Biomedical subjects

L E Williams

Publications and source records attributed to L E Williams.

At least 73 records · Page 4Linked to original sources

PubMed1993

Benefits of clinical pharmacy services in a community hospital.

The purpose of this analysis was to itemize the long term cost-avoidance and benefits of the Clinical Pharmacy Program at York Hospital and compare them to the cost of the program. It was assumed that the major actual reduction in drug cost would occur within the first year of clinical activities. Therefore, to determine the long term benefits, the hypothetical cost-avoidance of drug expenditures were calculated for the subsequent years after the clinical programs were instituted. For fiscal year 1991 these significant benefits amounted to an estimated monetary cost-avoidance of $416,000, a reduction in numerous hours in preparations and administration of 39,000 IVs, and numerous non-quantifiable benefits. The cost of the program in fiscal year 1991 for the pharmacist and administrative salaries related to the Pharmacy Clinical Program was approximately $140,000. Thus, the Clinical Pharmacy Program was cost-effective at York Hospital.

Concurrent Review↗

PubMed1993

Pharmacokinetics of an anti-carcinoembryonic antigen monoclonal antibody conjugated to a bifunctional transition metal carborane complex (venus flytrap cluster) in tumor-bearing mice.

An anticarcinoembryonic antigen (CEA) monoclonal antibody, T84.66, has been conjugated to a metallocarborane complex (Venus flytrap cluster, VFC) containing 57Co. This radioimmunoconjugate, 57Co-VFC-T84.66, retained > 90% immunoreactivity, was stable in serum (7 days) and demonstrated good localization in LS174T tumor xenografts. Pharmacokinetics of 57Co-VFC-T84.66 in tumor-bearing mice were compared to T84.66 Mab conjugated with either DTPA or its benzylisothiocyanate derivative (BzDTPA) labeled with 111In. Whole-body half-life for VFC-T84.66 was less (t1/2 = 62 hr) than that for either DTPA-T84.66 (t1/2 = 157 hr) or BzDTPA-T84.66 (t1/2 = 167 hr). Blood clearance was similar for all three radioimmunoconjugates (t1/2 = 22 hr). Hepatic uptake of the radiolabel was rapid and remained constant for 7 days for both DTPA radioimmunoconjugates (DTPA radioimmunoconjugate = 13.7 +/- 1.5 %ID/g; BzDTPA radioimmunoconjugate = 10.4 +/- 1.7%ID/g). For VFC, however, liver radioactivity decreased from 19.1 +/- 0.6%ID/g at 1 hr to 0.9 +/- 0.1 %ID/g 7 days postinjection, suggesting a possible role for VFC radioimmunoconjugate in the imaging and therapy of liver metastases.

Animals↗

PubMed1992

Gamma-interferon enhancement of carcinoembryonic antigen expression in human colon carcinoma xenografts.

Athymic nu/nu mice bearing a subcutaneous human colon cancer xenograft (WiDr, low CEA expression) were treated with gamma-interferon (gamma IFN) at varying doses, frequencies, and periods of duration. CEA content (micrograms/g) and uptake of radiolabeled anti-CEA monoclonal antibody (MAB) (percent injected dose per gram, % ID/g) were measured at 48 h following administration of the MAB, The optimal enhancement of tumor CEA content and tumor localization of [111In] anti-CEA monoclonal antibody (MAB) was seen at gamma IFN doses of 100,000 U i.p. every 8 h for 4 days (4.7 micrograms/g; 29% ID/g) compared to control animals (0.9 micrograms/g; 10% ID/g). The effects of gamma IFN on CEA content and MAB localization were less pronounced when administered (a) at lower doses: 5,000 to 50,000 U i.p. every 8 h, (b) at varying frequencies: 300,000 U/day delivered in divided doses every 4 or 24 h, or (c) for varying periods: 2 or 6 days of therapy. In each case, the biologic effects on tumor CEA content and uptake of [111In]MAB correlated closely with the serum gamma IFN level. Therefore, we conclude that enhancement of in vivo CEA expression by gamma IFN may have clinical relevance for tumor imaging and therapy using radiolabeled monoclonal antibodies.

Animals↗

PubMed1992

Origin of urinary epidermal growth factor in humans: excretion of endogenous EGF and infused [131I]-human EGF and kidney histochemistry.

1. This study examined (i) whether blood-infused epidermal growth factor (EGF) can pass into urine; (ii) whether infused labelled EGF behaves like endogenous plasma immunoreactive EGF; and (iii) which parts of the human nephron show morphological evidence of EGF synthesis? 2. We infused human [131I]-EGF into a volunteer. After 6 min, only 66% of the plasma counts represented intact EGF. At the end of infusion, the T1/2 of EGF was calculated to be 1.6 min. The tail of the curve lasted for at least another 2 h. The total excretion of the labelled EGF was 2.45% of the infused dose and was proportional to the urine volume. 3. After a water load, the excretion of endogenous EGF was, on the contrary, inversely related to urine volume. 4. Immunohistochemically, human kidneys were not stained by monoclonal anti-EGF antibodies but showed positive in situ hybridization for EGF mRNA in the nuclei of glomerular mesangial cells, distal convoluted tubules and collecting tubules. 5. We conclude that human kidneys synthesize EGF and release it into urine. Plasma-derived EGF constitutes under normal conditions only a small part of the urinary EGF. Contrasting volume-dependency of the excretion of endogenous and [131I]-EGF requires further study and cautions against extrapolating results obtained with labelled EGF to physiological conditions.

Epidermal Growth Factor↗

PubMed1992

An immunoradiometric assay for squirrel monkey prolactin.

Determination of immunoreactive prolactin in squirrel monkeys has been hampered by the lack of specific antibodies. We investigated the adaptability of a commercially available immunoradiometric assay for human prolactin, which employs two separate monoclonal antibodies (MAb I and II) to human prolactin, to determine the presence of squirrel monkey prolactin. We found that immunoreactivity curves for prolactin in squirrel monkey pituitary homogenates and serum were parallel to human prolactin standards, suggesting that the epitopes recognized by these antibodies were common to both human and squirrel monkey prolactin. Both nonglycosylated (23 kD) and glycosylated (26 kD) forms of squirrel monkey prolactin were detected in squirrel monkey pituitary homogenates by Western blot analysis using [125I]-MAb II. Neither sheep nor rat prolactin was recognized by Western blot analysis, indicating that the assay may be specific for primate prolactins. We examined the effect of ketamine HCl, an anesthetic that has been shown to elevate serum prolactin levels in other primates, on prolactin secretion in squirrel monkeys. Serum prolactin levels increased greater than fourfold after the administration of ketamine HCl (30 mg/kg b.w., i.m.) compared with control levels. Serum prolactin levels were unaffected by anesthesia with pentobarbital sodium (15 mg/kg b.w., i.v.). This assay provides a reliable and sensitive method for determining immunoreactive squirrel monkey prolactin.

Animals↗

PubMed1991

Comparison of immunoscintigraphy and computerized tomography in identifying colorectal cancer: individual lesion analysis.

Monoclonal antibody scintigraphy with 111In-ZCE025 was used in presurgical staging of 45 patients prior to abdominal exploration for primary, recurrent or metastatic colorectal carcinoma. A total of 186 lesions were identified, of which 147 were evaluated by abdominal surgery and pathology. Sensitivity was 40.5% (49 of 121) for immunoscintigraphy (IS), 61.2% (74 of 121) for computerized tomography (CT), and 72.7% (88 of 121) for IS and CT combined. The positive predictive value was 83.1% (49 of 59) for IS and 88.1% (74 of 84) for CT. Sensitivity of IS was 100% (23 of 23) for primary tumors, 17.7% (11 of 62) for hepatic metastases, and 41.7% (15 of 36) for extrahepatic abdominal metastases. Of the 50 hepatic lesions evaluated by single-proton emission computerized tomography, 11 were localized by IS. Only one was visualized by planar scintigraphy. Sensitivity of CT was 87% (20 of 23) for primary tumors, 67.7% (42 of 62) for hepatic metastases, and 33.3% (12 of 36) for extrahepatic abdominal metastases. Sensitivity of IS combined with CT was 72.6% (45 of 62) for hepatic and 55.6% (20 of 36) for extrahepatic abdominal metastases. Of 24 malignant lesions measured by the pathologist to be less than 3.0 cm (maximum dimension), 7 (29.2%) were detected by IS and 3 (12.5%) by CT. Of 28 malignant lesions greater than 3.0 cm, 23 (82.1%) were detected by IS and 24 (85.7%) by CT. Overall, IS and CT complemented each other in presurgical staging of colorectal carcinoma. IS was of greater value for identification of extrahepatic and small metastases. CT was more effective for identification of hepatic metastases.

Abdominal Neoplasms↗

PubMed1991

Interferon enhancement of radioimmunotherapy for colon carcinoma.

Recombinant human gamma-interferon (IFN-gamma) has recently been shown to enhance localization of radiolabeled monoclonal antibodies (MAb) to human colon carcinoma xenografts in athymic mice. The present study investigates the ability of gamma-interferon to enhance radioimmunotherapy of a low carcinoembryonic antigen-expressing human colon cancer (WiDr) in athymic mice. Growth curve analysis, antibody localization, and dose estimation studies were performed. A significant tumor growth delay, measured as the time to reach 1.0 g, was noted for animals receiving specific anti-carcinoembryonic antigen 90Y-MAb (ZCE025, 120 microCi) plus IFN-gamma (61.8 days) as compared to animals that received specific 90Y-MAb with phosphate-buffered saline (34.9 days; P less than 0.005). IFN-gamma (100,000 units) was given i.p. every 8 h for 2 days before and 4 days after 90Y-MAb therapy. The time required to reach 1.0 g for animals treated with nonspecific 90Y-MAb (ZME018) was significantly less either with (38.3 days) or without (34.4 days) IFN-gamma. The difference was more apparent when compared to animals receiving IFN-gamma alone (30.0 days) or phosphate-buffered saline alone (28.9 days; P less than 0.001). Increased antibody localization in the tumors of animals treated with IFN-gamma plus specific 90Y-MAb (43.2% injected dose/g) was seen in comparison to animals treated with specific 90Y-MAb without IFN-gamma (18.2% injected dose/g). The estimate of radiation dose delivered to the tumors, based on biodistribution data over time, revealed significantly higher levels in animals treated with specific 90Y-MAb with IFN-gamma (2477 cGy) compared to animals treated without IFN-gamma (1217 cGy). These results provide support for the use of gamma-interferon as an immunomodulating agent prior to radioimmunotherapy.

Animals↗

PubMed1991

A transition metal complex (Venus flytrap cluster) for radioimmunodetection and radioimmunotherapy.

A novel transition metal complex, Venus flytrap cluster (VFC), is described for the preparation of radio-labeled antibodies. VFC contained 57Co, which was held tightly between the faces of two covalently bridged carborane ligands by cluster bonding of the metal with appropriate ligand orbitals. Anti-carcinoembryonic antigen monoclonal antibody T84.66 was conjugated to 57Co-VFC with full retention of immunological activity. Biodistribution studies in nude mice bearing carcinoembryonic antigen-producing tumors showed excellent tumor localization of 57Co-VFC-T84.66. The accumulation of radionuclide in normal liver was low and independent of dose, which may reflect the stability of the radionuclide complex. These results presage the use of VFC systems for binding transition metals that are clinically useful for radioimmunodiagnosis and radioimmunotherapy.

Animals↗

PubMed1991

Radiobiologic studies comparing Yttrium-90 irradiation and external beam irradiation in vitro.

The purpose of this study was to compare the effectiveness of Yttrium-90 (Y-90) labeled antibody irradiation to 60Co external beam irradiation in vitro by colony formation assay. Two human colon carcinoma cell lines, LS174T, a high CEA producer, and WiDr, a low CEA producer, were exposed to specific activities of Y-90 labeled murine monoclonal anti-CEA antibody ranging from 2.5 to 30 microCi/ml for a fixed period of time. This resulted in calculated doses of 2.25 to 27 Gy and initial dose rates of 2.5 to 29 cGy/hr. Results were compared to similar doses of Y-90 labeled non-specific antibody, unlabeled specific and non-specific antibody, and 60Co external beam irradiation. External beam irradiation studies showed that WiDr, compared to LS174T, was more radioresistant with a larger shoulder to the survival curve, indicating a greater capacity for radiation-induced sublethal damage repair. WiDr was also more radioresistant to Y-90 antibody irradiation. When compared to external beam irradiation, Y-90 labeled antibody irradiation resulted in less cell killing by a factor of 2.4 for LS174T and 3.4 for WiDr. Unlabeled antibody had no significant effect on cell survival. Radiation-induced cell cycle delay experiments demonstrated that WiDr had less cell cycle delay (0.9 to 1.0 min/cGy) compared to LS174T (1.2 min/cGy) after single fraction external beam irradiation. Our results indicate that Y-90 low dose-rate irradiation is radiobiologically less effective in vitro than high dose-rate external beam irradiation by a factor of about 2.4 to 3.4. The results also suggest that the magnitude of this difference depends on the cell line's ability to repair sublethal radiation damage and the degree of cell cycle prolongation after irradiation.

Adenocarcinoma↗

PubMed1991

The effect of different atmospheric ozone partial pressures on photosynthesis and growth of nine fruit and nut tree species.

Nursery stock of peach (Prunus persica L. Batsch, cv. O'Henry), nectarine (P. persica L. Batsch, cv. Fantasia), plum (P. salicina Lindel., cv. Casselman), apricot (P. armeniaca L., cv. Tilton), almond (P. dulcis Mill., cv. Nonpareil), prune (P. domestica L., cv. Improved French), cherry (P. avium L., cv. Bing), oriental pear (Pyrus pyrifolia Rehd., cv. 20th Century), and apple (Malus pumula Mill., cv. Granny Smith) were planted in open-top chambers on April 1, 1988 at the University of California's Kearney Agricultural Center located in the San Joaquin Valley (30 degrees 40' N 119 degrees 40' W). Trees were exposed to three atmospheric ozone partial pressures (charcoal-filtered air (C), ambient air (A), or ambient air + ozone (T)) from August 1 to November 17, 1988. The mean 12-h (0800 to 2000 h) ozone partial pressures measured in open-top chambers during the experimental period were 0.030, 0.051, and 0.117 microPa Pa(-1) in the C, A and T treatments, respectively. Leaf net CO(2) assimilation rate decreased linearly with increasing 12-h mean ozone partial pressure for the almond, plum, apricot, prune, pear, and apple cultivars. Stomatal conductances of apricot, apple, almond, and plum decreased linearly with increasing ozone partial pressure. Cross-sectional area relative growth rates of almond, plum, apricot, and pear decreased linearly with increasing ozone partial pressure. Net CO(2) assimilation rate, stomatal conductance, and trunk growth of cherry, peach and nectarine were unaffected by the ozone treatments. Reduced leaf gas exchange probably contributed to ozone-induced growth reduction of the susceptible species and cultivars. Several of the commercial fruit tree species and cultivars studied were relatively tolerant to the ozone treatments.

Journal Article↗

PubMed1991

Mating-related estradiol fluctuations during the estrous cycle of the Bolivian squirrel monkey (Saimiri boliviensis boliviensis).

The female squirrel monkey, Saimiri boliviensis, a New World monkey, has 10-day estrous cycles during the annual breeding season. Measurements of serum estradiol (E) concentrations in females housed with males in breeding pens revealed markedly higher levels than previously reported. Additionally, females in breeding pens appeared to have two distinct patterns of serum E peaks relative to the LH surge. Serum estrogen peaks averaging 5-fold greater than levels on the preceding day were observed on the same day as the LH surge, whereas other females had only a small E rise on the day of the LH surge followed by a 6-fold E rise on the next day. The serum progesterone (P) levels in all animals were depressed for 1-2 days before the LH surge but frequently started to rise on the day of the LH surge. The effect of the presence of a breeding male was examined by studying females housed in a group pen without exposure to a breeding male. In contrast to breeding-pen patterns, relatively small E rises were found in the 10 cycles observed. To further elucidate estrus-related E rises, a limited male-access paradigm was used to isolate mating-related hormone fluctuations. Pre-mating E levels had no marked rises; however, 4 h after mating, whether on the day of the LH surge or the next day, large E rises were found. These studies indicate that the LH surge in cycling squirrel monkeys is consistently preceded by a marked P nadir and associated with relatively small E rises.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Developmental changes in ECG associated with heart rate are similar in squirrel monkey and human infants.

Interest in refining noninvasive methods of diagnosis and further characterization of squirrel monkeys (Saimiri sp.) as a model for pediatric cardiology studies led to this investigation of electrocardiogram (ECG) changes associated with changes in age and position. During a single delivery season, ECGs were performed at 1 day, 1 month, and 1 year of age. For each age group, ECGs were recorded with animals in dorsal, ventral, and right lateral recumbency. The 1-day-old group had the lowest heart rates (271 +/- 10, right lateral recumbency, mean +/- SEM) relative to the other age groups. One-year-old monkeys had heart rates of 333 +/- 18. One-month-old infants had rates significantly higher than the other two age groups (366 +/- 4). The QRS frontal-plane axis showed an age-related leftward change from 1 day (151 +/- 28 degrees) to 1 year of age (121 +/- 44 degrees) while the P-wave frontal plane axis remained nearly constant over a narrow range at all ages. The pattern of heart rate changes with age were similar to those in humans, although the ranges of absolute heart rates were markedly different. These data suggest that factors that influence maturational changes in heart rate, conduction time (as reflected by ECG intervals) and cardiac chamber size and position (inferred from axis and voltage) are similar among primates of widely variant body sizes.

Animals↗

PubMed1990

Preliminary report: imaging of Kaposi sarcoma and lymphoma in AIDS with indium-111-labelled liposomes.

Kaposi sarcoma and malignant lymphoma were successfully imaged with high purity liposomes containing indium-111 in two patients with AIDS. Gamma camera images of the patient with Kaposi sarcoma showed four discrete lesions along the left foot and calf with no foci along the right foot, and no uptake into clinically enlarged but non-neoplastic lymph nodes. The spread of the Kaposi sarcoma was proximal along the leg. The neoplastic cervical lymph nodes in the second patient who had large-cell diffuse intermediate grade lymphoma were also imaged successfully. Since Kaposi sarcoma and lymphoma frequently involve occult sites, liposome imaging may prove useful in the diagnosis and management of these diseases.

Acquired Immunodeficiency Syndrome↗

PubMed1990

Estimation of monoclonal antibody-associated 90Y activity needed to achieve certain tumor radiation doses in colorectal cancer patients.

In these measurements, we quantitated, via surgical samples, human primary tumor uptake of the anti-carcinoembryonic antigen monoclonal antibody T84.66. Uptake was measured in units of percentage of injected dose/kg with 111In as the radiolabel. All 11 colorectal lesions were nonnecrotic and were visualized upon scanning. Tumor volume was calculated using the three orthogonal dimensions as described by pathology. Uptake mean +/- SD was 6.55 +/- 3.55% injected dose/kg with a range of 1.2 to 10.4% injected dose/kg. Lesion mean volume was 36 cm3 with a range of 1.5 to 304 cm3. Using mean values, assuming no biological clearance and that the biodistribution of the monoclonal is independent of its radiolabel, the predicted human tumor 90Y beta dose was 0.12 Gy/mCi. Therefore a 10-Gy tumor dose would require 83 mCi of i.v. activity. Using least and highest uptake results, requisite activity values were 3-fold larger and smaller respectively. Thus, there was approximately an order of magnitude variation in the amount of 90Y predicted to achieve a given tumor dose in colorectal cancer patients. Murine and human uptake values were consistent if lesion mass and carcinoembryonic antigen content were taken into account.

Antibodies, Monoclonal↗

PubMed1990

Presurgical imaging with indium-labeled anti-carcinoembryonic antigen for colon cancer staging.

Over a 4-year period, 108 patients with known or suspected colorectal cancer were studied by radioimmunoconjugate scintigraphy prior to operative procedures. Study subjects received 0.2 to 40 mg i.v. of murine anti-carcinoembryonic antigen monoclonal antibody labeled with 2-5 mCi of 111In (Indacea). Resected tissues were analyzed for 111In and carcinoembryonic antigen content. Tumor, liver, and draining lymph nodes had over 10% injected dose/kg compared to less than 2.5% injected dose/kg for other normal tissues. Primary tumors that were successfully imaged were significantly larger and had higher 111In and carcinoembryonic antigen content. In 54 patients, primary tumors were visualized with a sensitivity of 78%. Hepatic metastases (58 patients) were visualized as negative filling defects (sensitivity, 45%). Extrahepatic (intraabdominal) metastases (25 patients) were visualized (sensitivity, 48%) as areas of increased uptake. Extraabdominal metastases were uncommon (10 patients; sensitivity, 80%). Of 56 patients with known or suspected hepatic metastases who presented with no evidence of extrahepatic disease by conventional tests (X-ray, computerized tomographic scan), 20 (36%) were documented to have extrahepatic metastases at exploratory surgery and 10 of these (50%) had the extrahepatic disease localized by the Indacea scan. The management of these 10 patients was, or could have been, modified by the scan findings and unnecessary surgery eliminated.

Adult↗

PubMed1990

Radioimmunotherapy of human colon cancer in nude mice.

Nude mice bearing subcutaneous human colon cancer xenografts (LS174T) were treated with 120 microCi of yttrium 90-labeled anti-carcinoembryonic antigen monoclonal antibodies (specific therapy), 120 microCi of 90Y-labeled anti-melanoma monoclonal antibodies (nonspecific therapy), or phosphate-buffered saline solution (no treatment control). Mean (+/- SD) tumor growth rates (percent increase per day) over the first 30 days of the study were as follows: 0.6% +/- 0.2% per day (specific therapy); 17.7% +/- 5.7% per day (nonspecific therapy); and 30.5% +/- 4.2% per day (control). In all three groups, tumors over 1 g had similar doubling times (5.74 +/- 0.71 d). Specific therapy caused a lag in tumor growth corresponding to a 3-logarithm cell kill. Estimated tumor dose of radiation obtained by tissue analysis was 34 and 14 Gy for specific and nonspecific therapy, respectively. In conclusion, 120 microCi of 90Y-labeled anti-carcinoembryonic antigen monoclonal antibodies was effective in suppressing growth of human colon cancer xenografts. Clinical studies with this preparation are recommended.

Animals↗

PubMed1990

Localization of intraperitoneal xenografts of human colon cancer by radiolabeled anti-CEA antibodies.

An intraperitoneal xenograft tumor model was developed in the nude mouse to represent advanced colorectal disease in the human patient. Intraperitoneal (ip) and subcutaneous (sc) tumor xenografts were successfully localized by indium 111-labeled anti-carcinoembryonic antigen monoclonal antibodies (Indacea) administered intravenously (IV) or intraperitoneally (IP). In the sc model, tumor uptake (% injected dose per g of tumor tissue--%ID/g) was significantly improved at 72 hours postinjection when Indacea was administered IP (44.01 +/- 1.94 vs. 33.74 +/- 0.87, P less than 0.005). In the ip model, tumor uptake at 72 hours was improved with IP Indacea (28.23 +/- 5.42 vs. 19.36 +/- 5.50, P less than 0.01) and the tumor to blood ratio was significantly improved for IP Indacea (17.83 +/- 2.95 vs. 8.45 +/- 1.38, P less than 0.01). Tumor mass was not a contributing factor in these differences. This study demonstrates that ip xenografts can be successfully imaged using radiolabeled antibodies and that the IP route of administration results in better tumor uptake of the antibody in ip lesions.

Animals↗

PubMed1990

Biochemical genetic markers of squirrel monkeys and their use for pedigree validation.

Family data for 14 biochemical genetic markers fo squirrel monkeys (genus Saimiri) were derived from 73 pedigreed progeny and both parents of each, as well as from 16 additional progeny and one parent of each. The data for each marker and the phenotypic patterns were consistent with autosomal codominant inheritance. It was concluded from the genetic marker data that the pedigree records of seven progeny were incorrect. Retrospective investigations of colony records followed by typing of animals that might possibly have been a parent enabled five of the pedigree records to be corrected. Although five of the pedigree errors were cases of mistaken paternity, the other two apparently were the consequence of infant swapping between dams shortly after birth. Because squirrel monkeys exhibit a high degree of allomaternal behavior, infant swapping between dams may occur more frequently than in many other nonhuman primate species.

Alleles↗