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National audience; The history of ketamine begins in 1962, when Calvin Stevens of the pharmaceutical laboratory Parke-Davis synthesizes it from phencyclidine, a molecule with psychodysleptic, hallucinogenic and dissociative properties. Following the first administration of ketamine to humans in 1964 in Jackson prison (Michigan, USA), its dissociative effects associated with short anaesthesia were reported, and a patent for its human use was filed in 1966. In the 1990s, the discovery of opioid-induced hyperalgesia sparked interest in ketamine as an analgesic. In recent years, the human use of ketamine, and in particular its esketamine enantiomer, has shifted towards the treatment of depression. The first cases of ketamine abuse were reported in 1992 in France, leading to special surveillance by the health authorities, and its inclusion in the list of narcotic drugs in 1997. Today, ketamine has become an attractive substance for recreational use, gradually emerging from alternative techno circles to spread to more commercial party scenes. These elements represent a public health concern, associated with the risk of developing new chemically synthesized analogues, the harmful effects of which are still little known.

We describe a calix[6]arene-based wheel that binds, in non-polar media, a stilbazolium salt to yield a mixture of pseudorotaxane orientational isomers. The isomers abundance ratio evolves with time and can be reversibly tuned by playing on temperature. The spectroscopic properties, and notably the emission spectrum, of the bound guest depend on its orientation inside the non-palindromic wheel, suggesting such a system as a switch with spectroscopic readout., info:eu-repo/semantics/published

Background: Enantioselective analysis of amphetamine (AM), methamphetamine (MA), 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA), and 3,4-methylenedioxyethylamphetamine (MDEA) helps interpret toxicological results. Methods have been described for various matrices, but so far not for oral fluid, a matrix of increasing importance in testing for drugs of abuse, especially in the context of driving under the influence of drugs (DUID). Methods: After dilution with 200 μL carbonate buffer (pH 9), oral fluid samples (10–50 μL) were derivatized with S-heptafluorobutyrylprolyl chloride. The resulting diastereomers were extracted into 100 μL of cyclohexane, separated by gas chromatography (HP-5MS column), and detected by mass spectrometry in the negative-ion chemical ionization mode (GC-NICI-MS). The method was validated and applied to samples from a controlled study with MDMA and from authentic DUID cases. Results: The derivatized AM, MA, MDA, MDMA, and MDEA enantiomers were well separated from each other. The method was linear from 5–250 μg/L per enantiomer of MDA and from 25–1250 μg/L per enantiomer of AM, MA, MDMA, and MDEA. With the exception of MDEA, analytical recoveries, repeatability, and intermediate precision were within required limits. The analyte concentrations and enantiomer ratios in the application samples correlated only weakly with corresponding published plasma data. Conclusions: This sensitive, reliable, and fast GC-NICI-MS assay enantioselectively measures AM, MA, MDA, and MDMA in oral fluid samples. Prediction of plasma concentrations and enantiomer ratios from respective oral fluid data is not possible.

Structural diversity oriented synthesis aims to fulfill the unoccupied tridimensional "chemical space" gap left by traditional chemical libraries. Through the development of novel synthetic strategies relying on divergent reactions, chemist is now able to realize in only two or three steps such library that ensures the access of a large number of products having a good quality in term of structural diversity. A few examples are presented to illustrate how this can be done in the context of increasing molecular complexity and diversity devoted to the discovery and optimization of bioactive compounds.

This work is focused on the synthesis and study of 3π-2spiro molecules, DiSpiroFluorene-IndenoFluorene (DSF-IF), having different structures. These compounds are aimed to be used as blue light emitting layer in OLED. The first chapter describes the working principles of OLEDs and their different structures. It focuses then on different approaches of molecular engineering towards ambipolar molecules that can be used in single layer devices. The second chapter is devoted to the study of two different families of DSF-IF isomers that are obtained through one and the same synthetic intermediate. The different structure of the indenofluorene backbone, (1,2-b) or (2,1-a), leads to different properties, mainly because of intramolecular π-π interactions. The third chapter is related to the development of functionalized DSF-IF with electron donor and/or acceptor groups. The impact of the electron donor or acceptor groups substituted on the DSF-IF are discussed, especially the intramolecular charge transfer phenomena. In the last part, some of these new molecules have been tested as emitting layers in OLEDs; Ce travail porte sur la synthèse et l'étude de molécules d'architecture 3π-2spiro, DiSpiroFluorène-IndénoFluorène (DSF-IF), de structures différentes. La finalité de ces composés est leur utilisation en tant que couche émissive de lumière bleue dans des diodes électroluminescentes organiques (OLED). Le premier chapitre bibliographique décrit tout d'abord le principe de fonctionnement des OLEDs et leurs différentes structures. Il se poursuit par la description de différentes approches d'ingénierie moléculaires visant à obtenir des molécules ambipolaires capables d'être utilisées dans des dispositifs monocouches. Le second chapitre concerne l'étude de deux familles d'isomères de DSF-IF obtenus au travers d'un seul et même intermédiaire de synthèse. La structure différente du corps indénofluorène, (1,2-b) ou (2,1-a), entraîne des propriétés différentes, en particuliers liées à des interactions π-π intramoléculaires dans les isomères de géométrie (2,1-a). Le troisième chapitre est consacré à la mise au point de DSF-IF fonctionnalisés par des groupements donneur et/ou accepteurs d'électrons. L'impact de l'ajout de groupements transporteurs de charges sur le corps DSF-IF est discuté et en particulier les phénomènes de transfert de charge intramoléculaires. Enfin, le dernier chapitre traite de l'étude de certaines molécules synthétisées précédemment en tant que couches émissives dans des OLEDs.

Among the numerous applications of cyclodextrins in separative sciences, organic synthesis, pharmacy and biotechnology, supramolecular host-guest complexation plays a major role due to the macrocyclic geometry of the host and the hydrophobic properties of the inner cavity. A less developed application of native or chemically modified cyclodextrins is their use for the preparative enantioseparation using co-crystallization methods. The intrinsic chirality of cyclodextrins enables the crystallization of diastereomeric compounds when the macrocyclic host interacts with a racemic mixture of the guest molecule. The preferential nucleation of one of these compounds, the amplification of the enantiomeric enrichment during the crystal growth and successive recrystallizations may lead to complete chiral separations. This alternative method of chiral discrimination is illustrated here with permethylated beta-cyclodextrin and (+/-)-1-(4-bromophenyl)ethanol. The results could be partially rationalized thanks to crystal growth studies and through the systematic determination of crystal structures by X-ray diffraction on single crystals. This study has shown that both inclusion geometries and crystal packing features determine the capability of modified cyclodextrins for chiral discrimination by crystallization.

A large number of pharmaceutical drugs possess one or more centers of asymmetry giving rise to enantiomers whose pharmacological properties and toxicity are often different. At successive stages of drug discovery, the enantiomers of any chiral molecule must be isolated and analyzed and their enantiomeric purity determined. The electrophoretic and chromatographic techniques have become the most important tools to routinely determine the enantiomeric purity of pharmaceutical molecules. Liquid chromatography (LC) is the most widely used because of the large number of columns marketed, the variety of selectivities available and the ease at which analytical results can be scaled up to the preparative level. In particular, more than 80% of enantioseparations of pharmaceutical molecules are successful with polysaccharide-derivative stationary phases (cellulose, amylose) for multiple system solvents (normal phase, polar organic phase or reverse phase). Complementary selectivities can be achieved more rapidly with other types of stationary phase (glycopeptides, Pirkle, cyclodextrins) but their application is hindered by problems of stability (proteins) or transfer to the preparative scale (cyclodextrins). At the present time, glycopeptide phases offer very promising prospects for the separation of amino acids (and derivatives) and peptide enantiomers. In addition, because of its faster analysis and environmental benefits, supercritical chromatography (SFC) has given rise to renewed interest. Capillary electrophoresis (CE) is an orthogonal technique complementary to chromatographic methods. Its principle involves the formation of diastereoisomer complexes after addition of anionic (HS-beta-CD, HS-gamma-CD CM-beta-CD) or neutral (TM-beta -CD, HP-beta-CD, DM-beta-CD, HP-gamma-CD) cyclodextrins to the running buffer. Compared to LC, CE analyses are cheaper (no chiral column, no solvent, low consumption of chiral selector) and peak efficiencies are higher by one order of magnitude. Furthermore, the mechanism of separation in CE is much simpler to understand and predict. However, the low capacity of CD column prevents its use at the preparative scale and consequently hampers its development as an analytical technique. Today, the increasing number of new drug candidate molecules produced daily, and for which the determination of enantiomeric purity is required before further development, encourages the pharmaceutical industry to seek fast chiral analysis methods based on simple protocols. The speed of analysis is more important than resolution. Thus, screening strategies are implemented with HPLC, SFC and CE including the selection of a limited number of chiral selectors with strong powers of chiral recognition.

Various aspects of the chiral discrimination in the solid state are examined. The interests of the conglomerate are illustrated by two applications: the preparative enantiomeric purification and the preferential crystallization. The latter process is described by a careful examination of the heterogeneous equilibria that govern the crystallization and its selectivity. Two variants of the preferential crystallization are detailed. A "good" example illustrates the productivity at the laboratory scale. The ratio between homochiral interaction energies and heterochiral interaction energies at different (hkl) interfaces are involved in the "difficult" cases where the entrainment effect is limited.

Betablockers reduce mortality by 30% after a myocardial infarction. The anti anginal effects of betablockers are also very well established. They improve survival after a non cardiac surgery in patients at high cardiovascular risk. Atenolol should nevertheless be avoided for primary cardiovascular protection in patients with hypertension older than 55 yrs. This may not apply to more selective betablockers, or betablockers with vasodilator effects. We also now have another bradycardic agent, ivabradine, which may prove very useful in heart failure patients who cannot tolerate a betablocker.

Citalopram, a selective serotonin reuptake inhibitor, is composed of 2 enantiomers, R-citalopram and S-citalopram, 2 different non-superimposable mirror image forms of the same molecule. Separating these 2 enantiomers has enabled studying their individual properties. Citalopram's pharmacologic activity is centered on the S enantiomer's high affinity for the serotonin transporter which is twice as high as citalopram's and 30 to 40 times higher than R-citalopram. This leads to an inhibition of serotonin reuptake two times higher for escitalopram compared with citalopram and confirms that citalopram's pharmacologic activity is due to the S-enantiomer. Contrary to what might be expected, the effect of escitalopram (DCI of S-citalopram) is not superimposable on an equivalent dose of citalopram but is superior. Several hypotheses could explain this superiority. First, conversions of the S-enantiomer into the R-enantiomer may occur, but there is no reason why this phenomenon would happen more when both enantiomers are present than when escitalopram is alone. Furthermore, pharmacokinetic studies have shown that S or R configurations are stable in vivo. Second, a particular action of R-citalopram may influence the S-enantiomer's kinetic from intestinal absorption to blood-brain barrier. But concentrations of both enantiomers in the frontal cortex are the same. Therefore, R-citalopram does not interfere with escitalopram's kinetic. Finally, interactions may appear at the synaptic level. Results of experimentation, after in situ injection to the cortex level, confirm that an interaction between the 2 enantiomers takes place at that level. A direct negative interaction of R-citalopram on one or several effectors that create the antidepressive effect seems justified. This negative interaction has been studied in depth. Animal models have shown that the R-enantiomer has no antidepressive potential and when associated with escitalopram prohedonic effects disappear. Escitalopram is more powerful than citalopram in reducing anxiety but the presence of R-citalopram reduces the positive effects of escitalopram. We then may conclude that R-citalopram antagonizes the antidepressive effects of escitalopram and that its presence limits the therapeutic effect and reduces the speed of action of citalopram. The antagonism of escitalopram by R-citalopram was not expected and one hypothesis is that a direct interaction between the 2 enantiomers may occur on a particular site of the serotonin transporter. Results have shown that R-citalopram has a significant affinity only for the allosteric site of the transporter, which regulates the affinity of the ligand for the active site at the origin of serotonin reuptake inhibition. Unlike citalopram, escitalopram's pharmacologic action is not blocked by R-citalopram explaining its greater therapeutic efficacy and more rapid mode of action.

The use of levobupivacaine and of ropivacaine may increase the safety of regional anaesthesia. These pure enantiomers have similar pharmacokinetic properties as those of the racemic mixtures. However, they are less cardiotoxic than the racemic mixtures, especially at the high heart rate usually encountered in infants. We may then recommend the use of these agents in the paediatric patients.

Apoptotic pathways in breast cancer cells are frequently altered, reducing the efficiency of radiotherapy. Conjugated linoleic acid (CLA), known to trigger apoptosis, was tested as radiosensitizer in breast cancer cells MCF-7 and MDA-MB-231. The CLA-mix, made up of the isomers CLA-9cis 11trans and CLA-10trans 12cis, was compared to three purified isomers, i.e., the CLA-9cis 11cis, CLA-9cis 11trans, and CLA-10trans 12cis. Using the apoptotic marker YO-PRO-1, the CLA-9cis 11cis at 50 micro mol/L turned out to be the best apoptotic inducer leading to a 10-fold increase in MCF-7 cells and a 2,5-fold increase in MDA-MB-231 cells, comparatively to the CLA-mix. Contrary to previous studies on colorectal and prostate cancer cells, CLA-10trans 12cis does not lead to an apoptotic response on breast cancer cell lines MCF-7 and MDA-MB-231. Our results also suggest that the main components of the CLA-mix (CLA-9cis 11trans and CLA-10trans 12cis) are not involved in the induction of apoptosis in the breast cancer cells studied. A dose of 5 Gy did not induce apoptosis in MCF-7 and MDA-MB-231 cells. The addition of CLA-9cis 11cis or CLA-mix has allowed us to observe a radiation-induced apoptosis, with the CLA-9cis 11cis being about 8-fold better than the CLA-mix. CLA-9cis 11cis turned out to be the best radiosensitizer, although the isomers CLA-9cis 11trans and CLA-10trans 12cis have also reduced the cell survival following irradiation, but using a mechanism not related to apoptosis. In conclusion, the radiosensitizing property of CLA-9cis 11cis supports its potential as an agent to improve radiotherapy against breast carcinoma.

Polymorphism characterizes the ability of a molecule to crystallize in different crystallographic systems (in the case of a simple atom the term allotropy is used). This phenomenon, known for a long time, leads to significantly different physicochemical properties between the different crystalline forms. In the pharmaceutical domain, the potential polymorphism of the active substances and the excipients could affect Since most of the pharmaceutical products consist of solid dosage forms administered by the oral route, it is not surprising that studies on polymorphism have become a mandatory chapter of any pharmaceutical dossier whether it concerns a new chemical entity or a generic. In fact, beyond the polymorphism phenomenon, it is the crystallization process which deserves to be highlighted. We will show how it controls the appearance of the polymorphism and the crystalline growth which is a second feature at least as important as the polymorphism itself (external aspect of the solid particles/habit) in terms of processability and dissolution. After having recalled some thermodynamic considerations which characterize the polymorphism, we will illustrate succinctly the impact of these phenomena on some important aspects of the pharmaceutical development such as the dissolution, the bioavailability and the stability.

Synthesis and physico-chemical properties of six 5-arylidène-3-benzyl-1-methyl-2-thioxoimidazolidin-4-ones and three 2-arylidene-6-nitro-2H-1,4-benzothiazin-3(4H)-ones have been described. These new compounds were synthetised by Knoevenagel condensation reaction from aromatic aldehydes. The N-alkylation reaction of arylidenebenzothiazines by methyl iodide give the N-methylarylidenebenzothiazines.

The two enantiomers of a chiral drug may have vastly different pharmacodynamic and pharmacokinetic properties. As a result, the research and development of chiral drugs raises specific problems some of which are discussed here. Thus, various pharmacokinetic interactions may involve two enantiomers, as seen for example when one enantiomer inhibits the metabolism of the other and modifies its effects. A different situation occurs when a third compound stereoselectively inhibits the metabolism of one of the two enantiomers. Another problem examined here results from the lack of configurational stability of some chiral drugs, a little known phenomenon whose consequences can be of pharmacological or pharmaceutical significance depending on the rate of the reaction of racemization or epimerisation. In-depth investigations are needed before choosing between a eutomer or a racemate.

We present the crystal and molecular structures of two new N-phthalyl-3-amino-2-arylpropionic acid pantolactonyl ester derivatives with 4-fluorophenyl and 3,4-dimethoxyphenyl as the aryl group, 2,3,4,5-tetrahydro-4,4-dimethyl-2-oxofuran-3-yl 3-phthalimido-2-(4-fluorophenyl)propanoate, C23H20FNO6, and 2,3,4,5-tetrahydro-4,4-dimethyl-2-oxofuran-3-yl 3-phthalimido-2-(3,4-dimethoxyphenyl)propanoate ethyl acetate hemisolvate, C25H25NO8.0.5C4H8O2. This structural study confirms the S configuration of the C2 and validates the stereospecificity of our synthesis strategy.

Cerivastatin sodium a synthetic and pure enantiomeric 3-hydroxy-3-methylglutaril-coenzyme A (HMG-CoA) reductase inhibitor, is considered effective in the treatment of mild-to-moderate primary hypercholesterolemia (total cholesterolor = 220-259 mg/dL) at a daily dose of 0.15 mg. We compared the efficacy and tolerability of a dosage of 0.3 mg/d with those of a dosage of 0.15 mg/d in patients with severe primary hypercholesterolemia (serum total cholesterolor = 260 mg/dL). After a minimum of 4 week's lead-in with placebo, 73 patients with severe primary hypercholesterolemia were randomly assigned to receive either 0.15 or 0.3 mg of cerivastatin sodium once daily after the evening meal for 12 weeks. In 58 patients, the same drug was continued at a flexible dosage for an additional 36 weeks or longer to assess the long-term efficacy and tolerability of cerivastatin sodium. During the 12-week treatment period, serum total cholesterol levels decreased significantly from baseline in both dosage groups, but the percentage reduction was significantly greater in the 0.3-mg group (range, 24.4% to 25.6%) than in the 0.15-mg group (range, 19.4% to 21.6%). The percentage reduction in levels of low-density lipoprotein cholesterol, triglycerides, and apolipoprotein B and the percentage increase in levels of high-density lipoprotein cholesterol were significantly greater in the 0.3-mg group than in the 0.15-mg group. When the results for the 0.3- and 0.15-mg groups were combined, the percentage of change in serum lipid levels at 48 weeks remained as stable as at 12 weeks. No serious adverse reactions were observed. We concluded that the higher dose of cerivastatin sodium was more effective than the lower dose, with comparable tolerability, in the treatment of patients with severe primary hypercholesterolemia.

Determination of optical isomers is based on some molecule properties to have one or more chiral asymmetrical carbon center. Enantiomers can be resolved by high performance liquid chromatography (HPLC) with a chiral mobile phase additive, by change into diastereoisomers by derivatization or by separation on chiral column. We retained the last technique for the separation of seven beta-blockers (atenolol, alprenolol, labetalol, nadolol, oxprenolol, pindolol and propranolol) using an alpha 1-AGP column. Results indicate that the mobile phase was specific to each beta-blocker. The wavelength chosen was lambda = 225 nm and the flow rate was 0.9 ml/min. A part from that, determinations of isomers of propranolol and atenolol in different fluids biologicals were also achieved.

Following a brief historical review of the notion of chirality, the importance of the relationship between pharmacological activity and the enantiomeric forms of drugs is indicated. Different approaches for the preparation of optically-pure molecules are discussed, and an original strategy, known as the "CN(R,S) method", is described. To conclude, an application of this method in the synthesis of a pharmacologically-active molecule is presented.

After administration of the racemic drug, the stereoselective quantification of the enantiomers of free and conjugated carprofen was performed in human plasma and in plasma, urine and bile of dogs and horses. In humans, the plasma profile of free carprofen and its glucuronides is not stereoselective and the glucuronides excreted in urine are close to a racemate. In dogs and horses on the contrary, the R(-) enantiomer of the free drug is predominant in plasma, while urine and/or bile concentrations of the glucuronides are high in comparison to plasma with a strong selectivity for the S(+) enantiomer. Because glucuronidation of carprofen, as a carboxylic compound, is known to be the major metabolic pathway in most species, interspecies discrepancies in the stereoselective disposition of carprofen seem to be mainly related to the stereoselectivity in the excretion of the glucuronides. Finally, the high plasma concentrations of carprofen glucuronides in human in comparison to other animal species suggest that the former could be specifically subjected to immunological side effects in the time course of treatments by this type of compounds.

The study of the kinetic of cyclisation reaction of the additional compound of the mercaptoacetic ethylester on a benzylideneacetophenone was proposed. With the chromatography a retro-Michael reaction was obtained. The H NMR alone permitted to show the order 1 for the kinetic of cyclization and according to the amine used like reaction catalyst, two diastereoisomers could be formed.

The synthetic apiosyl-glucosides having (S)-3,7-dimethyl-1,6-octadien-3-yl (linalyl); (R)-1-methyl-1-(4-methyl-3-cyclohexen-1-yl)ethyl (terpineyl); (E) and (Z)-3,7-dimethyl-2,6-octadien-1-yl (geranyl and neryl); (S)-3,7-dimethyl-6-octen-1-yl (citronellyl); benzyl and 2-phenylethyl as aglycon moiety were prepared using the stereospecific trichloroacetimidate Schmidt method. The key intermediate diholoside 1,2,3,4-tetra-O-acetyl-6-O-[(3-C-acetoxymethyl)-2,3-di-O-acetyl-beta-D- erythrofuranosyl)-beta-D-glucopyranose was obtained by Kochetkov glycosylation of a branched-chain tetrofuranose cyanoethylidene derivative. The NMR data (1H and 13C) of the synthetic compounds and the glycosylation shifts of the apiose moiety are reported.

Viscosity values of marrow cells from patients suffering from acute promyelocytic leukemia (acute myeloid leukemia of type 3) have been determined before and during a treatment with all-trans retinoïc acid (active metabolite of the vitamin A, inducing cell differentiation and maturation). Evaluated from aspiration tests into a glass micropipette, the marrow cell viscosity has been compared to that of normal neutrophils. Results seem to point out that the induced hyperleucocytosis is favoured by both a low standard deviation of pathological cell viscosity and a cell viscosity value close to that of normal neutrophils. The systematic study of cell viscosity could therefore help the clinicians to individualize the treatment.

Non steroidal anti-inflammatory drugs (NSAIDs) contain a chiral carbon alpha to carboxyl function. Except for naproxen, chiral NSAIDs are marketed for clinical use as racemate, ie an equimolar mixture of the two enantiomers R(-) and S(+). However, in vitro studies have shown that the anti-inflammatory activity exists almost solely in the S form. The unbound fraction is able to diffuse into tissues and to reach sites of action. It represents also the pharmacological active form. Stereoselective protein binding studies carried out at various concentrations of NSAIDs and albumin are used to evaluate the free fraction of the active enantiomer. Two optical isomers do not interact in the same manner with proteins and this binding stereoselectivity depends on NSAID and experimental conditions. Thus, it seems difficult to predict the in vivo free concentration of each enantiomer and protein binding experiments should be achieved taking into account the physiopathological parameters which influence this biological process. This enantioselectivity is determinant for the pharmacokinetic properties and could be responsible of the parameters variation obtained for each enantiomer. It could explain the variability in response to NSAIDs too. In fact, the anti-inflammatory effect is directly function of the free concentration of the S isomer. To correlate the NSAID dose with its activity, it should be better to determine this free fraction in the site of action, in particular in the synovial fluid. But the clinical response, as for example the antalgic effect, remains very far from the pharmacological activity, ie the cyclooxygenase inhibition.

Until now, folinic acid (FA) has been available the racemic mixture d1 FA, whose biological activity is supported by natural 1 FA. The purpose of this trial was to compare, on a pharmacokinetic, biological, and clinical basis, the racemic mixture dl FA with the pure 1 FA in the rescue of high-dose methotrexate (MTX) therapy. Eighteen children with acute lymphocytic leukemia (ALL) were entered in this trial planned with a cross-over design. Four cycles of MTX (5 g/m2, 24h CVI) were administered to each patient, with a 2-week interval between cycles. The rescue was achieved orally every 6h, starting 12h after the end of the MTX infusion, at a dose of 12 mg/m2 for dl FA and 6 mg/m2 for pure 1 FA. dl FA and 1 FA rescues were alternated from one cycle to the next. d FA, 1 FA, and the active metabolite 5-methyltetrahydrofolate (5-MTHF) were measured in plasma using a stereospecific HPLC assay. After administration of dl FA, the accumulation of d FA in plasma was confirmed: mean residual concentrations were 420 and 652 nM after 2 and 6 intakes respectively. Total active folate concentrations (1 FA + 5-MTHF) were similar between the two types of rescue: 92 and 100 nM respectively for dl FA rescue and 1 FA rescue after two intakes, 186 and 184 nM respectively for dl FA rescue and 1 FA rescue after six intakes. Intra-individual statistical analysis of total active folates (1 FA + 5-MTHF) performed on 17 patients did not show any significant difference between dl FA rescue and 1 FA rescue. For both types of rescue, MTX terminal half-lives were identical (average value 13.9 h). Considering each type of toxicity (hematologic, hepatic, renal and digestive) there was no significant difference in the proportion of toxic cycles following l FA rescue or dl FA rescue. In conclusion, the administration of the pure l FA, as compared with the administration of the racemic mixture, results in comparable blood profiles of active folates and MTX, and leads to equivalent treatment tolerance.

After the administration of racemic ketoprofen and carprofen to man, both enantiomers of each compound exhibit similar plasma profiles. This contrasts with the rat where the active S(+) enantiomer is predominant. For carprofen, regardless of the route of administration, the R(-) enantiomer is predominant in the plasma of all investigated animal species. The S(+)/R(-) ratio of the "areas under the curves" during the time course of the kinetics, is: 0.60 in dogs, 0.53 in Yucatan micro-pigs, 0.48 in mini-goats, 0.67 in calves and 0.19 in horses. For ketoprofen, the S(+) enantiomer is predominant in dogs, cats and horses, with ratios of 30.3, 5.3 and 1.5, respectively, while R(-) is the predominant enantiomer in sheep. The interpretation of these inter-species differences can be supported by experimental evidence, however some informations are lacking and additional investigation is required. In the case of ketoprofen where S(+) is predominant in rats, dogs and horses, the metabolic chiral inversion from R(-) to S(+), which has been demonstrated in rats, may also take place in the latter two species. In addition, the well documented stereoselective clearance of the glucuronides, possibly in favour of the enantiomer S(+), may explain the lower body clearance of the R(-) enantiomer in sheep. For carprofen, no metabolic chiral inversion was shown in rats and dogs after administration of each enantiomer individually, but for this compound, stereoselective clearance of glucuronides has been demonstrated which may support the idea of a plasma concentration shift of the enantiomeric proportions vs time in favour of the R(-) enantiomer. Regardless of the possible biological mechanisms which are responsible for these inter-species differences, the existence of these differences gives rise to at least two important issues: The choice of animal species which can be used in the research of drugs destined for human therapeutics: the most pertinent animal species will be the one which demonstrates an enantiomeric plasma profile closest to that observed in man. The present data show that the ideal animal species from this respect has still to be identified. For application in veterinary therapeutics, a careful balance must be established between the requirement of favourable bioavailability of the active S(+) enantiomer and the potential of any possible chiral inversion of R(-) to generate hybrid molecules in meat and milk which in turn may lead to residues, the toxicity of which to the human consumer is still unknown.

Radioisotopic studies have been performed on insulin secreting cells in order to characterize the mode of action of the "K+ channel openers". The study reveals that these pharmacologic agents interfere with the K(+)-ATP channels.

In an on going effort to optimize ibuprofen antiinflammatory therapy, development studies on the active stereoisomer of ibuprofen have been conducted. The effects of pharmaceutical processing on the racemate (RAC-ibuprofen) and the enantiomer (S(+)-ibuprofen) were investigated. The formulation of the new stereospecific system, was impossible using wet granulation. The pharmaceutical development of S(+)-ibuprofen using direct compression appeared as a practical solution to this problem. The biopharmaceutical properties of the resulting tablets were well within pharmacopeia requirements. Nevertheless, mixing S(+)-ibuprofen with the excipients induced a drop in the enthalpy of fusion and after compaction, a low temperature eutectic appeared on the differential scanning calorimetry endotherms. Aging studies indicated that the raw material and pharmaceutical mixtures of S(+)-ibuprofen should be stored under strictly controlled conditions or processed immediately.

The fenfluramine racemate belongs to a new therapeutic class of molecules acting on food intake, without psychostimulant or addictive potential. This molecule was extensively studied in the treatment of obesity and its action was better understood by studying the dextrogyre and levogyre enantiomers. New methods allowed to show that dexfenfluramine (the dextrogyre isomer) worked through a serotoninergic activity which was responsible for the effect on food intake and disorders of eating behavior. New pharmacological concepts have emerged by using this molecule and new animal models, nearer to human pathology, were found (stress induced eating, carbohydrate selection...). Molecular Biology and Neurosciences have already led to a better knowledge of the central mechanism of action of the molecule by describing its effect on receptors and binding sites; however a lot of other concepts remain to be discovered.

Many drugs have one or more asymmetric centres and are used as a racemate: equimolar mixture of enantiomers. Drug enantiomers may interact differently with biological macromolecules. Hence, the influence of chirality in relation to pharmacokinetics and pharmacodynamics needs to be studied. Many pharmacokinetic and pharmacodynamic examples stress on the major influence of chirality. The valuable knowledge acquired from such studies can lead to a better understanding of drug interactions and mechanisms of drug action and to an optimization of drug therapy either by a better use of still marketed racemate drugs of by the development of pure enantiomers.

Various issues connected with chiral drugs are discussed. They include definitions, the concept of stereoselectivity in pharmacodynamic and pharmacokinetic processes, the need for a stereochemically informative generic name system, and the debate surrounding eutomers versus racemates in pharmacotherapy.