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Biomedical subjects

W J Adams

Publications and source records attributed to W J Adams.

At least 37 records · Page 2Linked to original sources
PubMed1996

Ranitidine and cimetidine differ in their in vitro and in vivo effects on human colonic cancer growth.

Histamine has recently been shown to be a growth factor for some gastric and colorectal cancer cells. Previous studies have shown that cimetidine blocks in vitro and in vivo histamine-stimulated growth and cAMP release from the human colonic cancer cell line, C170. In this study, ranitidine, another H2 receptor antagonist, did not affect either basal or histamine-stimulated in vitro proliferation of C170, and failed to prevent cAMP release in vitro. Ranitidine did not inhibit in vivo growth of C170 at a dose of 1, 10, 25, 50 or 100 mg/kg, in contrast to 50 mg/kg/day cimetidine, which produced 39.3% inhibition of tumour volume (p<0.01) after 23 days' treatment. Ranitidine did not inhibit in vivo histamine-stimulated growth of C170 cells . LIM2412, another colonic cancer cell line, was significantly stimulated by both cimetidine and ranitidine in vivo. Ranitidine had no effect on in vitro cell proliferation.

Adenocarcinoma↗
PubMed1996

Physiology and pharmacokinetics of a novel hemoglobin-based oxygen carrier in humans.

OBJECTIVE: To evaluate the physiology and pharmacokinetics of a novel hemoglobin-based oxygen carrier of bovine origin. DESIGN: Randomized, single-blind, placebo-controlled, dose-escalation study. SETTING: The Upjohn Research Clinics (Kalamazoo, MI). SUBJECTS: Normal healthy adult men between the ages of 18 and 45 yrs. There were 18 subjects who received active treatment and 23 controls. INTERVENTIONS: All subjects had phlebotomy of 15% of blood volume (performed in <15 mins) followed by isovolemic hemodilution (3:1, Ringer's lactate to the volume of whole blood removed) over a 90-min period, and either active drug (polymerized bovine hemoglobin) or a control infusion of lactated Ringer's solution (each infusion given over a total of 4.3 hrs). The subjects randomized to active treatment received a loading dose and a continuous infusion of polymerized bovine hemoglobin for a total dose of 16.5, 24.1, 30.2, 38.0, or 45.0 g. All subjects had an indwelling radial artery catheter (for blood pressure and arterial blood gas measurements), determination of cardiac function (by impedance plethysmography), serial pulmonary function tests (spirometry and diffusion capacity), and metabolic cart measurements. MEASUREMENTS AND MAIN RESULTS: Pharmacokinetics of the plasma bovine hemoglobin demonstrated that the elimination of the hemoglobin-based oxygen carrier was a linear, first-order process and that there was no renal excretion. Peak plasma concentrations were between 1 to 2 g/dL and plasma half-life approached 20 hrs at the highest doses given. Diffusion capacity of oxygen was increased up to 20% above baseline in the 38.0 and 45.0 g groups in comparison with controls (approximately 14% below baseline) between 2 and 24 hrs after the infusion (p < .01). Other pulmonary function tests and arterial blood gas measurements were unremarkable. Arterial oxygen content and oxygen delivery tended to be greater in active groups than in controls. CONCLUSIONS: The plasma concentrations of bovine hemoglobin were directly proportional to the doses administered. An increase in diffusion capacity paralleled the plasma bovine hemoglobin concentrations. Dosing of the hemoglobin-based oxygen carrier of bovine origin to a target plasma hemoglobin concentration can be achieved using pharmacokinetic principles with measurable effects on oxygen physiology.

Adolescent↗
PubMed1995

Simple, rapid and sensitive high-performance liquid chromatographic determination of delavirdine and its N-desisopropyl metabolite in human plasma.

A method for the determination of a bisheteroarylpiperazine, non-nucleoside HIV-1 reverse transcriptase inhibitor, delavirdine, and its N-desisopropyl metabolite in human plasma, is described. Samples were deproteinized by addition of two parts of a solution of internal standard in acetonitrile (1 microgram/ml) to one part plasma. The supernatant was diluted with 10 mM phosphate buffer, pH 6.0, and injected onto the HPLC system. Fluorescence of the eluent was monitored with excitation at 302 nm and emission at 425 nm. Quantitation of delavirdine and its metabolite was achieved by comparing the peak-height ratio of each component relative to the internal standard to a through-the-origin linear regression curve determined from fortified plasma calibration standards. The assay was linear over the concentration range 0.02-17 microM for both delavirdine and its metabolite. The precision of the method, as expressed by the mean C.V. of the back-calculated, non-zero, standard concentrations, was +/- 4.4% for delavirdine and +/- 4.3% for the metabolite. The assay has been validated and utilized to analyze samples from human and animal pharmacokinetic studies.

Artifacts↗
PubMed1995

Endorectal ultrasonic detection of malignancy within rectal villous lesions.

PURPOSE: The ability of endorectal ultrasonography (EU) to detect the presence of a malignant focus within rectal villous adenomas was studied. METHODS: Clinical charts were reviewed of 62 consecutive patients undergoing EU of rectal villous adenomas, in whom histologic confirmation was available. RESULTS: Twelve lesions were found to contain cancer, of which only two demonstrated clinical signs of induration. Positive predictive value of EU for detecting a malignant focus was 66.7 percent, negative predictive value was 88.7 percent, sensitivity was 50 percent, and specificity was 94 percent. There was moderate overall agreement between pathologic and ultrasound staging (kappa statistic, 0.48). When an optimal image was obtained, all cancers that penetrated the submucosa were detected. Sensitivity of the technique was compromised in some large exophytic lesions and those at the level of the anal sphincter because of artefacts produced in the ultrasonographic image. CONCLUSION: A clear EU image can detect a malignant focus within a villous adenoma and direct the surgeon to the appropriate plane of surgical resection. In lesions with an ambiguous image, a malignancy cannot be excluded.

Adenoma, Villous↗
PubMed1995

A randomized trial of cimetidine with 5-fluorouracil and folinic acid in metastatic colorectal cancer.

Cimetidine has demonstrated a survival benefit in a randomized trial as adjuvant therapy for gastric cancer. We have demonstrated expression of histamine receptors on colon cancer cell lines and inhibition of their growth with cimetidine. Cimetidine also activates suppressor T cells and stimulates cell-mediated immunity. We therefore performed a randomized controlled clinical trial to determine the effect of cimetidine 400 mg given twice daily in conjunction with chemotherapy vs chemotherapy alone. Thirty-eight patients were randomized and 35 patients were eligible for further analysis. Both groups were well matched for pre-treatment characteristics. There was no difference in overall response. There was, however, a significantly increased rate of CEA response in the cimetidine group. Four of 11 patients (36%) in the cimetidine group had a CEA response compared to none of eight in the control. Meaningful comparisons of overall survival cannot yet be made. This study demonstrates that cimetidine has encouraging activity in increasing CEA response in patients with metastatic colorectal cancer treated with chemotherapy. This observation needs to be extended in a larger randomized study, which is currently underway.

Adult↗
PubMed1995

Autonomic nerves cross the posterior plane of rectal dissection.

This investigation was an anatomical study to determine whether branches of the pre-sacral autonomic plexus cross the posterior plane of surgical dissection to supply the rectum. Initially four cadaver hemi-pelves were dissected. Twelve patients undergoing full rectal mobilization were then studied at operation. In all subjects the pre-sacral nerves were arranged as a plexus below the sacral promontory, rather than as individual left and right nerve trunks. Structures thought to be nerves were identified crossing the plane of posterior mobilization of the rectum. They were traced towards their origin and destination, photographed and representative fibres biopsied. A total of 42 such structures were biopsied (16 in cadavers, 26 in operative cases) and 40 were confirmed to be nerves. These nerves connect the pre-sacral autonomic plexus with the posterior aspect of the rectum and were found at all sacral levels. In the operative cases the level of the positive biopsies were S1-six, S2-six, S3-five, S4-four, S5-three. The posterior plane of rectal dissection is therefore crossed by autonomic nerves that innervate the rectum. The pre-sacral nerves have been found to form a plexus in all subjects.

Adult↗
PubMed1995

Focused US system for MR imaging-guided tumor ablation.

PURPOSE: To measure the performance characteristics of a focused ultrasound (US) system for magnetic resonance (MR) imaging-guided tumor ablation. MATERIALS AND METHODS: The authors constructed a focused US system for MR imaging-guided tumor ablation. The location of the heated region and thermal dose were monitored with temperature-sensitive MR images obtained in phantoms and rabbit skeletal muscle after application of each sonic pulse. RESULTS: The region heated by the focused ultrasound beam was within 1 mm of that observed on temperature-sensitive fast gradient-echo MR images of in vivo rabbit skeletal muscle. Analysis of heat flow and the rate of coagulation necrosis provided an estimate of the size of the ablated region that was in agreement with experimental findings. CONCLUSION: MR imaging provides target definition and control for thermal therapy in regions of variable perfusion or in tissues that are not well characterized.

Animals↗
PubMed1995

Hematologic effects of a novel hemoglobin-based oxygen carrier in normal male and female subjects.

The objective of this study was to assess the relationship between iron metabolism and pharmacokinetics of hemoglobin-based oxygen carrier-201 (HBOC-201), a polymerized hemoglobin product of bovine origin. A randomized, single-blind, single-dose study design was used. The study was performed at the Upjohn Research Clinics in Kalamazoo, Michigan. Four groups of healthy men and women (n = 24), who either received HBOC-201 (9 men, 9 women) or a control solution (Ringer's lactate) (3 men, 3 women) participated in the study. All subjects had phlebotomy (approximately 15% blood volume) followed by 3:1 hemodilution with Ringer's lactate and an intravenous infusion of HBOC-201 (up to 45 gm or 350 ml) or control solution (Ringer's lactate). Serial arterial blood gas samples with a radial artery catheter and simultaneous pulse oximetry were done during the first 24 hours. Serial samples for serum iron, ferritin, erythropoietin, and plasma HBOC-201 levels were taken over a 1-month period. In the HBOC-201-treated groups, serum iron and ferritin levels increased. Peak serum iron and ferritin levels occurred by hours 8 (up to 220 micrograms/dl) and 48 (up to 180 ng/ml), respectively. Serum iron levels paralleled HBOC-201 concentrations. Plasma half-life of HBOC-201 was about 20 hours. Serum erythropoietin increased by twofold to sixfold over baseline (p < 0.001) at 24 hours. No urinary hemoglobin was detected in the groups with HBOC-201-treated subjects. This study demonstrates that HBOC-201 produces increases in serum iron, ferritin, and erythropoietin that closely parallel plasma levels of HBOC-201 in men and women.

Adult↗
PubMed1994

A one-dimensional velocity technique for NMR measurement of aortic distensibility.

A technique is presented for rapidly and noninvasively determining aortic distensibility, by NMR measurement of wave velocity in the aorta. A two-dimensional NMR selective-excitation pulse is used to repeatedly excite a cylinder of magnetization in the aorta, with magnetization read out along the cylinder axis each time. A toggled bipolar flow-encoding pulse is applied prior to readout, to produce a non-dimensional phase-contrast flow image. Cardiac gating and data interleaving are employed to improve the effective time resolution to 2 ms. Wave velocities are determined from the slope of the leading edge of flow measured on the resulting M-mode velocity image. The technique is sensitive over a range of distensibilities from 10(-6) to 10(-3) m s2/kg. The average value in the descending thoracic aorta in seven normal subjects was found to be 4.8 x 10(-5) m s2/kg, with a significant inverse correlation with age.

Adult↗
PubMed1994

Bisacodyl reduces the volume of polyethylene glycol solution required for bowel preparation.

PURPOSE: This study was designed to compare the efficacy and patient tolerance of standard orthograde bowel preparation using 4 liters of polyethylene glycol solution with only 2 liters of polyethylene glycol preceded by the stimulant laxative bisacodyl. METHODS: Three hundred eighty-two consecutive patients undergoing outpatient colonoscopy under two surgeons over a six-month period were randomized to receive one of the two preparations. Patients were asked to record the effects of the preparation and to give it a "discomfort rating" on a scale from 1 to 5. Surgeons were blinded to the preparation used and rated the quality of bowel cleansing on a scale of 1 to 5. One hundred ninety-one patients were randomized to the 4-liter preparation and 191 to the 2-liter preparation. RESULTS: Ninety-three percent of patients in the 2-liter group drank all of the solution as opposed to only 66 percent of patients in the 4-liter group. Patients in the 4-liter group gave the preparation significantly lower comfort scores than those in the 2-liter group (Fisher's exact test; P = 0.0001). The quality of bowel cleansing was not significantly different between the groups (P = 0.88). A total of 6.8 percent of the 2-liter group and 9.4 percent of the 4-liter group were considered by the surgeon to have had a poor preparation (rating 4 or 5). The quality of the preparation was found to correlate with the patients' age and compliance with the preparation regimen, and was found not to correlate with presenting symptoms, pathology, or a previous colonic resection. CONCLUSION: Bowel preparation with bisacodyl and 2 liters of polyethylene glycol is more acceptable to patients than a 4-liter regimen and is equally effective in cleansing the colon.

Adult↗
PubMed1994

The effect of misoprostol on colon cancer.

A synthetic prostaglandin E1 (PGE1) analogue, misoprostol, was investigated for its effects on the growth of colon cancer in two in vivo models. Human colon cancer cell lines C170, LIM2412 and LIM2405 were grown as subcutaneous xenografts on T-lymphocyte deficient ARC(s) nu/nu mice. Tumour volumes were found to be significantly inhibited compared with control in misoprostol-treated animals with two cell lines. C170 was inhibited by 70.5% (P = 0.0001) and LIM2412 by 68.2% (P = 0.01). LIM2405 was inhibited by 33% (P = 0.14) which was not significantly different from the control. In a second experiment, colon cancers were induced in Sprague-Dawley rats using 1,2 dimethyl-hydrazine (DMH). After 10 weeks of treatment, rats were randomized to receive a 5 week course of 20 micrograms/kg per day of oral misoprostol. Misoprostol-treated rats were found to have a similar tumour incidence and staging compared with control animals. Oral administration of misoprostol has an inhibitory effect on early tumour growth of some colonic cancers, but not on established tumours.

Adenocarcinoma↗
PubMed1994

Cimetidine preserves non-specific immune function after colonic resection for cancer.

Fifty consecutive patients undergoing resection of colorectal cancer were randomized to either receive cimetidine at a dose of 400 mg bd for a minimum of 5 pre-operative days, then intravenously for 2 postoperative days, or to act as controls. Baseline immune function was determined in all patients by in vitro testing of lymphocyte proliferation (LP) in response to mitogen, skin testing for cell mediated immunity (CMI) and measurement of lymphocyte subsets. Immune function was retested in both groups on the second postoperative day. In control patients the mean postoperative LP value was 41% of pre-operative levels (P < 0.0001) and the mean CMI reduced to 29% (P < 0.0001). Patients treated with cimetidine had no significant fall in these parameters. Numbers of T and natural killer (NK) cells fell after surgery in both groups, and B cell numbers were maintained in the cimetidine group. It is concluded that cimetidine reduces the immunosuppression that follows colonic resection.

Aged↗
PubMed1994

Cimetidine inhibits in vivo growth of human colon cancer and reverses histamine stimulated in vitro and in vivo growth.

The effect of histamine and cimetidine on the growth of four human colon cancer cell lines was studied. Histamine significantly stimulated the uptake of tritiated thymidine in vitro in a dose dependent manner, to a maximum of 120% and 116% of controls for C170 and LIM2412, respectively. This effect was antagonised by cimetidine, but not diphenhydramine. Histamine also stimulated a dose dependent increase in cyclic adenosine monophosphate accumulation in C170 cells, antagonised by cimetidine. When grown as subcutaneous xenografts in Balb/c nu/nu mice, cimetidine had a significant inhibitory effect on the same two cell lines. The final volume of C170 tumours in animals given cimetidine was 44% of controls. This response was dose dependent, plateauing at a cimetidine dose of 50 mg/kg/day. The final volume of LIM2412 tumours in animals given cimetidine was 60% of controls. Histamine administered locally by a mini-osmotic pump stimulated C170 tumour growth to 164% of controls, was antagonised by cimetidine at a dose of 200 mg/kg/day, but not by lower concentrations. Histamine has a trophic effect on at least two colorectal cancer cell lines in vivo and in vitro. As this effect is antagonised by cimetidine, it may be mediated via tumour histamine type 2 receptors.

Animals↗
PubMed1993

Real-time acquisition, display, and interactive graphic control of NMR cardiac profiles and images.

A highly interactive MRI scanner interface has been developed that allows, for the first time, real-time graphic control of one-dimensional (1D) and two-dimensional (2D) cardiac MRI exams. The system comprises a Mercury array processor (AP) in a Sun SPARCserver with two connections to the MRI scanner, a data link that passes the NMR data directly to the AP as they are collected, and a control link that passes commands from the Sun to the scanner to redirect the imaging pulse sequence in real time. In the 1D techniques, a cylinder or "pencil" of magnetization is repeatedly excited using gradient-echo or spin-echo line-scan sequences, with the magnetization read out each time along the length of the cylinder, and a scrolling display generated on the Sun monitor. Rubber-band lines drawn on the scout image redirect the pencil or imaging slice to different locations, with the changes immediately visible in the display. M-mode imaging, 1D flow imaging, and 2D fast cardiac imaging have been demonstrated on normal volunteers using this system. This platform represents an operator-"friendly" way of directing real-time imaging of the heart.

Computer Systems↗
PubMed1993

A phase I clinical and pharmacokinetic study of the oral and the oral/intravenous administration of menogaril.

Thirty-five patients with advanced refractory cancer were enrolled on this phase I study of menogaril administered orally every 4 weeks at dosages ranging from 85 mg/m2 to 625 mg/m2. An additional 12 patients received alternating oral and IV doses of menogaril (250 mg/m2 IV; 250-500 mg/m2 oral) with accompanying blood and urine sampling for pharmacokinetics analysis. Nausea and vomiting were the dose-limiting toxicities at the 625 mg/m2 dosage level; vomiting was inadequately relieved by prophylactic antiemetics at this dosage level. Other toxicities included sporadic leukopenia at all dosage levels; at dosages of 500 mg/m2 and 625 mg/m2, leukopenia < 3000/microliters occurred in 7 of 24 patients. Anemia and thrombocytopenia were much less frequent toxicities. Among the patients receiving IV menogaril, peripheral vein phlebitis, leukopenia and anemia were the predominant toxicities. No antitumor responses were observed, yet one patient with non-small cell lung cancer experienced a 30% reduction in metastatic tumor nodules. For the patients receiving alternating oral and IV menogaril, comparative pharmacokinetic analyses were performed by HPLC. After oral administration, maximum plasma concentrations were achieved in an average of 6 hours; maximum plasma concentrations were less than one-quarter of those achieved after intravenous administration. The harmonic mean (+/- SD) terminal disposition half-life after oral dosing was 29.3 +/- 9.2 hours; mean systemic bioavailability was 33.6 +/- 10.5% after oral dosing. Forty-eight hours after an oral dose, mean cumulative urinary excretions of menogaril and the primary metabolite, N-demethylmenogaril, were 4.00 +/- 0.96% and 0.44 +/- 0.16%, respectively. Because of the poor tolerance of oral menogaril and minimal evidence of biological activity, this schedule of drug administration is not recommended for phase II evaluation. Based on this and other published studies of oral menogaril, frequent chronic low-intermediate dosages of the drug may be given orally with potentially better tolerance and antitumor activity.

Administration, Oral↗