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The single radial immunodiffusion assay has been the accepted method for determining the potency of inactivated influenza vaccines since 1978. The worldwide adoption of this assay for vaccine standardisation was facilitated through collaborative studies that demonstrated a high level of reproducibility and its applicability to the different types of influenza vaccine being produced at that time. Clinical evidence indicated the relevance of SRID as a potency assay. Unique features of the SRID assay are likely responsible for its longevity even as newer technologies for vaccine characterisation have been developed and refined. Nevertheless, there are significant limitations to the SRID assay that indicate the need for improvement, and there has been a substantial amount of work undertaken in recent years to develop and evaluate alternative potency assays, including collaborative studies involving research laboratories, regulatory agencies and vaccine manufacturers. Here, we provide an overview of the history of inactivated influenza vaccine potency testing, the current state of alternative assay development and the some of the major challenges to be overcome before implementation of new assays for potency determination., (© 2018 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.)

This article explores the role of testing in the allocation of royal monopoly privileges for drugs in eighteenth-century France by following the multi-generational fortunes of a single "secret remedy" from 1713 to 1776: the poudre fébrifuge of the Chevalier de Guiller. On at least five occasions, this drug was tested on patients in order to decide whether it should be protected by a privilege and whether or not its vendors should be awarded lucrative contracts to supply it in bulk to the French military. Although efforts were made early in the century to test the drug through large-scale hospital trials and to relegate privilege granting to a bureaucratic commission, the case of the poudre fébrifuge instead suggests that military expediency and relatively small-scale trials administered personally by royal practitioners remained decisive in determining whether or not a drug received a monopoly privilege or a military contract.

The article series provides a written and pictorial account of the Danish pharmaceutical industry's products from their introduction until about 1950. Part 8 deals with products from Lundbeck. Lundbeck which today is known as a considerable international pharmaceutical company could in 2015 celebrate its 100 years' jubilee. Among the early Danish medicinal companies H. Lundbeck & Co. is in many ways an exception as the company was not originally established as a pharmaceutical company. Not until several years after the foundation the company began to import foreign ready-made medicinal products and later-on to manufacture these medicinal products in own factory and even later to do research and development of own innovative products. When Lundbeck was established in 1915 several Danish medicinal companies, not only the well-known such as Alfred Benzon and Løvens kemiske Fabrik (LEO Pharma), but also Skelskør Frugtplantage, Ferrin and Ferraton, had emerged due to the respective enterprising pharmacy owners who had expanded their traditional pharmacy business and even with commercial success. Other medicinal companies, such as C.R. Evers & Co., Leerbeck & Holms kemiske Fabriker, Chr. F. Petri, Erslevs kemiske Laboratorium, Edward Jacobsen, Th. Fallesen-Schmidt, and yet other companies which were named after the founder had all been established by pharmacists with the primary intention to manufacture and sell medicinal products. Also for the limited companies Medicinalco, Ferrosan, Pharmacia, and GEA the primary task was to manufacture and sell medicinal products, and also in these companies pharmacists were involved in the foundation. Not until 1924, fully 9 years after the foundation, Lundbeck started to be interested in medicinal products and initiated import and sale of foreign medicinal products manufactured by a.o. German and French companies which had not established their own sales companies in Denmark. Almost all contemporary Danish manufacturers of medicinal products could exclusively determine own proprietary names of the articles and could themselves make their own homogeneous and easily recognisable design, a.o. by frequent use of prefixes as Afa, Asa, Gea, Ido, Leo, and Meco which associated to for instance the company name. However, it goes without saying that Lundbeck had to market the articles in commission according to the different contracts with their partners. Consequently their range of products appeared heterogeneously. The international financial crisis and the consequent unemployment in the 1920s and 1930s had in Denmark a.o. resulted in national regulation in order to complicate import of ready-made goods and thus support the domestic manufacture of such articles. This was one of the reasons why Lundbeck decided to initiate its own manufacture of medicinal products in Denmark instead of continuing only with the import business which had been obstructed by the authorities. This article does not mention all Lundbeck's medicinal products which were marketed in Denmark until 1955 where a new Pharmacy Act came into force though undoubtedly a lot of interest can be written about all of them. The products mentioned in this article have been carefully selected, not only because they are representative for Lundbeck's development during the first decades, but also because the Danish Collection of the History of Pharmacy has acquired consumer packages of many of the articles. Several of these packages include patient information leaflets with an instruction for use and/or other information, and especially these leaflets represent a source material which has not previously been given much attention. It does not appear from the available source material whether these earliest medicinal products from Lundbeck were assembled in Danish packages on the production sites, or whether they were repacked in Copenhagen. It is not unlikely that the assembling originally was finalized abroad, and that instructions for the production of packaging material with Danish text were supplied by Lundbeck to the respective manufacturers. However, it is not unlikely either that the currency restrictions which were made after 1932 encouraged Lundbeck, where possible, first of all to import raw materials and bulk products and then manufacture the finished products in Valby. This was the case with Anusol, which Lundbeck certainly emphazised in the advertisement. It has to be pointed out that at that time there were no legal requirements regarding dating, neither of the user instructions nor of advertisements. Thus it is not due to mistakes or omissions made by Lundbeck that these materials are undated. The user instructions which Lundbeck had inserted in the packages were made and distributed at a time where no legal restrictions were in force neither regarding form nor content of such. The user instructions for products marketed after 1932 had probably been presented to the Pharmacopoeia Commission as this was statutory. It is, however, uncertain whether the Commission has dealt with the contents and the look of the user instructions. The most important task of the Commission was besides of the work with maintaining the Pharmacopoeia to look after the economic interests of the pharmacies so that only new drug substances could be marketed by the pharmaceutical industry, cf. below. In order to find out whether, and if so to which extent, the Pharmacopoeia Commission has been occupied in evaluating the informative and promoting printed matters of the industry, would require studies of the unprinted files of the Commission, and that is outside the scope of this article. At that time it was not against the law to inform in a user instruction that in case of a longer period of treatment, it would be more economical for the patient to buy a larger package. If you look at these patient information leaflets with today's eyes in the light of the present detailed, comprehensive and rigid regulations which the EU Commission has stated regarding patient information leaflets, you will find that Lundbeck's patient information leaflets were both simple and easy to read. On a free sample of Gelonida meant for the prescribing physician Lundbeck stated, besides of indication, dosage and warnings, also that the article was "Manufactured in Denmark". At that time it was not required to print information of production sites on packaging materials, however, it was not unusual to use this sales promoting claim in times of unemployment. In 1949 the original packaging material for Beatin was modified because certain text elements, the therapeutic indications were removed as it appeared that they since 1933 had violated the Pharmacy Act against advertisements for medicinal products aimed at the public. The packaging material for Beatin is a model example of the possibilities to combine practical information about the use of a medicinal product with sales claims in a reliable way. The above text modification and thus the legalisation of the packaging material took place upon request from the company as the violation of the advertising rules of the Pharmacy Act apparently had not resulted in any legal problems. Studies of unpublished files from the National Board of Health may possibly explain the background of this sequence of events, however, that is outside the scope of this article. The paragraph of the Pharmacy Act of 1932, stating that a medicinal product containing a common commodity as the active ingredient could not be marketed as a proprietary medicinal product, was meant to protect the pharmacies against the increasing competition from the industry. At first the paragraph did put a strain on the industry which from then on either had to manufacture own originator products or to copy other originator products without breaking patents. In the long run it has probably caused that not only Lundbeck, but also other Danish pharmaceutical companies became research-oriented and thus have been able to develop a relatively large number of originator products. In this context a product like Lucamid can hardly be regarded as an example of such a compulsory development of an originator product, an acetylsalicylic acid analogue. There were already such products on the market, but the wish to develop a better active ingredient has probably been bigger. From the three first editions of The Tariff of Medicines from 1935, 1937 and 1939 respectively it appears how Lundbeck's business within the area of medicines developed during the last half of the 1930s. In 1935 Lundbeck had placed 36 different medicinal products on the market, and all of them were in-licensing products. 4 years later, in 1939 Lundbeck had placed 40 different medicinal products on the market, and the number of in-licensing products had been reduced to 18 and 22 products were Lundbeck products. However, the increased focus on the development of own new medicinal products as Epicutan and Klianyl did not stop the in-licensing activities. Varex which Lundbeck brought on the market in 1942 came from a German pharmaceutical company with which Lundbeck had not previously collaborated. In Denmark Lundbeck had the intention to market 4 of Goedecke's 6 different medicinal products which all had Gelonida as part of the proprietary name. However, only one of these products got a longer life and with a simplified name, namely Gelonida. The fixed combination with three compounds of acetylsalicylic acid, phenacetin and codeine was without doubt effective, however, already at the end of the 1950s concern was raised about the safety of phenacetin. The Card Index of Medicines is a primary source of knowledge of how Lundbeck marketed the earliest medicinal products to the prescribing physicians. (ABSTRACT TRUNCATED)

A major constraint in oral controlled release drug delivery is that not all the drug candidates are absorbed uniformly throughout the gastrointestinal tract (GIT). Drugs having "absorption window" are absorbed in a particular portion of GIT only or are absorbed to a different extent in various segments of the GIT. Thus, only the drug released in the region preceding and in close vicinity to the absorption window is available for absorption. The drug must be released from the dosage form in solution form; otherwise, it is generally not absorbed. Hence, much research has been dedicated to the development of gastroretentive drug delivery systems that may optimize the bioavailability and subsequent therapeutic efficacy of such drugs, as these systems have unique properties to bypass the gastric emptying process. These systems show excellent in vitro results but fail to give desirable in vivo performance. During the last 2-3 decades, researchers from the academia and industries are giving considerable importance in this field. Unfortunately, till date, few so-called gastroretentive dosage forms have been brought to the market in spite of numerous academic publications. The manuscript considers strategies that are commonly used in the development of gastroretentive drug delivery systems with a special attention on various parameters, which needs to be monitored during formulation development.

On account of the dense cuticles of the fresh stem and the light, hard and pliable texture of the dried stem, Dendrobii Caulis is difficult to dry or pulverize. So, it is very important to the ancient doctors that Dendrobii Caulis should be properly treated and applied to keep or evoke its medicinal effects. The current textual research results about the preliminary processing, processing and usage methods of Dendrobii Caulis showed that: (1) In history the clinical use of fresh or processed Dendrobii Caulis as teas and tinctures were very common. (2) Its roots and rhizomes would be removed before using. (3) Some ancillary approaches were applied to shorten drying times, such as rinsing with boiling mulberry-ash soup, washing or soaking with liquor, mixing with rice pulp and then basking, etc. (4) According to the ancients knowledge, the sufficient pulverization, by means of slicing, rasping, hitting or pestling techniques, was necessary for Dendrobii Caulis to take its effects. (5) The heat processing methods for Dendrobii Caulis included stir-baking, stir-frying, steaming, decocting and stewing techniques, usually with liquor as an auxiliary material. Among above mentioned, steaming by pretreating with liquor was most commonly used, and this scheme was colorfully drawn in Bu Yi Lei Gong Pao Zhi Bian Lan (Ming Dynasty, 1591 CE) ; moreover, decocting in advance or long-time simmering so as to prepare paste products were recommended in the Qing Dynasty. (6) Some different processing programs involving stir-baking with grit, air-tightly baking with ondol (Kangs), fumigating with sulfur, which appeared in modern times and brought attractive outward appearance of the drug, went against ancients original intentions of ensuring drug efficacy.

Transdermal patches are now widely used as cosmetic, topical and transdermal delivery systems. These patches represent a key outcome from the growth in skin science, technology and expertise developed through trial and error, clinical observation and evidence-based studies that date back to the first existing human records. This review begins with the earliest topical therapies and traces topical delivery to the present-day transdermal patches, describing along the way the initial trials, devices and drug delivery systems that underpin current transdermal patches and their actives. This is followed by consideration of the evolution in the various patch designs and their limitations as well as requirements for actives to be used for transdermal delivery. The properties of and issues associated with the use of currently marketed products, such as variability, safety and regulatory aspects, are then described. The review concludes by examining future prospects for transdermal patches and drug delivery systems, such as the combination of active delivery systems with patches, minimally invasive microneedle patches and cutaneous solutions, including metered-dose systems., (© 2015 The British Pharmacological Society.)

Penicillin production in Chile was a pioneering development; however there is not much information to learn about it. The Chilean Institute for Bacteriology (Instituto Bacteriológico de Chile) produced penicillin between 1944 and 1973. The stage starting in 1953 is better known since there was an agreement with United Nations. Our research focused on building a story about production between 1944 and 1954 based on archival information and the national and international historic context. Our results place Chile amongst the pioneer countries in the successful industrialization of the drug. Our conclusions are that this was a proper industrial production as opposite to a pilot plant - a name commonly used to call the early factory. We explain the production plant trajectory by making relations between technological change and governance. Finally, we believe the later expansion of the plant, in the context of the agreement with the United Nations, took place under unpromising governance conditions, which called for passive innovation and technology management.

In the early 1900s, the abnormal toxicity test (ATT) was developed as an auxiliary means to ensure safe and consistent antiserum production. Today, the ATT is utilized as a quality control (QC) release test according to pharmacopoeial or other regulatory requirements. The study design has not been changed since around 1940. The evidence of abnormal toxicity testing as a prediction for harmful batches is highly questionable and lacks a scientific rationale. Numerous reviews of historical ATT results have revealed that no reliable conclusions can be drawn from this QC measure. Modern pharmaceutical manufacturers have thorough control of the manufacturing process and comply with good manufacturing practice rules. Contaminants are appropriately controlled by complying with the validated manufacturing processes and strict QC batch release confirming batch-to-batch consistency. Recognizing that product safety, efficacy, and stability can be ensured with strict QC measures, nowadays most regulatory authorities do not require the ATT for most product classes. In line with the replacement, reduction, and refinement (3Rs) initiative, the test requirement has been deleted from approximately 80 monographs of the European Pharmacopoeia and for the majority of product classes in the United States. For these reasons, it is recommended that the ATT should be consistently omitted world-wide and be removed from pharmacopoeias and other regulatory requirements., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

This text illustrates some unknown aspects of the history and beginnings of clinical pharmacology in France in the late 1970s and early 1980s From the current situation, development and objectives of clinical pharmacology are recalled as well as obstacles necessary to overcome to change the paradigm in the field of drug evaluation and appropriate use in France. The text recalls this important moment where French medicine and medical pharmacology entered the modern era., (© 2014 Société Française de Pharmacologie et de Thérapeutique.)

The article series provides a written and pictorial account of the Danish pharmaceutical industry's products from their introduction until about 1950. Part 6 deals with products from A/S Pharmacia. A/S Pharmacia was established in Copenhagen in 1922 as a Danish limited company by the enterprising pharmacist Edward Jacobsen. Pharmacia was not Jacobsen's first pharmaceutical company as previously he had established a pharmaceutical agency already in 1913 which in 1919 was reorganized to a limited company by the name of A/S Edward Jacobsen. This agency was later extended to include a production of generics. Jacobsen remained the co-owner and manager of Pharmacia until 1934 where he resigned and established another company, A/S Ejco, for the manufacture of generics. It is worth mentioning that already in 1911 a Swedish pharmaceutical company was established named AB Pharmacia. Today we do not know whether Edward Jacobsen knew about this Swedish company. Later on in 1936 AB Pharmacia and A/S Pharmacia made a contract concerning mutual market sharing, and a research cooperation was brought about between the two companies which resulted in an increase of turnover for A/S Pharmacia. In 1955 the cooperation between the two companies was increased as the Swedish company joined as principal shareholder with the purpose of continuing and developing the Danish company as an independent pharmaceutical company with its own research and development as well as manufacture, control and marketing. Therefore Pharmacia in Denmark was able to establish a synthesis factory in Koge and move the domicile to new premises in Hillered. In 1993 Pharmacia was presented in a printed matter as "The largest Nordic pharmaceutical company" as a result of the merger between the Swedish Kabi Pharmacia, formerly established by a merger between Kabi Vitrum and AB Pharmacia, and the Italian Farmitalia Carlo Erba. Only two years later in 1995 Pharmacia merged with the American pharmaceutical company The Upjohn Company under the name of Pharmacia & Upjohn. In 2000 this company was merged with the chemical group Monsanto under a new name, Pharmacia Corporation. Pharmacia Corporation was taken over by Pfizer in 2003. The early activities of A/S Pharmacia included not only the import of raw materials and ready-made articles, such as medicinal products, but also the manufacture of own medicinal products. This is not surprising considering the founder Edward Jacobsen's pharmaceutical career. Pharmacia's early manufacture of own medicinal products consisted mainly of generics, however, not only the expensive foreign medicinal products, but also any available Danish generics such as easily manufactured pharmacopeia products. It is thus worth mentioning that Pharmacia's own technological production capacity at that time was limited and required a cooperation with other (Danish) pharmaceutical companies. Pharmacia was able to produce tablet cores, but the sugarcoating had to be made by external business partners. Pharmacia was able to produce digitalis preparations, but the standardization of these had to be effected elsewhere. The total production of one of Pharmacia's products took place at an external business partner. Pharmacia was established at a time where the increasing use of industrially manufactured medicinal products, both Danish and foreign ones, had resulted in a considerable decrease in sales of pharmacy produced medicinal products. This had for a long time worried The Danish Association of Pharmacies, and this resulted in a reaction from the association, namely the DAK-products which by nature were produced in Denmark and thus became the most essential element in the fight against the industrially manufactured products--a fight which according to the association had to be fought with all legal means. Therefore The Danish Association of Pharmacies obviously reacted precipitated when in 1926 the association in writing stated that Pharmacia's products were not manufactured in Denmark in spite of the fact that they were labelled as such according to agreement with Landsforeningen Dansk Arbejde, i.e., The National Association Danish Work, which in 1925 allowed Pharmacia to use the labels of the association. The unemployment was high in the 1920'ies and increasing so when Pharmacia subsequently took legal action against the Association of Pharmacies and claimed that the statement was unjustified and might harm Pharmacia, it may indicate that the public of that time looked positively upon the manufacture and the use of Danish manufactured products. The Danish Association of Pharmacies lost the case as the claim according to the court was unjustified and thus unlawful. The suspicions of the association were not supported by facts, however, they were not either completely groundless. Following this The National Association Danish Work gave notice to terminate the contract with Pharmacia concerning the right to use the labels of the association. By expanding the cooperation and later on by merging with the Swedish Pharmacia AB the Danish A/S Pharmacia succeeded in continuing and developing a company where research, development and production of innovative medicinal products as well as of generics could take place in Denmark.

Vaccination against influenza represents our most effective form of prevention. Historical approaches toward vaccine creation and production have yielded highly effective vaccines that are safe and immunogenic. Despite their effectiveness, these historical approaches do not allow for the incorporation of changes into the vaccine in a timely manner. In 2013, a recombinant protein-based vaccine that induces immunity toward the influenza virus hemagglutinin was approved for use in the USA. This vaccine represents the first approved vaccine formulation that does not require an influenza virus intermediate for production. This review presents a brief history of influenza vaccines, with insight into the potential future application of vaccines generated using recombinant technology.

A/S GEA Farmaceutisk Fabrik was established as a family business in 1927 by the pharmacist Knud L. Gad Andresen who until then had been employed in the pharmaceutical industry. Gad Andresen wanted to run a company focusing on the development of generics, and he wanted this development to take place in a close cooperation with Danish physicians. This has indeed been achieved with success. In 1995 GEA was purchase'd by the American pharmaceutical company Bristol-Myers Squibb who in a press release characterized GEA as Denmark's second largest manufacturer of generics. Immediately after this takeover GEA's R&D department ceased the research in innovative products and from now on exclusively focused on the development of generics. Three years later GEA was sold to the German generic company Hexal who later on resold GEA to the Swiss generic company Sandoz. GEA changed ownership another couple of times until the last owner went bankrupt in 2011. GEA is yet again a model example of an early Danish pharmaceutical company which was established as an individual company, and which had a long commercial success with the production and marketing of generics. GEA's earliest products, the organotherapeutics, were not innovations. The innovative products were developed already in the 1890s in Denmark by Alfred Benzon, and later on copies followed a.o. from Medicinalco and from foreign companies before GEA marketed their generics. Therefore GEA had to promote their preparations as especially qualified medicinal products and to intimate that the products of the competitors were less "active'". At the end of the 1920s the Ministry of Health became aware of the fact that there might be health problems related to the none-existing control of both the or- ganotherapeutic preparations and actually also the other medicinal products of the pharmaceutical industry. Therefore the Ministry had requested the National Board of Health for a statement regarding this problem. The National Board of Health was, however, at that time of the opinion that there were no serious problems with organotherapeutics from those companies marketing such products. It requires studies in the unprinted journals of the Ministry of Health and the National Board of Health to find the background for and the causes of the request from the Ministry at this point concerning the control of the organotherapeutic products of the pharmaceutical industry. Neither were GEA's barbiturates innovative products. The "Gad Andresen Case" is interesting for two reasons. Firstly, it illustrates that the development of generics at this stage could not always take place exclusively in a pharmaceutical-chemical laboratory, but also required a certain minimum of clinical trials including human beings. Secondly, it shows that the industrial products had now slowly, but surely gained market shares and displaced the pharmacy-produced medicinal products to such an extent that it did not only worry the pharmacy owners and their trade orga- nization. Now this concern had also resulted in a counteract so that the pharmacies in the manufacture of their products had to copy the industrial products, however, in certain cases with a dubious result. Gealgica tablets and especially their content of fenacetine is not only a model example of how the opinion of the positive and negative properties of a medicinal product changes over time. It also shows how long time could pass before the health authorities took measures against a substance with problematic side effects in spite of the fact that less damaging substances had been available for a long time, in this case paracetamol. Medicinal products containing fenacetine were on the market for almost 100 years. On the contrary meprobamat is a model example of a drug substance where the opinion of its positive and negative properties changed essentially over a relatively short period. In spite of this it remained on the market for a little less than 40 years. Restenil and Trihistan are mentioned on Knud & Dagny Gad Andresen's homepage (in 2014) as new medicinal products developed by GEA. This is not quite correct. Both drug substances in these preparations had been developed in the USA. In Denmark GEA had the possibility to market these substances under GEA's own brand names along with corresponding foreign brand names. It can be concluded that GEA's own research on the whole was confined to the development of own patentable syntheses of already known drug substances. During the later marketing of generics GEA appealed to the national feeling of the Danish population in the same way as a.o. Pharmacia did in the 1920s. From the very start GEA specialized in the manufacture of generics, and GEA was able to follow this way with commercial success--as a Danish alternative--for almost 90 years.

Modern tablet compression was instituted in England in 1844 by William Brockedon (1787-1854). The first tablets made according to Brockedon´s procedures contained watersoluble salts and were most likely compressed without expedients. In USA a watershed occurred around 1887 when starch (amylum maydis) was introduced to disperse tablets in aqueous milieu in order to corroborate bioavailability of drugs in the almentary canal. About the same time great advances in tablet production were introduced by the British firm Burroughs Wellcome and Co. In Denmark on the other hand tablet production remained on low scale until after 1920. As Icelandic pharmacies and drug firms modelled themselves mostly upon Danish firms tablet production was first instituted in Iceland around 1930. The first tablet machines in Iceland were hand-driven. More efficent machines came after 1945. Around 1960 three sizeable tablet producers were in Iceland; now there is only one. Numbers of individual tablet species (generic and proprietary) on the market rose from less than 10 in 1913 to 500 in 1965, with wide variations in numbers in between. Tablets have not wiped out other medicinal forms for peroral use but most new peroral drugs have been marketed in the form of tablets during the last decades.

The huge amount of information, the big number of scientists and their efforts, labs, man/hrs, fund, companies all and others factors build the success of the amazing new branch of genetic engineering the 'protein engineering' (PE). It concerns with the modification of protein structure/function(s) or building protein from scratch. The engineered proteins usually have new criteria(s). Engineering proteins can be mediated on the level of genes or proteins. PE fined its way in different important sectors including industrial, pharmaceutical and medicinal ones. Aspects about PE and its applications will be discussed with this review. The concept, tools, and the industrial applications of the protein, engineered proteins and PE will be under focus. In order to get up to date knowledge about the applications of PE in basic protein and molecular biology, several examples are discussed. PE can play a significant role in different industrial and pharmaceutical sectors if used wisely and selectively.

"Fifteen" since, our country Chinese traditional medicine industry science and technology has made remarkable achievements. In this paper, the development of science and technology policy, Chinese medicine industry, platform construction and other aspects were analyzed, showing 10 years of Chinese traditional medicine industry development of science and technology innovation achievement and development, and on the current development of traditional Chinese medicine industry facing the main tasks and guarantee measures are analyzed.

A major challenge for global rabies prevention and control is the lack of sufficient and affordable high quality vaccines. Such candidates should be pure, potent, safe, effective and economical to produce, with broad cross-reactivity against viral variants of public health and veterinary importance. The history of licensed human vaccines reviewed herein demonstrates clearly how the field has evolved to the current state of more passive development and postexposure management. Modern cell culture techniques provide adequate viral substrates for production of representative verified virus seeds. In contrast to outdated nervous tissue-based rabies vaccines, once a suitable substrate is identified, production of high titer virus results in a major qualitative and quantitative difference. Given the current scenario of only inactivated vaccines for humans, highly cell-adapted and stable, attenuated rabies viruses are ideal candidates for consideration to meet the need for seed viruses in the future.

The lipid fractions of residues from historical pharmaceutical ointments were analysed by reversed-phase liquid chromatography coupled with atmospheric pressure chemical ionization and mass spectrometer detection. The residues were contained in a series of historical apothecary jars, dating from the eighteenth century and conserved at the "Aboca Museum" in Sansepolcro (Arezzo, Italy) and at the pharmacy of the "Real Cartuja de Valldemossa" in Palma de Majorca (Spain). The analytical protocol was set up using a comparative study based on the evaluation of triacylglycerol (TAG) compositions in raw natural lipid materials and in laboratory-reproduced ointments. These ointments were prepared following pharmaceutical recipes reported in historical treatises and used as reference materials. The reference materials were also subjected to stress treatments in order to evaluate the modification occurring in the TAG profiles as an effect of ageing. TAGs were successfully detected in the reproduced formulations even in mixtures of up to ten ingredients and after harsh degradative treatments, and also in real historical samples. No particular interferences were detected from other non-lipid ingredients of the formulations. The TAG compositions detected in the historical ointments indicated a predominant use of olive oil and pig adipose material as lipid ingredients. The detection of a high level of tristearine and myristyl-palmitoyl-stearyl glycerol in two of the samples suggested the presence of a fatty material of a different origin (maybe a ruminant). On the basis of the positional isomer ratio, sn-PPO/sn-POP, it was possible to hypothesize an exclusive use of pig fat in one sample. We also evaluated the application of principal component analysis of TAG profiles as an approach for the multivariate statistical comparison of the reference and historical ointments.

A study of the composition of the remains of ancient ointments from museums was undertaken to enable understanding of the preparation techniques. Comparison of ancient recipes from different historical periods and spectroscopic characteristics of inorganic and/or organic remains recovered in museum vessels enabled preparation of ancient pharmaceutical-cosmetic formulations. Farmacopea Augustana by Occo was one the most important books studied for the 14 formulations prepared in the laboratory. Three formulations are discussed in detail and raw materials and new preparations were proposed for ozone ageing. The most important micro Raman results are discussed. The spectra of the raw materials lipids, beeswax, and resins are discussed; beeswax and pig suet (axŭngia) Raman spectra were found to be similar, but different from those of the aged oils. SERS was applied to ancient ointments and galbanum and the Raman spectra are reported and discussed for the first time.

Historical nomenclature has not always been unequivocally associated with the botanical origin of natural resins. The availability of natural resins has changed throughout the centuries and so have their trade names. Furthermore, adulterations and lack of knowledge have led to variations in the composition of the products traded under the same name. This investigation aims at a new understanding of the interrelation between the historical and modern terms for natural resins. Different Pinaceae and Pistacia resins, mastic, sandarac, copaiba balm and burgundy pitch from Vigani's Cabinet, a 300-year-old pharmaceutical collection owned by Queens' College, Cambridge (UK) were investigated. Related reference materials from modern collections were analysed together with natural resins derived from reliable botanical sources. The analytical method was gas chromatography/mass spectrometry (GC-MS) with and without derivatisation with trimethylsulfonium hydroxide. This technique provided detailed molecular compositions of the studied materials, which in turn led to particular data profiles of the materials. Marker molecules of Copaifera, Pinaceae, Cupressaceae and Pistacia resins were identified. By comparing the GC-MS data profiles to the reference samples, a clearer picture of the connection between nomenclature and botanical origin was obtained. With the aid of the marker molecules and data profiles, it was then possible to clarify the nomenclature of the aged resins sampled from Vigani's Cabinet.

Chemical analysis of ancient residues of pharmaceutical or cosmetic preparations such as balms or ointments is made problematic by the high complexity of these mixtures, composed of organic and inorganic materials. Consequently, a multi-analytical approach and special caution in the interpretation of the results are necessary. In order to contribute to the improvement of analytical strategies for the characterization of complex residues and to reconstruct ancient medical practices, a replica of a pharmaceutical formulation of the seventeenth century was prepared in the laboratory according to a historically documented recipe. In a round robin exercise, a portion of the preparation was analysed as a blind sample by 11 laboratories using various analytical techniques. These included spectroscopic, chromatographic and mass spectrometric methods. None of the laboratories was able to completely reconstruct the complex formulation, but each of them gave partial positive results. The round robin exercise has demonstrated that the application of a multi-analytical approach can permit a complete and reliable reconstruction of the composition. Finally, on the basis of the results, an analytical protocol for the study of residues of ancient medical and pharmaceutical preparations has been outlined.

Natural organic materials used to prepare pharmaceutical mixtures including ointments and balsams have been characterized by a combined non-destructive spectroscopic analytical approach. Three classes of materials which include vegetable oils (olive, almond and palm tree), gums (Arabic and Tragacanth) and beeswax are considered in this study according to their widespread use reported in ancient recipes. Micro-FTIR, micro-Raman and fluorescence spectroscopies have been applied to fresh and mildly thermally aged samples. Vibrational characterization of these organic compounds is reported together with tabulated frequencies, highlighting all spectral features and changes in spectra which occur following artificial aging. Synchronous fluorescence spectroscopy has been shown to be particularly useful for the assessment of changes in oils after aging; spectral difference between Tragacanth and Arabic gum could be due to variations in origin and processing of raw materials. Analysis of these materials using non-destructive spectroscopic techniques provided important analytical information which could be used to guide further study.

The science and policy of pharmaceuticals produced and/or delivered by plants has evolved over the past twenty-one years from a backyard remedy to regulated, purified products. After seemingly frozen at Phase I human clinical trials with six orally delivered plant-made vaccines not progressing past this stage over seven years, plant-made pharmaceuticals have made a breakthrough with several purified plant-based products advancing to Phase II trials and beyond. Though fraught with the usual difficulties of pharmaceutical development, pharmaceuticals made by plants have achieved pertinent milestones albeit slowly compared to other pharmaceutical production systems and are now at the cusp of reaching the consumer. Though the current economic climate begs for cautious investment as opposed to trail blazing, it is perhaps a good time to look to the future of plant-made pharmaceutical technology to assist in planning for future developments in order not to slow this technology's momentum. To encourage continued progress, we highlight the advances made so far by this technology, particularly the change in paradigms, comparing developmental timelines, and summarizing the current status and future possibilities of plant-made pharmaceuticals.

This article examined i) how traditional medico-pharmaceutical custom from the late 19th century influenced such changes, ii) how medical laws of Daehan Empire and early colonial period influenced the differentiation of medico-pharmaceutical profession, and iii) what the responses of medico-pharmaceutical professionals were like, and arrived at following conclusions. First, in late Chosun, there was a nationwide spread of pharmacies (medicine room, medicine store) as general medical institutions in charge of prescription and medication as well as diagnosis. Therefore, Koreans' perception of Western medicine was not very different from that of traditional pharmacy. Second, Western pharmacies were established by various entities including oriental doctors, Western doctors and drug manufacturers.Their business ranged from medical consultation, prescription, medication and drug manufacture. This was in a way the extension of traditional medico-pharmaceutical custom, which did not draw a sharp line between medical and pharmaceutical practices. Also, regulations on medical and pharmaceutical business of Daehan Empire did not distinguish oriental and Western medicine. Third, clinics attached to pharmacy began to emerge after 1908, as some Western pharmacies that had grown their business based on selling medicine began to hire doctors trained in Western medicine. This trend resulted from Government General's control over medico-pharmaceutical business that began in 1908, following a large-scale dismissal of army surgeons trained in medical schools in 1907. Fourth, as specialization increased within medico-pharmaceutical business following the colonial medical law in early 1910s, such comprehensive business practices as Western pharmacy disappeared and existing businesses were differentiated into dealers of medical ingredients, drug manufacturer, patent medicine businessmen and herbalists. And private practice gradually became the general trend by establishment of medical system with doctors at the pinnacle and spread of modern Western medicine, and support of capitalists.

The article series provides an account in words and pictures of the Danish pharmaceutical industry's products from the earliest times until about 1950. Part 2 deals with products from 16 minor pharmaceutical companies, founded in the last decades of the 19th century and the first decades of the 20th century. Mentioned in chronological order, according to year of foundation, the companies are: C.R. Evers & Co., Jensen & Langebek-Petersens chemisk-techniske Fabrik, Leerbeck & Holms kemiske Fabriker, A/S Skelskør Frugtplantage, Fabriken Ferrin, Chr. F. Petri, Erslevs kemiske Laboratorium, A/S Edward Jacobsen, Th. Fallesen-Schmidt, Fabriken Ferraton, Chemia, Fabriken Kemisan, Central-Laboratoriet, F.F. Gonget & Co., A/S Ejco, and M. Schultz chemiske Fabrik. None of these minor pharmaceutical companies exist today as independent firms. All of them are either closed down or merged into other firms after a number of years. The bigger pharmaceutical companies ensured their continued existence by research and development of new products. The minor companies were not innovative to the same extent, but they played a role at an early stage in the production of Danish copy medicine and in that way a role in the establishment of a Danish generic pharmaceutical industry. The earliest products included dietetic preparations as malt products and albumin maltose products, and iron preparations, often with an admixture of medicine substances. Real medicines such as sleeping, analgesic and antipyretic medicines as well as anesthetics followed later.

Penicillin, discovered now eighty years ago (1929) by Alexander Fleming in London, was developed during the world war II into a revolutionizing drug by Howard Florey and Michael Chain in Oxford. At first, industrial production of penicillin was exclusively in the hands of a consortium of large U.S. pharmaceutical companies. However, the war being ended, European entrepreneurs likewise ventured to set up penicillin production units. Amongst them, in Belgium, was Jacques Lannoye, director and co-owner of 'Papeteries de Genval' and of a modest pharmaceutical company, called 'Soprolac'. Through his connections with several medical faculty professors of the Catholic University of Leuven, Lannoye came in touch with Piet De Somer, then a young researcher at the Leuven 'Institute of Bacteriology', with an interest in production of penicillin. A years-long collaboration followed, from which emerged a booming antibiotic and vaccine factory, 'RIT' (Recherche et Industrie Thérapeutiques) in Genval, as well an industry-supported research laboratory, the later Rega Institute, at the University of Leuven. From 1947 to 1952, while coping with the practical problems of setting up large-scale production of penicillin, De Somer maintained a lively correspondence with some other players in the field, sharing with them the ups and downs of the enterprise. Fortunately these letters have been preserved in the archives of the Rega Institute, such that they allow for a reconstruction of this interesting episode in the medical history of Belgium.

The interplay of factors contributing to the development of adrenal cortical hormones into drugs is reviewed. Clinical research performed during long periods by the physicians T. Addison and P.S. Hench in a nearly obsessional way stimulated basic research in physiology and biochemistry of the adrenal glands. From about 1900 increasing public interest in the "new hormones"coincided with expansion in research and development in academic and industrial settings. Pharmaceutical companies developed skill by production of much demanded organ-extracts, both effective ones as insulin and preparations of questionable clinical value. In 1949 the powerful anti-inflammatory effect of the cortical hormone, cortisone was discovered. As the supply of that hormone was scanty, it had temporarily to be substituted by the adrenocorticotropic hormone (ACTH) from animal hypophyses. Thereafter development accelerated through the combined effect of many years' painstaking research on the adrenal cortical hormones, technological breakthroughs, a climate positive for bold clinical experimentation and vigorous competition among mainly American pharmaceutical companies. Within a decade prednisone, the successor of cortisone, was launched, its clinical use established and large-scale inexpensive production instituted.

Today, thousands of tons of vitamin C (l-ascorbic acid) is synthesized every year by the pharmaceutical industry. Synthetically produced vitamin C is widely accepted as having the same physiological effects as vitamin C isolated from natural sources. This is an important difference compared to the 1930s when vitamin C was synthesized for the first time. The identity of synthetic vitamin C with natural vitamin C had to be established. First of all, the scientific community had to accept that artificial I-ascorbic acid and natural vitamin C were chemically identical and had the same physiological effects. Second, other communities like food manufacturers, military health officials, and the broader public also had to be persuaded that these substances were equal. This article demonstrates how Hoffmann-La Roche, a Swiss pharmaceutical company and world-leading producer of synthetic vitamins in the 20th century, tried to coax its adversaries into supporting artificial vitamin C. In doing so, synthetic vitamin C was naturalized in different ways. In the case of Switzerland during the Second World War era, the mentality of national defense and the quest for products supporting autarchy helped to convince perspective consumers. Thus in order to sell a new chemical substance, cultural meaning had to be attached to it.

The following review provides a comprehensive summary of antimicrobial preservatives that are commonly used in licensed parenteral products to date. The information reviewed includes the general properties of the preservatives, the doses and frequency of their use, the classes of the preserved products (peptide, protein, vaccine, and small molecule products), the interactions with other formulation components, and the criteria commonly used for their selection in parental product formulations. It was revealed that phenol and benzyl alcohol are the two most common antimicrobial preservatives used in peptide and protein products, while phenoxyethanol is the most frequently used preservative in vaccines. Benzyl alcohol or a combination of methylparaben and propylparaben are generally found in small molecule parenteral formulations. The key criteria for antimicrobial preservative selection are the preservative's dose, antimicrobial functionality, and effect on the active ingredient. Additionally, the use of spectroscopic techniques (circular dicroism (CD) and fluorescence) and differential scanning calorimetry (DSC) were identified as common techniques used in evaluating an antimicrobial preservative for its impact on the conformational stability of peptide, protein, and vaccine antigens. The future use of preservatives is also discussed, including antimicrobial agents such as peptides, and regulatory requirements for antimicrobial effectiveness testing., ((c) 2007 Wiley-Liss, Inc.)

Medicinal preparations in a manuscript of a fifteen-century Franciscan monk in Brno An unknown Franciscan monk, who worked in his monastery's apothecary in Brno at the beginning of the 15th century, translated many extracts from Ancient and medieval authors into Czech. The collection, supplemented perhaps also from other manuscripts, contains a number of articles on treatment. It was repeatedly copied and has been preserved in several variants. The collection lists about two hundred medicinal preparations and many other pieces of advice and recommendations, mainly based on folk wisdom and knowledge. The most frequently listed items are aromatic waters, electuaries, potions, ointments, and plasters. The paper deals primarily with the technologies of their preparation and documents them by examples from the text of the collection. The collection includes also a herbarium. Some parts of the collection are markedly similar to other Czech manuscripts.