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Biomedical subjects

R E Gibson

Publications and source records attributed to R E Gibson.

At least 55 records · Page 3Linked to original sources
PubMed1987

Effect of intranasal histamine on nasal mucosal blood flow and the antidiuretic activity of desmopressin.

The effects of exogenous histamine on nasal mucosal blood flow and the systemic activity of intranasally administered desmopressin, a vasopressin analogue, were studied in normal volunteers. Ten subjects received either saline or histamine (1, 20, 100, and 500 micrograms) by intranasal spray. Maximal nasal mucosal blood flow response, determined by laser doppler velocimetry, demonstrated a significant (P less than 0.05) linear relationship to histamine dose. Eight additional subjects received each of the following intranasal treatments: 20 micrograms histamine followed by 10 micrograms desmopressin; normal saline followed by 10 micrograms desmopressin; 20 micrograms histamine followed by vehicle; or normal saline and vehicle. Nasal blood flow was determined before and after each treatment. Desmopressin activity was assessed by measuring urine osmolality, flow rate, electrolyte, and creatinine concentration for 24 h after each treatment. The effect of histamine and desmopressin was greater than desmopressin alone, with respect to nasal blood flow response (103 +/- 24 vs. 4 +/- 17%, mean +/- SEM, P less than 0.02), initial urine osmolality (520 +/- 123 vs. 333 +/- 75 mosM, P less than 0.03), urine electrolyte (potassium, 45 +/- 11 vs. 28 +/- 7 meq/liter; sodium, 68 +/- 21 vs. 36 +/- 8 meq/liter, P less than 0.03) and creatinine concentrations (95 +/- 23 vs. 60 +/- 13 mg/dl, P less than 0.03), and the duration of decrease in urine flow rate compared with saline and vehicle. These results suggest that the systemic activity of intranasal desmopressin is enhanced by increasing local nasal blood flow and are consistent with increased transnasal absorption of the peptide.

Administration, Intranasal↗
PubMed1986

Progestin and antiprogestin effects on progesterone receptor transformation.

Transformation of the rabbit uterine progesterone receptor following binding to several synthetic steroids was studied. Cytosolic receptors were prepared with and without 10 mM sodium molybdate. Following incubation with the 3H-ligands the cytosols were chromatographed on phosphocellulose minicolumns. The rank order of the compounds to promote transformation in the absence of molybdate was: medroxyprogesterone acetate (MPA) greater than 17 alpha, 21-dimethyl-19-nor-4,9-pregnadiene-3,20-dione (R5020) greater than progesterone much greater than deoxycorticosterone (DOC) much greater than 20 alpha-hydroxyprogesterone (20 alpha OH-P). The rank order was the same in the presence of molybdate, but the amount of transformation was reduced by 35-90%. Molybdate inhibited transformation to a greater extent when the receptor was bound to progesterone, DOC and 20 alpha OH-P than when bound to MPA or R5020. The antiprogestin, 11 beta-[4-(dimethylamino)phenyl]-17 beta-hydroxy-17-(1-propynyl)-4,9-estradiene-3-one (RU38486, synthesized by The Upjohn Company and designated U-66990), promoted approximately twice as much receptor transformation as did progesterone. MPA, R5020 and U-66990 all dissociated from the progesterone receptor much more slowly than did progesterone. In all cases dissociation was faster in the presence of molybdate than in its absence. These data demonstrate that potent progestins (MPA and R5020) promote a greater amount of receptor transformation than does progesterone, and that steroids with little progestin bioactivity (DOC and 20 alpha OH-P) promote very little transformation. In addition, the antiprogestin activity of U-66990 cannot be attributed to a lack of progesterone receptor transformation nor to a rapid rate of dissociation from the receptor.

Animals↗
PubMed1986

Binding characteristics and biological activity of 17 alpha-[125I]iodovinyl-11 beta-methoxyestradiol, an estrogen receptor-binding radiopharmaceutical, in human breast cancer cells (MCF-7).

17 alpha-[125I]Iodovinyl-11 beta-methoxyestradiol ([125I]MIVE2), a gamma-emitting analogue of estradiol, previously shown to bind to rat uterine estradiol receptor, was studied to determine the binding characteristics and biological activity in human breast cancer cells. In vitro determination of receptor binding by dextran-coated charcoal assays indicates that [125I]-MIVE2 binds specifically and with a high affinity to cytosolic estrogen receptors in the human breast cancer cell line, MCF-7. [3H]Estradiol binds to the receptor with approximately four times the affinity of [125I]-MIVE2 (Kd = 2.55 X 10(-9) M for [125I]MIVE2; Kd = 6.4 X 10(-10) M for [3H]estradiol). Unlabeled MIVE2 produces estrogenic effects similar to those of estradiol such as progesterone receptor induction and increases in thymidine incorporation in MCF-7 cells in culture. Cytosolic progesterone receptor levels were elevated 2.8-fold over control levels by 6 X 10(-9) M MIVE2. Stimulation of thymidine incorporation (approximately 300% above control levels) was observed after exposure to 1 X 10(-9) M MIVE2. Preliminary data show receptor-mediated uptake by the uterus in biodistribution studies in athymic nude mice given injections of [125I] MIVE2 (32-34 microCi). At 4 h, uterus:blood ratios are 20.5 and target tissue:nontarget tissue ratios are 12.9. In light of the fact that this compound can be prepared with a high specific activity, [125I]MIVE2 may have potential as a radiotracer for imaging estrogen receptor-positive breast tumors or metastatic lesions in human breast cancer patients.

Animals↗
PubMed1985

Muscarinic acetylcholine receptors in Alzheimer's disease. In vivo imaging with iodine 123-labeled 3-quinuclidinyl-4-iodobenzilate and emission tomography.

In vivo imaging of muscarinic acetylcholine receptor binding function in a patient with Alzheimer's disease, using single-photon emission computed tomography and iodine 123-labeled 3-quinuclidinyl-4-iodobenzilate (123I-QNB), and perfusion imaging using 123I-N-isopropyl p-iodoamphetamine are described. A profound decrease in perfusion to the posterior temporal and parietal cortex and a more uniform uptake of 123I-QNB throughout the cerebral cortex were observed. The 123I-QNB activity ratio was reduced compared with that of a normal age-matched subject, suggesting a moderate impairment in muscarinic receptor binding function in Alzheimer's disease. Furthermore, and more importantly, our study demonstrates that images of in vivo receptor binding can be obtained easily and nontraumatically using 123I-QNB and single-photon emission computed tomography.

Alzheimer Disease↗
PubMed1985

Receptor-selective localization in pancreas.

We examined the distribution of three tritiated ligands and two radioiodinated ligands for their ability to localize in the pancreas of rat and rabbit. The ligands examined are selective for the alpha- and beta-adrenoceptors and the muscarinic acetylcholine receptor. Of the ligands examined, the results indicate that only (R) 3H-3-quinuclidinyl benzilate (QNB) localized in the pancreas by the receptor-mediated mechanism. The % dose/g tissue, the pancreas-to-blood and pancreas-to-liver ratios are such that a 18F-labeled derivative of QNB should provide images of the pancreas.

Adrenergic beta-Antagonists↗
PubMed1985

Use of 3-quinuclidinyl 4-iodobenzilate as a receptor binding radiotracer.

3-Quinuclidinyl 4-iodobenzilate was shown to bind to the muscarinic acetylcholine receptor (mAChR) by testing the saturability and the stereoselectivity in the corpus striatum, cerebellum, and the heart. But the ratio of radioactivity in tissues containing different concentrations of mAChR was less than the ratio of mAChR concentrations determined by in vitro saturation assay. As a result, the sensitivity to change in receptor concentration by external imaging will be reduced for this receptor binding radiotracer.

Animals↗
PubMed1984

[125I] 3-quinuclidinyl 4-iodobenzilate: a high affinity, high specific activity radioligand for the M1 and M2-acetylcholine receptors.

We have prepared a radioiodinated ligand which binds with high affinity to the muscarinic acetylcholine receptor (m-AChR). A derivative of 3-quinuclidinyl benzilate, [125I] labeled (R) 1-aza-bicyclo(2.2.2)oct-3-yl (R,S)-alpha-hydroxy-alpha-(4-[125I]iodophenyl)phenyl acetate (4- IQNB ) exhibits an affinity for the m-AChR from corpus striatum higher than that of (R) [3H] QNB. Additionally, [125I] 4- IQNB exhibits receptor selectivity for the M1 receptor since the affinity for the receptor from dog and rat heart is lower than that using dog or rat corpus striatum.

Animals↗
PubMed1984

External imaging of cerebral muscarinic acetylcholine receptors.

A radioiodinated ligand that binds to muscarinic acetylcholine receptors was shown to distribute in the brain by a receptor-mediated process. With single-photon-emission imaging techniques, radioactivity was detected in the cerebrum but not in the cerebellum, whereas with a flow-limited radiotracer, radioactivity was detected in cerebrum and cerebellum. Single-photon-emission computed tomography showed good definition of the caudate putamen and cortex in man.

Animals↗
PubMed1984

In vivo competition studies with analogues of 3-quinuclidinyl benzilate.

Among ligands that bind to the alpha- and beta-adrenoceptors and to the muscarinic acetylcholine receptor (m-AChR), those that bind to the latter have the best properties for external detection of receptor sites by gamma-camera imaging. To develop the optimal radiotracer, nonradioactive analogues of 3-quinuclidinyl benzilate (I) were tested in in vivo displacement studies with (-)-[3H]I to determine their ability to compete with (-)-[3H]I for the muscarinic acetylcholine receptor. There is a linear correlation between the ability to compete with (-)-[3H]I for the m-AChR and the affinity constant of the analogue as determined by in vitro assay, suggesting that the test is a valid indicator of in vivo distribution. One radioiodinated analogue, 3-quinuclidinyl p- iodobenzilate , bound to m-AChR in the heart and brain of rats.

Animals↗
PubMed1984

Synthesis and evaluation of radioiodinated derivatives of 1-azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(4-iodophenyl)-alpha- phenylacetate as potential radiopharmaceuticals.

Two derivatives of (RS)-1-azabicyclo[2.2.2]oct-3-yl (RS)-alpha-hydroxy-alpha-(4-iodophenyl)-alpha-phenylacetate (1a) and three partially resolved (R)- or (S)-1-azabicyclo[2.2.2]oct-3-yl (RS)-alpha-hydroxy-alpha-(4-iodophenyl)-alpha-phenylacetates labeled with no carrier added iodine-125 (1b, 18, and 19) and iodine-123 (1c and 18a) were synthesized by the Wallach triazene approach. We have found that this approach is necessary to obtain no carrier added labeling and gives far better results than the direct electrophilic iodination. The obtained yields were 7 to 18% when using iodine-123 (yield dependent on the source of iodide) and up to 17% for iodine-123 (yield dependent on the source of iodide) and up to 17% for iodine-125 labeled compounds. Our preliminary distribution studies indicate that 1b localizes in the organs known to have a large concentration of muscarinic receptors and that this localization is due to binding to those receptors.

Animals↗
PubMed1984

Synthesis and evaluation of (17 alpha,20E)-21-[125I]iodo-19-norpregna-1,3,5(10),20-tetraene-3,17 -diol and (17 alpha,20E)-21-[125I]iodo-11 beta-methoxy-19-norpregna-1,3,5(10),20-tetraene-3,17-diol (17 alpha-(iodovinyl)estradiol derivatives) as high specific activity potential radiopharmaceuticals.

Two 17 alpha-[125I]iodovinyl estradiol derivatives 4b,d possessing high specific activity have been prepared and tested as potential radiopharmaceuticals. The use of the 3-acetyl derivatives 2c,e and the replacement of iodine monochloride with sodium iodide and Chloramine-T in THF/phosphate buffer (pH 7.0) permitted us to synthesize no-carrier-added (17 alpha,20E)-21-[125I]iodo-19-norpregna-1,3,5(10),20-tetraene-3,17-d iol (4b) and (17 alpha,20E)-21-[125I]iodo-11 beta-methoxy-19-norpregna-1,3,5(10),20-tetraene-3,17-diol (4d) with 50% radiochemical yield and high purity. Although the specific activity represents only half of the theoretical value in some cases, this modified approach is a substantial improvement over the previously published method. Our preliminary distribution studies indicate that although both 4b and 4d localize in the tissues known to have a large concentration of estrogen receptors, 4d accumulates in higher amounts in target tissues and provides a high target to nontarget ratio.

Animals↗
PubMed1984

[I-125] 17 alpha-Iodovinyl 11 beta-methoxyestradiol: in vivo and in vitro properties of a high-affinity estrogen-receptor radiopharmaceutical.

17 alpha-[125I[Iodovinyl 11 beta-methoxyestradiol ([I-125]MIVE2) has been prepared with high specific activity (1500-2000 Ci/mmol) and a high affinity for the estrogen receptor (KA = 6.8 x 10(9) M/Ml). In vivo distribution studies using immature rats result in high levels of activity in the uterus (20-30% dose/g) with uterus-to-plasma ratios on the order of 68 to 100. Peak activity in the uterus is obtained between 2 and 4 hr, and by 6 hr 50% of the activity has washed out. The [I-125]MIVE2 exhibits a slower rate of washout relative to the washout of H-3 estradiol. By in vivo competition studies with nonradioactive estradiol, we found that 95% of the [I-125]MIVE2 bound in the uterus is specifically bound to estrogen receptors. The radioactive labeling of MIVE2 is sufficiently rapid so that [I-123]MIVE2 has been synthesized and is currently in clinical trials. These results suggest that MIVE2 would be an excellent agent for the study of estrogen receptors in vivo and in vitro.

Animals↗
PubMed1984

The characteristics of I-125 4-IQNB and H-3 QNB in vivo and in vitro.

The accumulation of (R)-(H-3)-3-quinuclidinyl benzilate (H-3 QNB) and (R,S)-1-azabicyclo(2.2.2)oct-3-yl (R,S)-alpha-hydroxy-(4-[I-125]iodophenyl) benzeneacetate (I-125 4- IQNB ) in heart, caudate/putamen, and cerebellum of rats was determined at intervals from 15 min to 4 hr after injection. The behavior of the two radiotracers in the heart is consistent with in vitro results with respect to affinities and specificities. In the brain, however, the compounds differ in tissue selectivity. At high specific activity, neither compound provides localization that is consistent with the concentration of receptor in the tissues. The results of this study do not indicate quantification of receptor concentration by means of single external images.

Animals↗
PubMed1983

Differences in affinities of muscarinic acetylcholine receptor antagonists for brain and heart receptors.

The affinities of atropine, scopolamine, 3-quinuclidinyl benzilate and twelve analogues of 3-quinuclidinyl benzilate were determined for the muscarinic acetylcholine receptor (m-AChR) using membrane preparations from caudate/putamen. The affinity constants thus obtained were compared with affinities previously reported for the m-AChR obtained from ventricular muscle. The affinities differed significantly for six of the compounds, the largest difference being 16-fold. Neither solubilization nor variation of physiologically significant salts led to a significant change in the affinity of that compound. These results are interpreted as supporting the subclassification of the muscarinic acetylcholine receptor.

Animals↗
PubMed1983

Cardioselectivity of beta-adrenoceptor blocking agents. 2. Role of the amino group substituent.

A series of 1-(aralkylamino)-3-(aryloxy)propan-2-ols were synthesized, and their apparent dissociation constants (Kapp) were determined by using rat ventricular muscle (RVM) and rat lung membrane (RLM) preparations. Analysis of the binding studies suggests the existence of different modes of binding dependent on the presence or absence of the 4-substituent in the aryloxy ring and the nature of that ring. Without 4-substitution only one compound (4), bearing the 2-(2-methoxyphenoxy)ethyl substituent on the amino group, shows high cardioselectivity. Introduction of the 4-acylamido substituent into the phenoxy ring renders all compounds cardioselective. The cardioselective influence of 4-substitution is diminished or eliminated when the phenoxy ring is replaced by naphth-1-yloxy.

Adrenergic beta-Antagonists↗