Induced synchronization by endogenous noise modulation in finite-size random neural networks: A stochastic mean-field study.

Event-related synchronization and desynchronization (ERS/ERD) are well-known features found experimentally in brain signals during cognitive tasks. Their understanding promises to have much better insights into neural information processes in cognition. Under the hypothesis that neural information affects the endogenous neural noise level in populations, we propose to employ a stochastic mean-field model to explain ERS/ERD in the γ-frequency range. The work extends previous mean-field studies by deriving novel effects from finite network size. Moreover, numerical simulations of ERS/ERD and their analytical explanation by the mean-field model suggest several endogenous noise modulation schemes, which may modulate the system's synchronization.

Impact of the COVID-19 pandemic on clinical research in hospitals: observational study in the first epicenter of the epidemic during the general lockdown in France.

OBJECTIVE: The COVID-19 epidemic has had a strong impact on the entire healthcare sector in France with priority being given to research for new therapeutic options for COVID-19. Nevertheless, continuity of care for patients suffering from other diseases represents a crucial challenge, and clinical research is no exception in this respect. This study aims to assess the impact of the strict Covid-19 lockdown on non-Covid-19 clinical research in the French University Hospital of Strasbourg. MATERIALS AND METHODS: Clinical research activity (non-Covid-19) from the point of view of pharmacy department was estimated and compared to the pre-lockdown period. The impact of lockdown was assessed through five indicators: site initiation visits, the initiation of experimental therapies in non-Covid-19 patients, the delivery of non-Covid-19 investigational medical products, the number of drug shipments to patients' homes, and the number of monitoring or closure visits. RESULTS: During the study period, the number of site initiation visits decreased by 90%, total inclusions by 72%, and delivery of investigational medical products by 30%. During the lockdown period, 15 treatments were sent to patients' homes. Monitoring activity decreased by 98%. CONCLUSIONS: Although the COVID-19 outbreak has created an incredible momentum in the field of clinical research, research not focused on SaRS-CoV-2 has suffered greatly from this situation. The impact on patients is difficult to estimate but should be further investigated.

[Blockers of beta-adrenergic receptors--a group of chiral agents stereoselective synthesis of beta-blockers]. / Blokátory beta-adrenergických receptorov--skupina chirálnych lieciv stereoselektívna syntéza beta-blokátorov.

Besides chromatographic methods and biocatalyzed reactions, another alternative method of obtaining enantiomeric forms of beta-blockers is stereoselective synthesis. This paper links up with two preceding surveys concerning beta-blockers--groups of chiral agents and presents a survey of the hitherto published enantioselective syntheses of (R)- and (S)-enantiomers of beta-blockers. In the group of arylaminoethanols, mainly selective reduction of prochiral ketones in the presence of metallic complexes is used in this type of synthesis. Enantiomerically pure beta-blockers of the aryloxyaminopropanol type are synthesized by means of a reaction of pertinent phenols with different chiral precursors, such as (R) and (S)-chloromethyloxirans, (S)-glycidoltosylate, (S)- or (R)-2,3-O-isopropylideneglyceroltosylate, E-(2S,3S)-3-trimethylsilylglycidol and (S)-3-terc-butyl-5-phenyl-oxazolidine-5-ylmethanol. Many of these chiral semiproducts can be prepared from natural substances, such as D-mannitol and L-ascorbic acid.

Effects of nonlocal feedback on traveling fronts in neural fields subject to transmission delay.

The work introduces a model for reciprocal connections in neural fields by a nonlocal feedback mechanism, while the neural field exhibits nonlocal interactions and intra-areal transmission delays. We study the speed of traveling fronts with respect to the transmission delay, the spatial feedback range, and the feedback delay for general axonal and feedback connectivity kernels. In addition, we find a novel shape of traveling fronts due to the applied feedback and criteria for its occurrence are derived.

[Chiral switch: pure enantiomers of drugs instead of racemic mixtures]. / Chirální zamena--"chiral switch": cisté enantiomery léciv místo racemických smesí.

Chirality of drugs, particularly the comparison of efficacy of enantiomers and their racemic mixtures, has become an object of serious interest of pharmaceutical researchers in recent ten or fifteen years. Advances in chemical technologies connected with the synthesis, separation, and analysis of pure enantiomers from racemates, together with administrative regulatory measures, have resulted in an increase in the number of newly registered chiral drugs containing only one of the enantiomers. Besides new chemical entities, many "old" racemates are being re-evaluated as potentially new sources of pure enantiomers which should improve the therapeutic profile of the drug. Due to this replacement of a racemic mixture with a pure enantiomer, the literature lists both drugs containing a racemate and drugs containing only one of the enantiomers. Nevertheless, the required therapeutic effect is not always achieved, and unexpected undesirable effects have also occurred. The paper summarizes therapeutic and economic problems concerning chiral switch drugs.

Disposition of flurbiprofen in man: influence of stereochemistry and age.

1. The stereoselective metabolism and pharmacokinetics of the enantiomers of flurbiprofen were investigated following the oral administration of the racemic drug (100 mg) to four young and four elderly healthy volunteers (two males and two females per group). 2. The stereochemical composition of the drug and the 4'-hydroxy- metabolite in serum and the drug, 4'-hydroxy- and 3'-hydroxy-4'-methoxy- metabolites, both free and conjugated, in urine were determined by a direct chromatographic method of enantiomeric analysis. 3. Modest enantioselectivity in clearance (CL S/R: young, 0.86; elderly, 0.88) was largely responsible for the apparent elimination half-life of (S)-flurbiprofen being significantly greater (p<0.01) than that of the R-enantiomer in both age groups (young, S: 5.2 +/- 0.7 versus R: 4.5 +/- 0.6 h; elderly, S: 9.6 +/- 1.2 versus R: 7.1 +/- 1.0 h). The serum concentrations of 4'-hydroxyflurbiprofen were five- to 20-fold lower than those of the corresponding drug enantiomers, stereoselective disposition being evident in the significantly greater (p<0.05) apparent half-lives of the S- compared with the R-enantiomer in both groups (young, S: 10.6 +/- 2.4 versus R: 6.7 +/- 1.1 h; elderly, S: 13.7 +/- 1.7 versus R: 10.2 +/- 1.2 h). 4. Some 60 and 72% of the dose was excreted in 24-h urine in elderly and young volunteers, respectively, a significantly greater (p<0.05) proportion of which was of the R-configuration in both age groups (S/R: young, 0.87; elderly, 0.81). The major urinary excretion products were flurbiprofen and 4'-hydroxyflurbiprofen, and their acyl-conjugates in both groups. 5. Age-associated differences in the pharmacokinetics of flurbiprofen occurred in a non-stereoselective manner and were primarily as a consequence of a significant approximately 40% decrease (p<0.01) in clearance of both enantiomers in the elderly due to reduced metabolic activity. Consequently, the elderly had greater exposure to both enantiomers, as reflected by the AUCs(0-inf) being significantly higher (p<0.05), by 60%, in this age group compared with the young. 6. The findings suggest that age-related alterations in the disposition of flurbiprofen could have significant implications for the use of the drug in the elderly.

Detection of mutual phase synchronization in multivariate signals and application to phase ensembles and chaotic data.

This work presents a method for the detection of mutual phase synchronization in nonstationary time series. We show how the application of a cluster algorithm that considers spatiotemporal structures of data follows from the general condition of phase-synchronized data. In view of the topology of phasic data, we reformulate the K-means cluster algorithm on a flat torus and apply a segmentation index derived in an earlier work [A. Hutt and H. Riedel, Physica D 177, 203 (2003)]. This index is extended by means of averaging in order to reflect phase synchronization in ensembles of multivariate time series. The method is illustrated using simulated multivariate phase dynamics and arrays of chaotic systems, in which temporal segments of phase-synchronized states are registered. A comparison with results from an existing bivariate synchronization index reveals major advantages of our method.

Stereoselectivity of ibuprofen metabolism and pharmacokinetics following the administration of the racemate to healthy volunteers.

1. The stereoselective metabolism and pharmacokinetics of the enantiomers of ibuprofen have been investigated following the oral administration of the racemic drug (400 mg) to 12 healthy volunteers.2. The stereochemical composition of the drug in serum, both total and unbound, and drug and metabolites, both free and conjugated, in urine were determined by a combination of the direct and indirect chromatographic procedures to enantiomeric analysis. 3. The oral clearance of (S)-ibuprofen was significantly greater than that of the R-enantiomer (74.5 +/- 18.1 versus 57.1 +/- 11.7 ml min(-1); p < 0.05) and the clearance of (R)-ibuprofen via inversion was ca two fold that via alternative pathways. 4. Some 74.0 +/- 9.6% of the dose was recovered in urine over 24 h as ibuprofen, 2-hydroxyibuprofen and carboxyibuprofen, both free and conjugated with glucuronic acid. Analysis of the stereochemical composition of the urinary excretion products indicated that 68% of the dose of (R)-ibuprofen had undergone chiral inversion. 5. Metabolism via glucuronidation and both routes of oxidation, showed enantio-selectivity for (S)-ibuprofen, the enantiomeric ratios (S/R) in partial metabolic clearance being 7.1, 4.8 and 3.4 for formation of ibuprofen glucuronide, 2-hydroxyibuprofen and carboxyibuprofen respectively.6. Modest stereoselectivity was observed in the formation of (2'R, 2R)- and (2'S, 2S)-carboxyibuprofen in comparison to the alternative diastereoisomers, the ratios in formation clearance being 1.6 and 1.2 respectively.

Action of MDMA (ecstasy) and its metabolites on arginine vasopressin release.

3,4-Methylenedioxymethamphetamine (MDMA) has been reported to cause hyponatraemia, which appears to result from inappropriate secretion of the antidiuretic hormone arginine vasopressin (AVP). After administration of a low dose of (R,S)-MDMA (40 mg) to eight healthy drug-free male volunteers, concentrations of AVP in plasma increased significantly at 1, 2, and 4 hours. Although no relation between plasma MDMA and AVP was found on an examination of the entire data set over the 24-hour study period, a statistically significant negative correlation was observed at 1 hour. As this occurred at a time when both AVP and MDMA concentrations were rising, it was postulated that a metabolite, or metabolites, could primarily be responsible for the increase in AVP. To test this hypothesis we examined the effect of MDMA and five of its metabolites, in the dose range 0.1-1,000 nM, on AVP release from the isolated rat hypothalamus. All compounds tested were found to increase AVP release (using 10 nM and 1,000 nM concentrations), with 4-hydroxy-3-methoxymethamphetamine (HMMA), the major metabolite of MDMA, being the most potent, and 3,4-dihydroxymethamphetamine (DHMA) the least potent. Each compound (1,000 nM), with the exception of DHMA, also enhanced the response to 40-mM potassium stimulation. Our findings confirm that metabolites of MDMA, in addition to the parent drug, contribute to AVP secretion in vitro. Further work will demonstrate whether this is also true in vivo.

Arginine vasopressin release in response to the administration of 3,4-methylenedioxymethamphetamine ("ecstasy"): is metabolism a contributory factor?

The aim of this investigation was to examine the effect of 3,4-methylenedioxymethamphetamine (MDMA) administration on arginine vasopressin (AVP) release. (R,S)-MDMA (40 mg) was administered to eight normally hydrated healthy male volunteers (22-32 years) and blood samples were collected up to 24 h. Plasma was assayed for AVP and cortisol by radioimmunoassays, and for MDMA and the N-demethylated metabolite, MDA, by gas chromatography-mass spectrometry. Sodium concentrations and osmolality were also determined. Plasma AVP increased in all subjects after MDMA administration and a significant negative correlation was observed between concentrations of AVP and both single and total enantiomer MDMA at 1 h (r < -0.91, P < 0.01). This had disappeared by 2 h (P > 0.7). Compared with basal values, no significant change was observed for osmolality or cortisol at 1 h after drug administration. In conclusion, plasma AVP concentrations increase after MDMA administration, but the increase is not part of a generalized stress response since cortisol did not increase concurrently. A significant negative correlation between plasma MDMA and AVP was observed soon after administration. The possibility that a pharmacological effect of MDMA is primarily mediated via one or more metabolites, rather than by the parent drug, should be considered.

The effects of a synthetic diet on the pharmacokinetics of ethyl methyl sulphide and its sulphoxide and sulphone metabolites in rats.

Ethyl methyl sulphide (EMS) is a simple dialkyl sulphide, which occurs naturally and forms part structures of more complex drug molecules. EMS is oxidized to the corresponding sulphoxide (EMSO) and sulphone (EMSO2) derivatives both in vitro and in vivo. Two distinct enzymatic pathways appear to be involved in this sulphoxidation process; the flavin-containing monooxygenase (FMO) is largely responsible for the S-oxidation of EMS to its sulphoxide while both cytochrome P450 and FMO are involved in the further oxidation of the sulphoxide to the sulphone. The pharmacokinetics of EMS and its sulphoxide and sulphone metabolites were examined in male wistar rats placed on normal rat chow and those placed on a synthetic diet. Blood levels of EMS were analysed by a sensitive headspace gas chromatographic assay. A separate gas chromatographic assay was developed to monitor the blood levels of EMSO and EMSO2. The pharmacokinetics of EMS in control rats were linear from 10 to 40 mg/kg dose range. The blood concentration-time profile of EMS declined monoexponentially. EMS was rapidly eliminated from rat blood with a terminal half-life of 0.14 h and was not dytectable 1 h after administration. Following intravenous administration of EMSO (5 mg/kg), the blood concentration-time profile of EMSO declined with a terminal half-life (t 1/2) of 1.46 h, about ten times longer than that of the parent sulphide. After administration of EMSO2 (15 mg/kg), the sulphone was metabolically stable and was eliminated very slowly from the blood. The in vivo disposition of EMS and EMSO were clearly altered in rats maintained on a synthetic diet following administration of EMS or EMSO. The pharmacokinetic data were consistent with a diminished drug oxidising capacity in rats placed on the synthetic diet and could serve as a useful probe for monitoring the regulation of FMO in animals.

Characterization and purification of the vitamin K1 2,3 epoxide reductases system from rat liver.

The enzyme vitamin K1 2,3 epoxide reductase is responsible for converting vitamin K1 2,3 epoxide to vitamin K1 quinone thus completing the vitamin K cycle. The enzyme is also the target of inhibition by the oral anticoagulant, R,S-warfarin. Purification of this protein would enable the interaction of the inhibitor with its target to be elucidated. To date a single protein possessing vitamin K1 2,3 epoxide reductase activity and binding R,S-warfarin has yet to be purified to homogeneity, but recent studies have indicated that the enzyme is in fact at least two interacting proteins. We report on the attempted purification of the vitamin K1 2,3 epoxide reductase complex from rat liver microsomes by ion exchange and size exclusion chromatography techniques. The intact system consisted of a warfarin-binding factor, which possessed no vitamin K1 2,3 epoxide reductase activity and a catalytic protein. This catalytic protein was purified 327-fold and was insensitive to R,S-warfarin inhibition at concentrations up to 5 mM. The addition of the S-200 size exclusion chromatography fraction containing the inhibitor-binding factor resulted in the return of R,S-warfarin inhibition. Thus, to function normally, the rat liver endoplasmic reticulum vitamin K1 2,3 epoxide reductase system requires the association of two components, one with catalytic activity for the conversion of the epoxide to the quinone and the second, the inhibitor binding factor. This latter enzyme forms the thiol-disulphide redox centre that in the oxidized form binds R,S-warfarin.

Improvement of source localization by dynamical systems based modeling (DSBM).

Recently, we have proposed a new concept for analyzing EEG/MEG data (Uhl et al. 1998), which leads to a dynamical systems based modeling (DSBM) of neurophysiological data. We report the application of this approach to four different classes of simulated noisy data sets, to investigate the impact of DSBM-filtering on source localization. An improvement is demonstrated of up to above 50% of the distance between simulated and estimated dipole positions compared to principal component filtered and unfiltered data. On a noise level on which two underlying dipoles cannot be resolved from the unfiltered data, DSBM allows for an extraction of the two sources.

Neutron reflection from a dimyristoylphosphatidylcholine monolayer adsorbed on a hydrophobised silicon support.

Neutron specular reflection has been used to study the structure of a monolayer of dimyristoylphosphatidylcholine (DMPC) deposited using the Langmuir-Blodgett technique onto a silicon oxide substrate. A self-assembled monolayer of octadecyltrichlorosilane with a deuterated alkyl chain (d-OTS) had been previously bonded onto this silicon oxide substrate which rendered it hydrophobic. In the system under study, the alkyl chains of the phospholipid were found to penetrate extensively into the d-OTS layer with the mixed chain region (d-OTS and DMPC) having a total thickness of 30.5 A. This mixed region was divided into two halves for analysis; the 'lower half' (nearest to the substrate surface) was found to comprise anchored d-OTS chains mixed with the lipid chains in the volume ratio approx. 0.60:0.35. The corresponding volume ratio in the 'upper half' of this region was determined to be approx. 0.50:0.40. The thicknesses of these regions were found to be 17.9 A (incorporating approx. 6% solvent) and 12.6 A (incorporating approx. 9% solvent) for the lower and upper halves respectively. The DMPC head groups were found to be confined to the most external layer (furthest away from the silicon substrate). This layer was found to have a thickness of 9.4 A and included a small fraction of the lipid alkyl chains with approx. 47% solvent.

Detection of fixed points in spatiotemporal signals by a clustering method.

We present a method to determine fixed points in spatiotemporal signals. The method combines a clustering algorithm and a nonlinear analysis method fitting temporal dynamics. A 144-dimensional simulated signal, similar to a Kueppers-Lortz instability, is analyzed and its fixed points are reconstructed.

Enantiospecific analysis by capillary electrophoresis: applications in drug metabolism and pharmacokinetics.

Enantiospecific analysis has an important role in drug metabolism and pharmacokinetic investigations and its now no longer acceptable to determine total drug, or metabolite, concentrations following the administration of a racemate. Inspite of the fact that capillary electrophoresis (CE) has become an essential technique in pharmaceutical and enantiospecific analysis, the chromatographic methodologies remain the most commonly used approach for the determination of the enantiomeric composition of drugs in biological fluids. The application of CE to bioanalysis has been slow, which is in part associated with the complexity of biological matrices together with the relatively poor concentration limits of detection achievable. However, as a result of its versatility, high separation efficiency, minimal sample requirements, speed of analysis and low consumable expense CE is likely to play an increasingly significant role in the area. This review present an overview of enantiospecific CE in bioanalysis in which the approaches to enantiomeric resolution and the problems associated with biological matrices are briefly discussed. The application of enantiospecific CE to samples of biological origin is illustrated using examples where the methodology has either solved an analytical problem, or provided a useful alternative to the currently available chromatographic methods. Such improvements in methodology are associated with either the high separation efficiency and/or microanalytical capabilities of the technique. Enantiospecific CE will not replace the chromatographic methodologies but does provide the bioanalyst with a useful addition to his armamentarium.

Chromatographic resolution, chiroptical characterization and preliminary pharmacological evaluation of the enantiomers of butibufen: a comparison with ibuprofen.

Enantiomeric resolution of butibufen has been achieved on a cellulose tris(3,5-dimethylphenylcarbamate) chiral stationary phase with hexane-isopropanol-trifluoroacetic acid, 100:1.2:0.02 (v/v/v) as mobile phase at a flow rate of 1.0 mL min(-1). Semi-preparative isolation of the enantiomers then chiroptical characterization indicated that the order of elution was (-)-R- before (+)-S-butibufen. When tested for their effects on the cyclooxygenase and 5-lipoxygenase pathways of eicosanoid metabolism in calcium ionophore-activated rat peritoneal leukocytes it was found that (+)-S-butibufen inhibited generation of thromboxane B2 (TXB2) and prostaglandin E2 (PGE2) (cyclooxygenase pathway), with an IC50 of 1.5 microM (approx.), whereas the (-)-R enantiomer was essentially inactive. Neither enantiomer inhibited the 5-lipoxygenase pathway. In this regard, (+)-S-butibufen was approximately five times less potent as a cyclooxygenase inhibitor than (+)-S-ibuprofen. These results show the enantiomeric specificity and pathway selectivity of this novel non-steroidal anti-inflammatory drug.

Ibuprofen stereochemistry: double-the-trouble?

Racemic ibuprofen is an important NSAID used in the treatment of pain and inflammation in a variety of musculoskeletal and rheumatic disorders. The metabolism of ibuprofen, and that of a number of the related 2-arylpropionic acid NSAIDs, involves chiral inversion of the relatively inactive R-enantiomers to their active S-antipodes, together with other potentially stereoselective conjugative and oxidative pathways. Enantiospecific analytical methodology suitable for the determination of both the drug and its metabolites is essential in order to evaluate the significance of stereoselectivity both in terms of drug action and disposition. Recent investigations have also indicated that the R-enantiomers of these agents may not be totally devoid of useful biological activity, that the formation of acyl-coenzyme A derivatives results in interactions with lipid biochemistry, and has provided new insights into the disposition of these drugs in man. Ibuprofen represents a classical example of a drug where stereochemical considerations are essential for an understanding of its biological properties.

Stereospecific analysis and enantiomeric disposition of 3, 4-methylenedioxymethamphetamine (Ecstasy) in humans.

BACKGROUND: Little is known concerning the enantioselective disposition of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) in humans. In addition, the potential of utilizing the stereochemical composition of an analyte in biological media for forensic purposes requires investigation. METHODS: The enantiomers of MDMA and its demethylated metabolite, 3,4-methylenedioxyamphetamine (MDA), present in plasma and urine extracts were derivatized with (-)-(R)-alpha-methoxy-alpha-trifluoromethylphenylacetyl chloride and analyzed by gas chromatography-mass spectrometry and gas chromatography, respectively. The enantioselective disposition of MDMA and MDA was determined following oral administration of racemic MDMA (40 mg) to eight male volunteers. RESULTS: The plasma concentrations of (R)-MDMA exceeded those of the S-enantiomer [ratio R:S of the area under the curve (AUC), 2.4 +/- 0.3], and the plasma half-life of (R)-MDMA (5.8 +/- 2.2 h) was significantly longer than that of the S-enantiomer (3.6 +/- 0.9 h). The majority of the recovered material in urine was excreted within 24 h after dosing, with the recovery of (R)-MDMA (21.4% +/- 11.6%) being significantly greater than that of (S)-MDMA (9.3% +/- 4.9%), and with (S)- and (R)-MDA accounting for 1.4% +/- 0.5% and 1.0% +/- 0.3% of the dose, respectively. Mathematical modeling of plasma enantiomeric composition vs sampling time demonstrated the applicability of using stereochemical data for the prediction of time elapsed after drug administration. CONCLUSIONS: Analytical methods for determining the enantiomeric composition of MDMA and MDA in plasma and urine were developed. The disposition of MDMA in humans is stereoselective, with the more active S-enantiomer having a reduced AUC and shorter half-life than (R)-MDMA. The determination of stereochemical composition may be applicable for forensic purposes.

[Chiral compounds and their pharmacologic effects]. / Chirálne zlúceniny a ich farmakologické úcinky.

The present contribution to the problems of the stereochemistry of drugs is an attempt at stressing the importance of a stereochemical view of pharmacology and at informing about the advances of "chiral pharmacology" within the framework of the contemporary knowledge of selective effects of drugs. There are no simple solutions in the "racemates versus enantiomers" problems and each substance must be considered and tested individually, i.e. on the case-by-case principle. For many racemates available at present there exist relatively few items of knowledge concerning the pharmacological, toxicological and pharmacokinetic properties of their individual enantiomers, or concerning the influence of age, health condition, sex and genetic factors on biological availability and response of the organism to the drug. Additional testing of the enantiomers of the racemates used in practice can lead to the discovery of new indications of the original drug, improve its clinical use and result in increasing its safety and efficacy. If it is so, in this case the "chiral meditations" in pharmacology are double worth the problems they pose.