) caused a dose-dependent inhibition of bethanechol induced and tonic pressure change. At 32.0 micrograms/kg/min, verapamil produced significantly greater inhibition of bethanechol induced contractions when compared with inhibition of basal LES tone (57.4 versus 4.8%, P less than .02, n = 5). Verapamil also caused a parallel decrease in LES spike activity associated with bethanechol induced contractions. In contrast, lower doses of nitroprusside (0.5 micrograms/kg/min) inhibited LES tone by over 50% (50.6 +/- 21.8%) yet had no significant effect (16.8 +/- 23.4%) on bethanechol induced contractions. Also, inhibition of basal LES tone correlated poorly with its effect on associated spike activity. It is concluded that in the in vivo feline LES, spike dependent cholinergic contractions can be distinguished from LES tone by the use of low dose verapamil and nitroprusside, respectively. This selective inhibition suggests that two cellular mechanisms mediate LES contractions and that these pathways can be distinguished pharmacologically in vivo.
Two-site immunometric assays using mouse monoclonal antibodies are gaining increasingly widespread popularity and use. Patients with circulating antimurine immunoglobulin antibodies capable of interfering in these assays have been encountered and described sporadically. Parenteral administration of murine monoclonal antibodies for imaging and therapeutic purposes is increasing and is known to induce human anti-murine antibodies frequently. We examined 60 serum samples from 48 individuals who received such murine immunoglobulin to determine whether iatrogenically induced anti-murine antibodies could interfere in a two-site (sandwich) immunoradiometric assay for serum thyrotropin. We found that these circulating antibodies can indeed interfere in an "unblocked" assay, but that the interference appears to be suppressed by including nonspecific IgG in the commercial version of the assay kit.
UNLABELLED: Intrinsic reflexes of the feline lower esophageal sphincter (LES) have been shown to be mediated by specific arrangements of excitatory peptidergic interneurons. Inhibition of intrinsic reflexes may also be mediated by neuropeptides. The specific aims of this study were: (1) to examine the effect of somatostatin (SOM) and vasoactive intestinal peptide (VIP) on basal LES tone, and (2) to determine if these transmitters exert selective inhibitory effects on excitatory contractile pathways. Intraluminal pressures were recorded from the LES, esophagus and fundus by a fixed perfused catheter assembly in anesthetized cats. Peptides were administered via the left gastric artery. SOM had no effect on basal LES pressure with doses ranging from 10(-9) to 10(-5) g/kg. VIP induced a dose-dependent inhibition of basal LES pressure. The maximal effective dose of VIP, 10(-6) g/kg, completely inhibited basal LES pressure (34.7 +/- 6.8 to 1.0 +/- 0.6 mmHg, P less than 0.001). We have previously shown that bombesin (BN) but not substance P (SP) or bethanechol contracts the LES via tetrodotoxin-sensitive pathways. BN at the D50 (5.10(-8) g/kg) increased LES pressure by 32.1 +/- 3.6 mmHg. SOM (10(-5) g/kg) decreased this BN response to 19.2 +/- 5.0 mmHg, P less than 0.05. In contrast, while the D50 of SP (5.10(-8) g/kg) gave a similar increase in LES pressure, 28.8 +/- 5.1 mmHg, this effect was not altered by SOM (23.8 +/- 6.7 mmHg, P greater than 0.10). SOM also had no effect on bethanechol-induced LES contractions (P greater than 0.10). VIP (10(-6) g/kg) totally inhibited the LES response to the D50 of BN, SP, and bethanechol. A submaximal dose of VIP (10(-7) g/kg) partially inhibited the contractile response of all three. CONCLUSIONS: (1) VIP, but not SOM, inhibits basal LES tone. (2) SOM selectively inhibits BN but not SP- or bethanechol-induced LES contraction. (3) VIP inhibits BN, SP and bethanechol-induced LES contractions. These studies suggest that somatostatin can selectively inhibit excitatory interneurons at the LES.
Tumor targeting by monoclonal antibodies (MAbs) can be enhanced by (a) increasing the percentage of injected dose taken up by the tumor and/or (b) increasing the tumor:nontumor ratios. Several groups have demonstrated that one can increase tumor to nontumor ratios by the use of antibody fragments or the administration of second antibodies. Several other modalities are also possible: (a) the use of recombinant interferons to up-regulate the expression of specific tumor associated antigens such as carcinoembryonic antigen or TAG-72 on the surface of carcinoma cells and thus increase MAb tumor binding has proved successful in both in vitro and in vivo studies; (b) the intracavitary administration of MAbs. Recent studies have demonstrated that when radiolabeled B72.3 is administered i.p. to patients with carcinoma of the peritoneal cavity, it localizes tumor masses with greater efficiency than does concurrent i.v. administered antibody. Studies involving the comparative pharmacology of intracavitary administration of radiolabeled MAb in patients and several animal models will be discussed; (c) it has been reported that prior exposure of hepatoma to external beam radiation will increase radiolabeled MAb tumor targeting. We and others have not been able to duplicate this phenomenon with a human colon cancer xenograft model and radiolabeled MAbs to two different colon carcinoma associated antigens. The possible reasons for these differences will be discussed; (d) the cloning and expression of recombinant MAbs with human constant regions and subsequent size modification constructs will also undoubtedly alter the pharmacology of MAb tumor binding in both diagnostic and therapeutic applications.
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We evaluated the differences in catabolism of 125I, 111In and 90Y-T101 monoclonal antibody (anti-CD5) by peripheral blood mononuclear cells (PBMNC), HUT 102, CCRF-CEM and MOLT-4 cells. All cells showed higher retention of 111In than of 125I. PBMNC showed similar retention of 90Y and 111In. The release of 125I was reduced by using metabolic inhibitors, F(ab')2 of T101, pure lymphocytes or incubating at 4 degrees C. Our findings suggest differences in the intracellular catabolism of the radionuclides.
The overall safety of a given drug is determined by its toxicity, side effects, and drug-drug interactions. Thus, a clarification of the mechanisms, importance, and clinical implications of any drug-drug interaction with antiulcer therapy is critical to the use of antiulcer medications. Drug-drug interactions may occur as a result of changes in absorption, metabolism, distribution, or excretion. Fortunately, drug distribution or protein binding is unchanged by antiulcer therapy. Antiulcer drugs may affect absorption by several mechanisms. Ionized medications may bind to the divalent cations of antacids and sucralfate to result in poorly absorbed complexes. Reduced gastric acid may decrease the absorption of medications that are weak bases while enhancing the absorption of weak acids. Drug absorption may be impaired by delayed gastric emptying. Several H2-receptor antagonists, including cimetidine and to a lesser extent ranitidine, and the proton pump inhibitor, omeprazole, may reduce the hepatic degradation of drugs metabolized by the cytochrome P450 system. The degree to which such agents alter drug metabolism is determined by the patient's age, genetics, duration of therapy, degree of cytochrome P450 binding, and the regimen. Because the clinical importance of this interaction cannot always be predicted, caution is recommended whenever drugs metabolized by this system are used concurrently. Development of an understanding of the ways in which drug metabolism interactions occur may lead to more effective and safe use of these medications.
Two human immunoglobulin M (IgM) monoclonal antibodies (MoAbs), 16.88 and 28A32, which react with cytoplasmic (28A32 and 16.88) or cell surface (28A32) determinants on human colon carcinoma cells, were administered intravenously to 26 patients with metastatic colorectal carcinoma to determine if they could localize to sites of metastatic disease, if they had any antitumor or toxic effects, and to determine whether they would elicit an antihuman MoAb response. Serial scans showed tumor uptake of radioisotope in 12 of 16 patients receiving 131I-labeled 28A32 and in nine of 12 patients receiving 131I-labeled 16.88. No antitumor effects were seen with either antibody. No antibody-related toxic effects were observed following administration of 16.88, but two patients developed localized urticarial reactions following injection with antibody 28A32. No patient developed an antibody response to 16.88. Anti-28A32 reactivity was found in five of 12 (42%) normal sera and in seven of 23 (30%) patients before receiving any antibody. Following administration of 28A32, a low titer (1:10 dilution) of anti-28A32 developed in four patients with no preexisting antibody, a decrease in the preexisting titer was seen in three other patients, the titer remained constant in one patient, and no anti-28A32 was ever detected in six patients. In most cases, anti-28A32 activity was lost at dilutions greater than 1:10 and did not appear to affect antibody half-life in the serum or whole body retention of the antibody. We conclude that these human IgM MoAbs are capable of localizing at sites of disease in vivo, are nontoxic, and are poorly immunogenic in humans. Further studies to determine the specificity of targeting and to improve the delivery of antibody to sites of tumor are indicated.
Monoclonal antibody (MAb) B72.3 coupled to 131I is currently being used in clinical trials for the diagnostic imaging of gastrointestinal, ovarian, and breast carcinomas. The MAb has also been used extensively in immunohistochemical studies and in the development of radioimmunoassays to define antigen levels in tissues and sera of cancer patients. When administered intravenously, the radionuclide-conjugated MAb has localized tumor in over 70 percent of patients. When intraperitoneal administration was studied, the MAb-radionuclide conjugate successfully imaged peritoneal lesions; moreover, in 3 of 10 patients, B72.3 detected lesions not found by conventional methods. Concomitant administration of 131I labeled B72.3 intraperitoneally and 125I labeled B72.3 intravenously showed that the intraperitoneal route localized peritoneal implants at least two times better than the intravenously administered MAb. Conversely, hematogenously borne or non-implant lesions were better localized with intravenously administered B72.3.
Hydroxylapatite high performance liquid chromatography was used to prepare two fractions from 125I- Fab 96.5. One fraction (peak 1) had relatively low immunoreactivity (25-38%) and the second fraction (peak 2) had high immunoreactivity (70-81%). Scatchard analysis showed similar affinity constants for the two preparations (2.9 x 10(9) M-1 for peak 1; 3.4 x 10(9) M-1 for peak 2). In biodistribution and imaging studies in athymic mice with human melanoma (FEMX-II) xenografts the high immunoreactivity preparation rapidly cleared from the blood and nontumor organs while retention of radioactivity in the tumor was prolonged. The low immunoreactivity preparation, had slower blood and nontumor organ clearance but faster tumor clearance than the high immunoreactivity fraction. Thus, in these studies highly immunoreactive antibody gave higher tumor to nontumor ratios and enhanced the target to nontarget image contrast.
Radiolabeled B72.3 (anti-TAG-72) has been shown to selectively localize metastatic lesions in 70%-80% of the cases. Serum samples from 27 colorectal carcinoma patients who received iodine-131-(131I) B72.3 by i.v. administration were analyzed. Circulating immunoreactive antibody followed a biphasic clearance pattern. High-performance liquid chromatography (HPLC) and SDS-polyacrylamide gel electrophoresis demonstrated that 131I-B72.3 retained its integrity in the patients' sera. HPLC analysis also demonstrated the presence of immune complexes in the sera of 12 patients; this correlated with elevated levels of circulating TAG-72. Several different HAMA response patterns were detected in the 25 patients' sera that were analyzed; some patients developed HAMA as early as 5-7 days post-MAb injection. Higher doses of administered MAb B72.3 correlated with the development of HAMA (p = 0.007). The presence of elevated levels of TAG-72 in the patients' pre-inoculum serum was shown to correlate with the detection of lesions by gamma scanning. Serum TAG-72 may serve as a criteria for patient selection for immunodiagnostic or immunotherapeutic procedures using MAb B72.3.
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OBJECTIVE: To identify factors that influence the rate of healing of duodenal ulcers. DESIGN: A stepwise multivariable statistical analysis of patients with duodenal ulcer in a multicenter, prospective, open-label study. Healing was assessed by endoscopy at 4 or 8 weeks. Antacid use and symptoms were recorded in a daily diary. SUBJECTS: Of 135 patients, ages 19 to 86, 50% had a previous duodenal ulcer, 46.7% smoked, and 34.8% had melena or hematemesis. INTERVENTIONS: Famotidine, 40 mg orally, at bedtime for 4 or 8 weeks depending on endoscopic evaluation of ulcer healing. Limited antacid use was permitted. SETTING: Office practices, hospital practices, and university-based medical centers. MEASUREMENTS AND MAIN RESULTS: Multivariable analysis identified five independent predictors present at the time of diagnosis that influenced ulcer healing. The odds of not healing for each risk factor after simultaneous adjustment of the other risk factors were as follows: alcohol use, 6.5 (CI, 2.0 to 20.7, P less than 0.002); ulcer size greater than 10 mm, 4.2 (CI, 1.5 to 11.6, P less than 0.005), bleeding symptoms. 3.5 (CI, 1.2 to 10.2, P less than 0.03); and a previous duodenal ulcer, 3.1 (CI, 1.05 to 9.0, P less than 0.04). The use of salicylates or nonsteroidal anti-inflammatory drugs before treatment was associated with an improved odds of healing (adjusted odds ratio, 0.2; CI, 0.1 to 0.9, P less than 0.04). The percentage of patients achieving complete ulcer healing after 4 weeks of famotidine decreased inversely with the number of risk factors present, ulcer size, and the quantity of daily alcohol use (P less than 0.001). Fewer than half of those patients who still had severe pain at day 7 achieved healing at 4 weeks (P less than 0.001). In contrast, smoking and 23 other factors had no statistically discernible effect on ulcer healing with famotidine. CONCLUSIONS: Five variables present at the time of diagnosis independently influenced the rate of ulcer healing at 4 weeks: alcohol use, ulcer size, bleeding symptoms, a previous duodenal ulcer, and previous use of salicylates or nonsteroidal anti-inflammatory drugs.