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PubMed2002

Trans isomeric octadecenoic acids are related inversely to arachidonic acid and DHA and positively related to mead acid in umbilical vessel wall lipids.

Long-chain PUFA play an important role in early human neurodevelopment. Significant inverse correlations were reported between values of trans isomeric and long-chain PUFA in plasma lipids of preterm infants and children aged 1-15 yr as well as in venous cord blood lipids of full-term infants. Here we report FA compositional data of cord blood vessel wall lipids in 308 healthy, full-term infants (gestational age: 39.7 +/- 1.2 wk, birth weight: 3528 +/- 429 g, mean +/- SD). The median (interquartile range) of the sum of 18-carbon trans FA was 0.22 (0.13) % w/w in umbilical artery and 0.16 (0.10) % w/w in umbilical vein lipids. Nonparametric correlation analysis showed significant inverse correlations between the sum of 18-carbon trans FA and both arachidonic acid and DHA in artery (r = -0.38, P < 0.01, and r = -0.20, P < 0.01) and vein (r = -0.36, P < 0.01, and -0.17, P < 0.01) wall lipids. In addition, the sum of 18-carbon trans FA was significantly positively correlated to Mead acid, a general indicator of EFA deficiency, in both artery (r = +0.35, P < 0.01) and vein (r = +0.31, P< 0.01) wall lipids. The present results obtained in a large group of full-term infants suggest that maternal trans FA intake is inversely associated with long-chain PUFA status of the infant at birth.

8,11,14-Eicosatrienoic Acid↗
PubMed1989

Contamination by a competitive ligand as an explanation for the inverse dependence of HABA binding parameters upon the protein concentration.

There is evidence that the apparent association constant (K) and/or the number of binding sites (n) are inversely dependent upon protein concentration for a number and variety of ligands with no obvious structure-activity relationships. A model recently shown to explain this effect with an inorganic ligand has now been applied to 2-(4'-hydroxybenzeneazo) benzoic acid (HABA) and also explains the inverse protein dependence of the binding of this compound to human albumin. The model explains this inverse dependence on the basis of a highly bound contaminant which competes with the ligand for the high affinity site. HABA was found to interact with human albumin at three or more sites, the high affinity site which was about 95% contaminated had an association constant of 2 x 10(5)/M, an order of magnitude higher than that found previously when the effect of a contaminant was not considered. The association constant of the competitive contaminant was estimated to be about 5 x 10(6)/M. Since the model accounts for the phenomenon in terms of a property of the protein, rather than of the ligand, it could provide a general explanation for this effect with other ligand-acceptor combinations including a wide variety of drug and hormone receptor preparations.

Albumins↗
PubMed1991

Chiral inversion of 2-arylpropionic acid non-steroidal anti-inflammatory drugs--II. Racemization and hydrolysis of (R)- and (S)-ibuprofen-CoA thioesters.

The inversion of 2-arylpropionic acids (2-APAs) has become the subject of much attention. It is a unique reaction specific to this group of drugs. Inversion proceeds via stereoselective activation of the R-enantiomer to its CoA thioester whereby it is then racemized and hydrolysed to release free drug. The racemization and hydrolysis processes have been examined in this study using chemically synthesized CoA thioesters of the ibuprofen enantiomers and in vitro models employing rat liver homogenate and the mitochondrial and microsomal fractions as the source of the 'racemase' enzymes. Rat liver homogenate mediated the racemization and hydrolysis of both (R)- and (S)-ibuprofen-CoA thioesters. The rat liver mitochondrial fraction similarly mediated racemization and hydrolysis of both CoA thioesters. There was less racemase activity in the rat liver microsomal fraction and the data indicated that this fraction may contain two hydrolases which act separately on the (R)- and (S)-ibuprofen-CoA thioesters. The data are further evidence that the stereoselectivity of the CoA synthetase controls the overall stereoselectivity of inversion.

Animals↗
PubMed1992

Influence of palmitate and benzoate on the unidirectional chiral inversion of ibuprofen in isolated rat hepatocytes.

The influence of benzoic acid, a typical substrate of medium-chain acyl-CoA synthetase, and of palmitic acid, a substrate of long-chain acyl-CoA synthetase, on the metabolic chiral inversion of ibuprofen was investigated in freshly isolated hepatocytes. It was shown that the conjugation of benzoid to hippuric acid does not influence the chiral inversion of ibuprofen. In contrast, palmitic acid inhibited markedly the R-to-S inversion of ibuprofen. It was concluded that this inhibition is due to competition between (R)-ibuprofen and palmitic acid for long-chain acyl-CoA synthetases.

Animals↗
PubMed1994

Chiral inversion of drug: role of intestinal bacteria in the stereoselective sulphoxide reduction of flosequinan.

Chiral inversion at a sulphoxide position of flosequinan enantiomers [(+/-)-7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone] occurred in conventional rats but not in either germ-free rats or rats treated with antibiotics after an oral administration of each enantiomer. Thus, it was postulated that the chiral inversion occurred by mechanisms mediated by intestinal bacteria. The intestinal content isolated from conventional rats reduced R(+)- and S(-)-flosequinan to produce the sulphide, while intestinal content from rats treated with antibiotics did not reduce the drug. Several strains of facultative anaerobes possessed a high flosequinan reducing activity. Escherichia coli, Klebsiella oxytoca and Klebsiella pneumoniae reduced R(+)-flosequinan to the sulphide stereoselectively. On the other hand, Enterobacter aerogenes and Micrococcus agilis exclusively reduced S(-)-flosequinan. The sulphide, which could be produced by intestinal bacteria from R(+)- and S(-)-flosequinan, was readily absorbed upon an oral administration to rats, and was oxidized fairly rapidly to R(+)- and S(-)-flosequinan and further to the sulphone form. Based on these data, it has been confirmed that chiral inversion at the sulphoxide position of flosequinan enantiomers occur via stereoselective reduction of sulphoxide by intestinal bacteria to form the sulphide, followed by oxidation of the sulphide in the body to produce R(+)- and S(-)-flosequinan.

Animals↗
PubMed1994

Is the formation of R-ibuprofenyl-adenylate the first stereoselective step of chiral inversion?

Coenzyme A thioester formation is reported to be the first step of chiral inversion of R-ibuprofen. In order to investigate the mechanism of this reaction adenylate derivatives of the ibuprofen enantiomers were synthesized chemically. R- and S-ibuprofenyl-adenylates as well as free acids were incubated with rat liver mitochondria in the presence of coenzyme A, MgCl2 with or without ATP. The optical antipodes formed by inversion and the coenzyme A thioester derivatives of both enantiomers were found after incubation of both R- or S-ibuprofenyl-adenylate and R-ibuprofen. By contrast, after incubation with S-ibuprofen neither R-enantiomer nor coenzyme A thioesters were detected. These experiments suggest that the formation of R-ibuprofenyl-adenylate may be the first stereoselective step of chiral inversion.

Animals↗
PubMed1980

EEG transient detection by matched inverse digital filtering.

A computer technique for detection of EEG transients or non-stationarities is described. The procedure entails obtaining the amplitude spectrum (as the square root of the power density spectrum) of a sample of the EEG, in which the non-stationarities themselves have not necessarily been excluded. An inverse digital filter is then formed by inverse Fourier transformation of the inverted smoothed amplitude spectrum, through which the same EEG is then passed. The occurrence of non-stationarities is then signalled if the output of the inverse filter exceeds a preset threshold.

Computers↗
PubMed1990

The magnetic field of cortical current sources: the application of a spatial filtering model to the forward and inverse problems.

We extend our theoretical model based on spatial filtering to determine the ability of a SQUID magnetometer to resolve 2 localized current sources in the brain. We find that in order to resolve 2 separated but coaxial cortical sources, the source-to-pickup coil distance must be comparable to the distance between the 2 sources. The size of the current sources affects the resolving power of a magnetometer, but an anisotropy of 3 in the cortical tissue does not produce a significant effect. The model also provides a solution of the inverse calculation, either to reconstruct the original current source distribution from the measured magnetic field, or to continue the field at the magnetometer inward towards the sources. Both the inverse and inward calculations are limited by the fact that the inverse filter function serves as a high-pass filter, which leads to instabilities at high spatial frequencies, particularly in the presence of noise. The instabilities can be minimized by choosing an appropriate window to attenuate the noise, but this in turn reduces the spatial resolution.

Cerebral Cortex↗
PubMed1984

Proconflict effect of benzodiazepine receptor inverse agonists and other inhibitors of GABA function.

GABA seems to be a neurotransmitter with great impact on conflict behaviour in rats. We studied the effects of different types of GABA function inhibitors on conflict behaviour in rats. Among these inhibitors, the benzodiazepine (BZ) receptor inverse agonists are a new type of compound downregulating GABA-mediated functions allosterically. The most effective proconflict inducing compounds were pentylenetetrazol and the three BZ inverse agonists beta-CCM, beta-CCE and ZK 90886. The BZ receptor inverse agonists, FG 7142, DMCM and CGS 8216, the GABA antagonist bicuculline and the GABA synthesis inhibitor isoniazid were moderately active. Only a weak effect was seen with just subconvulsive doses of picrotoxin, a chloride channel inhibitor. These results show that the mode of GABA function inhibition determines the degree to which proconflict action is elicited and that proconflict effects and proconvulsant or convulsant effects may be separated. Evidence is presented that proconflict action in rats is predictive of an anxiogenic action in man.

Animals↗
PubMed1989

Antagonism of methoxyflurane-induced anesthesia in rats by benzodiazepine inverse agonists.

Injection of the partial benzodiazepine inverse agonist Ro15-4513 (1-32 mg/kg i.p.) or nonconvulsant i.v. doses of the full benzodiazepine inverse agonist beta-CCE immediately following cessation of exposure of rats to an anesthetic concentration of methoxyflurane significantly antagonized the duration of methoxyflurane anesthesia as measured by recovery of the righting reflex and/or pain sensitivity. This antagonism was inhibited by the benzodiazepine antagonist Ro15-1788 at doses which alone did not alter the duration of methoxyflurane anesthesia. In addition, high-dose Ro15-4513 pretreatment (32 mg/kg) antagonized the induction and duration of methoxyflurane anesthesia but was unable to prevent methoxyflurane anesthesia or affect the induction or duration of anesthesia induced by the dissociative anesthetic ketamine (100 mg/kg). These findings indicate that methoxyflurane anesthesia can be selectively antagonized by the inverse agonistic action of Ro15-4513 and beta-CCE.

Anesthesia↗
PubMed1991

The effects of benzodiazepine-receptor antagonists and partial inverse agonists on acute hepatic encephalopathy in the rat.

Two benzodiazepine-receptor partial inverse agonists (Ro 15-4513, Ro 15-3505) and one benzodiazepine-receptor antagonist (flumazenil) were administered to rats with hepatic encephalopathy due to acute liver ischemia. Significant improvement (P less than 0.002) of both the clinical grade of hepatic encephalopathy and the electroencephalographic abnormalities was observed after administration of the benzodiazepine-receptor partial inverse agonists: comatose rats with no spontaneous righting reflex regained consciousness immediately after injection of the drug. Only slight improvement in clinical hepatic encephalopathy grade was seen after administration of 25 mg/kg of flumazenil. The present data strongly support a role of increased gamma-aminobutyric acid-ergic tone in the pathogenesis of acute hepatic encephalopathy and provide a rationale for trials of benzodiazepine-receptor partial inverse agonists to restore consciousness in hepatic encephalopathy in humans in the near future.

Animals↗
PubMed1995

An inverse dynamics model for the analysis, reconstruction and prediction of bipedal walking.

Walking is a constrained movement which may best be observed during the double stance phase when both feet contact the floor. When analyzing a measured movement with an inverse dynamics model, a violation of these constraints will always occur due to measuring errors and deviations of the segments model from reality, leading to inconsistent results. Consistency is obtained by implementing the constraints into the model. This makes it possible to combine the inverse dynamics model with optimization techniques in order to predict walking patterns or to reconstruct non-measured rotations when only a part of the three-dimensional joint rotations is measured. In this paper the outlines of the extended inverse dynamics method are presented, the constraints which define walking are defined and the optimization procedure is described. The model is applied to analyze a normal walking pattern of which only the hip, knee and ankle flexions/extensions are measured. This input movement is reconstructed to a kinematically and dynamically consistent three-dimensional movement, and the joint forces (including the ground reaction forces) and joint moments of force, needed to bring about this movement are estimated.

Acceleration↗
PubMed1993

Acute pulmonary embolism as the cause of global T wave inversion and QT prolongation. A case report.

A 57-year-old man without prior history of organic heart disease was admitted with a diagnosis of unstable angina because of chest pain and new electrocardiographic (ECG) changes of global T wave inversion and QT interval prolongation. Left and right heart catheterization with coronary angiography, pulmonary angiography, ventilation-perfusion scintigraphy, and echocardiography showed absence of coronary artery disease but unequivocally acute pulmonary embolism. Within days following anticoagulant therapy, the lengthened QT interval became normalized while the global T wave inversion persisted. A follow-up ECG 15 months later revealed complete resolution of the T wave inversion. The possible pathophysiologic mechanism of the ECG changes is discussed.

Acute Disease↗
PubMed1996

Inverse PCR amplification of low-abundancy message of gamma delta T cell receptor genes.

The technique of inverse PCR permits the rapid amplification and identification of unknown DNA segments adjacent to well characterized core regions. In the field of immunology anchored PCR and inverse PCR are useful methods for examining junctional diversity and unknown variable gene segments of rearranged T cell receptor genes. We have applied an improved inverse PCR protocol to study the repertoire of gamma delta T cell receptor genes in the developing thymus of the mouse.

Amino Acid Sequence↗
PubMed1985

Discriminative stimulus properties of methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), an inverse agonist at benzodiazepine receptors.

Rats (N = 8) were trained to discriminate the stimulus properties of the potent benzodiazepine (BZ) receptor inverse agonist methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) from saline in a two-lever operant task. The initial training dose of DMCM was 0.4 mg/kg at which the discrimination developed slowly; increasing the dose to 0.8 mg/kg resulted in rapid acquisition. However, since convulsions eventually developed during further training (sensitization), the training dose was finally individualized below the convulsive threshold (0.4-0.7 mg/kg). The DMCM cue was mimicked by FG 7142 (10 mg/kg), a non-convulsant anxiogenic beta-carboline, by pentylenetrazol (20-30 mg/kg), and by the GABA antagonist bicuculline (2 mg/kg). The DMCM cue was not, or marginally, blocked by diazepam (2.5 mg/kg) or pentobarbital (10-15 mg/kg). Furthermore, the BZ receptor antagonists CGS 8216 (2.5 mg/kg), ZK 93426 (20 mg/kg), and Ro 15-1788 (20-80 mg/kg) also did not, or only marginally, block the DMCM cue. However, the receptor antagonists (alone) substituted for DMCM although Ro 15-1788 was less effective. The partial BZ receptor agonist ZK 91296 (25 mg/kg), which is structurally similar to DMCM, blocked completely the DMCM stimulus effect. THIP (4 mg/kg) did not block the DMCM cue. To explain these results, we suggest that the repeated DMCM treatment, necessary for maintaining the discrimination, shifts the balancing point ("set-point") for positive (i.e., BZ-like) agonist efficacy versus inverse agonist efficacy, towards inverse action. This hypothesis was supported by the finding of an enhanced ability of GABA to reduce 3H-DMCM binding to cortical neuronal membranes of animals treated chronically with DMCM in a regimen similar to that used to maintain the DMCM discrimination. Furthermore, this treatment did not affect baseline 3H-DMCM binding, baseline or GABA stimulated 3H-diazepam binding, or 35S-TBPS binding (to chloride channels).

Animals↗
PubMed1988

The benzodiazepine recognition site inverse agonists Ro 15-4513 and FG 7142 both antagonize the EEG effects of ethanol in the rat.

The aim of the present study was to compare the ability of Ro 15-4513 and FG 7142, two inverse agonists for benzodiazepine recognition sites, to antagonize the EEG effects of ethanol in freely moving rats. Ethanol (2.5 g/kg, p.o.) induced sedation and ataxia associated with a progressive suppression of the fast cortical activities and an enhancement of low frequencies in both cortical and hippocampal tracings. In contrast, Ro 15-4513 (2 mg/kg, i.p.) and FG 7142 (10 mg/kg, i.p.) both caused a state of alertness associated with desynchronized cortical activity and theta hippocampal rhythm as well as spiking activity which was predominantly observed in the cortical tracings. When rats were treated with FG 7142 or RO 15-4513 either before or after ethanol, a reciprocal antagonism of the behavioral and EEG effects of ethanol and of the partial inverse agonists was observed. These data support the view that the anti-ethanol effects of Ro 15-4513 may be related to its partial inverse agonist properties.

Animals↗
PubMed1996

Further evidence that naloxone acts as an inverse opiate agonist: implications for drug dependence and withdrawal.

To test if naloxone behaved as an inverse agonist rather than as an antagonist we evaluated its responses in guinea-pig ilea with and without morphine (480 nM, 24 h). In control ilea, naloxone (100 nM) had no effect. In morphine-treated ilea, naloxone as a bolus, but not as an infusion, elicited an abstinence response. Preadministration of naloxone blocked the response to subsequent administrations. Similarly, naloxone failed to produce an abstinence response in ilea pretreated with kappa compounds (bremazocine, U50488 or xorphanol 100 nM) or with kinase inhibitors (H7 or H8 30 microM). These findings can be interpreted in the light of the two-state receptor model if naloxone behaves as an inverse agonist: Incubation with morphine increased the active state of receptors making them susceptible to the inverse agonist (naloxone); exposure to naloxone favored the inactive conformation making them insensitive to further administration of naloxone; kappa compounds behaved as antagonists preventing the response to naloxone; and kinase inhibitors interfered with the active conformation making the system insensitive to naloxone. According to this model, dependence can be viewed as an overexpression of the active receptors and withdrawal as an abrupt change from the active to the inactive state.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1992

A new method for regularization of the inverse problem of electrocardiography.

The inverse problem of electrocardiography (specifically, that part concerned with the computation of the ventricular surface activation isochrones) is shown to be formally equivalent to the problem of identification and measurement of discontinuities in derivatives of body surface potentials. This is based on the demonstration that such measurements allow localization of the relative extrema of the ventricular surface activation map (given a forward problem solution), which in turn restricts the space of admissible solution maps to a compact set. Although the inverse problem and the problem of identifying derivative discontinuities are both ill-posed, it is possible that the latter may be more easily or justifiably resolved with available information, particularly as current methods for regularizing the inverse problem typically rely on a regularization parameter chosen in an a posteriori fashion. An example of the power of the approach is the demonstration that a recent Uniform Dipole Layer Hypothesis-based method for producing the ventricular surface activation map is largely independent on that hypothesis and capable in principle of generating maps that are very similar in a precise sense to those that would result from the usual epicardial potential formulation (assuming the latter were capable of producing intrinsic deflections in computed epicardial electrograms sufficiently steep to accurately compute the activation map). This is consistent with the preliminary success of the former method, despite the significant inaccuracy of its underlying assumption.

Animals↗