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Biomedical subjects

R E Gibson

Publications and source records attributed to R E Gibson.

At least 37 records · Page 2Linked to original sources
PubMed1993

Antithrombotic activity of recombinant tick anticoagulant peptide and heparin in a rabbit model of venous thrombosis.

An in vivo rabbit model of venous thrombosis which includes physiological blood flow was used to compare the efficacy of the potent and specific factor Xa inhibitor recombinant tick anticoagulant peptide (rTAP) with standard heparin in the prevention of venous thrombus formation. In anesthetized rabbits, an autologous thrombus was induced with thrombin in a jugular vein and the increase in thrombus size was determined by measuring the accretion of intravenously injected [125I]fibrin(ogen) onto the developing thrombus. The effects of rTAP on hemostasis were monitored by changes in APTT values and template bleeding times. Inhibition of thrombus formation by an intravenous bolus followed by infusion of either rTAP or heparin exhibited a dose-response relationship with an IC50 of 0.9 micrograms/kg/min and 0.12 units/kg/min, respectively. At the IC50 doses, both rTAP and heparin inhibited fibrin(ogen) deposition without any significant effect on APTT or bleeding times. Bleeding times were modestly elevated at the fully efficacious doses of rTAP and heparin. Significant changes in APTT (1.9 +/- 0.3 fold over baseline) were only evident at the highest dose of rTAP while heparin caused a significant dose-dependent increase from 1.3 +/- 0.2 to greater than 4.2 +/- 0.6 fold over baseline. Therefore, in this rabbit model of venous thrombosis, specific inhibition of factor Xa by rTAP is an effective antithrombotic mechanism that does not require changes in systemic hemostatic parameters.

Animals↗
PubMed1993

Synthesis, receptor binding and tissue distribution of 17 alpha-E[125I]iodovinyl-11 beta-ethyl-estradiol.

In this study we prepared and evaluated a derivative of estradiol with an ethyl group at the 11 beta-position and an E-iodovinyl group at the 17 alpha-position. This new ligand binds to the estrogen receptor with an affinity slightly less than estradiol (RBA = 43%) at 0 degree C but much greater (RBA = 890%) at 25 degrees C. The 125I-labeled derivative was obtained by radioiododestannylation of the tri-n-butylstannyl precursor in good radiochemical yield with a specific activity exceeding 1500 Ci/mmol. The tissue distribution in immature female rats was evaluated over a 48 h period to determine uterine uptake and selectivity. Peak uterine uptake at 2 h was 6% ID/g and was significantly greater than that of [3H]estradiol, 2.4% ID/g. Substantial uptake in the uterus was still present at 48 h (2.4% ID/g). Co-administration of estradiol reduced the uptake at 2 and 24 h by 85%. Uterus-to-plasma ratios increased with time, from about 25:1 at 2 h to nearly 90:1 at 48 h. The affinity, ease of radiosynthesis and tissue distribution of the 17 alpha-E-[125I]iodovinyl-11 beta-ethyl-estradiol suggest that further evaluation of this agent as an imaging agent for estrogen-receptor-positive breast cancer is warranted.

Animals↗
PubMed1992

Synthesis and receptor affinities of new 3-quinuclidinyl alpha-heteroaryl-alpha-aryl-alpha-hydroxyacetates.

Five analogues of 3-quinuclidinyl benzilate were prepared in which one phenyl ring was substituted by a heterocycle; a bromine was included on either the remaining phenyl or the heterocycle to provide information relating to the affinity of potential radiohalogenated derivatives. Their affinities for the muscarinic cholinergic receptor were determined. Replacing a phenyl ring with either the 2- or 3-furyl moiety or the 2- or 3-thienyl moiety did not significantly alter the affinity to the muscarinic receptor compared with 3-quinuclidinyl 4-bromobenzilate.

Animals↗
PubMed1992

Immunocytochemical localization of platelets in baboon hepatic sinusoids using monoclonal mouse anti-human platelet glycoprotein IIIa following induction of thrombocytopenia.

A commercially available mouse monoclonal antibody to human platelet glycoprotein IIIa was used to demonstrate sequestration of platelets in hepatic biopsies obtained from baboons following intravenous infusion of echistatin, a novel fibrinogen receptor antagonist derived from the venom of the snake Echis carinatus. Biopsies of liver and spleen were taken prior to administration of echistatin. The hepatic biopsies were either snap-frozen in Freon-22/liquid nitrogen or fixed in 10% neutral buffered formalin. Biopsies of spleen were snap-frozen. During infusion of echistatin (2.3 micrograms/kg/min), circulating platelet counts decreased from 331,000/mm3 to 167,000/mm3. Selective sequestration within the liver was confirmed using whole body gamma camera imaging to demonstrate 111Indium-oxine labeled platelet accumulation within the liver during the thrombocytopenic episode. Hepatic biopsies were again taken and either snap-frozen in Freon-22/liquid nitrogen or fixed in 10% neutral buffered formalin. Biopsies of spleen and inguinal lymph node were also snap-frozen. Platelet rich plasma smears, included as positive controls, dewaxed paraffin sections, and cryosections of liver, spleen, and lymph node were stained with monoclonal mouse anti-human platelet glycoprotein IIIa using an avidin biotinylated peroxidase complex (ABC) technique. Prior to infusion of echistatin, platelet staining within the liver was minimal. After echistatin infusion, hepatic cryosections showed prominent platelet staining within hepatic sinusoids. No localization was shown in lymph node, however, the spleen showed prominent platelet staining both before and after echistatin infusion. Platelet rich plasma smears were intensely positive. No prominent platelet staining was observed in formalin-fixed, paraffin-embedded material. Thus, this immunocytochemical technique may help localize platelets in cryosections of tissues from baboons and other primate species.

Animals↗
PubMed1992

The in vitro dissociation kinetics of (R,R)-[125I]4IQNB is reflected in the in vivo washout of the radioligand from rat brain.

We have determined the kinetics of dissociation of (R)-3-Quinuclidinyl (R)-4-[125I]Iodobenzilate ((R,R)-[125I]4IQNB) from muscarinic acetylcholine receptor preparations from the cortex, hippocampus, caudate/putamen, thalamus, pons and colliculate bodies. The dissociation curves are well described by a biexponential function and are consistent with subtype selectivity favoring slow dissociation from the M1, M3, and M4 receptors with a 20-fold faster dissociation rate for the M2 receptor. Following intravenous injection, (R,R)-[125I]4IQNB binds to receptor in the rat brain in concentrations which reflect the receptor concentration present in a structure. We determined the extent of radioligand present at two times, 2 and 24 hrs, as an indication of the relative proportions of m-AChR which exhibits rapid vs. slow dissociation of (R,R)-[125I]4IQNB. A good correlation between in vitro and in vivo results suggests that the relative populations of receptor subtypes can be imaged using in vivo pharmacokinetics of (R,R)-[125I]4IQNB.

Animals↗
PubMed1991

In vivo dissociation kinetics of [3H]quinuclidinyl benzilate: relationship to muscarinic receptor concentration and in vitro kinetics.

The in vivo washout kinetics of [3H]quinuclidinyl benzilate ([3H]QNB) varies significantly in various structures in the rat brain. The slowest washout rates are from the hippocampus, corpus striatum, and cortex, intermediate rates are exhibited from the thalamus and colliculi, while the fastest washout rate is from the cerebellum. We have also demonstrated a difference in the in vitro dissociation rates (k-1) of [3H]QNB from various structures. The k-1 for the hippocampus, corpus striatum and cortex, is two-fold slower than that observed in the thalamus, colliculi, and cerebellum. The differences in the in vitro dissociation kinetics are not, however, sufficient to explain the differences in the in vivo washout kinetics. We have developed a theoretical formulation which describes conditions under which the washout kinetics are a function of the concentration of receptor in a structure. Furthermore, we present a graphical method in which a plot of the reciprocal of the observed washout rate constant, 1/k(obs), vs receptor concentration is linear. Analysis of the washout kinetics of [3H]QNB from various structures of the CNS of rat were well described by this theory when the differences in in vitro k-1 are included.

Animals↗
PubMed1991

Synthesis and muscarinic cholinergic receptor affinities of 3-quinuclidinyl alpha-(alkoxyalkyl)-alpha-aryl-alpha-hydroxyacetates.

Seven analogues of 3-quinuclidinyl benzilate (QNB) in which one phenyl ring was replaced by an alkoxyalkyl moiety were synthesized and their affinities for the muscarinic cholinergic receptor determined. An oxygen in the beta-position of the moiety was not well-tolerated. By contrast, an oxygen in the gamma-position did not change the affinity for the muscarinic receptor. However, when a bromine was placed on the remaining phenyl ring, the affinity was significantly reduced in striking contrast to results obtained on halogenation of QNB.

Animals↗
PubMed1991

Angiotensin II receptor subtypes in renal cortex of rats and rhesus monkeys.

The angiotensin II (ANG II) receptor has recently been shown to exhibit subtypes with respect to antagonist binding. Of particular interest are the potent nonpeptide antagonists, DUP 753 and PD 121981, which exhibit selectivity for the subtype 1 (AT1) and subtype 2 (AT2) receptors, respectively. We used these high-affinity antagonists in competition with 125I-[Sar1,Ile8]ANG II to determine autoradiographically the distribution of these ANG II-receptor subtypes in the renal cortex of rats and rhesus monkeys. Binding of the radioligand to receptor in sections of rat renal cortex was inhibited by DUP 753; inhibition by PD 121981 was not detected. By contrast, AT1 and AT2 receptors are present in the renal cortex of rhesus monkeys in regionally distinct structures. DUP 753 inhibited binding to the ANG II receptor in glomeruli. PD 121981 inhibited binding to arterial smooth muscle and the juxtaglomerular (JG) apparatus. The JG apparatus also exhibits radioligand binding, which is inhibited by DUP 753. The effect of DUP 753 and PD 123177 (a more water-soluble analogue of PD 121981) on changes in plasma renin activity was examined to determine if one or both of these subtypes participate in the ANG II-mediated negative feedback of control of renin release. Although DUP 753 increased plasma renin activity to the same extent as the angiotensin-converting enzyme inhibitor, enalaprilat, in rats and rhesus monkeys, the AT2 antagonists did not affect renin release in either species. Thus both subtypes of ANG II receptor are present in rhesus monkey cortex, but a function for only the AT1 subtype was demonstrated.

Aldosterone↗
PubMed1990

(+)-3-[123I]Iodo-MK-801: synthesis and characterization of binding to the N-methyl-D-aspartate receptor complex.

Synthetic methods have been established for preparing high specific activity (+)-3-[123I]Iodo-MK-801 in high radiochemical yield. The binding of the radiotracer to rat cortical membranes has been examined to assess its potential use as an in vivo imaging agent for the N-methyl-D-aspartate (NMDA) receptor-ion channel complex. Under the conditions of the assay, specific (+)-3-[123I]Iodo-MK-801 binding to membrane homogenates represented greater than 95% of the total binding. Several structurally distinct, noncompetitive NMDA receptor antagonists inhibited binding with potencies in accordance with their reported inhibitory activity at the receptor complex. The concentration of (+/-)-3-Iodo-MK-801 required to inhibit 50% of (+)-3-[123I]Iodo-MK-801 binding (IC50) was 3.4 nM when using a low ionic strength assay buffer and 5.5 nM in a physiological buffer. In a thoroughly washed membrane preparation, (+)-3-[123I]Iodo-MK-801 binding was enhanced by L-glutamate and glycine at concentrations known to activate the NMDA receptor. The results indicate that (+)-3-[123I]Iodo-MK-801 specifically labels the NMDA receptor complex in rat brain membranes and the retention of high affinity under near physiological assay conditions suggests that it may be useful as a SPECT imaging agent for the receptor in vivo.

Animals↗
PubMed1989

Preparation and properties of (R)-(-)-1-azabicyclo[2.2.2]oct-3-yl- (R)-(+)-alpha-hydroxy-alpha-(4-[125I]iodophenyl)-alpha-phenyl acetate and (R)-(-)-1-azabicyclo[2.2.2]oct-3-yl-(S)-(-)-alpha-hydroxy-alpha- (4-[125I]iodophenyl)-alpha-phenyl acetate as potential radiopharmaceuticals.

rac-4-Nitrobenzilic acid was synthesized and resolved with quinidine and quinine to give the corresponding (R)- and (S)-salts. The resolved diastereomeric salts were converted to (R)- and (S)-4-nitrobenzilic acids and subsequent esterification gave their corresponding ethyl esters. Transesterification with (R)-(-)-3-quinuclidinol afforded (R)-(-)-1-azabicyclo[2.2.2]oct-3-yl-(R)-(+)-alpha-hydroxy-alpha- (4-nitrophenyl)-alpha-phenyl acetate and (R)-(-)-1-azabicyclo[2.2.2]oct-3-yl-(S)-(-)-alpha-hydroxy- alpha-(4-nitrophenyl)-alpha-phenyl acetate. After hydrogenation, the (R,R)- and (R,S)-amines were converted to the respective triazene derivatives. The triazene derivatives reacted with sodium [125I]iodide to give (R)-(-)-1-azabicyclo[2.2.2]oct-3-yl-(R)-(+)- alpha-hydroxy-alpha-(4-[125I]iodophenyl)-alpha-phenyl acetate and (R)-(-)-1-azabicyclo[2.2.2]oct-3-yl-(S)-(-)-alpha-hydroxy- alpha-(4-[125I]iodophenyl)-alpha-phenyl acetate. The evaluation of their affinities to muscarinic acetylcholine receptors (MAcChR) shows that (R)-(-)-1-azabicyclo[2.2.2]oct-3-yl-(S)-(-)-alpha-hydroxy-alpha-(4- [125I]iodophenyl)-alpha-phenyl acetate exhibits an affinity for the MAcChR from corpus striatum that is approximately threefold lower than that of (R)-(-)-1-azabicyclo[2.2.2]oct-3-yl-(R)-(+)-alpha-hydroxy-alpha-(4- [125I]iodophenyl)-alpha-phenyl acetate.

Animals↗
PubMed1989

In vitro and in vivo characteristics of [iodine-125] 3-(R)-quinuclidinyl (S)-4-iodobenzilate.

The radioiodinated muscarinic acetylcholine receptor antagonist, [125I] 3-quinuclidinyl 4-iodobenzilate, has two high affinity diastereomeric forms, the (R,R) and (R,S)-isomers. The (R,S)-diastereomer is only threefold lower in affinity than the (R,R)-isomer, but the kinetic properties are considerably different--the dissociation rate constant is 13-fold faster for the (R,S)-isomer and the association rate constant is two to threefold faster. The calculated affinity is therefore only fourfold lower. In vivo, the clearance of (R,S)-4IQNB from receptor-rich tissue is also more rapid than that of the (R,R)-isomer, that is a reflection of the more rapid in vitro kinetic properties since the physicochemical properties and the metabolic clearance of the diastereomers is the same.

Animals↗
PubMed1988

An autoradiographic study of muscarinic cholinoceptors in blood vessels: no localization on vascular endothelium.

In vitro labelling and autoradiographic techniques were used to examine the localization of [3H]quinuclidinyl benzilate ([3H]QNB) and [125I]4-iodo-QNB ([125I]4IQNB) to slide-mounted sections of rabbit aorta and pulmonary artery, cat aorta, pulmonary and superior mesenteric arteries. These vessels all respond to acetylcholine (ACh) with endothelium-dependent relaxation, yet there was no evidence for endothelium-related binding of either [3H]QNB or [125I]4IQNB. Muscarinic receptors were localized over the medial smooth muscle and, in the rabbit pulmonary artery, the density of binding increased towards the adventitia. Binding of either radioligand to sections of rabbit pulmonary artery was not affected by the muscarinic M1 receptor antagonist pirenzepine (20 nM) but was markedly reduced by the muscarinic M2 antagonist 4DAMP (4-diphenylacetoxy-N-methyl-piperidine methobromide) (1 nM). This study provides evidence for muscarinic receptors located directly on smooth muscle cells, indicating that endothelium-dependent relaxation to ACh results from an indirect mechanism involving smooth muscle muscarinic receptors.

Acetylcholine↗
PubMed1988

A comparison of the efficacy and safety of alprazolam and desipramine in depressed outpatients.

Fifty-two adult depressed outpatients fulfilling Research Diagnostic Criteria for Definite Major Depressive Disorder were enrolled in a double-blind study comparing the antidepressant effects of alprazolam versus desipramine. Twenty-nine patients completed the seven week (one week placebo followed by six weeks of active drug) study. The mean daily dose of alprazolam and desipramine at study termination was 3.34 mg and 192 mg respectively. Based on psychometric ratings of depression (Hamilton Scale) and severity of illness (Clinical Global Impressions) there was no significant difference between alprazolam and desipramine at the end of six weeks of active drug treatment. Both medications were well tolerated with drowsiness being the most common side effect of alprazolam, and insomnia, dry mouth, and constipation, the complaints most associated with desipramine.

Adult↗
PubMed1987

[125I]17-alpha-iodovinyl 11-beta-methoxyestradiol interaction in vivo with estrogen receptors in hormone-independent MCF-7 human breast cancer transfected with the v-rasH oncogene.

[125I]17-alpha-Iodovinyl 11-beta-methoxyestradiol [( 125I]MIVE2) has been evaluated as a potential radiotracer for the diagnostic imaging of estrogen receptor (ER)-positive human breast cancer. In vivo distribution experiments with athymic ovariectomized nude mice bearing human breast tumors revealed an apparent correlation between uptake of 125I-labeled compound and estrogen receptor concentration in the tumors. At 4 h after i.v. injection of [125I]MIVE2, HS578T (ER negative), ZR75-B (intermediate ER), and MCF-7ras (high ER) tumors accumulated 0.320 +/- 0.186, 0.679 +/- 0.467, and 2.6163 +/- 1.0121% injected dose/g, respectively. With coinjection of unlabeled 17-beta-estradiol, levels of radioactivity in MCF-7ras tumors were decreased to 0.4859 +/- 0.1424% injected dose/g, indicating a receptor-mediated process. Peak activity of radioligand in MCF-7ras tumors and uteri was observed at 2 h and was retained for the 8-h time course. Blood and nontarget tissue, such as muscle, revealed a rapid clearance of 125I-labeled compound by 8 h. Eight hours after injection, uterus and tumor-to-blood ratios were calculated to be 225 and 21, respectively. Also, MCF-7ras tumors were shown to accumulate 6.5-fold more radioactivity than muscle. These data suggest that [125I]MIVE2 has the capability of interacting specifically and with high affinity with estrogen receptors in human breast tumors in nude mice and may possibly be used for imaging receptor-positive tumors in breast cancer patients with very low serum estrogen levels. Selective uptake of compound in MCF-7ras tumors emphasizes the usefulness of an estrogen receptor-positive tumor model which has a unique ability to grow in a host system without circulating estrogens.

Animals↗
PubMed1987

Synthesis and structure-activity relationships of new muscarinic antagonists.

In an attempt to develop more selective muscarinic acetylcholine receptor (m-AcChR) antagonists, (R)-1-azabicyclo[2.2.2]oct-3-yl-thioxanthene-9-carboxylate, (R,S)-thiochromane-4-carboxylate, and (R,S)-chromane-4-carboxylate were synthesized. Evaluation of the binding affinities of these compounds to muscarinic receptors indicates that replacing the oxygen by sulfur in the xanthenyl and chromanyl moieties does not significantly change selectivity, but does reduce the affinity of 5 and enhance the affinity of 9a.

Animals↗