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Biomedical subjects

A Gill

Publications and source records attributed to A Gill.

At least 55 records · Page 3Linked to original sources
PubMed1995

Immunomodulation by LFA3TIP, an LFA-3/IgG1 fusion protein: cell line dependent glycosylation effects on pharmacokinetics and pharmacodynamic markers.

LFA3TIP, a fusion protein comprised of the first extracellular domain of LFA-3 fused to the hinge, CH2, and CH3 domains of human IgG1 inhibits responses of human and non-human primate T cells in vitro. In seeking to optimize the expression efficiency to prepare large quantities of LFA3TIP for primate studies, the protein was produced in both the CHO (Chinese hamster ovary) and murine NS-0 myeloma cell lines. Although LFA3TIP derived from these cell lines performs identically in vitro in CD2 receptor binding and T cell assays, examination of a pharmacodynamic marker-the reduction in CD2+ lymphocyte numbers-following the administration of equal doses of NS-0 or CHO derived LFA3TIP to baboons, suggested that the effect of the NS-0 derived material was less sustained. Pharmacokinetic analysis of the materials in baboons and mice shows that LFA3TIP produced by NS-0 cells is rapidly cleared from circulation relative to the product derived from CHO cells. The disparate clearance profiles correlate with distinct glycosylation patterns, with LFA3TIP derived from NS-0 cells being less extensively sialylated than that from CHO cells due in part to alpha-galactosyl capping of selected lactosamine moieties in the N-linked glycans of NS-0 derived LFA3TIP. Moreover, enzymatic desialylation of CHO derived LFA3TIP results in a glycoprotein with an evanescent serum profile when administered to mice and baboons. These results correlate the extent of N-acetylneuraminic acid capping with the clearance rates of LFA3TIP derived from the two distinct cell lines, and underscore the importance of evaluating glycosylation dependent PK parameters when choosing production cell lines for recombinant immunotherapeutics.

Adjuvants, Immunologic↗
PubMed1994

Pitfalls in the prenatal diagnosis of peroxisomal beta-oxidation defects by chorionic villus sampling.

Variability in the level of expression of very long chain fatty acids (VLCFAs) is documented in cultured chorionic villus (CV) cells derived from two fetuses, one at risk for an unusual peroxisomal fatty acid beta-oxidation defect, and the other at risk for the X-linked form of adrenoleucodystrophy (ALD). Cells from early subcultures of chorionic cells from both cases gave normal values for VLCFA ratios. The results for the fetus at risk for the beta-oxidation defect were interpreted to indicate that the fetus was not affected; however, at birth, the infant was clinically and biochemically affected. In the case of the fetus at risk for X-linked ALD, although VLCFAs were normal in subculture 1, the levels of these fatty acids increased dramatically in subculture 3, suggesting an abnormal fetus. Termination of the pregnancy and subsequent biochemical and morphological follow-up confirmed that the fetus was indeed affected by ALD.

Adrenal Cortex↗
PubMed1994

The developmental expression of the asparagus intracellular PR protein (AoPR1) gene correlates with sites of phenylpropanoid biosynthesis.

Previous reports have described the induction, by either wounding or attempted pathogen invasion, of an Asparagus officinalis intracellular pathogenesis-related (AoPR1) promoter-GUS gene fusion in transgenic tobacco. Here we describe the unexpected developmental expression pattern of the AoPR1-GUS gene which correlates well, temporally and spatially, with the developmental expression observed for GUS fusions with promoters derived from genes coding for enzymes in the 'core phenylpropanoid pathway'. Analysis of endogenous AoPR1 gene expression in asparagus and both AoPR1-GUS and AoPR1-luciferase gene fusions in transgenic tobacco suggests that the AoPR1 promoter directs similar cell-specific transcription patterns in both asparagus and transgenic tobacco. The AoPR1 promoter contains sequence motifs similar to those implicated as important in the regulation of phenylpropanoid pathway genes and another 'intracellular' PR gene. Treatment with salicylic acid enhances AoPR1 promoter gene activity both in tobacco and in asparagus.

Base Sequence↗
PubMed1994

A prospective study of the adverse effects of midazolam on withdrawal in critically ill children.

Fifty-three critically ill infants and children received midazolam as sedation in a regional intensive care unit. Assessment of the level of sedation was carried out at regular intervals on withdrawal of midazolam. Forty-nine patients were fully alert within 4 h of midazolam being stopped. Four patients took from 6 h to 1 week to become fully alert. Four patients had abnormal behaviour highly suggestive of midazolam withdrawal. The onset of abnormal behaviour was within 12 h of discontinuation of midazolam. The duration of the abnormal behaviour ranged from 3 h to 1 week. One child had a paradoxical reaction to midazolam. The overall incidence of adverse effects to midazolam in the patients studied was 17%. No adverse effects were observed in infants; all adverse effects were observed in children. We have shown that it is possible to prospectively study the toxicity of sedatives in critically ill infants and children.

Child↗
PubMed1992

Pharmacology of bepridil.

Bepridil is an antianginal agent with multiple therapeutic actions. It decreases calcium influx through potential-dependent and receptor-operated sarcolemmic calcium channels and acts intracellularly as a calmodulin antagonist and calcium sensitizer. Thus, in cardiac muscle it enhances the sensitivity of troponin C to calcium, stimulates myofibrillar adenosine triphosphatase activity, removes calmodulin's inhibitory effect on sarcoplasmic reticulum calcium release, and inhibits sodium-calcium exchange--actions that tend to offset the effects of calcium influx blockade on cardiac contractile force. However, in vascular smooth muscle where the calcium-calmodulin complex promotes muscle contraction by activating myosin light-chain kinase phosphorylation of contractile proteins, calmodulin antagonism, coupled with bepridil's blockade of calcium influx, leads to vasorelaxation. In animal models of ischemia, bepridil and other calmodulin inhibitors show antiarrhythmic efficacy following reperfusion. Additionally, interfering with calmodulin's role in sympathetic nerve terminal function may help to limit the ischemia-induced catecholamine release that contributes to arrhythmogenesis. Bepridil shows a lidocaine-like fast kinetic block of inward sodium current (as distinct from the slow or intermediate kinetic inhibition expressed by encainide or quinidine, respectively). This inhibition is pH-dependent; activity is expressed to a greater degree at lower pH levels. This, this potentially antiarrhythmic mechanism is activated by conditions of ischemia. Bepridil's blockade of outward potassium currents and its inhibition of sodium-calcium exchange increase action potential duration and ventricular refractoriness, prolong the QT interval, and form the basis for a class III antiarrhythmic mechanism. Because hypokalemia also prolongs the QT interval, the addition of bepridil in the presence of hypokalemia can lead to excessive prolongation. Bepridil both increases myocardial oxygen supply through coronary vasodilation and decreases myocardial oxygen demand through mild heart rate and afterload reduction, and shows potential antiarrhythmic activity through class IB, III, and IV mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Supraspinal administration of [D-Met2]FMRFamide produces a naloxone-sensitive increase in heart rate in unrestrained spontaneously hypertensive rats.

Intracerebroventricular (i.c.v.) administration of either Phe-Met-Arg-Phe-NH2 (FMRFamide; molluscan cardioexcitatory neuropeptide; 3-30 micrograms) or the FMRFamide analog Phe-D-Met-Arg-Phe-NH2 ([D-Met2]FMRFamide; 15 micrograms) to conscious unrestrained spontaneously hypertensive rats (SHR) produced a relatively long lasting (greater than 1 h) increase in heart rate. The increase in heart rate produced by [D-Met2]FMRFamide was attenuated by i.c.v. injection of the opiate antagonist naloxone (2 micrograms). These results extend to a second endpoint an apparent opioid agonist-like (naloxone-reversible) action of [D-Met2]FMRFamide.

Animals↗
PubMed1991

Structurally novel antihypertensive compound, McN-5691, is a calcium channel blocker in vascular smooth muscle.

These studies were conducted to gain greater understanding of the mechanism of action of the chemically novel antihypertensive agent, McN-5691. McN-5691 (1 and 10 microM) prevented 60 mM KCl-induced contraction and calcium uptake and caused concentration-dependent relaxation (EC50 = 190 microM) of 30 mM KCl-contracted aortic rings. At or below 10 microM, McN-5691 had no effects on basal tone or calcium uptake (45Ca) in isolated rings of rabbit thoracic aorta. McN-5691 caused complete high affinity inhibition (Kd = 39.5 nM) of specific diltiazem binding to the benzothiazepine receptor on the voltage-sensitive calcium channel in skeletal muscle microsomal membranes. In contrast to diltiazem, McN-5691 inhibited specific dihydropyridine receptor binding, but the effect was biphasic with high (Kd = 4.7 nM) and low (Kd = 919.8 nM) affinity components. These findings suggest that McN-5691 is a voltage-sensitive calcium channel blocker. Unlike other calcium channel blockers, McN-5691 inhibited norepinephrine (NE)-induced contraction (10 microM) and calcium uptake (1 and 10 microM) and caused concentration-dependent relaxation (EC50 = 159 microM) of 1 microM NE-contracted rings of rabbit thoracic aorta. The vascular relaxant effects of McN-5691 were not related to increased calcium (45Ca) efflux from vascular smooth muscle cells. The effects of McN-5691 on NE-induced contraction were unrelated to intracellular mechanisms because McN-5691 did not affect NE-induced contraction in the absence of extracellular calcium. McN-5691 had weak activity in rat cerebral cortical membrane alpha-1 or alpha-2 adrenergic receptor binding assays. McN-5691-induced vasodilation of phenylephrine-contracted rat aortic strips was not reversible by high potassium, indicating that McN-5691 does not induce relaxation of blood vessels through potassium channel activation. In summary, these studies suggest that the primary vasodilator mechanism of McN-5691 is calcium channel blockade through competitive binding at the diltiazem site on the voltage sensitive calcium channel. McN-5691 may possess an additional vasodilator mechanism of action distinct from alpha adrenergic receptor blockade but involving a cell membrane-related event apparently leading to attenuation of receptor-operated calcium channel activity.

Animals↗
PubMed1990

Genetic toxicity of a pharmacologically active group of ortho-(arylalkynyl)phenoxypropanolamines.

A series of ortho-(arylalkynyl)phenoxypropanolamines with antihypertensive activity in laboratory animals was screened in vitro for mutagenicity using the Ames test and the mouse lymphoma assay, and for DNA damaging potential in the primary rat hepatocyte/DNA repair assay. Those compounds with a dialkylamino group on the para position of the arylalkynyl function were shown to be genotoxic in both mutagenicity assays when tested in the presence of an Aroclor 1254-induced rat liver S-9 mix. They were also active in the DNA repair assay. Removal of the para-dialkylamino group or changing the position of this group on the aryl ring eliminated the genotoxic effect in these test systems. This collaborative effort between chemists, pharmacologists, and toxicologists successfully identified the structural feature responsible for the genotoxic activity and indicated structural alterations that would yield a pharmacologically active compound with no genotoxicity in these in vitro assays.

Animals↗
PubMed1990

Antihypertensive dihydropyridines with 1,4,4-trisubstitution.

Dihydropyridines with 1,4,4-trisubstitution were synthesized and tested for antihypertensive activity in a spontaneously hypertensive rat model. This substitution pattern on the dihydropyridine nucleus differs markedly from that found most active in the structure-activity relationship established for nifedipine-like compounds. However, some were found to significantly lower blood pressure at testing doses (30 mg/kg, ip and 100 mg/kg, po) for up to 24 h. Methyl 1,4-dihydro-4,4-dimethyl-1-pyridinepropanoate (2-1), for example, lowered blood pressure 71 mmHg at 30 mg/kg, ip and the effect endured for greater than 24 h. Unlike prototypical dihydropyridines such as nifedipine, these compounds did not seem to have any effect on calcium channels.

Animals↗
PubMed1990

Effects of the novel coronary selective calcium channel blocker, McN-6186, on cardiocirculatory dynamics, coronary vascular resistance, and cardiac output distribution in normal, conscious rats.

The purpose of this study was to characterize the cardiocirculatory effects of the novel calcium channel blocker, McN-6186 (McN), normal, conscious rats. Animals were instrumented under halothane anesthesia for right atrial, left ventricular, arterial, and venous pressure recordings. The radioactive microsphere technique was used to measure regional blood flow (RBF) and cardiac output (CO) before (control) and during intravenous (i.v.) infusion of either McN at three doses (0.03, 0.1, 0.3 mg/kg) or vehicle at an equal infusion rate (0.0408 ml/min). Nifedipine (NIF) was also studied at three similar blood pressure (BP)-lowering doses (0.025, 0.150, and 0.375 mg/kg). The predominant effect of McN in conscious rats was to cause coronary vasodilation. The coronary vasodilator potency of McN was similar to NIF (ED25, McN = 0.03 mg/kg, NIF = 0.025 mg/kg). Neither McN nor NIF significantly changed systemic vascular resistance (SVR) over their respective coronary vasodilator dose ranges, suggesting that both compounds are selective coronary vasodilators. The doses of McN and NIF that reduced mean arterial pressure (MAP) by 25% (ED25) were similar (McN = 0.3 mg/kg, NIF = 0.375 mg/kg). At equal BP-lowering doses, McN increased coronary flow by 145% versus 110% for NIF. McN did not have major effects on other regions of the peripheral circulation. There was, however, some vasodilator activity in the renal and cerebral vascular beds. Because McN reduced coronary vascular resistance at a dose lower than that required to reduce resistance in other vascular beds, this compound appears to be a selective coronary vasodilator and may have therapeutic efficacy as an antianginal agent.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1990

Cardiac electrophysiologic effects of McN-5691, a new calcium-channel blocking antihypertensive agent.

The purpose of this study was to evaluate the cardiac electrophysiological effects of McN-5691, a new calcium-channel blocking antihypertensive drug. In anesthetized dogs, the primary electrophysiological effect of McN-5691 was dose-related prolongation of AV-nodal conduction time and refractoriness (0.1-1.0 mg/kg i.v.), which correlated with McN-5691 plasma levels. There were no significant effects on atrial or ventricular conduction times, QTc, or ventricular monophasic action potential duration. This profile was similar to that of verapamil. McN-5691 caused concentration-related, rate-dependent reductions in Vmax and amplitude of slow-response action potentials in guinea pig papillary muscle: ED-20% for depression of Vmax was 0.72 +/- 0.32 microM. Verapamil was more potent in depressing these action potentials: ED-20% for depression of Vmax was 0.03 +/- 0.01 microM. McN-5691 also caused rate-dependent reduction in Vmax and amplitude of canine Purkinje fiber action potentials, but only at relatively high concentrations: ED-20% for depression of Vmax was 55 +/- 12 microM. McN-5691 also reduced the action potential duration (0.3-30 microM) without affecting the slope of phase 4 depolarization and the maximum diastolic potential. Verapamil also reduced Vmax in Purkinje fibers (ED-20% for depression of Vmax was 32 +/- 3 microM) and shortened the action potential duration. The results show that McN-5691 has cardiac electrophysiological effects consistent with blockade of the slow inward calcium current, and that this activity occurs at concentrations well below those having local anesthetic activity. In addition, its lower potency in comparison to verapamil in depressing slow responses suggests a lesser propensity for negative inotropic effects.

Action Potentials↗
PubMed1990

Clinical experience with preterm formulas in very low birthweight infants.

Infants below 1500 g at birth were randomly assigned to receive one of two preterm infant formulars: S26 Low Birthweight (S26-LBW, 25 infants) or Enfalac Premature (EPF, 24 infants). They were either exclusively formula-fed (13 infants) or the formula was used to supplement their own mother's fresh breast milk (36 infants). The mean age when milk feeds were commenced was 7 days and the mean age when birthweight was regained was 12 days. The mean age when 2000 g was reached was 45 days at which time 10 (20%) infants were below the tenth centile on the intrauterine growth chart. None of the above variables were significantly different between the S26-LBW and EPF groups. However, the S26-LBW group established full enteral feeding significantly earlier compared to the EPF group (42 versus 64 d) and the number with adverse gastrointestinal effects was lower (4 versus 10 infants). Both preterm infant formulas supported a growth rate in excess of that in utero without stressing the infants' metabolic system. The growth rate of infants fed preterm breast milk supplemented with preterm infant formula was quantitatively similar to those exclusively fed preterm infant formula.

Bottle Feeding↗
PubMed1989

A summary of 7q interstitial deletions and exclusion mapping of the gene for beta-glucuronidase.

Three patients are described with different phenotypes and differing de novo interstitial deletions of the long arm of a chromosome 7. The first patient has a deletion with loss of the proximal 7q11.23 band. Only three other cases have been reported with this particular deletion. Our second case shows mild dysmorphism similar to the other four patients reported with deletion of bands 7q21.12----21.3. Our third patient has a deletion of the 7q22.1----32.2 segment and has many of the phenotypic features of the other reported cases of del 7q22----32. GUSB, the gene for beta-glucuronidase, has been localised to the 7cen----q22 region. Analysis of beta-glucuronidase levels in blood leucocytes of our patients has helped more precisely to assign this gene locus to 7q21.11 or 7q22.1.

Abnormalities, Multiple↗
PubMed1989

A new interstitial deletion of 4q (q21.1::q22.1).

A unique case of de novo interstitial deletion of chromosome 4 is described involving loss of band q21. The male newborn had multiple abnormalities including frontal bossing, prominent occiput, low set ears, micrognathia, short sternum, short, broad hands and feet, agenesis of the corpus callosum, and cardiac defects. The phenotypic abnormalities are compared with other reported cases of deletion 4q involving adjacent regions.

Abnormalities, Multiple↗