Showing papers by "Solvay published in 1993"

Clinical Pharmacokinetics of Selective Serotonin Reuptake Inhibitors

Abstract: A feature common to all selective serotonin reuptake inhibitors (SSRIs) is that they are believed to act as antidepressant drugs because of their ability to reversibly block the reuptake of serotonin (5-hydroxytryptamine; 5-HT) in the synaptic cleft From a chemical perspective, however, they show distinct differences Consequently, the pharmacokinetic behaviour of of the drugs can be very different, and these pharmacokinetic differences may have a major influence on their clinical profiles of action All SSRIs have a great affinity for the 5-HT reuptake carrier in the synaptic cleft in the central nervous system, with much less affinity for the noradrenaline (norepinephrine) reuptake carrier, and for alpha- and beta-adrenergic, dopamine, histamine, 5-HT and muscarine receptors Fluoxetine and citalopram are available as racemic mixtures, the isomers of fluoxetine having almost equal affinity to the 5-HT reuptake carrier, while the reuptake inhibitor properties of citalopram reside almost exclusively in the (+)-isomer Norfluoxetine, one of the metabolites of fluoxetine, has a selectivity for the 5-HT reuptake carrier comparable with that of fluoxetine Gastrointestinal absorption of the SSRIs is generally good, with peak plasma concentrations observed after approximately 4 to 6h Absolute bioavailability of citalopram is almost 100%, whereas it is likely that the other compounds undergo (substantial) first-pass metabolism Apparent oral clearance values after single doses range from 26 L/h (citalopram) to 167 L/h (paroxetine), while after multiple doses oral clearance is markedly reduced, particularly for fluoxetine and paroxetine Plasma protein binding of fluoxetine, paroxetine and sertraline is > or = 95%; values for fluvoxamine (77%) and citalopram (50%) are much lower For all compounds, however, protein binding interactions do not seem to be of great importance Although many attempts were made, to date no convincing evidence exists of a relationship between plasma concentrations of any of the SSRIs and clinical efficacy Elimination occurs via metabolism, probably in the liver Renal excretion of the parent compounds is of minor importance Metabolites of fluvoxamine and fluoxetine are predominantly excreted in urine; larger quantities of metabolites of paroxetine (36%) and sertraline (44%) are excreted in faeces The half-lives of fluvoxamine, paroxetine, sertraline and citalopram are approximately 1 day The half-life of fluoxetine is approximately 2 days (6 days after multiple doses), and that of the active metabolite norfluoxetine is 7 to 15 days The metabolism of paroxetine, and possibly also of fluoxetine, is under genetic control of the sparteine/debrisoquine type Available data indicate that metabolism of SSRIs is impaired with reduced liver function(ABSTRACT TRUNCATED AT 400 WORDS)

Intrinsic irreversibility and integrability of dynamics

Abstract: Irreversibility as the emergence of a priviledged direction of time arises in an intrinsic way at the fundamental level for highly unstable dynamical systems, such as Kolmogorov systems or large Poincare systems. The presence of resonances in large Poincare systems causes a breakdown of the conventional perturbation methods analytic in the coupling parameter. These difficulties are manifestations of general limitations to computability for unstable dynamical systems. However, a natural ordering of the dynamical states leads to a well-defined prescription for the regularization of the propagators which lifts the divergence and gives rise to an extension of the eigenvalue problem to the complex plane. The extension acquires meaning in suitable rigged Hilbert spaces which are constructed explicitly for the Friedrichs model. We show that the unitary evolution group, when extended, splits into two semigroups, one decaying in the future and the other in the past. Irreversibility emerges as the selection of the semigroup compatible with our future observations. In this way the problems of integration and irreversibility both enjoy a common solution in the extended space.

Generalized spectral decompositions of mixing dynamical systems

Abstract: We introduce a method for the explicit computation of the eigenvalue problem of the evolution operator of mixing dynamical systems. The method is based on the subdynamics decomposition of the Brussels–Austin groups directed by Professor I. Prigogine. We apply the method to three different representatives of mixing systems, namely, the Renyi maps, baker's transformations, and the Friedrichs model. The obtained spectral decompositions acquire meaning in suitable rigged Hilbert spaces that we construct explicitly for the three models. The resulting spectral decompositions show explicitly the intrinsic irreversibility of baker's transformations and Friedrichs model and the intrinsically probabilistic characters of the Renyi maps and baker's transformations. The dynamical properties are reflected in the spectrum because the eigenvalues are the powers of the Lyapunov times for the Renyi and baker systems and include the lifetimes for the Friedrichs model. © 1993 John Wiley & Sons, Inc.

Process for producing a catalyst system, process for the (co) polymerization of olefins and (co) polymers of at least one olefin

Abstract: A method (I) of preparing a catalyst uses (i) an organoaluminium compound of formula AlTT'T'' (II), where T, T', T'' = hydrocarbon groups optionally containing O, (ii) at least one neutral metallocene of formula (Cp)a(Cp')bMXxZz (III), where Cp, Cp' = unsaturated hydrocarbon group or (Cp') only a group derived from a metal of Group VA or VIA, and which are bonded to M and possibly to each other; derived from a transition metal, and (iii) at least one ionising agent (IV). In (III), M = Group IIIB, IVB, VB or VIB transition metal; X = halogen; Z = hydrocarbon group of formula Rt-Si(R')(R'')(R'''); R = alkyl, alkenyl, aryl, alkoxy or cycloalkyl group; R', R'', R''' = halogen or alkyl, alkenyl, aryl, alkoxy or cycloalkyl group; (a+b+x+z) = m; m = valency of transition metal; t = 0 or 1; x ≥ 1, z ≥ 0; a and/or b are not 0. In this method, (III) and (IV) are deposited on a support (V). The method comprises mixing (II) and (III) in at least one hydrocarbon solvent and adding (IV). Also claimed is a method of (co)polymerising at least one alkene comprising using a catalyst prepared according to (I).

Kainate‐Induced Changes in Opioid Peptide Genes and AP‐1 Protein Expression in the Rat Hippocampus

Abstract: In the rat hippocampus, jun, c-fos, and fos-related antigen immunoreactivity, AP-1 DNA binding, and opioid peptide gene expression were examined after kainate treatment to determine whether the induction and DNA binding of AP-1 transcription factors are correlated with the expression of the opioid peptide genes. One and one-half hours after kainate administration, fos-related antigen and jun immunoreactivity and AP-1 DNA binding were induced; maximal elevation was observed after 4.5 h. Transcription factor expression and DNA binding increased in a dose-dependent manner. Preprodynorphin and preproenkephalin mRNA induction was also dose dependent. The anticonvulsants, pentobarbital and diazepam, effectively blocked electroencephalographic seizure activity caused by kainate treatment, whereas valproic acid was approximately 50% effective. Opioid peptide gene expression, fos-related antigen and jun immunoreactivity, and AP-1 DNA binding all reflected similar reductions after anticonvulsant treatment. Therefore, expression and DNA binding activity of the AP-1 transcription factors are correlated with opioid peptide gene expression in the rat hippocampus.

Development of high-affinity 5-HT3 receptor antagonists. Structure-affinity relationships of novel 1,7-annelated indole derivatives.

Abstract: On the basis of the structures of ondansetron and GR 65,630, its ring-opened C-linked methylimidazole analogue, novel 1,7-annelated indole derivatives were synthesized as potential 5-HT3 antagonists. Receptor binding studies show that all compounds display a high affinity for the 5-HT3 receptors. In both series annelation results in compounds being 7 and 4 times more potent than the references ondansetron and GR 65,630, respectively. Similar to ondansetron, the 1,7-annelated indoles show little stereoselectivity. The (-)-isomers are only slightly more potent than the (+)-isomers. The receptor binding profile of l-10-[(2-methyl-1H-imidazol-1-yl)methyl]-5,6,8,9,10,11-hexahydro-4H-pyri do [3,2,1-jk]carbazol-11-one hydrochloride (24b) (INN cilansetron) shows that the compound displays, besides a high affinity for 5-HT3 receptors (Ki = 0.19 nM), a weak affinity for sigma-receptors (Ki = 340 nM), muscarine M1 receptors (Ki = 910 nM), and 5-HT4 receptors (Ki = 960 nM) and no affinity (Ki > or = 5000 nM) for all the other receptor types tested (n = 37). The new compounds fit the proposed necessary chemical template for binding: a heteroaromatic ring system, a coplanar carbonyl group, and a nitrogen center at well-defined distances. The enhanced potency of the annelated 1,7-indole derivatives indicates that the extra ring provides a favorable hydrophobic area for interaction with the 5-HT3 receptor site. In vivo cilansetron is more potent and induces less central side effects than ondansetron. At present cilansetron is in clinical trials.

Structure-affinity relationship studies on 5-HT1A receptor ligands. 2. Heterobicyclic phenylpiperazines with N4-aralkyl substituents

Abstract: Structure-affinity relationship (SAR) studies for the 5-HT1A receptor site are presented for two series of heterobicyclic phenylpiperazines with N4-aralkyl substituents: 4-aralkyl derivatives of 1-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazine (3) and 1-(benzo[b]furan-7-yl)piperazine (4). Their affinities for 5-HT1A receptors range from 0.15 to 28 nM and thus emphasize the importance of N4-substitution. By combining the SAR of these N4-aralkyl series with the recently published SAR of the N4-alkyl-substituted phenylpiperazines, the nature of the interaction of the N4-substituted phenylpiperazines and the 5-HT1A receptor was further examined using comparative molecular field analysis (CoMFA). To discriminate between two postulated hypotheses, CoMFA models were built and validated utilizing cross-validation, bootstrapping, and randomizing techniques. The model based on a N4-substituent alignment in which all N4-substituents are equally oriented in space was selected for further evaluation. According to the CoMFA/PLS analysis, the steric and electrostatic field properties contribute in a 98:2 ratio to the affinity found for the 5-HT1A receptor. Increasing steric bulk was found to be positively as well as negatively related to affinity depending on the distance of the bulk's center from the N4-nitrogen. The location of these steric CoMFA contour levels are well defined in space when the defined alignment rules are followed. Because CoMFA does not take hydrogen bonding into account, this could indicate that the contribution of the amide function (its ability to interact through hydrogen bonding), as present in the N4-substituents, to affinity is of minor importance.

Use of the accelerating rate calorimeter and the thermal activity monitor to estimate stability temperatures

Abstract: Self-accelerating decomposition temperatures derived from accelerating rate calorimetry measurements and heat accumulation or Dewar tests are compared with those from the definitive United States self-accelerating decomposition temperature test. Neither simulation is biased on average relative to the United States test. However, the use of the accelerating rate calorimeter, as recently proposed, or the Dewar test, as currently recommended, to estimate self-accelerating decomposition temperatures requires wide safety margins to be applied. Closer and more consistent agreement with US test results is achieved by estimating self-accelerating decomposition temperatures from accelerating rate calorimeter and thermal activity monitor data together.

Topical calcitriol in the treatment of chronic plaque psoriasis: a double‐blind study

Abstract: A randomized, double-blind, left-right, vehicle-controlled study to assess the therapeutic efficacy and safety of twice daily application of 15 micrograms/g calcitriol ointment for a period of 6 weeks was performed in 32 patients suffering from bilateral, symmetrical, severe chronic plaque psoriasis. Twice daily 15 micrograms/g calcitriol ointment significantly improved erythema, induration, scaling and global severity of psoriatic plaques, and was much more effective than vehicle ointment. The difference in overall clinical efficacy between calcitriol and vehicle was statistically significant from week 1 onwards, and was maintained over the entire study. On completion of the study, clearance of psoriatic lesions was found in 47% of calcitriol-treated sides and in 13% of vehicle-treated sides. Skin histopathology of calcitriol-treated sides revealed a return to normal keratinization, with decreased inflammatory cell infiltration in the dermis and disappearance of the inflammatory infiltrate from the epidermis. Three patients had asymptomatic hypercalcaemia during the study. Mean serum levels of total calcium, albumin-adjusted total calcium, phosphorus, 25-hydroxyvitamin D and calcitriol did not show statistically significant changes in the baseline/end-point comparisons.

Sulphation and glucuronidation of ritodrine in human foetal and adult tissues

Abstract: Ritodrine is a β2-adrenoceptor agonist used for the management of preterm labour. It is inactivated by conjugation with sulphate and glucuronic acid. There is more ritodrine sulphate than ritodrine glucuronide in urine from the newborn whereas equal amounts of ritodrine glucoronide and sulphate are excreted in maternal urine [Clin. Pharmacol. Ther 44, 634–641, 1988]. We show that, in the mid-gestational human fetal liver, ritodrine sulphotransferase is well expressed, whereas the glucuronidation of ritodrine is little developed compared to the adult liver. The average sulphotransferase activity was 308 pmol·min−1 per mg protein in fetal (N=48) and 145 pmol·min−1 per mg protein in adult (N=32) liver. The rates of ritodrine sulphation in fetal gut, lung and kidney were higher than in the corresponding adult tissues. The development and tissue distribution patterns of ritodrine sulphotransferase are consistent with those of dopamine sulphotransferase. Ritodrine and dopamine are sulphated by thermolabile enzymes. The activity of glucuronyl transferase was measurable in only 5 of the 48 foetal livers assayed, and in those in which could be assayed, the average activity was 44.6 pmol·min−1 per mg protein, one-tenth of that in adult livers (524 pmol·min−1 per mg protein).

Cosmetic deodorant preparations containing di- or triglycerin esters.

Abstract: The cosmetic deodorants proposed are characterized by an effective content of monocarboxylic-acid esters of di- and/or triglycerin.

Preclinical evidence on the psychotropic profile of fluvoxamine

Abstract: Serotonin (5-HT) reuptake inhibitors (SSRIs) such as fluvoxamine are interesting compounds. Initially launched as antidepressants, they have been found to be active in various psychiatric disorders besides depression, including obsessive-compulsive disorder, panic disorder, and eating disturbances. Preliminary data suggest their efficacy in alcohol and drug abuse, aggression, and posttraumatic stress disorder as well. Along with those clinical findings, new preclinical data have emerged. For example, fluvoxamine has demonstrated activity in various models of anxiety in rodents. Its anxiolytic activity can be clearly discriminated from that of the benzodiazepines. In the DRL 72-sec paradigm, fluvoxamine exhibits a good antidepressant profile, similar to those of imipramine and flesinoxan. Studies have shown that fluvoxamine does not down-regulate beta-adrenoceptors; apparently, that property is not a conditio sine qua non for antidepressant activity. Results of studies of the mechanism of action of fluvoxamine in which drug discrimination tests were performed with rats and pigeons suggest that the fluvoxamine stimulus is not (or is only to a very limited degree) dependent on activation of 5-HT1A receptors or 5-HT1B/1D receptors, or both. Experimentation is ongoing in those animal models.

Synthesis of chiral diaza-18-crown-6 derivatives from optically active diethanolamines

Abstract: Homotopic 1,10-diaza-18-crown-6 derivatives with two, four, and six chiral centers have been prepared in optically active form from diethanolamines via a cyclization reaction with tosylates 39 and 48. The requisite optically active diethanolamines were prepared from chiral cyanohydrins and chiral ethanolamines by a one-pot Grignard-transimination-reduction or a one-pot reduction-transimination-reduction procedure. Yields were strongly affected by the size of the substituents α to the nitrogen atom. The stereoselectivity of the diethanolamine synthesis was found to depend on the configuration of the ethanolamine used

Process for the production of epichlorohydrin

Abstract: Process for the production of epichlorohydrin in which the chloroaliphatic impurities formed at the hypochlorination of allyl chloride to dichloropropanols are removed from the crude aqueous solution of dichloropropanols before dehydrochlorination, by extraction with a recycled organic solvent which is rich in 1,2,3-trichloropropane.

Proteases of altered stability to autolytic degradation

Abstract: Proteases are susceptible to autolytic degradation. The method of the invention provides a method to identify susceptible autolysis sites which are cleaved to produce a few discrete fragments. Once identified, amino acid(s) at or in the vicinity of the cleavage site may be chemically modified or the DNA sequence capable of encoding the amino acid present at the site may be changed or deleted by site directed mutagenesis to produce an autolysis stable protease. The invention is particularly applicable to alkaline proteases which are produced in large quantities and used as detergent additives. Stable alkaline proteases could then be used in liquid detergent formulations.

Process for treating waste water

Abstract: The present invention relates to a process for decreasing the content of organic-chemical substances in waste water by chemical oxidation, preferably in the presence of chlorine, and optionally additional alkaline thermal treatment of the waste water, in which the waste water, which has a COD content (chemical oxygen demand) and is alkaline or is rendered alkaline, is introduced into at least one reactor and is treated at a temperature of more than 15° C. with a chlorine-containing and/or chlorine-releasing chemical substance, the introduction of chlorine taking place in a quantity of more than 1 g chlorine/g COD (relative to the chlorine content of the chlorine-containing and/or chlorine-releasing chemical substance), and a molar ratio of OH - to chlorine of more than 1.5 and a pH value of the waste water of ≧5 being maintained or set, and the resulting chlorine-treated, hypochlorite-containing waste water is subjected to a reaction time of more than 0.25 hours, with the organic compounds being at least partially oxidized, and subsequently the waste water is treated further and/or is discharged or drained from the reactor.

Pharmacokinetics of Fluvoxamine Maleate in Patients with Liver Cirrhosis after Single-Dose Oral Administration

Abstract: The pharmacokinetics of fluvoxamine maleate were investigated in 13 patients with biopsy-proven liver cirrhosis. They received a single oral 100mg dose as an enteric-coated tablet, and plasma samples were collected up to 168h after administration. Geometric mean values for peak plasma concentrations and area under the plasma concentration-time curves (AUC) were 39 micrograms/L and 1338 micrograms.h/L, respectively. Mean (+/- SD) elimination half-life (t1/2) was 25 +/- 11h, and increased with higher plasma bilirubin levels, although no relationship between bilirubin and AUC was observed. AUC was about 50% higher in patients than in healthy volunteers from another similar study. This was mainly because of a longer t1/2. Although there is a great overlap between AUC values of fluvoxamine in patients and healthy volunteers, it is nevertheless concluded that in patients with signs of active liver disease, e.g. raised bilirubin, it is wise to lower the initial daily dose and to carefully monitor the patient during subsequent upward dose adjustments.

Process for producing an ethylene polymer composition, ethylene polymer composition and its use

Abstract: Process for the preparation of an ethylene polymer composition comprising a polymer with a melt index MI2 of 5 to 1000 g/10 min and a polymer with a melt index MI5 of 0.01 to 2 g/10 min, the ratio of these indices being from 500 to 50,000 and the weight ratio of the two polymers being equal to (30 to 70): (70 to 30), according to which part of the ethylene, a catalyst derived from a transition metal showing an intrinsic molecular weight distribution defined by an intrinsic Mw/Mn ratio which is less than or equal to 10 and a deactivation constant which is less than or equal to 0.5 h , and a cocatalyst are introduced into a first reactor, a polymerisation of the ethylene is carried out therein, a mixture comprising one of the polymers, the catalyst and the cocatalyst is drawn off from this reactor, the mixture and another part of the ethylene are introduced into a second reactor and polymerisation is carried out in order to form the other polymer.

Polyglycerol fatty acid ester mixture

Abstract: Polyglycerol fatty acid ester mixtures of mono- di- and polyesters of polyglycerols having a degree of polymerization of 2 to 8 and at least one saturated and/or unsaturated fatty acid, the mixtures having an HLB of greater than 8 and containing 0 to less than 5 wt-% diglycerol fatty acid esters, 20 to 65 wt-% triglycerol fatty acid esters, 20 to 50 wt-% tetraglycerol fatty acid esters and 5 to 40 wt-% higher polyglycerol fatty acid esters, in which the fatty acid component consists of one or more fatty acids selected from the saturated and/or unsaturated, branched and/or unbranched C6 - to C14 -fatty acids containing less than 10 wt-% fatty acids having more than 14 carbon atoms; bath additive preparations containing such polyglycerol fatty acid ester mixtures; methods of using such polyglycerol fatty acid ester mixtures, and a process for preparing such mixtures.

Retinoic Acid Enhances Fibrinolytic Activity In-Vivo by Enhancing Tissue Type Plasminogen Activator (t-PA) Activity and Inhibits Venous Thrombosis

Abstract: We studied the profibrinolytic effect and the anti-thrombotic potential of retinoic acid in-vivo. Male Wistar rats were treated with retinoic acid either acutely or twice daily for a period of 5 consecutive days in a dose range of 0.01 to 3.0 mg/kg. Fibrinolytic activity was measured ex-vivo using the diluted blood clot lysis test and net t-PA activity in tissue extracts was measured in a spectrophotometric rate assay. Clot lysis was dose dependently increased by retinoic acid up to about 170% (relative to vehicle treated rats) at a dose of 3 mg/kg. No tachyphylaxis could be detected. Ex-vivo measured fibrinolytic activity after single administration of 1 mg/kg of retinoic acid peaked at 3 h after ingestion. Even after 18 h a significantly higher clot lysis rate was measured. Lysis of blood clots from vehicle and retinoic acid treated rats could be completely blocked by addition of tranexamic acid or antibodies against rat t-PA before clot formation. t-PA activity in plasma was slightly increased after retinoic acid treatment; no effects were measured on plasma PAI-1, u-PA, plasminogen, and α2-antiplasmin levels. t-PA activity in lung and kidney was marginally enhanced by retinoic acid but in heart and aortic tissue extracts t-PA activity was increased by about 50%. We confirmed this potential anti-thrombotic property in an in-vivo venous thrombosis model. A reduced clot size was observed after retinoic acid administration (35% reduction at a dose of 1 mg/kg). We could not detect any effect on ex-vivo measured platelet aggregation, bleeding time, prothrombin time, thrombin time, partial thromboplastin time or plasma fibrinogen level, indicating that there were no effects on platelet aggregation or blood coagulation. We conclude that retinoic acid enhanced fibrinolytic activity in-vivo by selectively enhancing t-PA activity and that retinoic acid is a potential anti-thrombotic agent in-vivo.

Process for treating waste water containing chlorinated organic compounds from production of epichlorohydrin

Abstract: A process for treating waste water containing chlorinated organic substances, particularly waste water from production of epichlorohydrin which contains more than 10 mg of adsorbable organic halogen compounds (AOX) per liter, comprising charging the waste water at a pH of 10 to 14 (measured at room temperature) into a reactor and maintaining a temperature of at least 75°C., a pressure of at least 1 bar (abs.), and a residence time of at least 0.5 hours in said reactor, thereby partially dechlorinating and/or dehydrochlorinating chlorinated organic compounds contained in the waste water, and thereafter subjecting the waste water to further dechlorination and/or dehydrochlorination treatment in the presence of a hydrogen-containing gas, a hydrogen-releasing compound and/or a catalytically active material; and optionally subjecting the waste water to a biological treatment with the use of microorganisms; and apparatus for carrying out the foregoing process.