[The origins of analysis and of drugs control]. / Les origines de l'analyse et du contrôle des médicaments.

Analytical concerns were quite ancient. As soon as the 12th century, Al-Chayzari searched drugs falsifications. During the 17th century, retort analysis was much practiced. Selective extraction constituted a great progress. During the 18th century, gas volumetric analysis appeared. Descroizilles created volumetric analysis in liquid phase, and that gave him the opportunity for creating acidi-alcalimetry methods. Following the works of Gay-Lussac and Thénard, Liebig invented an apparatus for performing elemental analysis of organic compounds. Michael Tswett created chromatography. Polarimetry was used for dosing glucose in human urines. Kirchhoff and Bunsen created spectroscopic analysis. All these methods allowed the great development of analysis during the 20th century.

[Vauquelin: route from a thatched cottage to Institute of France]. / Vauquelin : itinéraire d'une chaumière à l'Institut.

Nicolas Louis Vauquelin was born in a little thatched cottage in Saint-André-d'Hébertot, in Normandy, on May 16th 1763. He went to Rouen and then to Paris where he met Antoine de Fourcroy and became his co-worker and his friend. They published together sixty articles, and he published alone a hundred and twenty articles. He became a pharmacist in 1787. He occupied simultaneously or not many important University positions. He was Associate Professor at École polytechnique, Professor at École des mines, Professor at Collège de France, Director of School of Pharmacy, Professor at Museum d'histoire naturelle, Professor at Faculty of Medicine. He became Empire Knight, Member of Institute of France, Member and President of Academy of Medicine, Member and President of Society of Pharmacy. He discovered and isolated chrome and discovered beryllium. He was a very efficient professor and many of his students were well-known scientists. He died on November 14th 1829.

[Parmentier hygiene and public health]. / Parmentier, hygiène et santé publique.

The legend about Parmentier is quite reductive when it limits his activity to the promotion of potato. This military pharmacist intended mainly to make science serve human being, whatever could be his various activities. Actor of the foundation of food chemistry, reorganizer of military pharmacy, he has always been highly concerned with hygiene and public health. He then studied the quality of water, particularly in the case of river Seine, or the purity of air, especially in hospitals. The affair of Dunkerque exhumations or that of cesspools, or the utilisation of human excrements in agriculture were parts of the occurrences for which he had the opportunity to find a scientific approach allowing to solve the difficult questions that were asked to him, for the best benefit of public health. The exhaustive study he published in "Bulletin de pharmacie" for the conservation of meat shows that he did not ignore anything about freezing of food in order to preserve it. It is necessary not to forget the important role he played, as soon as he were informed of Jenner's discovery, for the diffusion of vaccination in France. It is simply astounding to observe how modern were the questions he solved and how intense was his spirit of dedication to the public good, when exerting his functions in "Comité de Salubrité de la Seine" or "Conseil de Santé des Armées", as well as outside these prestigious institutions.

Functionalized cyclodextrins bearing an alpha nucleophile--a promising way to degrade nerve agents.

Organophosphorus nerve agents are irreversible inhibitors of acetylcholinesterase. Current treatment of nerve agent poisoning has limited efficacy and more efficient medical countermeasures need to be developed. A promising approach is to design chemical scavengers more stable during storage and less immunogenic than bioscavengers. Furthermore, they could be produced at lowest production costs. Cyclodextrins are attractive cyclic oligosaccharides that can be used to develop chemical scavengers of organophosphorus nerve agents. Their abilities to form inclusion and non-inclusion complexes with organic substrates are useful to trap chemical warfare agents. Selective introduction of an α-nucleophile residue on the secondary face of ß-cyclodextrin allowed to obtain supramolecular derivatives active against organophosphorus compounds. The degradation activity of these monosubstituted cyclodextrins was determined against paraoxon and chemical warfare agents. These tests showed that the structure of the scavengers mainly influences the interaction between the organophosphorus substrate, or its reaction products, and the cyclodextrin moiety. All the tested G-type agents were efficiently degraded. According to the binding modes of cyclosarin, some oligosaccharidic scavengers led to an enantioselective degradation of this nerve agent. These promising derivatives open the way to further investigations of new structural modifications to reach more sophisticated and efficient scavengers for prophylactic and curative medical applications.

Detoxification of nerve agents by a substituted beta-cyclodextrin: application of a modified biological assay.

Chemical warfare agents (nerve agents) are still available and present a real threat to the population. Numerous in vitro and in vivo studies showed that various nerve agents, e.g. tabun and cyclosarin, are resistant towards standard therapy with atropine and oxime. Based on these facts we applied a modified biological assay for the easy, semi-quantitative testing of the detoxifying properties of the beta-cyclodextrin derivative CD-IBA. Cyclosarin, sarin, tabun and VX were incubated with CD-IBA for 1-50 min at 37 degrees C, then an aliquot was added to erythrocyte acetylcholinesterase (AChE) and the percentage of AChE inhibition was determined. The validity of the assay was confirmed by concomitant quantification of tabun by GC-MS. Different concentrations of cyclosarin were detoxified by CD-IBA in a concentration-dependent velocity. The ability to detoxify various nerve agents decreased in the order cyclosarin>sarin>tabun>>VX. Hereby, no detoxification of VX could be detected. Sarin was detoxified in a biphasic reaction with a fast reduction of inhibitory potential in the first phase and a slower detoxification in the second phase. CD-IBA detoxified tabun in a one phase decay and, compared to cyclosarin and sarin, a longer half-life was determined with tabun. The modified biological assay is appropriate for the initial semi-quantitative screening of candidate compounds for the detoxification of nerve agents. The beta-cyclodextrin derivative CD-IBA demonstrated its ability to detoxify different nerve agents.

[From apprenticeship to Nobel Prize: Henri Moissan's fabulous destiny]. / De l'apprentissage au Prix Nobel: le fabuleux destin d'Henri Moissan.

Born in Paris on September 28, 1852, son of an eastern railways' employee and of a dressmaker, Henri Moissan's secondary schooling in Meaux did not allow him to get access to the sesame diploma "baccalauréat" (GCE). In 1869, he did obtain a special certificate of secondary schooling so that he could become an apprentice in watch making. That could have been the end of the story, but dreadful event for France appeared to have beneficial effects for Moissan. Under the threat of the Prussian army, Moissan's family took refuge near Paris. This gave the young Henri the opportunity to register as a student for the second-class pharmacy diploma, which did not need, at the time, the GCE. Moissan became then a trainee in pharmacy in 1871. Meanwhile, he followed the special schooling of "Ecole de chimie" founded by E. Frémy, and then joined the laboratory of Dehérain at the Museum, where he worked in plant physiology. He finally obtained the famous "baccalauréat" (GCE) and could register as a student in first-class pharmacy. He became a pharmacist as well as a doctor in sciences. In 1883, Moissan was named professor at the school of pharmacy in Paris. In 1886, he isolated fluorine by electrolysis of fluorhydric acid, in the presence of potassium fluoride, at a low temperature. He then studied diamond synthesis and gave a start to high temperature chemistry, designing his famous furnace. These findings and many others allowed Moissan to rise to membership in many learned academies around the world. Crowning achievement, Moissan won the Nobel Prize in 1906. A man of culture, collector of autographs and paintings, he died in 1907. Nothing of that would have been possible if there had not been a second-class pharmacist diploma. The history of Henri Moissan is one of a rise from apprenticeship to the Nobel Prize.

[Substituted cyclodextrins: an example of biomimetic catalyzers]. / Les cyclodextrines substituées: un exemple de catalyseurs biomimétiques.

Among all molecules used to develop biomimetic catalysts, cyclodextrins are extremely attractive compounds. These oligosaccharides can form inclusion complexes with various organic substrates and in particular with organophosphorus poisons, which are widely used as chemical weapons and insecticides. Soman, a frightening neurotoxic agent, once "trapped" in the internal cavity of beta-cyclodextrin can moreover undergo the nucleophilic attack of an oligosaccharide hydroxyl group, miming the first step of the enzymatic process. Selective substitution of beta-cyclodextrin by a 2-iodosobenzoic acid derivative has enabled effective synthesis of scavangers against organophosphorus compounds. Hydrolysis trials were carried out with paraoxon, as an organophosphorus model. The OP-hydrolyzing activity could reach more than two order of magnitude compared with free 2-iodosobenzoïc acid. Nevertheless, hydrolysis of paraoxon showed saturation kinetics. Although the activity was strongly dependent on the relative position of the reactive group, these results showed the interest of a strategy, resulting in the "trapping" of the organophosphorus substrate in the internal cavity of the oligosaccharide in order to maintain it near the catalytic function.

[Porphyrin catalysts: a tool for preparation of metabolite models]. / Les catalyseurs porphyriniques: un outil pour la préparation de modèles de métabolites.

The porphyrin complexes of manganese catalysts are biomimetic catalysts whose structural analogy with the active site of cytochrome P-450 enzymes can be used to obtain synthetic models of therapeutic agent metabolites. Mn(TDCOO)Cl, a second generation porphyrin, has proven robust enout to be used for scaled-up production in the presence of hydrogen peroxide and imidazole. For this purpose, an improvement in substrate oxidation was obtained by adjunction of formic acid to the reaction medium which preserved the cocatalyst and the catalyst. It was shown that addition of acid played an active role in the oxidation process. After this optimization, the system was used to oxidate the two enantiomers of methyloctalone, an essential chiral intermediate in the synthesis of terpenoids and steroids. The efficacy of this biomimetic method for the preparation of large amounts of oxidized chiral synthons was better than obtained with biological ex vivo pathways.

Aminoglutethimide included in nanocapsules suspension: comparison of GC-MS and HPLC methods for control.

Gas chromatography-mass spectrometry (GC-MS) and high performance liquid chromatography (HPLC) offer highly efficient and potentially sensitive separation and detection techniques. This work describes the quantification of aminoglutethimide (AG) in nanocapsules suspension with both techniques. The analysis of different lots containing known concentrations of drug (1, 2, 3 and 4 mg ml(-1)) were used to investigate the quantitative capabilities of both chromatographic techniques. Both chromatographic methods were successful and on an analytical point of view the validations of aminoglutethimide dosing were suitable in both cases. In routine, the determination of the quality of nanocapsules suspension could be preferentially evaluated by difference between total AG concentration in suspension (evaluated by direct HPLC measure of the suspension diluted in acetonitrile) and free AG concentration (evaluated by direct HPLC measure of simple dilution of the supernatant).

Effects of encapsulation of primidone on its oxidative metabolism in rats.

The aim of this study was to evaluate the influence of primidone (PRM) nanoencapsulation on its metabolism. Suspensions of PRM powder and PRM-loaded poly-epsilon-caprolactone nanocapsules were administered orally in the same way to rats. Primidone-loaded poly-epsilon-caprolactone nanocapsules were prepared according to the interfacial deposition technique. Free PRM suspensions were obtained by addition of PRM powder to a suspension of 0.212% carboxymethylcellulose CMC 12H in water. The dose was 20 mg/kg, n = 6, for each experiment. Urinary and faecal levels of PRM and of its three major metabolites, phenylethylmalonamide (PEMA), phenobarbital (PB), and p-hydroxyphenobarbital (p-HO-PB), were determined. Concentrations were evaluated by high-performance liquid chromatography (HPLC) according to a validated analytical method. After PRM nanocapsule administration, non-metabolised PRM urinary levels were increased compared to those observed after administration of a suspension of primidone powder (43.7+/-8.8% after PRM-loaded nanocapsule and 37.7+/-8.1% after free PRM administration). For phenylethylmalonamide, no difference was observed in urinary excretion in the two cases. For two of the oxidised metabolites, PB and p-HO-PB, excretion was delayed and shortened. The amount of these oxidised metabolites was lowered from 0.95% after free PRM administration to 0.25% after PRM-loaded nanocapsule administration. No difference was noted in non-metabolised primidone excretion in faeces. These results suggest that primidone-loaded nanocapsules could be used as a vehicle for oral primidone administration in order to minimise the phenobarbital metabolic pathway.

[Aspirin throughout the ages: a historical review]. / L'aspirine à travers les siècles: rappel historique.

Even at the beginning of the next millennium, aspirin will still offer surprises. Its relatively young pharmacological history compares with the early use of salicylate-containing plants since antiquity. The Assyrians and the Egyptians were aware of the analgesic effects of a decoction of myrtle or willow leaves for joint pains. Hippocrates recommended chewing willow leaves for analgesia in childbirth and the Reverend Edward Stones is acknowledged as the first person to scientifically define the beneficial antipyretic effects of willow bark. At the beginning of the 19th century salicin was extracted from willow bark and purified. Although a French chemist, Charles Gerhardt, was the first to synthesize aspirin in a crude form, the compound was ignored, and later studied by Felix Hoffmann. He reportedly tested the rediscovered agent on himself and on his father, who suffered from chronic arthritis--a legend was born and Bayer Laboratories rose to the heights of the pharmacological world. First used for its potent analgesic, antipyretic and anti-inflammatory properties, aspirin was successfully used as an antithrombotic agent. Sir John Vane elucidated aspirin's active mechanism as an inhibitor of prostaglandin synthetase and received the Nobel Price in Medicine for this work in 1982. Two isoform of cyclooxygenase (COX-1 and COX-2) have now been identified, each possessing similar activities, but differing in characteristic tissue expression. The cox enzyme is now a target of drug interventions against the inflammatory process. After two centuries of evaluation, aspirin remains topical, and new therapeutic indications are increasingly being studied.

Competition between the beta-hydroxylation of a primary and a tertiary carbon atom in rats.

In order to study the effect of steric hindrance on competition between two kinds of beta-hydroxylation, a compound bearing on a pyrimidinetrione nucleus both a branched side chain with a tertiary carbon atom in position beta (isobutyl group) and a linear side chain (ethyl group), was selected and administered to rats. Urine and faeces were collected and extracted. Hydroxymetabolites and their derivatives were isolated and then identified. The beta-hydroxylation of the linear chain was more important than the beta-hydroxylation of the branched chain. Steric hindrance plays a decisive role in this regioselectivity.

University education of medicinal chemists: comparison of eight countries.

Medicinal chemists are mainly taught in faculties or schools of pharmacy and are available for employment. Yet major pharmaceutical research companies seek organic chemists, rather than medicinal chemists, for new drug discovery. This apparent contradiction led the Medicinal Chemistry Section of IUPAC to send a questionnaire regarding postgraduate academic education for medicinal chemists to the faculties or schools of pharmacy in eight countries, namely, France, Germany, Italy, Japan, Spain, Switzerland, UK and USA. The questionnaire aimed to elicit information about postgraduate medicinal chemistry students, their courses and training, and the occupations taken up after graduation. The replies representing 109 medicinal chemistry departments or sections have been analysed and the results are presented to provide a data base on modern medicinal chemistry curricula for comparative purposes. The information should help guide discussion of the optimum paths to be followed by students in preparation for their careers. The evidence suggests that academic training of medicinal chemists equips them to enter a wide range of occupations, many of which are in industry.

[Latin and the training of apothecaries in France]. / Le latin et la formation des apothicaires en France.

Reading pharmacopoeias and prescriptions, redacted in this degenerated latin which was the language of science, required a sufficient knowledge of that language. A study of the statutes of apothecaries' communities, is a good method to evaluate the role of latin in the training of apothecaries. These statutes could be divided into four groups: statutes redacted in latin, statutes redacted in french, but mentioning that latin was used for the examinations, statutes which mention a control of the capacity of the candidates to understand latin, statutes which do not mention latin. Some examples show the reality of latin knowledge. During the XVIth century, apothecaries used to travel to foreign counties in order to improve their knowledge. They had not to learn the language of the country, because masters and students used to speak latin. Young Balthazar Hummel, from Basel, went to Montpellier, in the house of the apothecary, Laurent Catelan, and never had to learn french, because he used only latin. During the XVIIIth century, apothecaries of Hôtel-Dieu, a hospital in Rouen, were reunited after a competitive examination. On friday May 15th 1722, two candidates, Pierre Lechandelier and Michel Delaisement, had to answer in latin to the questions of the members of the jury. One of them, Lechandelier said that be was not able to do so in latin. He was then told that it was the rule and that he was not allowed to continue the examination. Delaisement answered to the questions in very good latin and became the apothecary of the hospital. His study shows that latin knowledge was required for apothecaries, even if differences appeared between the various french towns. So far as pharmacopoeias were concerned, an evolution took place at the end of the XVIIth century, Charas and Lémery wrote their famous books in french. But until 1818, the official pharmakopoeias were redacted in latin, which was still required for the training of apothecaries.

[Some steps of the history of Pharmacy in Rouen]. / Quelques etapes de l'histoire de la pharmacie rouennaise.

The community of apothecaries was created in Rouen, in 1508, and its statutes were completed in 1588. The Le Chandelier family was a good example of a dynasty of apothecaries. Precise information on the way of life of XVIIth century apothecaries was given by Jacob Congnard's post mortem inventory. This document revealed also the part played by the apothecaries in foreign trade. The contribution to science was represented by Nicolas Lemery and Francois-Antoine-Henri Descroizilles. After the modifications of the rules by the law of Germinal an XI, the Preparatory School of Medicine and Pharmacy was created in 1841, but it became a faculty, only in 1966.

[Wholesale dealers and apothecaries in Rouen]. / Les marchands grossiers et les apothicaires rouennais.

Wholesale dealers are merchants who sell only great amounts of drugs. Since the XVIth century, the conditions under which they practiced were governed by apothecaries' statutes. The control of drugs, which was performed by apothecaries, was often contested by wholesale dealers. After many proceedings, the court decided in favor of apothecaries.

Primidone-loaded poly-epsilon-caprolactone nanocapsules: incorporation efficiency and in vitro release profiles.

This paper describes the preparation of primidone-loaded poly-epsilon-caprolactone nanocapsules according to the interfacial deposition technique. The colloidal suspension obtained showed a monomodal size distribution with a mean diameter ranging from 308 to 352 nm. By adjusting the process parameters, the encapsulation efficiency was about 74% with good reproducibility. Primidone release from the nanocapsules was found to be slower as compared to the oily control solution despite an important burst-effect. The release profile was not influenced by the pH of the release medium.

[The 1791 project of rules for pharmacy: an attempt, in Rouen, to find an alternative to apothecaries' communities]. / Le projet de reglement pour la pharmacie de 1791: une tentative rouennaise pour remplacer les communautes d'apothicaries.

In 1791, the apothecaries' communities were suppressed, but two weeks later the ancients rules were restored. Nevertheless this situation was provisional and it was time to think of new regulations. The apothecaries from Rouen redacted a project inspired by both the 1508 regulations and the Royal 1777 declaration creating the College of Pharmacy in Paris. This project does not seem to have received any application. The statutes of the free society of pharmacists of Rouen created in 1802, did not refer to this project.