bluuebunny/crossref_metadata_2025 huggingface dataset:
The kinetics of the bimolecular self‐reaction of t‐butyl radicals in solution. II. Disproportionation/combination ratios
Authors: Schuh Hans‐Herbert , Fischer Hanns
Published: December 2004

Disproportionation/combination ratios Pd/Pc of self‐reacting t‐butyl radicals are determined as a function of solvent and temperature. the observed large solvent and temperature dependences are ascribed to anisotropic reorientational motions of the radicals during their encounter in the solvent cage. Results for other alkyl radicals are compatible with this concept.
Michael‐Addition von Thiocarbonsäureestern Anwendung bei der Synthese von (±)‐Jasminketolacton
Authors: Gerlach Hans , Künzler Peter
Published: December 2004

Michael addition of carbothioates. Application to the synthesis of (±)‐jasmine ketolactone

It is shown that the lithium enolate of S‐t‐butyl thioacetate adds to 2‐cyclopentenone in the β‐position and that fluoride ions catalyze the 1, 4‐addition of the trimethylsilyl enol ether of S‐t‐butyl thioacetate (5) to 2‐cyclopentenone (4) to give 6. These novel versions of the Michael addition have been applied to a synthesis of jasmonoid compounds. Cleavage of the trimethylsilyl enol ether in 6 with tetrabutylammonium fluoride produced the corresponding ketone enolate which could be trapped in situ by alkylation with 1‐bromo‐5‐(2′‐tetrahydropyranoxy)‐2‐pentyne (7) to form 8. Removal of the alcohol protecting group in 8, followed by partial hydrogenation of the triple bond over Lindlar palladium and mercury ion promoted hydrolysis of the carbothioate moiety in 9, led to 5′‐hydroxy jasmonic acid (10, Scheme 3). 10 was converted into the S‐(2‐pyridyl) carbothioate and cyclized in dilute benzene solution under the influence of silver ion to give (±)‐jasmine ketolactone (1, Scheme 4), a component of the essential oil of Jasminum grandiflorum, in 72% yield. Similarly, methyljasmonate (2, Scheme 2) was obtained from 6 by the reaction with 1‐bromo‐2‐pentyne and tetrabutylammonium fluoride followed by methanolysis and partial hydrogenation of the triple bond.
The Partition Coefficient of Protonated Antihistamines. Its calculation and interpretation in terms of hydrophobic fragmental constants
Authors: Testa Bernard , Murset‐Rossetti Livia
Published: December 2004

The octanol/water partition coefficient (P+) of nineteen monoprotonated antihistaminic drugs has been measured. These values are compared with the partition coefficient (P) of the neutral molecules, suggesting the variations in partition coefficient seen upon protonation to obey simple rules. Indeed, the (log P–log P+) values are multiples of a constant term 0.28 (Rekker's ‘magic constant’ cM[6]), each functional group contributing with a fixed incremental value. The incremental values are confirmed by multiple linear regression analysis, and their physical significance is discussed.
Nucleophilic Addition to a Triple Bond; Preliminary ab initio study
Authors: Eisenstein Odile , Procter Garry , Dunitz Jack D.
Published: December 2004

Preliminary ab initio, calculations (minimal basis set STO‐3 G) suggest that the preferred direction of approach of a nucleophilic centre towards a CC triple bond makes an obtuse angle (∼120°) with this bond. The stereoelectronic requirements for nucleophilic addition to triple bonds and to ketones are thus rather similar.
Synthese von optisch aktiven, natürlichen Carotinoiden und strukturell verwandten Naturprodukten. II. Synthese von (3 S, 3′S)‐Astaxanthin
Authors: Kienzle Frank , Mayer Hans
Published: December 2004

Synthesis of optically active natural carotenoids and structurally related compounds. II. Synthesis of (3S, 3′S)‐astaxanthin

The syntheses of rac. astaxanthin, (3 S, 3′S)‐astaxanthin (1), its 15‐cis isomer (21), its diacetate (22), and of (3 S, 3′ S)‐15, 15′‐didehydroastaxanthin (20) are reported.
Valenzisomerisierungsversuche an substituierten 2‐Phenyl‐4‐phenylazo‐benzotriazolen: Grenzen derBoulton‐Katritzky‐Umlagerung
Authors: Balli Heinz , Gunzenhauser Sigmund
Published: December 2004

Attempts of Valence Isomerization on Substituted 2‐Phenyl‐4‐phenylazo‐benzotriazoles: Limits of theBoulton‐KatrizkyRearrangement

Substituted 2‐phenyl‐4‐phenylazo‐benzotriazoles are prepared and their UV./VIS.,1H‐NMR. and mass spectra discussed. A thermic or photochemical valence tautomerization according to theBoulton‐Katritzkyrearrangement could not be proved.
Die Struktur des Spermin‐Alkaloides Aphelandrin aus Aphelandra squarrosa NEES. 170. Mitteilung über organische Naturstoffe
Authors: Dätwyler Peter , Bosshardt Herbert , Bernhard Heinz O. , Hesse Manfred , Johne Siegfried
Published: December 2004

The structure of the spermine alkaloid aphelandrine from Aphelandra squarrosa NEES

The new spermine alkaloid aphelandrine (2) has been isolated from Aphelandra squarrosa NEES. By oxidation of 2 with KMnO4 followed by methylation (CH2N2) 12 and 14 could be prepared (Scheme 2). Fusion of 2 with KOH yielded spermine (1) whereas hydrolysis of 2 in hot hydrochloric acid results in lacton 17, the structure of which could be elucidated by comparison with a synthetically prepared model compound (Scheme 3). The benzylic bonds N (10), C(11) as well as O(16), C(17) of 2 could be cleaved by hydrogenolysis (compare 23 and 26; Scheme 4). The elucidation of the correct linkage of the spermine moiety with the aromatic dicarboxylic acid is based mainly on chemical and spectroscopic evidence of the tetrahydro derivative 26, the Hofmann‐degradation products 28, 30 and 31 (Scheme 6) as well as the ester 35, prepared by partial hydrolysis of 2 (Scheme 7).
Neue Macrolide und einige Sesquiterpen‐Derivate aus dem Galbanum‐Harz
Authors: Kaiser Roman , Lamparsky Dietmar
Published: December 2004

New Macrolides and Some Sesquiterpenoid Derivatives Occurring in Galbanum Absolute

Analytical investigations of a Galbanum absolute have revealed for the first time the presence of four macrolides 1–4 derived from the corresponding hydroxylated C13–C16 fatty acids by lactonization of a secondary alcoholic group with the carboxylic group. The musky odor strengthens with increasing number of members in the macrocycle, whereas the woody note is predominant in the smaller rings. Isolation, identification and synthesis of the new naturally occurring substances are described.

Shyobunol (24) epishyobunol (25) as well as their acetates 26 and 27 were identified ‐ together with 10‐epijunenyl acetate (28) ‐ in the same substrate, thus indicating 25 and 26 to be natural products. The corresponding known and already naturally occurring ketones 23 and 24 are trace components in the investigated material derived from the so‐called Galbanum oleo‐gum‐resin.
Über Pterinchemie. 68 Mitteilung [1]. Regiospezifische Deuterierungen von Folsäure
Authors: Khalifa Esam , Furrer Hans‐Jürg , Bieri Jost H. , Viscontini Max
Published: December 2004

Regiospecific deuteriation of folic acid

Introduction of a nitroso function at the N (10)‐position of folic acid activates the C(9)‐hydrogen atoms in such a way, that the exchange of H with D at this position, in NaOD‐solution, is extremely facilitated. This fact is utilized in the synthesis of 9,9‐dideuterio‐folic acid (IV), 7,9,9‐trideuterio‐folic acid (VII) and 7‐deuterio‐folic acid (IX). These three products are necessary for the 1H‐NMR.‐spectroscopical determination of the conformation of 5,6,7,8‐tetrahydrofolic acid and its derivatives.
Eine decarboxylative Dimerisierung von Maleinsäureanhydrid zu Dimethylmaleinsäureanhydrid
Authors: Baumann Marcus E. , Bosshard Hans
Published: December 2004

Decarboxylative Dimerization of maleic Anhydride to Dimethylmaleic Anhydride

We have found a simple synthesis of dimethylmaleic anhydride (1). Treatment of maleic anhydride (2) in boiling acetic acid in presence of 2‐aminopyridine gives, with decarboxylation, 1 in a one‐pot reaction in good yield.
Retro‐Aldol Reaction of Retinylidene‐1,3‐Diketones; Correlation with Biological Activity
Authors: Acton Nancy , Brossi Arnold
Published: December 2004

Retro‐Aldol reaction of retinylidene‐dimedone is reported.
Stoffwechselprodukte von Mikroorganismen. 193. Mitteilung. Ferrithiocin
Authors: Naegeli Hans‐Ulrich , Zähner Hans
Published: December 2004

Metabolites of Microorganisms. Ferrithiocin

The strain Tü 1998 from Streptomyces antibioticus produces besides the indicator antibiotics β‐ and γ‐rubromycins a new sulfur containing metabolite. This metabolite, called ferrithiocin, has been isolated in the form of a iron complex. The structure 1 of the iron‐free compound was elucidated by spectroscopic studies and chemical degradation.
Formation of N‐Hydroxy‐amines of Spin Labeled Nucleosides for 1H‐NMR. Analysis
Authors: Ozinskas Alvydas J. , Bobst Albert M.
Published: December 2004

Amine‐oxide radical 1a was efficiently converted to the corresponding N‐hydroxy‐amine 2a with sodium dithionite in acetone/water. This reaction was used to develop a procedure for monitoring the NMR. spectra of sodium dithionite reduced amine‐oxide radicals and of novel reduced amine‐oxide‐labeled nucleosides.
Notizen zur Synthese von 2‐Aminophenylsulfonen
Authors: Courtin Alfred , von Tobel Hans‐Rudolf , Auerbach Günther
Published: December 2004

Syntheses of some Alkyl, Cycloalkyl and Aryl 2‐Aminophenyl Sulfones

Syntheses of the alkyl, cycloalkyl and aryl 2‐aminophenyl sulfones 10 were achieved by oxidation of the corresponding 2‐nitrophenyl sulfides 7 to the 2‐nitrophenyl sulfones 9 followed by ethanolic Béchamp‐reduction. The sulfides 7 in turn were obtained either by reactions of 2‐nitro‐thiophenol (8) with the appropriate alkyl and cycloalkyl halides or of 2‐chloro‐nitrobenzene (5) with the relevant thiols. Condensation of 2‐nitrobenzenesulfinic acid (3) with bromoacetic acid in aqueous alkaline solution led ‐ presumably via 2‐nitrophenylsulfonylacetic acid (4) ‐ to methyl 2 nitrophenyl sulfone (1), reduction of which gave 2‐aminophenyl methyl sulfone (2). Treatment of 2‐aminothiophenol (11) with t‐butyl alcohol in aqueous sulfuric acid gave 2‐aminophenyl t‐butyl sulfide (12), which was acetylated to o‐t‐butylthio‐acetanilide (13). Oxidation of the latter to o‐t‐butylsulfonyl‐acetanilide (14) followed by hydrolysis led to 2‐aminophenyl t‐butyl sulfone (15).
Synthese von aromatischen Verbindungen mit einer prostaglandin‐ähnlichen Struktur
Authors: Kienzle Frank , Minder Rudolf E.
Published: December 2004

Synthesis of Aromatic Compounds with a Prostaglandin‐like Structure

The syntheses of two prostaglandin‐like molecules with aromatic nuclei instead of the usual 5membered ring are described.
Selectivity of Intramolecular Radical Addition Reactions Cyclization of ω‐Alkenyl Radicals
Authors: Bischof Peter
Published: December 2004

Small ω‐alkenyl radicals are known to cyclize exclusively via the unexpected Anti‐Markownikow pathway which leads to cycloalkyl‐methyl radicals as the observed reaction products. The strong kinetic preference diminishes, as the linking methylene chain becomes larger. Semiempirical calculations using MINDO/3‐UHF allow to classify the observed reaction pathways as individual probes between allowed (n = 1, route A) and electronically favourable (n = ∞, route M) routes of reactions.
Synthese von optisch aktiven, natürlichen Carotinoiden und strukturell verwandten Naturprodukten. IV. Synthese von (3R, 3′R, 6′R)‐Lutein. Vorläufige Mitteilung
Authors: Mayer Hans , Rüttimann August
Published: December 2004

Synthesis of optically active natural carotenoids and structurally related compounds. IV. Synthesis of (3R, 3′R, 6′R)‐lutein

The synthesis of (3R, 3′R, 6′R)‐lutein (19) according to the building principle C25+C15C40 is reported utilizing (R)‐4‐hydroxy‐2,6,6‐trimethyl‐2‐cyclohexen‐1‐one (4) as a readily available key intermediate.
Synthese von optisch aktiven, natürlichen Carotinoiden und strukturell verwandten Naturprodukten. VI. Synthese von Picrocrocin
Authors: Mayer Hans , Santer Jean‐Marie
Published: December 2004

Synthesis of optically active natural carotenoids and structurally related compounds. VI. Synthesis of Picrocrocin

The synthesis of picrocrocin (6), the bitter essence of saffron (Crocus sativus L.) is reported utilizing (3R)‐3‐hydroxy‐β‐cyclogeranyl acetate (3) as a readily available building unit.
Photochemische Reaktionen. 110. Mitteilung [1]. Zur Photochemie γ,δ‐Methano‐α‐enone
Authors: Ishii Keitaro , Wolf Hans Richard , Jeger Oskar
Published: December 2004

Photochemistry of γ,δ‐Methano‐α‐enones

Direct excitation (λ = 254 or ≥ 347 nm) converts the γ,δ‐methano‐α‐enone (E)‐10 into the isomeric ether 23 and the isomeric diene‐ketone 24. Furthermore, on 1π,π*‐excitation (λ = 254 nm) (E)‐10 undergoes an 1,3‐homosigmatropic rearrangement yielding the enone (E)‐25. In addition (E → Z)‐isomerization of (E)‐10 and conversion of 10 to the isomeric furan 28 is observed.

The isomerization (E)‐10 → 23, 24 and (E)‐25 proceeds by photocleavage of the C(γ), C(δ)‐bond, whereas the formation of 28 occurs by photocleavage the C(γ), C(δ)‐bond together with that of the C(γ), C(δ′)‐bond of 10.

On direct excitation the bicyclic diene‐ether 23 yields the methano‐enone 10, the dieneketone 24 and the tricyclic ether 29. Evidence is given, that the conversion 23 → 10 is a singulet process. On the other hand, the isomerization 23 → 24 and the intramolecular [2 + 2]‐photocycloaddition 23 → 29 are shown to be triplet reactions.

Irradiation (λ = 254 nm) of the homoconjugated ketone 24 yields the isomeric ketone 27 by an 1,3‐acyl shift. The excitation of the (E)‐enone 25 induces (E → Z)‐isomerization and photoenolization to give the homoconjugated ketone 26.
Differential Hydrogen Exchange During Biosynthesis of Cytochalasins B and D
Authors: Wyss Ronald , Tamm Christoph , Vederas John C.
Published: December 2004

Sodium [2‐13C,2‐2H3]acetate was incorporated into cytochalasin B(1) by Phoma exigua and into cytochalasin D (2) by Zygosporium masonii. The 13C‐NMR. and 2H‐NMR. of the metabolites showed that most of the deuterium was lost except at carbon atoms which are in polyketide chain‐initiating units.
Steroide und Sexualhormone. 260. Mitteilung. Limonoide Bitterstoffe V. Untersuchungen zur Stereochemie der C(8)‐Alkylierung von 7‐Oxo‐13,17‐secosteroiden
Authors: Schlatter Hans‐Rudolf , Graf Walter
Published: December 2004

On the Stereochemistry of the C(8)‐Alkylation of 7‐Oxo‐13,17‐secosteroids

It is shown that the title compounds, e.g. 10, can be alkylated with methyl iodide under strongly basic conditions to afford 8α‐methylated products, e.g. 11 (Scheme 1). The configuration was assigned by 13C‐NMR.‐spectroscopy, CD. measurements, and finally proved by a X‐ray crystallographic structure analysis.
Steroide und Sexualhormone. 261. Mitteilung. Quassinoide Bitterstoffe II. Partialsynthetischer Zugang zu Quassin: Überführung von Testosteron in eine Schlüsselverbindung mit angulärer 8β‐Methylgruppe
Authors: Pfenninger Johannes , Graf Walter
Published: December 2004

Partial Synthesis of Quassin: Synthesis of a Key Intermediate with an Angular 8β‐Methyl Group from Testosterone

A key intermediate in the partial synthesis of quassin (1) was synthesized in 28 steps starting from testosterone (9) (Scheme 3). The key features are: (i) The conversion of testosterone (9) into the 1α, 2β, 3β‐O‐substituted 4α‐methylandrostane 19 (Scheme 3) and its transformation into an intermediate 26 with the ring A partial structure of quassin (Scheme 4). (ii) The conversion of 19 to the vinylogous α‐hydroxyketone 5 (Scheme 6 and 7). (iii) The photochemically induced [2+2]‐cycloaddition of allene to hydroxyenone 5, affording the 8β, 14β‐cyclobutano‐derivative 6 (Scheme 2 and 8). (iv) The conversion of 6 into the key compound 7.

In connection with this last transformation a new method for the degradation of phenylselenoesters of carboxylic acids to the corresponding nor‐alkanes was developed (see Scheme 8). Details of this reaction will be published elsewhere [18].
Synthese bicyclischer Retinoide aus Retinsäure
Authors: Loeliger Peter , Mayer Hans
Published: December 2004

Synthesis of Bicyclic Retinoids

Thermally induced ring formation of 2 and of its 1‐alkenyl silyl ether derivative leads selectively to new bicyclic derivatives. The new retinoid 8 was synthesized and found to have potent biological activity.
Beitrag zur Analytik und Synthese von 3‐Hydroxy‐4‐oxocarotinoiden
Authors: Müller Robert K. , Bernhard Kurt , Mayer Hans , Rüttimann August , Vecchi Max
Published: December 2004

Contribution to the Analytical Separation and the Synthesis of 3‐Hydroxy‐4‐oxocarotenoids

(3RS,3′RS)‐Astaxanthin (= 3,3′‐dihydroxy‐β,β‐carotene‐4,4′‐dione, 1:1‐mixture of racemate and meso‐form; 1) can be separated into its optical isomers (3S,3′S)‐1a, (3R,3′R)‐1b and meso‐(3R,3′S)‐1c via the corresponding diastereomeric di‐(−)‐camphanates. Some aspects of the configurational stability of astaxanthin are discussed. ‐ HPLC. analysis of the (−)‐camphanates of 3‐hydroxy‐4‐oxocarotenoids provides, in suitable cases and supported by spectroscopic data, an analytical method for the simultaneous determination of constitution and chirality.
1,3‐Dipolare Additionen an 7‐Methylthieno[2,3‐c]pyridin‐1,1‐dioxid
Authors: Fischer Ulf , Schneider Fernand
Published: December 2004

1,3‐Dipolar Additions to 7‐Methylthieno[2,3‐c]pyridine 1,1‐dioxide

1,3‐Dipolar additions of diazomethane, diazoethane, ethyl diazoacetate, phenyldiazomethane and phenyl azide to 7‐methylthieno[2,3‐c]pyridine 1,1‐dioxide have been examined. The structures of the primary products e.g. 2, 8, 18, 25 have been established and their behaviour towards elevated temperatures and/or basic conditions was investigated. Under these conditions the primary products lost SO2 or N2 to yield e.g. 4, 11, 19, 21, 23, 27, 28.
Synthese und Eigenschaften von 6‐Desoxy‐6‐halogen‐Derivaten der L‐Ascorbinsäure
Authors: Kiss Joseph , Berg Klaus Peter , Dirscherl Adolf , Oberhänsli Willi E. , Arnold Wolf
Published: December 2004

Synthesis and Properties of 6‐Deoxy‐6‐halogeno‐Derivatives of L‐Ascorbic Acid

6‐Deoxy‐6‐chloro‐, ‐6‐bromo‐, ‐6‐iodo‐ and ‐6‐fluoro derivatives of L‐ascorbic acid have been synthesized and characterized. The physiological properties of the chloro derivative have been investigated. It shows a high antiscurvy activity.

The chloro‐ and bromo‐derivatives have been reduced to the corresponding deoxy compound, which is an interesting chiral intermediate for the preparation of rare ω‐deoxy sugars.
Evidence for an Iminium Cation Intermediate and its Non‐Oxidative Decarboxylation in a Cerium (IV)‐Mediated Oxidative Decarboxylation. Preliminary communication
Authors: Hanna Samir B. , Moehlenkamp Marilyn E.
Published: December 2004

Evidence is provided for the occurrence of a non‐oxidative decarboxylation in an iminium cation intermediate which is produced in an oxidative decarboxylation induced by cerium (IV).
The chiral recognition of guest molecules in trio‐o‐thymotide clathrates: A semi‐empirical approach. Preliminary communication
Authors: Gerdil Raymond , Allemand Jacques
Published: December 2004

The enantiomers of a chiral solvent can be enclathrated to a different extent in a crystal lattice consisting of tri‐o‐thymotide (1) molecules of a given handedness. This property affords a mean of studying the stereoselective interaction of a chiral environment with an enclosed chiral component. The general approach to account for the observed differences in stereoselectivity is based on the calculation and comparison of the minimum energies for the respective inclusion of enantiomeric guest molecules within a rigid cage of given chirality. An interpretation of the fair chiral recognition of 2‐bromobutane as opposed to the unselective inclusion of 2‐butanol is attempted.
Stereoselective binding of 11C‐labelled piquindone (Ro 22–1319) to dopamine‐D2 receptors in the living human brain
Authors: Sedvall G. , Ehrin E. , Farde L.
Published: December 2004

The stereoenantiomers of piquindone (Ro 22–1319), a new antipsychotic pyrroloisoquinoline derivative, were labelled with the positron‐emitting isotope 11C. Only the (−)‐enantiomer inherits most of the biological activity of racemic piquindone. The compounds were examined by positron emission tomography (PET) for dopamine‐D2 receptor binding in the living brain of Cynomolgus monkeys and healthy human subjects. After i.v. administration of tracer doses the (−)‐enantiomer but not the (+)‐enantiomer was shown to accumulate markedly in the dopamine‐D2 receptor rich caudate/putamen in both species. After (−) 11C piquindone injection, radioactivity in the human caudate/putamen, and the putamen/cerebellar activity ratio increased to about 2 during the hour when radioactivity could be followed. (−)11C piquindone binding in the monkey putamen was not easily displaceable by haloperidol. The results demonstrate that (−) but not (+)‐11C piquindone has a high affinity for dopamine‐D2 receptors in the living human brain. The results are compatible with the view that clinical administration of piquindone produces a long‐lasting effect on central dopamine‐D2 receptors. (−)11C Piquindone is a useful ligand for visualization of dopamine‐D2 receptor binding by PET and for analysing relationships between antipsychotic effects of piquindone and blockade of specific binding sites in the brain of schizophrenic patients.
The pitfalls of the dexamethasone suppression test: A biological marker of endogenous depression?
Authors: Klein H. E. , Berger M.
Published: December 2004

In the past few years there have been numerous publications which have stressed the value of the dexamethasone suppression test (DST) as a diagnostic marker of endogenous depression. Our own studies in 333 psychiatric inpatients and 121 healthy subjects did not reveal a differential diagnostic use for the DST. This result is in good agreement with other results in the literature. Our data demonstrate that intervening variables such as severity of illness, weight loss, sleep disturbances, situational stress, drug and alcohol withdrawal, and the pharmacokinetics of dexamethasone have an important influence on DST results, regardless of the diagnostic classification.
Residual effects of zopiclone on subsequent daytime functions in normal humans
Authors: Mizuki Yasushi , Hirano Hitoshi , Miyoshi Akira , Hamasaki Junko , Yamada Michio , Tanaka Masatoshi , Inanaga Kazutoyo
Published: December 2004

The influence of zopiclone and nitrazepam on arousal level, muscle strength, psychomotor performance and memory function using the photopalpebral reflex (PPR), critical flicker frequency (CFF), tapping test, pursuit rotor test (PRT), choice reaction test (CRT) and memory drum test (MDT) were investigated on the day following drug administration. After the control tests were completed at 1800 h, nine healthy male university students were given zopiclone 10 mg, nitrazepam 10 mg and placebo in a double‐blind, crossover design at 2300 h. The performance on the tests, as well as the recording of subjective assessments, were repeated at 0800, 1100 and 1400 h the next day. Both nitrazepam and zopiclone produced a prolongation of PPR latency and a decrease of CFF. The effects of zopiclone were weaker and shorter in duration than those of nitrazepam. Tapping rate, PRT and CRT improved or did not change, and there were no significant differences between the drugs. The MDT was impaired by both drugs in the morning, with nitrazepam continuing to produce memory impairment, while zopiclone did not produce further deterioration. No significant changes were observed in the subjective assessment of the subjects. These results suggest that a medium dose of zopiclone lowers arousal level and impairs memory, especially during the morning following drug administration, but produces no change in muscle strength, psychomotor performance or self‐assessment. Finally, the residual effects of zopiclone appear to be weaker than those of nitrazepam.
Lithium prophylaxis of periodic hypersomnia unaccompanied by affective symptoms: A further adolescent case
Authors: Abe Kazuhiko
Published: December 2004

Lithium was administered to a 15‐year‐old boy who had four episodes of hypersomnia following his recovery from influenza. The episodes lasted about a week and were not associated with depression, hypomania or polyphagia, but were heralded by depersonalization. The episode did not recur during prophylactic lithium administration in the latter half of 1983, but recurred later on three occasions when lithium was discontinued or taken less than prescribed. This finding, together with a few cases reported in the literature, appear to indicate that lithium is potentially effective in preventing hypersomnia even in cases unassociated with affective symptoms. However, its preventive effect may not always be complete, as depersonalization recurred in the present case in March 1985 when the serum lithium level was in the therapeutic range.
Plasma concentration of neuroleptic and serum prolactin in patients chronically receiving depot fluphenazine: No evidence of tolerance
Authors: Cohen Bruce M. , Chouinard Guy , Waternaux Christine , Schachter Hyme , Jones Barry , Sommer Barbara R.
Published: December 2004

The authors determined neuroleptic dose, plasma level of drug, and serum prolactin in 76 outpatients receiving depot fluphenazine. The patients had received neuroleptic treatment for periods ranging from 3 to 23 years (median 13 years). Plasma level of drug correlated with dose (rs = 0·73, p>0·0001). Prolactin levels were linearly correlated with dose (rs = 0·42, p = 0·0001) and plasma level of drug (rs = 0·64, p>0·0001). There was a tendency for dose and, concomitantly, plasma level of drug, to decrease with age (rs = −0·29, p = 0·01, for each). However, dose, plasma level of drug adjusted for dose, and serum prolactin adjusted for plasma level of drug did not correlate with duration of treatment. Neither did any of these measures correlate with treatment duration when adjusted for age. The findings suggest that while older patients were given lower doses of medication, changes in the metabolism of fluphenazine or tolerance to its prolactin‐elevating effects did not occur during extended treatment.
Residual effects of temazepam versus nitrazepam on memory and vigilance in the normal subject
Authors: Bourin M. , Hubert C. , Colombel M. C. , Larousse C.
Published: December 2004

Eighteen normal volunteers with no sleep difficulties were given psychological tests and asked to fill out a self‐evaluation questionnaire 11 h after administration of a hypnotic drug, nitrazepam 5 mg or temazepam 20 mg (in the form of soft gelatin capsules), which was compared to a placebo. Subjects received all three treatments at 1‐week intervals, with the administration sequence determined by drawing lots. The tests used were the images test, the digit/symbol substitution test (DSST), choice reaction time and critical fusion frequency. The two benzodiazepines proved to be efficient hypnotics, improving sleep induction and quality, but nitrazepam caued residual effects, as evidenced by difficult awakening and modified behaviour in the morning, as well as disturbed performance during DSST.
Changes in cation transport during affective illness: Do they have therapeutic implications?
Authors: Wood Andrew J.
Published: December 2004

Changes in some of the specific mechanisms which transport cations across cell membranes have been demonstrated in patients suffering from affective illness. A number of novel strategies have been evaluated in the management of both mania and depression, based on the following observations: (1) State‐related changes in cation transport; (2) The effects of established psychotherapeutic drugs upon cation transport; and (3) theories regarding control of membrane ion flux. This article reviews the background to these novel strategies and evaluates the possible significance of changes in a number of different cation transport systems to the treatment of the affective disorders.
Monoamine function in anxiety and depression: Information from neuroendocrine challenge tests
Authors: Nutt D. J. , Cowen P. J.
Published: December 2004

Neuroendocrine challenge tests are being increasingly employed to assess brain monoamine function in man. This review describes some recent studies which have used neuroendocrine tests to investigate brain noradrenaline (NA) and 5‐hydroxytrytptamine function (5‐HT) in patients suffering from anxiety and depression. A number of abnormalities, particularly in the noradrenergic system, have been identified, and some interesting similarities and contrasts have emerged between panic disorder and depression. Challenge tests can also be used to identify adaptive changes in monoamine pathways following administration of psychotropic drugs. Tolerance has been demonstrated to the ability of benzodiazepines to reduce brain 5‐HT function, a finding which could underlie some of the symptoms of the withdrawal syndrome. In addition, it seems likely that long‐term administration of tricyclic antidepressants stabilizes NA synaptic function.
Cognitive sequelae of 1,4‐ and 1,5‐benzodiazepines
Authors: Cull Christine A. , Trimble Michael R.
Published: December 2004

Two studies were carried out comparing the effects of clobazam (a 1,5‐benzodiazepine), and clonazepam (a 1,4‐benzodiazepine), with placebo, in a double‐blind crossover design. Ten and nine healthy male volunteers, respectively, participated in each study. Performance on a series of automated psychological tests was assessed on four occassions: prior to any treatment; at the end of the first 2‐week treatment period; following a 2‐week washout phase, and again at the end of a second 2‐week treatment period. Blood samples were collected at the last three occasions for analysis of drug levels. Minimal impairment in cognitive functioning was found with clobazam, only two of the more complex tasks being affected. In contrast, the pattern of findings with clonazepam suggests that it may have adverse affects on a broader range of functions. A relationship was found between performance on three measures and serum level of clobazam, such that response latency decreased with increasing serum level. In contrast, for clonazepam, a significant correlation was found on one task, in the direction of increased response latency with increasing drug level. These findings are discussed in the light of clinical literature about the use and efficacy of these two benzodiazepines, as antiepileptic agents.
Irreversible hypothyroidism following prolonged use of lithium
Authors: Bovier P. , Toutoungi M. , Hilleret H. , Dick P. , Tissot R.
Published: December 2004

A 66‐year‐old white man developed hypothyroidism after 5 years of lithium therapy. The condition persisted after switching to carbamazepine. Thyroid hormone substitution improved the response to psychotropic drugs and has helped to maintain stable mood.
Performance and mood following partial sleep deprivation: A randomized, double‐blind crossover study of zopiclone, triazolam, flunitrazepam, ethanol and placebo
Authors: Wickstrøm Egil , Godtlibsen O. B. , Bredesen J. E. , Jensen M. H.
Published: December 2004

The effects of zopiclone 7.5 and 15 mg, triazolam 0.25 and 0.5 mg, flunitrazepam 1 and 2 mg, ethanol and placebo on performance, mood and sleep onset latency after partial sleep deprivation, were compared in a randomized, double‐blind, crossover, single‐dose study. Sixteen healthy volunteers of both sexes, aged 21–31 years, were included in the study. The overall assessment of the total psychological measurement indicated that zopiclone 7.5 mg, triazolam 0.25 mg and ethanol (Cmax = 0.40 parts per thousand) did not affect the daytime performance of an unacceptable degree even when given late at light. The findings for flunitrazepam 1 mg were not so uniform, but also seemed acceptable. Zopiclone 15 mg, triazolam 0.5 mg and flunitrazepam 2 mg were rated as not acceptable alternatives. No significant differences were shown concerning mood. The overall assessment for sleep onset latency and subjective alertness indicated that zopiclone 7.5 mg and triazolam 0.25 mg had a more appropriate profile than the other drugs and doses tested.
The effects of paroxetine and other antidepressants in combination with alcohol in psychomotor activity related to car driving
Authors: Hindmarch I. , Harrison C.
Published: December 2004

Ten healthy female volunteers received single doses of amitriptyline 50 mg (AMI); mianserin 20 mg (MIA); trazodone 50 mg (TRA); paroxetine 30 mg (PAR) and placebo (PLA), with or without a ‘social’ dose of alcohol (ALC) in a double‐blind, balanced crossover study where each subject acted as her own control.

Psychomotor activity related to car handling ability was measured on a battery of tests at 1.5 and 4 h following study drug. The tests included tracking accuracy (RMS) and latency of response to a peripheral stimulus (RT) as measures of sensorimotor co‐ordination; the Maddox Wing test (MW) for the balance of extraocular muscles; critical flicker fusion threshold (CFF) for overall levels of CNS activity; choice reaction time (CRT) for psychomotor performance and the latency of brake reaction time (BRT) measured in a driving simulator. Subjective ratings of sedation were measured on line analogue ratings scales (VARS) and the Leeds Sleep Evaluation Questionnaire (LSEQ).

When compared to PLA on objective tests, AMI significantly impaired RMS, RT, MW and CFF at 4 h post‐drug and AMI + ALC similarly impaired the same measures and BRT. MIA produced a significant impairment of RT, MW, CFF and CRT at both 1.5 and 4 h. MIA + ALC further impaired RMS at 1.5 and 4 h and BRT at 4 h. TRA showed a detrimental activity on CFF at 1.5 h and CFF, RT, MW and BRT at 4 h. TRA + ALC produced a greater effect than TRA alone at 1.5 h and significantly impaired RT, MW, TRT, BRT. There were no significant effects of TRA + ALC at 4 h. PAR alone had no measurable effect on any of the test measures at either 1.5 or 4 h after treatment. PAR + ALC impaired RT at 1.5 and 4 h but had no effect on any other measures at either test times. Indeed, compared to PLA, CFF levels were significantly improved at 4 h following both PAR and PAR + ALC and improvements in RRT were also measured 4 h after taking PAR.

Subjective measures (VARS) compared to placebo, show AMI at 4 h and AMI + ALC at 1.5 and 4 h, both MIA and MIA + ALC after 1.5 and 4 h, TRA + ALC after 1.5 h and PAR + ALC at 4 h to have significant sedative activity.

In this placebo‐controlled study, acute doses of AMI 50 mg, MIA 20 mg and TRA 50 mg alone and with alcohol showed evidence both of significant impairment of psychomotor skills related to vehicle handling and of perceived sedation at 1.5 and / or 4 h following treatment. Under identical circumstances PAR 30 mg produced no detrimental effect on any of the test measures, there was an impairment with PAR + ALC of one component of a divided attention task and on a subjective measurement of sedation.
Transdermal scopolamine: Effects upon psychological performance and visual functioning at sea
Authors: Parrott A. C.
Published: December 2004

The effects of transdermal scopolamine upon, psychological task performance, subjective feeling state, and visual functioning, were assessed with 28 naval volunteers at sea. The battery of assessment measures was given before drug administration, and following 24‐hour periods on transdermal scopolamine and transdermal placebo. Code substitution task performance was not affected, but letter cancellation errors were significantly increased, indicating an impairment in sustained attention with transdermal scopolamine. Subjective reports of dry mouth and drowsiness were significantly more frequent under scopolamine. Visual changes were also noted, with visual near point significantly increased for the overall group, and one hypermetropic subject developing a marked visual acuity decrement and severe blurred vision, following transdermal scopolamine.
Dose‐effect study of levomepromazine on psychomotor and memory tasks in healthy volunteers
Authors: Warot D. , Krebs M. O. , Bensimon G. , Payan C. , Danjou Ph. , Lacomblez L. , Puech A. J.
Published: December 2004

The effects of single doses of levomepromazine (3, 6 and 12 mg) on psychomotor skills and memory tasks, as well as haemodynamic and pupil diameter parameters, were assessed in 12 normal volunteers. Each subject was given three of the four treatments, at a weekly interval in a double‐blind crossover randomized balanced incomplete‐block design. The three doses and a placebo were monitored using a battery of tests including critical flicker fusion (CFF), choice reaction time (CRT), subjective ratings and memory tasks before, 3 and 6 hours after drug intake. Supine standing blood pressure and pupil diameter were recorded at the same times.

Compared to placebo, levomepromazine impaired both subjective and objective vigilance measures in a dose‐related manner, with 3 mg affecting only some subjective ratings, while 12 mg impaired most objective and subjective vigilance evaluations with a moderate effect on memory tasks (i.e. anterograde amnesia). Pupil diameter was reduced by the evaluations with a moderate effect on memory tasks (i.e. anterograde amnesia). Pupil diameter was reduced by the three doses. In conclusion, levomepromazine at low doses induced a sedative effect the intensity and duration of which are compatible with its use as an hypnotic.
Can animal tests of anxiety detect panic‐promoting agents?
Authors: Johnston Amanda L. , File Sandra E.
Published: December 2004

Sodium lactate (60 and 120 mg/kg), isoproterenol (0·1–0·6 mg/kg), and yohimbine (1·25‐5 mg/kg) were investigated in two animal tests of anxiety (the elevated plus‐maze and the social interaction test). Rats were also scored for panic‐like behaviour following administration of these panic‐inducing agents and following inhalation of air supplemented with CO2 (5 and 20 per cent). None of the drugs changed the time spent in social interaction or evoked panic‐like behaviour. In the elevated plus‐maze, sodium lactate was without effect. The highest dose of isoproterenol (0·6 mg/kg) reduced the percentage of time spent on the open arms, and yohimbine reduced both the percentage of entries made onto the open arms and the percentage of time spent on the open arms, indicating anxiogenic activity. The lack of a strong anxiogenic profile with the pro‐panic compounds suggests that anxiety and panic may be biologically distinct.
Vanadium in psychiatry
Authors: Chiu Leo P. W. , Rimón Ranan
Published: December 2004

It has been suggested that vanadium, a potent reversible inhibitor of sodium‐potassium‐sensitive adenosine triphosphatase (Na+/K+‐ATPase), is of aetiological importance in manic‐depressive illness. The present review submits to critical scrutiny the pertinent literature of (1) the existence of vanadium excess in various tissues; (2) Na+/K+‐ATPase activity in erythrocytes from patients with affective illness; and (3) treatment modalities applied to reduce body vanadium or to increase ‘sodium’ activity. Finally, data on vanadium deficiency as well as vanadium poisoning are discussed.
A psychopharmacological study to assess anti‐muscarinic and central nervous effects of medifoxamine in normal volunteers
Authors: Randhawa M. A. , Hedges A. , Johnston A. , Turner P.
Published: December 2004

Ten volunteers received single oral doses of medifoxamine 50 and 100 mg, atropine 1 mg, amitriptyline 50 mg or placebo in random order based on a Latin square design under double‐blind conditions. Tests of anti‐muscarinic and central nervous activity were carried out at hourly intervals for 6 hours. The tests were measurements of salivary volume, heart rate, pupil diameter, manual dexterity, choice reaction time, critical flicker frequency, and visual analogue rating scales for sedation, dryness of mouth, appetite, nausea and quality of sleep. The positive controls atropine and amitriptyline produced effects which were significantly different from placebo, but neither dose of medifoxamine produced any anti‐muscarinic activity nor influenced alertness.
Ritanserin in the treatment of generalized anxiety disorders: A placebo‐controlled trial
Authors: Pangalila‐Ratu Langi E. A. , Jansen A. A. I.
Published: December 2004

In a double‐blind trial, 22 patients treated with 5 mg b.i.d. of the selective serotonin‐S2 antagonist ritanserin for 4 weeks were compared with 26 patients treated with placebo for generalized anxiety disorder (DSM III: 300·02). Symptoms were assessed using the Hamilton Anxiety Rating Scale (HARS) and the Visual Analog Mood Rating Scale (Norris, Bond and Lader). Patients were further evaluated by means of a clinical global impression.

At the end of the treatment ritanserin was significantly superior to placebo in its effect on the psychic cluster of the HARS, especially for the items insomnia (already after 1 week of treatment) tension and depressed mood. According to the Mood Rating Scale, the ritanserin‐treated patients rated themselves as calmer, more energetic and more relaxed. This significant symptomatic improvement with ritanserin was confirmed by the clinical global impression. As only one side‐effect was reported in the ritanserin group versus five in the placebo group, the results suggest that ritanserin provides a novel well‐tolerated therapy for outpatients suffering from generalized anxiety disorder.
Effects of ro 15–1788 on the vigilance performance of sleep‐deprived men
Authors: O'Hanlon J. F. , Vermeeren A.
Published: December 2004

Ro 15–1788, a selective ‘benzodiazepine’, was recently recognized as possessing either intrinsic pharmacological activity or the capability of blocking activities of one or more hypothetical endogenous ligands at the benzodiazepine receptor. A study was designed to test the hypothesis that Ro 15–1788 effects will reverse those of sleep deprivation on the vigilance performance of healthy volunteers. Eight subjects were trained and then tested in five trials at hourly intervals over a morning following normal sleep (baseline session). On the latter occasions the subjects were treated 15 min before the 1st trial with Ro 15–1788, 3 mg, i.v. and placebo according to a double‐blind, counterbalanced, crossover design. Changes in the subjects' vigilance performance from baseline indicated first the expected overall effect of sleep deprivation; and secondly, a significant (p<0.05 or lower, depending upon the parameter and statistical test) interaction of treatments and trials. Placebo was followed by consistently poor performance over all trials. Drug was followed by superior performance in the first trial (nearly the same as baseline) and increasingly poorer performance on subsequent trials. The results of the trial‐by‐trial comparisons indicated that the significant interaction was attributable to a biphasic drug effect.
Assessment by antipyrine test of bupropion enzymic induction in elderly depressed patients
Authors: Bourin M. , Colin J. N. , Kergueris M. F. , Ortega A. , Nebout T. , Peck A. W.
Published: December 2004

Bupropion, a novel antidepressant drug, is known to be a moderate hepatic metabolism‐inducer in rodents at high doses but not in young human volunteers. Eleven elderly depressed patients (mean age 76·9 ± 8·7 years) entered in the study and received 100 mg of bupropion t.i.d. for 28 days. An antipyrine test was performed before and at day 28 of therapy. Antipyrine was taken orally (15 mg/kg) at 8 a.m. and blood samples were drawn at 11 a.m., 2, 5, and 8 p.m. Plasma levels were assayed using a GLC method. Results show a slight but significant increase of apparent clearance (+30 per cent) and decrease in the half‐life (–14 per cent) of antipyrine. Difference between these results and previous results in young volunteers might be explained by the usual decrease of hepatic function described in elderly patients. Bupropion can be considered in elderly people as a slight hepatic enzyme‐inducer.
The government, the pharmaceutical industry and the economics of psychotropic drug prescribing
Authors: Cantopher Tim , Guy Edwards J. , Olivieri Stefano
Published: December 2004

The numbers of NHS prescriptions for tranquillizers in England are falling, having peaked in the mid‐1970s. This fall is not mirrored by prescriptions for other psychotropic drugs. Drug costs have risen over the past ten years faster than inflation, though a temporary fall in the price of Valium (diazepam) and Librium (chlordiazepoxide) had a profound effect on this trend. The economics of psychotropic drug prescribing, including the reasons for these increases, are considered. Ways of cutting the drug bill are examined.
Body sway and the effects of psychoactive drugs — a review
Authors: McClelland G. R.
Published: December 2004

The published literature on the effects of single oral doses of psychoactive drugs on body sway in normal healthy young volunteers has been reviewed. Several methods are used to quantify sway objectively, including mechanical devices, balance platforms, and non‐contact techniques. No one method emerges as being most appropriate for use in psychopharmacology. Total sway path and Fourier analysis are the variables commonly studied. Although many factors can influence sway they have little impact on well‐designed studies. Ethanol has been consistently shown to increase body sway at doses above 0·5 g/kg, benzodiazepines also increase sway; both probably acting at a central site(s). Various other psychoactive drugs have been shown to increase sway; however, none has yet been shown to decrease the amount of sway in normal subjects. The objective measurement of body sway is therefore a useful test for inclusion in a battery of tests for studies in human psychopharmacology. It also has a potential application in other areas of research requiring the assessment of central nervous system function, and in other subject groups, such as the elderly.
Methylxanthines cause a decrease of prolactin plasma levels in healthy non‐pregnant women
Authors: Casas M. , Ferre S. , Rodriguez J. , Jane F.
Published: December 2004

The effect of different doses of caffeine and theophylline (2, 4 and 8 mg/kg p.o.) on prolactin plasma levels in volunteer non‐pregnant women has been analysed. The study of basal serum prolactin levels demonstrated great interindividual variation with a good reproducibility of the basal prolactin pattern for all subjects. We found a slight but significant decrease in prolactin levels following xanthine administration. The possible dopaminergic agonism of xanthines and the consequent social implications are discussed.
Clinical evidence of the effectiveness of vinpocetine in the treatment of organic psychosyndrome
Authors: Blaha L. , Erzigkeit H. , Adamczyk A. , Freytag S. , Schaltenbrand R.
Published: December 2004

This study was multi‐center, double‐blind, placebo controlled, and involved random assignment of patients. It was carried out in the ambulances of general practitioners and internists. The aim of the study was to evaluate the efficacy and tolerance of vinpocetine in patients with a mild to moderate severe organic psychosyndrome caused by cerebral blood supply disorders and / or metabolic disturbance. Dosage of 5, 10 and 20 mg vinpocetine or placebo t.i.d. Were examined over a treatment period of 12 weeks with 282 patients.

The study design required a programmed, standardized investigator training. In addition, a pre‐study test was used to ensure correct and uniform execution of study control.

The Clinical Global Impression (CGI) and the performance test SKT showed statistically significant differences between the verum groups and placebo. Self‐assessment of mood and performance capability (EDS), and life satisfaction (LZ) confirmed these outcomes. The results of the Hachinski Ischaemia Scores did not permit an unequivocal classification of patients into primary degenerative and multi‐infarct dementia types. The higher dosage groups experienced a greater therapeutic advantage than did the 5 mg t.i.d vinpocetine dosage group. Only a few side effects were observed.