The end of the theriac in modern medicine in the sixteenth to nineteenth century

Theriaca, after the Greco-Roman antiquity, survived centuries with some continuity. The formula used during the 17th century, inherited from the tradition of Hippocrates and Galen is closed to what it was centuries earlier, despite the difficulties of supply of raw materials. It is considered a mainstay of therapy by the apothecaries of the 16th century as Houel or Bauderon and 17th as Charas or Lemery. In contrast, the 18th and the "Lumières" with Baumé, will contrive to challenge the validity of the preparation. In France, the last public preparation of the Theriaca was performed in 1798. Official pharmacopoeias of the 19th century (from 1818 to 1884) will all retain a formulation of Theriaca, where, according to tradition, dozens of ingredients are mixed in terms of unproven effectiveness that will lead to the withdrawal of the final preparation at the beginning of the 20th century, when the Theriaca passes controversial drug status to that of ancient and obsolete myth.     

The influence of pharmacists on the development of pharmacy and chemistry as diciplines]

The aim of this article is to trace some features of the historical development of chemistry as an academic discipline in its relation to the emergence of pharmaceutical science. Franz Joel (1508-1579) was one of the first pharmacists whose work became very important for development of chemistry since the 17th century lectures in materia medica and in iatro-chemistry were frequent realized in university pharmacy. In the 18th century pharmacists were in some cases the precursors to professors of chemistry. In the paper there is also given a summary of the importance for the development of chemistry of J. B. Trommsdorff, S. F. Hermbstaedt, A. P. J. Du Menil and L. F. Bley.     

Click Chemistry with Polymers,Dendrimers, and Hydrogels for Drug Delivery

During the last decades, great efforts have been devoted to design polymers for reducing the toxicity, increasing the absorption, and improving the release profile of drugs. Advantage has been also taken from the inherent multivalency of polymers and dendrimers for the incorporation of diverse functional molecules of interest in targeting and diagnosis. In addition, polymeric hydrogels with the ability to encapsulate drugs and cells have been developed for drug delivery and tissue engineering applications. In the long road to this successful story, pharmaceutical sciences have been accompanied by parallel advances in synthetic methodologies allowing the preparation of precise polymeric materials with enhanced properties. In this context, the introduction of the click concept by Sharpless and coworkers in 2001 focusing the attention on modularity and orthogonality has greatly benefited polymer synthesis, an area where reaction efficiency and product purity are significantly challenged. The purpose of this Expert Review is to discuss the impact of click chemistry in the preparation and functionalization of polymers, dendrimers, and hydrogels of interest in drug delivery.     

Moyse Charas,apothecary and medical doctor (Uzés 1619 - Paris 1698)

Some new information, based on many unedited documents is presented, in order to complete the biography of Moyse Charas, as published in this revue by Dorveaux (1929) and Bouvet (1949). The origin of the protestant family Charas lies in Pont-Saint-Espirt, from where the parents of Moyse Charas, passing Uzés, moved to Orange, where he took up the profession of apothecary and was declared Master by Frederick Henry, prince of Orange. Later, in Paris, he had contacts with the Dutch diplomat Constantijn Huygens and his son, the scientist Christiaan Huygens, and with the English physician and philosopher John Locke. After shorter visits to London and the Royal Society he lived there for a certain time, being called to contribute to cure King Charles II. He revisited Orange to get his promotion as a doctor of medicine. After having practised for some time in Holland he went to Spain for five years, as a physician of the embassy of the States General in Madrid and later in Galice. The last six months he suffered imprisonment by the Inquisition. Liberated after his conversion to Catholicism, he could finally return to Paris.     

Phosphinic acid compounds in biochemistry, biology and medicine

This review summarizes our knowledge of biochemical, biological and medical applications and properties of phosphinic acid compounds. Phosphinic acid compounds (phosphinates) are derivatives of phosphinic acid H2P(O)(OH). The major attention of this article is focused on applications of phosphinates of a pseudopeptide character, however interesting examples of phosphinates of a non-peptide nature are mentioned too. Phosphinic acid peptides (phosphinic pseudopeptides) are peptide isosteres where one peptide bond is substituted by the nonhydrolysable phosphinate moiety -P(O)(OH)-CH2- or -P(O)(OH)-. This substitution represents a very convenient mimic of a substrate in the transition state for at least two distinct classes of hydrolytic enzymes, Zn-metalloproteinases and aspartic acid proteinases. In this review we discuss about thirty different protein targets for which the phosphinates have found applications as modulators of their functions in vitro and/or in vivo. These proteins are mainly proteinases, however other types of proteins such as transferases, synthetases, ligases or even receptors are also discussed. Genome sequencing projects have been identifying protein sequences faster than it is possible to discover their functions. The development of combinatorial chemistry in the past few years has boosted up the interest in the use of chemistry to address biological problems. We believe that phosphinates, especially in conjunction with combinatorial chemistry approaches, can represent an extremely versatile tool in the search for proteome and its function.     

American Association of Pharmaceutical Scientists--annual meeting and exposition: drug discovery and development. 15-19 November 1998, San Francisco, CA, USA

AAPS is the acronym for the American Association of Pharmaceutical Scientists, a relatively young organization, dedicated to the development of the pharmaceutical sciences in the widest sense, from basic research through discovery and development to regulatory affairs and marketing. The association has a membership of over 10,000 scientists, mostly in the US, but with a worldwide representation. The Annual Meeting and Exposition attract about 7000 delegates, including exhibitors. Despite its wide coverage, however, its strength lies in the development and use of technology rather than basic research. Thus in the search for lead compounds, the use of combinatorial chemistry and high-throughput screening was more evident than novel chemistry or pharmacology, and there was a preponderance of contract research organizations or service companies in the exposition. Nevertheless, the size of the meeting ensured that there was something of interest to everyone most of the time, and the areas of emphasis served as a guide to future trends in drug discovery and the direction of the industry as we approach the new millennium. Typically, at any one time, the delegate could choose amongst three round-table meetings, three symposia, three podium sessions with short papers, and numerous special interest semi-private gatherings, not to mention 2500 posters spread over six sessions during the week. This report concentrates on those aspects which contributed to novel research, or gave major pointers to future directions. Abstracts for the various papers were available to delegates as hard copy and on CD-ROM, in the form of the first supplement of an as yet unpublished all-electronic journal, to be known as PharmSci.     

A statistical model for the classification of imipramine response in depressed inpatients

We present a statistical model, recently developed for application in mathematical economics, that yields empirical evidence for the existence of two distinct subtypes of depression. We reanalyze previously reported data on 65 depressed patients treated with imipramine and repeatedly rated on the Hamilton Rating Scale (HRS). The estimated model paraeters suggest two underlying response processes. Patients in the first subgroup were initially more severely depressed (as measured by the total HRS score), but exhibited a rapid rate of symptomatic response over time. In contrast, patients in the second subgroup were initially less severely depressed, yet showed a much slower rate of improvement. These findings recommend a refinement of the clinical definitions of endogenous depression. While this model suggests that there are two underlying response processes, it does not classify individual patients. Subject classification was made possible by fitting an item-response model to the data. This model relates the 17 individual symptom ratings, at baseline, to the total post-treatment HRS scores. The results of this analysis suggest that the previously described relationship between high initial severity of depression and more rapid improvement over time is characteristic of subjects who exhibit initial motor retardation and decreased sexual interest. Graphical analysis clearly indicates that subjects who exhibit both motor retardation and decreased sexual interest at baseline have higher total HRS scores at baseline and show more pronounced improvement in total HRS scores in response to treatment with imipramine. Patients not exhibiting motor retardation and decreased sexual interest were less severely depressed initially and show virtually no clinical response over time.     

Franca, New-France, transposition of pharmaceutical knowledge in 18th century

The inventories after death have many details about houses of our ancestors and inform us about their way of life. The notary describes sometimes the library, if there is one. This one give us a good idea about the readings of our ancestors whom the apothecaries: Literature, Religion, History, Right, Medicine. These readings became some essential tools for their proprietary. The practitioners of health represent one example of this. With two representative areas of mother country and settlement, Low-Normandy (which gave many settlers in 17th century) and Canada, we are going to see the libraries of the practitioners of pharmacy in these two areas. What are the books present? Is the medical European knowledge transmitted between France and New France? Is there an influence of North-American middle?     

Solid‐phase precipitation and extraction,a new separation process applied to the isolation of synthetic peptides

Abstract: A new method for separation and purification is described. The process, referred to as solid‐phase precipitation and extraction (SPPE), was developed and applied to postcleavage isolation of synthetic peptides. The technique uses normal approaches of chromatography and solid‐phase extraction sorbents with a precipitation or drying procedure so that the sorbent becomes a support matrix for thin‐film deposition of the compounds of interest. This procedure causes precipitated compounds of interest to be trapped on the large surface area or in the pores of the matrix so that by‐products and impurities can be removed by strong wash solvents. In application to solid‐phase peptide synthesis chemistry, by‐products from the cleavage and deprotection are selectively extracted from the crude sample mixture under mild conditions. In comparison to the ether precipitation method used in peptide chemistry, the SPPE process provides isolated products that are 14–17% (w/w) higher purity.     

Structural determinants of opioid activity in derivatives of 14-aminomorphinones: effect of substitution in the aromatic ring of cinnamoylaminomorphinones and codeinones

In recent years there has been substantial interest in the 14-aminodihydromorphinone derivatives methoclocinnamox (MC-CAM) and clocinnamox (C-CAM). To investigate the importance of the cinnamoyl ring substituent, a series of analogues have been prepared with chloro, methyl, and nitro substituents in the 2' and 4' positions. Despite some discrepancies between the in vitro and in vivo data, a clear SAR could be observed where the 2'-chloro and 2'-methyl ligands consistently displayed higher efficacy than their 4'-substituted analogues. The new series also followed the well-established SAR that 17-methyl ligands have greater efficacy at the mu opioid receptor than their 17-cyclopropylmethyl counterparts.     

NMDA receptor subunits: function and pharmacology

N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels widely expressed in the central nervous system that play key roles in excitatory synaptic transmission. Because of their involvement in numerous neurological disorders, NMDARs are also targets of therapeutic interest. NMDARs occur as multiple subtypes which differ in their subunit composition and in their biophysical and pharmacological properties. In particular, NMDARs contain a diversity of sites at which endogenous ligands or pharmacological agents can act to modulate receptor activity in a subunit-selective manner, and recent structural and functional data have started to reveal the molecular determinants for this subunit selectivity. These include the binding sites for glutamate, the ion-channel pore and the recently identified allosteric sites on the N-terminal domain. Other potential sites yet unexplored by medicinal chemistry programs are also considered, in particular at the interface between subunits. Given the growing body of evidence that diverse brain disorders implicate different NMDAR subtypes, such as NR2B in pain or NR3A in white matter injury, there is a growing interest in exploiting the pharmacological heterogeneity of NMDARs for the development of novel NMDAR subtype-selective compounds.     

Detection time comparison of non-hydrolysed sulphated metabolites of metenolone,mesterolone and 17α-methyltestosterone analysed by four different mass spectrometric techniques

The frequent detection of anabolic androgenic steroids (AAS) indicates their popularity among rule-breaking athletes. The so called long-term metabolites play a crucial role in their detection, and non-hydrolysed sulphated metabolites have gained renewed interest, as research has demonstrated their extended detection time compared to the more conventional markers (e.g., for metenolone and mesterolone). Their potential has been investigated using liquid and gas chromatography–mass spectrometry (LC- and GC-MS). However, due to their complementary nature, chances are that the most promising metabolite on one technique does not necessarily exhibit the same behaviour on the other and vice versa. Therefore, a comparison was carried out where as a trial model, metenolone, mesterolone and 17α-methyltestosterone were selected and the most likely long-term sulphated metabolites identified on four mass spectrometric instruments. Additionally, using a modified sample preparation procedure, comparison between conventional and non-hydrolysed sulphated metabolites between different GC-MS instruments was also included. When focusing on each individual marker, no cases were observed where a single metabolite provided a superior detection time on all instruments. Furthermore, for each AAS, there were incidences where a metabolite provided the best detection time on one instrument but could only be detected for a shorter period or not at all on other instruments. This demonstrates that metabolite detection windows and hence their added-value as target substance are unique and dependent on the analytical technique and not only on their pharmacokinetic behaviour. Consequently, in each case, a metabolite versus instrument evaluation is needed to maximise the probabilities of detecting doping offences.     

Progress in the development of selective inhibitors of Aurora kinases

Errors in the mitotic process are thought to be one of the principal sources of the genetic instability that hallmarks cancer. Unsurprisingly, many of the proteins that regulate mitosis are aberrantly expressed in tumour cells when compared to their normal counterparts. These may represent a good source of targets for the development of novel anti-cancer agents. The Aurora kinases represent one such family of mitotic regulators. In recent years there has been intense interest in both understanding the role of the Aurora kinases in cell cycle regulation and also in developing small molecule inhibitors as potential novel anti-cancer drugs. With several companies now starting to take Aurora kinase inhibitors into clinical development, the time is right to review the medicinal chemistry contribution to developing the field, in particular to review the increasingly broad range of small molecule inhibitors with activity against this kinase family.     

An omics perspective to the molecular mechanisms of anticancer metallo-drugs in the computational microscope era

Introduction: Metallo-drugs have attracted enormous interest for cancer treatment. The achievements of this drug-type are summarized by the success story of cisplatin. That being said, there have been many drawbacks with its clinical use, which prompted decades worth of research efforts to move towards safer and more effective agents, either containing platinum or different metals.

Areas covered: In this review, the authors provide an atomistic picture of the molecular mechanisms involving selected metallo-drugs from structural and molecular simulation studies. They also provide an omics perspective, pointing out many unsettled aspects of the most relevant families of metallo-drugs at an epigenetic level.

Expert opinion: Molecular simulations are able to provide detailed information at atomistic and temporal (ps) resolutions that are rarely accessible to experiments. The increasing accuracy of computational methods and the growing performance of computational platforms, allow us to mirror wet lab experiments in silico. Consequently, the molecular mechanisms of drugs action/failure can be directly viewed on a computer screen, like a ‘computational microscope’, allowing us to harness this knowledge for the design of the next-generation of metallo-drugs.     

Progress in the development of selective inhibitors of aurora kinases

Errors in the mitotic process are thought to be one of the principal sources of the genetic instability that hallmarks cancer. Unsurprisingly, many of the proteins that regulate mitosis are aberrantly expressed in tumour cells when compared to their normal counterparts. These may represent a good source of targets for the development of novel anti-cancer agents. The Aurora kinases represent one such family of mitotic regulators. In recent years there has been intense interest in both understanding the role of the Aurora kinases in cell cycle regulation and also in developing small molecule inhibitors as potential novel anti-cancer drugs. With several companies now starting to take Aurora kinase inhibitors into clinical development, the time is right to review the medicinal chemistry contribution to developing the field, in particular to review the increasingly broad range of small molecule inhibitors with activity against this kinase family.     

Sepsis and beta-blockade: a look into diastolic function

There is growing interest on the modulation of the overwhelming sympathetic response of septic patients. Beta-blockers appear promising in this respect and, although we are at early stage, one large trial and a smaller one have demonstrated major beneficial effects. The modulation of diastolic function and the optimization of myocardial efficiency by beta-blockade is among the possible reason for the improvement in patients with severe sepsis or septic shock. It should be also considered that septic patients are at higher risk of cardiac arrhythmias and beta-blocker may have a protective effect in this regard. We are still at a preliminary stage and more research is needed it seems reasonable that beta-blockade will become an option for the treatment of septic patients over the next few years.     

Gambierol, a toxin produced by the dinoflagellate Gambierdiscus toxicus, is a potent blocker of voltage-gated potassium channels

In this study, we pharmacologically characterized gambierol, a marine polycyclic ether toxin which is produced by the dinoflagellate Gambierdiscus toxicus. Besides several other polycyclic ether toxins like ciguatoxins, this scarcely studied toxin is one of the compounds that may be responsible for ciguatera fish poisoning (CFP). Unfortunately, the biological target(s) that underlies CFP is still partly unknown. Today, ciguatoxins are described to specifically activate voltage-gated sodium channels by interacting with their receptor site 5. But some dispute about the role of gambierol in the CFP story shows up: some describe voltage-gated sodium channels as the target, while others pinpoint voltage-gated potassium channels as targets. Since gambierol was never tested on isolated ion channels before, it was subjected in this work to extensive screening on a panel of 17 ion channels: nine cloned voltage-gated ion channels (mammalian Na_v1.1–Na_v1.8 and insect Para) and eight cloned voltage-gated potassium channels (mammalian K_v1.1–K_v1.6, hERG and insect ShakerIR) expressed in Xenopus laevis oocytes using two-electrode voltage-clamp technique. All tested sodium channel subtypes are insensitive to gambierol concentrations up to 10 μM. In contrast, K_v1.2 is the most sensitive voltage-gated potassium channel subtype with almost full block (>97%) and an half maximal inhibitory concentration (IC₅₀) of 34.5 nM. To the best of our knowledge, this is the first study where the selectivity of gambierol is tested on isolated voltage-gated ion channels. Therefore, these results lead to a better understanding of gambierol and its possible role in CFP and they may also be useful in the development of more effective treatments.     

Henri Moissan: the man, the collector, the teacher

On December 10 1906, Henri Moissan was in Stockholm to receive the Nobel Prize for chemistry for his isolation of fluorine in 1886 and for his electric arc furnace he described for the first time in 1892 then later improved and which opened the way to the new field of high-temperature chemistry. This was the first Nobel Prize for chemistry awarded to a Frenchman and Moissan was the only French pharmacist to have received this high distinction. He died suddenly at the age of 54 years, two months after receiving his Nobel Prize. In this presentation, we report the main elements of his biography, recalling the man, the teacher and the great collector of paintings and autographs, particularly from the period of the French revolution. We have used several unpublished or little known documents concerning this great scientist who with is broad culture and malicious humor always found the time, despite his many obligations, to satisfy his literary and artistic tastes.     

Studies of cytotoxicity and metabolic competence with the rat intestinal cell line IEC-17

The characterization of metabolic activity of intestinal cells in culture may be of particular interest for the study of the effects of food additives and contaminants which, ingested through the diet, are absorbed primarily by the gut mucosa. IEC-17 cell line is derived from the intestine of newborn rat and has been shown to be competent for the metabolism of xenobiotics (Quaroni and Isselbacher, 1981), and to keep some degree of differentiation also in in vitro conditions. Our studies indicate that the xenobiotic metabolic activity of this cell line, as shown by measurement of 7-ethoxycoumarin (7-EC), can be induced by beta-naphthoflavone (NF) and not by phenobarbital (PB) and only at late subculturing stages, suggesting these cells undergo some kind of maturation in vitro. Induction of xenobiotic metabolism by beta-naphthoflavone seems also to elicit the toxicity of 9,10-dimethyl-1,2-benzathracene (DBA) but not that one of cyclophosphamide (CPA).     

MMR vaccination and autism: is there a link?

In 1998, a report was published describing 12 patients with inflammatory bowel conditions and regressive developmental disorders consisting primarily of autism. The authors hypothesised that MMR vaccine may have been responsible for the bowel dysfunction which subsequently resulted in the neurodevelopmental disorders. The suggestion that measles vaccine may cause autism through a persistent bowel infection generated much interest since it provided a possible biological mechanism for a causal association. Epidemiological studies, however, have not found an association between MMR vaccination and autism. Autism has a strong genetic component and its associated neurological defects probably occur during embryonic development. It seems unlikely that a vaccination that is given after birth could cause autism. In a minority of cases, autism may have onset after 1 year of age (regressive autism) but the one epidemiological study that included such cases did not find an association with MMR vaccination. Currently, the weight of the available epidemiological and related evidence does not support a causal link between MMR vaccine and autism.