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Biomedical subjects

A C Perkins

Publications and source records attributed to A C Perkins.

At least 55 records · Page 3Linked to original sources
PubMed1998

Reproducibility of gastric emptying of a pancake and milkshake meal in normal subjects.

Comparisons of gastric emptying between different centres are difficult because of wide variations in methods. Reproducibility of a method is very important before it is used to compare different subjects or to assess the effect of treatment. The aim of this study was to measure the reproducibility of gastric emptying of a solid and liquid meal in normal subjects. Ten males were studied on two occasions. After an overnight fast, the subjects ate a radiolabelled solid and liquid meal. There were no significant differences in T50 on the 2 days (136.6 +/- 23.2 vs 121.3 +/- 26.7 min for solid and 30.7 +/- 12.6 vs 32.6 +/- 18.7 min for liquid; mean +/- SD). Intra-subject variability was between 7 and 21% for the solid component and 1.5 and 63% for the liquid component. The mean difference in T50 between the 2 days was 15.3 +/- 21.9 min for the solid component and -5.1 +/- 19.7 min for the liquid component. Only one difference between the T50 results was not in the 95% confidence interval for the liquid component. Thus despite some inter- and intra-subject variability, the method showed good reproducibility.

Adult↗
PubMed1998

Ocular contact time of a carbomer gel (GelTears) in humans.

BACKGROUND/AIMS: Carbomers are widely used in products for the treatment of dry eye; however, the polymer gel thins on addition of probes (for example, fluorescein salt) confounding the comparison of products by objective clinical tests such as spectrophotofluorimetry or scintigraphy. A novel method of radiolabelling carbomer gels, with minimum change to their rheology, has permitted the non-invasive evaluation of precorneal residence of the gel in volunteers using gamma scintigraphy. The technique was used to evaluate the precorneal clearance of the liquid phase and of a suspended particulate in GelTears. METHODS: Low sodium technetium-99m labelled diethylenetriaminepentacetic acid (99mTc-DTPA) was used to label carbomer 940 gel, either adsorbed onto sterile charcoal to model an entrapped drug, or added directly to the gel to a final activity of 1 MBq per 25 microliters dose. The clearance of the labelled gels was then compared with 99mTc-DTPA labelled saline in 12 volunteers. RESULTS: The addition of the low sodium radiopharmaceutical produced insignificant rheological changes in the gel compared with conventional 99mTc-DTPA labelling. The residence times on the eye of the gel formulations were significantly greater than that of the saline control. At 8 minutes postdosing, the label levels retained (mean (SD)) on the ocular surface were: saline, 7% (7%); 99mTc-DTPA gel, 42% (27%); and 99mTc-carbon gel, 42% (20%) of administered dose. There was no difference observed in the precorneal distribution between 99mTc-DTPA solution and particulate markers. CONCLUSIONS: These data demonstrate that carbomer based gels significantly extend contact of solutes or suspended solids with the corneal surface. The method of labelling does not significantly change the initial viscosity and is superior to previous methods which have used sodium salts (for example, sodium fluorescein) and therefore underestimate contact time.

Acrylic Resins↗
PubMed1998

Small bowel transit of a bran meal residue in humans: sieving of solids from liquids and response to feeding.

BACKGROUND: Ileal motor patterns are adapted to the propulsion of viscous meal residue, such as bran, which accumulates in the distal ileum postprandially. AIMS: To examine the effects of a second liquid/solid meal on ileal emptying. SUBJECTS AND METHODS: Eleven healthy fasting subjects consumed a 1.47 MJ pancake containing 15 g bran and 5 MBq Technetium-99m labelled amberlite resin (meal A). Gastric emptying and transit through the left upper quadrant (proximal) and right lower quadrant (distal) small bowel regions and colon were assessed scintigraphically. Transit was compared with and without a second Indium-111 liquid/solid DTPA labelled 2.28 MJ meal (B) given three hours after the first meal. RESULTS: Gastric emptying of meal A was slower than meal B (the time for 50% of the activity to leave the stomach (T50) being 113 (11) minutes versus 48 (3) minutes respectively, p < 0.01, n = 11). Both meals passed rapidly through the proximal small bowel (T50 meal A = 57 (14) minutes versus T50 meal B = 42 (11) minutes). Transit of meal A through the distal small bowel was much slower (T50 more than 390 minutes versus 176 (29) minutes for meal B, p < 0.01), resulting in meal B overtaking meal A and entering the colon earlier. Ingestion of the second meal (B) resulted in significantly less meal A marker entering the colon (5 (3)%) at 11 hours than when meal A was taken alone (18 (4)%) (p < 0.05, n = 8). CONCLUSIONS: The distal small bowel selectively retains bran, allowing liquid phase markers through to the colon. Consuming a second liquid/solid meal does not stimulate ileal transit of bran which seems to be propelled quicker by fasting motor patterns.

Adult↗
PubMed1998

Polymer diagnostics: the next generation of image contrast agents.

Diagnostic imaging techniques are an essential component of modern patient management. To maximise the yield of diagnostic information from these procedures, pharmaceutical grade contrast agents can be administered which will enhance regions of the image by virtue of their presence in the patient. This concept is well established in X-ray investigations using radiographically dense materials such as intravascular iodine and oral barium. The widespread use of other imaging modalities such as nuclear medicine, magnetic resonance and ultrasound has led to the development of a broad range of pharmaceutical agents which are administered to obtain diagnostic information, rather than to result in a pharmacological effect. Synthetic polymers and polypeptides in particular offer a range of materials with properties highly suited for use as image contrast media. This article outlines the basis of the main imaging techniques and the physical attributes of materials used to obtain image contrast. The use of synthetic polymeric formulations appears to offer great potential as a range of elegant "designer contrast agents." Examples are given for each imaging modality.

Animals↗
PubMed1998

[The effect of pretreatment with ranitidine on the pharmacokinetics and gastrointestinal transit of a sustained-release theophylline preparation].

A scintigraphic and pharmacokinetic study of the behavior of Bronchoretard forte (theophylline, CAS 58-55-9) was carried out in 8 healthy male volunteers to evaluate the sensitivity of the preparation to changes in gastric pH. The volunteers were pretreated with ranitidine (CAS 66357-35-5) (150 mg b.i.d.) or placebo for three days prior to and on the study day to reduce gastric acidity. The effect of the pretreatment with ranitidine on gastric pH was measured on the day before study begin and the mean pH was significantly increased compared to the placebo (ranitidine pH 2.2 +/- 2.4; placebo pH 1.6 +/- 2.0, p < 0.01 Wilcoxon Signed Rank test). All subjects were pretreated with theophylline for 3 days (500 mg b.i.d.) to achieve steady state. On the study day, the volunteers swallowed two theophylline sustained release capsules, radiolabelled by inclusion of indium-111 micronised Amberlite resin, and the gastrointestinal transit was followed continuously for 14 h using gamma scintigraphy with a further image at 24 h. Blood samples were taken from each subject throughout the study to determine the pharmacokinetic profile of theophylline in the sustained release formulation. No significant differences were found in the gastrointestinal transit of the labelled microparticulates between the data obtained from the group treated with ranitidine and that from the placebo group. Plasma theophylline concentration profiles were identical for the two treatments. These data indicate that the theophylline sustained release formulation is not sensitive to the effects of major changes in gastric H+ concentration.

Adult↗
PubMed1997

Preclinical evaluation of copper-67 labelled anti-MUC1 mucin antibody C595 for therapeutic use in bladder cancer.

Transitional cell carcinoma of the bladder is the fifth commonest cause of death from cancer in men in the United Kingdom. Most patients present early with superficial disease, though with current treatment up to 20% progress to invasive disease, which has a poor prognosis. Better local treatments are required to limit this tumour progression. The ease of access to the bladder via a catheter provides the ideal opportunity for antibody (Ab) targeted therapy. We have previously shown that indium-111 labelled anti-MUC1 mucin Ab C595 selectively localises to bladder tumours after intravesical administration. We have selected copper-67 as an alternative radiolabel with suitable physical characteristics for radioimmunotherapy. This communication demonstrates that C595 can be reproducibly labelled with 67Cu and that the radioimmunoconjugate is both stable and maintains high immunoreactivity. Pilot studies on cystectomy specimens in a novel ex vivo system and in one patient confirmed the ability of this conjugate to localise to tumour after intravesical administration. On the basis of these studies we are now in a position to study the intravesical administration of 67Cu-labelled C595 in patients with bladder cancer with a view to a therapeutic trial.

Administration, Intravesical↗
PubMed1997

The effect of circulating antigen on the biodistribution of the engineered human antibody hCTM01 in a nude mice model.

Clinical studies are currently underway to assess the biodistribution and therapeutic potential of the genetically engineered human antibody hCTM01 directed against polymorphic epithelial mucin (PEM) in patients with ovarian carcinoma. The present study was undertaken to assess the effect of circulating PEM antigen on the biodistribution of the anti-PEM antibody in mice bearing MUC-1 transfected adenocarcinoma cell lines. Tumour xenografts were established from three cell lines: 413-BCR, which expressed antigen on the cell surface and also shed antigen into the circulation, E3P23, which expressed the antigen but did not shed into the circulation, and a negative control (410.4 MUCI). Groups of five mice were injected with 1.0 mg/kg antibody, imaged after 72 h and then sacrificed, followed by assay of tissue uptake. The results showed a clear difference in the tumour and liver uptake, with the non-secreting cell line showing almost twice the tumour uptake and approximately 20% of the liver uptake of the secreting cell line.

Adenocarcinoma↗
PubMed1997

Infusion of pramlintide, a human amylin analogue, delays gastric emptying in men with IDDM.

Pramlintide, a human amylin analogue, reduces hyperglycaemia after meals in patients with insulin-dependent diabetes mellitus (IDDM). We investigated whether this was due to delayed gastric emptying. Eight men with uncomplicated IDDM were studied twice in a randomised, double-blind crossover design. Euglycaemia was maintained overnight by intravenous infusion of glucose and/or insulin and the following morning a 5-h infusion of pramlintide 25 micrograms/h or placebo was started at 08.00 hours. At 08.30 hours the patients injected their normal morning insulin dose subcutaneously and 30 min later ate a meal (600 kcal, 50% carbohydrate) of which the solid component was labelled with Technetium-99 m and the liquid with Indium-111 to quantify gastric emptying. Gamma-scintigraphic images were obtained every 20 min for the next 4 h. Insulin and glucose were infused as necessary to maintain blood glucose levels within 3 mmol/l of the pre-meal value. Compared to placebo, pramlintide significantly delayed emptying of both liquid (median lag time 69 vs 7.5 min) and solid (median lag time 150 vs 44.5 min) components of the meal. Pramlintide delayed gastric emptying so much that t50 values could not be calculated for solid or liquid. Amylin agonists such as pramlintide may, therefore, be of value in improving glycaemic control in IDDM by modifying gastric emptying.

Adult↗
PubMed1997

Bedside nuclear medicine investigations in the intensive care unit.

The functional nature of nuclear medicine procedures makes them especially valuable in the management of patients undergoing intensive care. However, the severe nature of the patient's condition invariably prevents him or her from attending the nuclear medicine department for diagnostic investigations. We have piloted a bedside nuclear medicine service using a four-probe detector system linked to an IBM computer with curve processing software. Protocols for a range of radionuclide probe investigations, including renal, hepatobiliary, gastric outflow and lung vascular permeability, using 99Tcm and 111In radiopharmaceuticals have been established. The measurement of lung vascular permeability in patients with clinical symptoms of adult respiratory distress syndrome was considered to be a valuable procedure on the intensive care unit. Due to the poor availability of 113Inm, which had previously been used for the measurement of lung permeability, we used a technique based on in vivo labelling of serum transferrin with 111In-chloride together with 99Tcm-red blood cells for the calculation of the plasma protein accumulation index. Other procedures include the measurement of gastric outflow in patients previously on parenteral feeding, and the assessment of hepatobiliary and renal function. The equipment proved to be reliable and convenient for use at the bedside, although ultrasound imaging was essential for the correct positioning of the probe detectors over smaller organs such as the kidneys and the gallbladder. The high sensitivity of the probe detectors required only low administered amounts of activity, minimizing radiation protection measures for patients and staff. The administration of radiopharmaceuticals via indwelling lines and tubes presented particular problems and we recommend that parenteral injections should not be given through manifold giving set, or via Teflon cannulae.

Adult↗
PubMed1997

Effect of bran, ispaghula, and inert plastic particles on gastric emptying and small bowel transit in humans: the role of physical factors.

BACKGROUND: Coarse bran is known to accelerate transit through the whole gut and to increase stool weight. This effect is much reduced by grinding the bran, suggesting that particle size influences gut motor patterns. AIMS: To compare the effect of 15 g coarse bran with 15 g inert plastic particles and 7 g of ispaghula on the gastric emptying and small bowel transit of a rice pudding test meal. SUBJECTS: 13 healthy volunteers. METHODS: Transit of 99mTc labelled rice studied by gamma-scintigraphy measuring gastric emptying and colonic arrival over 10 hours. Small bowel transit was estimated from the difference between time to 50% gastric emptying and 50% colonic arrival. RESULTS: Bran delayed gastric emptying by 22 (SEM 8) minutes compared with control values of 88 (SEM 6) minutes p < 0.05. Ispaghula and plastic particles had no significant effect. Small bowel transit was accelerated compared with control values of 322 (SEM 29) minutes, decreasing by 95 (29) minutes and 62 (22) minutes after bran and plastic particles respectively. Ispaghula again showed no significant effect. CONCLUSION: Coarse bran delays gastric emptying and accelerates small bowel transit. The marked acceleration of small bowel transit also seen with inert plastic particles may be due to increased upper gut secretions after stimulation of enteric nerves.

Aged↗
PubMed1997

Human biodistribution of an ultrasound contrast agent (Quantison) by radiolabelling and gamma scintigraphy.

The biodistribution and kinetics of an air filled human serum albumin microcapsule formulation (Quantison) intended for use as an intravenous ultrasound contrast agent have been examined. 12 healthy subjects were administered with approximately 50 million microcapsules per kilogram body weight, radiolabelled with 50 MBq 123I. Imaging was performed over a period of 58 h using a large field-of-view gamma camera and the amount of labelled material present in the blood, urine and faeces measured. Imaging demonstrated that the liver was the organ with the highest uptake, with a mean uptake of 41.8% (SD 10.4%) of the administered dose 1 h following administration. The maximum uptake of the agent in the lungs was low, mean 4.0% (SD 3.4%). A small amount of uptake was visible in the bone marrow; however, this was not quantifiable. There was also evidence of minimal myocardial activity within 5 min of administration. No adverse events were observed and there were no changes in any of the individual post-study indices. The present study demonstrates the safety of Quantison. Gamma scintigraphy played a useful role in confirming the biodistribution of the agent with little lung uptake, high liver uptake and evidence of myocardial uptake.

Adult↗
PubMed1996

Biodistribution of (111)indium-labeled engineered human antibody CTMO1 in ovarian cancer patients: influence of protein dose.

Thirty-one patients suspected of having ovarian cancer received a single i.v. injection of radiolabeled (100 MBq (111)In) engineered human CTMO1 (hCTMO1) to investigate its potential as an internalizing drug carrier. hCTMO1 is a complementary-determining region-grafted human IgG4 monoclonal antibody recognizing an ovarian carcinoma-associated antigen, the MUC-1-gene product. The amount of radioactivity was determined in tumor tissue, various normal tissues, including liver biopsies, and blood samples obtained at laparotomy, 6 days after injection of either 0.1 or 1.0 mg hCTMO1/kg of body weight. Circulating antigen-15-3 was measurable in all patients before injection, and immune complex formation was already present at the end of infusion. In the 0.1 mg/kg group, most of the radioactivity was bound to immune complexes, whereas in the 1.0 mg/kg group, most was bound to IgG monomers. Increasing the hCTMO1 dose 10-fold did not influence the overall disappearance of (111)In from the blood, but the elimination half-life of (111)indium bound to immune complexes was increased 2-fold. Uptake in tumor tissue 6 days postinjection at the 0.1 mg/kg dose was 7.6 times higher (P = 0.0009) than in normal tissue and 2.5 times higher (P = 0.03) than in blood. At the 1.0 mg/kg dose, the uptake in tumor tissue was 14.0 times higher (P = 0.0003) than in normal tissue and 8.1 times higher (P = 0.0007) than in blood. Liver activity was substantial (23.7 +/- 10.5 and 18.3 +/- 6.7% of the injected dose/kg for the 0.1 and 1.0 mg/kg dose group, respectively). These results are superior to those found with other clinically tested anti-MUC-1 gene product antibodies. hCTMO1 seems to be a suitable carrier for cytotoxic agents in ovarian carcinoma patients; the better uptake results and tumor-to-blood ratios are obtained at the higher dose of 1.0 mg hCTMO1/kg body weight.

Adult↗
PubMed1996

Silencing of human fetal globin expression is impaired in the absence of the adult beta-globin gene activator protein EKLF.

Globin genes are subject to tissue-specific and developmental stage-specific regulation. A switch from human fetal (gamma)-to adult (beta)-globin expression occurs within erythroid precursor cells of the adult lineage. Previously we and others showed by targeted gene disruption that the zinc finger gene, erythroid Krüppel-like factor (EKLF), is required for expression of the beta-globin gene in mice, presumably through interaction with a high-affinity binding site in the proximal promoter. To examine the role of EKLF in the developmental regulation of the human gamma-globin gene we interbred EKLF heterozygotes (+/-) with mice harboring a human beta-globin yeast artificial chromosome transgene. We find that in the absence of EKLF, while human beta-globin expression is dramatically reduced, gamma-globin transcripts are elevated approximately 5-fold. Impaired silencing of gamma-globin expression identifies EKLF as the first transcription factor participating quantitatively in the gamma-globin to beta-globin switch. Our findings are compatible with a competitive model of switching in which EKLF mediates an adult stage-specific interaction between the beta-globin gene promoter and the locus control region that excludes the gamma-globin gene.

Adult↗
PubMed1996

Thrombopoietin rescues in vitro erythroid colony formation from mouse embryos lacking the erythropoietin receptor.

The interaction of the hormone erythropoietin and its receptor (EpoR) is though to be required for normal hematopoiesis. To define the role of EpoR in this process, the murine EpoR was disrupted by homologous recombination. Mice lacking the EpoR died in utero at embryonic day 11-12.5 with severe anemia. Embryonic erythropoiesis was markedly diminished, while fetal liver hematopoiesis was blocked at the proerythroblast stage. Other cell types known to express EpoR, including megakaryocytes, mast, and neural cells were morphologically normal. Reverse transcription-coupled PCR analysis of RNA from embryonic yolk sac, peripheral blood, and fetal liver demonstrated near normal transcripts levels for EKLF, thrombopoietin (Tpo), c-MPL, GATA-1, GATA-2, and alpha- and embryonic beta H1-globin but non for adult beta maj-globin. While colony-forming unit-erythroid (CFU-E) and burst-forming unit-erythroid (BFU-E) colonies were not present in cultures derived from EpoR-/- liver or yolk sac cells, hemoglobin-containing BFU-E colonies were detected in cultures treated with recombinant Tpo and Kit ligand or with Tpo and interleukin 3 and 11. Rescued BFU-E colonies expressed adult beta-globin and c-MPL and appeared morphologically normal. Thus, erythroid progenitors are formed in vivo in mice lacking the EpoR, and our studies demonstrate that a signal transmitted through the Tpo receptor c-MPL stimulates proliferation and terminal differentiation of these progenitors in vitro.

Animals↗
PubMed1996

Nuclear medicine techniques in the evaluation of pharmaceutical formulations.

Nuclear medicine imaging techniques have great potential in the study of the behaviour of drug formulations and drug delivery systems in human subjects. No other technique can locate so precisely the site of disintegration of a tablet in the G1 tract, the depth of penetration of a nebulised solution into the lung, or the residence time of a drug on the cornea. Using the gamma camera to image the in vivo distribution of pharmaceutical formulations radiolabelled with a suitable gamma emitting radionuclide, images may be used to quantify the biodistribution, release and kinetics of drug formulations and delivery from novel carrier systems and devices. Radionuclide tracer techniques allow correlation between the observed pharmacological effects and the precise site of delivery. The strength of the technique lies in the quantitative nature of radionuclide images. Such studies not only provide data on the nature and characteristics of a product, such as reliability and reproducibility but, may also be used in submission to Regulatory Authorities in product registration dossiers.

Chemistry, Pharmaceutical↗
PubMed1996

Peroperative (123)I-MIBG scan using a sterile probe for staging and resection of neuroblastoma in children.

Two children with neuroblastoma were treated at Bristol Children's Hospital. One had primary resection of a right adrenal tumor; the other had resection of a secondary lymph node located in the left supraclavicular fossa. In both cases, the patients received 123(I)-meta-iodobenzylguanidine (MIBG) preoperatively, and a sterilizable, hand-held Cadmium-Telluride (CdTe) solid-state detector was used for localization of the tumor. The surgical procedure was facilitated significantly by this peroperative radioisotope-guided technique.

3-Iodobenzylguanidine↗
PubMed1996

Assessment of completeness of thyroid ablation by estimation of neck uptake of 131I on whole-body scans: comparison of quantification and visual assessment of thyroid bed uptake.

Thyroid cancer is treated by thyroidectomy followed by radioiodine ablation of the residual active tissue in the thyroid bed. Completeness of ablation can be assessed from neck images of whole-body 131I scans by visual estimation or quantitative analysis By visual assessment, ablation can be considered complete if there is no uptake in the neck or the uptake is empirically considered too small. By quantification, ablation is considered complete if neck uptake is < 1%. Further radioiodine therapy is considered necessary only if neck uptake exceeds 1% of the administered dose. Both visual assessment and quantification of thyroid bed uptake were applied to 46 scans after diagnostic or therapeutic doses of 131I had been administered to 25 patients who were being followed up for follicular or papillary carcinoma of the thyroid. The results were compared to assess the effect of either method on determining the need for a further ablative dose of 131I. Visual assessment overestimated thyroid bed uptake in 10 of 46 (22%) of the scans. Bearing in mind the unpleasantness of radioiodine ablation and the potential for bone marrow toxicity, it is recommended that quantification of neck uptake should be routinely performed as a guide to completeness of ablation and to determine the need for a therapeutic dose of the isotope. This should help to avoid unnecessary radioiodine treatment in patients with thyroid cancer.

Adult↗