[Early achievements of the Danish pharmaceutical industry--8. Lundbeck]. / DANSK LAEGEMIDDELINDUSTRIS FØRSTE FRUGTER--8. Lundbeck.

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)

On the history of Cinchona bark in the treatment of Malaria.

How and when the medical value of Cinchona bark was discovered is obscure, but it is said that the powder was given to a European for malaria for the first time in the 1630s. The bark was brought to Europe by Spanish missionaries and it was recommended by the cardinal Juan de Lugo. In the 1660s, the use of Cinchona bark became known in England - and in Denmark by Thomas Bartholin. It was used for the treatment of malaria, but several debates on its value continued up to the 1730s. However, successful treatment of malaria was obtained by Thomas Sydenham, Robert Tabor and Francesco Torti. Sydenham emphasized a modern view that Cinchona bark was a unique specific drug for the treatment of malaria, and the treatment was fully accepted when Torti's Therapeutice specialis appeared. In the early 18th century, botanical expeditions were arranged in search of the most valuable Cinchona species for cultivation. The content of quinine was impor- tant, and determination of quinine was realized when Pierre Pelletier and Joseph Caventou isolated the alkaloid from the bark in 1820. Dutch plantations and quinine industry dominated the market, but the supply of quinine came to an end when the Japanese occupied Indonesia in 1942, cutting off the rest of the world from the main supplies of Cinchona. Synthetic antimalarials were developed and chloroquine became the drug of choice, but the intensive use of these drugs caused drug resistance. Chloroquine-resistant strains of P. falciparum are now treated with other drugs as artemisinin and artemether.

[On the history of barbiturates]. / Pionerer bag barbituraterne.

Throughout the history of humanity, numerous therapeutic agents have been employed for their sedative and hypnotic properties such as opium, henbane (Hyoscyamus niger) and deadly nightshade (Atropa belladonna), but also alcohol and wine. In the 19th century potassium bromide was introduced as a sedative - and antiepileptic drug and chloral hydrate as sedative-hypnotics. A new era was reached by the introduction of barbiturates. The story started with the chemist Adolf von Baeyer. His breakthrough in the synthesis of new agents as barbituric acid and indigo and his education of young chemists was of great importance for the science of organic chemistry and the development of the dye and medicine industry in the late 19th century. The next important step was the development of barbiturates. The pioneers were Josef von Mering and Emil Fischer. Using the Grimaux-method they synthesized various barbiturates. It was von Mering who got the idea of introducing ethyl groups in the inactive barbituric acid to obtain sedatives, but the synthesis was succeeded by the chemist Emil Fischer. Experiments with dogs clearly showed sedative and hypnotic effect of the barbiturates and the oral administration of barbital (Veronal) confirmed the effect in humans. Barbital was commercialized in 1903 and in 1911 phenobarbital (Luminal) was introduced in the clinic, and this drug showed hypnotic and antiepileptic effects. Thereafter a lot of new barbiturates appeared. Dangerous properties of the drugs were recognized as abuse, addiction, and poisoning. An optimum treatment of acute barbiturate intoxication was obtained by the "Scandinavian method", which was developed in the Poison Centre of the Bispebjerg Hospital in Copenhagen. The centre was established by Carl Clemmesen in 1949 and the intensive care treatment reduced the mortality of the admitted persons from 20% to less than 2%. To-day only a few barbiturates are used in connection with anaesthesia and for the treatment of epilepsy, and chemists are focusing on drugs with more selective effects.

The Operations of a Danish Provincial Pharmacy at the End of the 1600s.

In Denmark pharmacy practice, as previously mentioned, developed professionally from the middle of the 1500s. As publicly regulated and controlled businesses it was the pharmacies' task to sell medicines for the treatment of diseases in the population. Viewed in the light of these facts it appears that pharmaceutical service at the end of the 1600s according to the pharmacy legislation included selling a broader assortment of goods called pharmacy goods, which besides medicines also included groceries and confectionery for consumption, and technical remedies for domestic and craftsmanlike use. This assortment included 2,920 goods that the pharmacies were obliged to stock. The present investigation shows that proprietor-pharmacist J.F. Friedenreich of Aalborg Swan Pharmacy by and large was able to stock in his pharmacy the huge number of goods included in the legal stock of goods. Moreover the investigation shows that the number of pharmacy goods available in small and medium-sized quantities, among these almost the whole assortment of medicines of the pharmacy, amounted to 94% of the assortment of goods, but only represented 45% of the value of the stock. Furthermore, it can be seen that 43% of the pharmacy goods were available in such small quantities that they were almost a "dead" stock of goods without any turnover. The goods in question were most likely available because the pharmacy was obliged to keep these goods in stock. Furthermore the investigation shows that the pharmacy goods stocked in large quantities made up 6% of the assortment of goods, but represented 55% of the value of the stock, and that this assortment was dominated by groceries, confectionery, and technical remedies available in quantities corresponding to wholesale. As a provincial pharmacy the pharmacy was also allowed to sell wines which were also available wholesale. Thus, the investigation shows that the primary task of the pharmacy as a distributor of medicines for the treatment of diseases in the population financially accounted for a smaller part of the pharmaceutical service than the sale of other pharmacy goods such as groceries, confectionery, and technical remedies. Furthermore the investigation shows that the pharmacy sale of medicines was not profitable, but was subsidized by the pharmacy sale of goods mentioned for consumption and for domestic and craftsmanlike use as well as by the sale of wines.

[Early achievements of the Danish pharmaceutical industry-6 Pharmacia]. / Dansk lægemiddelindustris første frugter-6. Pharmacia.

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.

[Early achievements of the Danish pharmaceutical industry-7]. / Dansk lægemiddelindustris første frugter - 7. GEA.

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.

[On the history of vitamin K, dicoumarol and warfarin]. / Pionerer bag vitamin K, dikumarol og warfarin.

The history of the discovery and development of vitamin K and its antagonists, the oral anticoagulants dicoumarol and warfarin, are fascinating, triumphant landmarks in the annals of medicine. Vitamin K was found by Carl Peter Henrik Dam and Fritz Schønheyder from the University of Copenhagen. The discovery was initiated by Dam, by a lucky choice of chicks in the dissertation of sterol metabolism, since the vitamin is not formed by intestinal bacteria in these animals. In these experiments the lack of an unknown factor in the synthetic diet caused internal bleeding similar to that found in scurvy, but the bleeding was not reversed by vitamin C and it could not be explained by the lack of classical vitamins. In 1935 the unknown antihaemorrhagic factor was named vitamin K and a few months later the phenomenon was also observed by H.J. Almquist and E.L.R. Stokstad in Berkeley. The activity of the factor was determined by bioassay in different extracts of green vegetables and alfalfa by Dam and Schønheyder. Vitamin K was isolated in 1939 by Dam and Paul Karrer in Zurich and the structure was determined by Edward Adelbert Doisy. Dam and Doisy were awarded the Nobel Prize in 1943. A dramatic story starts the discovery of dicoumarol. In the 1920s cattle in Canada began dying of internal bleeding with no obvious precipitating cause. Frank W. Schofield, a veterinary pathologist in Alberta, found that the mysterious disease was connected to the consumption of spoiled sweet clover hay and noted a prolonged clotting time. Ten years after a farmer traveled in a blizzard with his dead cow and a milk can of the unclotted blood to the University of Wisconsin. Only the door to the biochemical department of Karl Paul Link was open. This event started the isolation of the anticoagulant agent dicou- marol which was formed by microbial induced oxidation of coumarin in the mouldy sweet clover hay. More than hundred dicoumarol-like anticoagulants were synthesized by Link and his co-workers. A potent hemorrhagic agent named warfarin was first used as an effective rat poison. However, warfarin became the drug of choice and the break- through in the treatment of thromboembolic diseases. Today new oral anticoagulants are competing with warfarin.

[Early achievements of the Danish pharmaceutical industry--3. Alfred Benzon]. / Dansk laegemiddelindustris første frugter--3. Alfred Benzon.

The article series provides a written and pictorial account of the Danish pharmaceutical industry's products from their introduction until about 1950. Part 3 deals with products from the company founded by Alfred Benzon in 1849. Alfred Nicolai Benzon owned the Swan Pharmacy in Copenhagen. In 1863 he started an independent company manufacturing branded pharmaceuticals, thus combining the pharmacy's activities with the wholesale business. The family owned the company until 1952, when it was converted into a foundation. After several restructuring rounds, the medicine production business continued as Benzon Pharma A/S until 1990, when Nycomed Pharma A/S bought up all the branded pharmaceuticals. As the first pharmaceutical company in Denmark, Alfred Benzon was an industrial frontrunner in the country at the time, supplying not only the domestic market but foreign markets as well. Alfred Benzon was the first Danish company to produce ether for anesthesia, and malt extract, a dietetic preparation. The high quality of both products made them valuable export articles. In the early 1890s, Alfred Benzon became the first Danish company to start the research-based production of extract of thyroid glands from slaughtered cattle. This was the beginning of a long-standing specialization in producing organotherapeutic substances from animal organs originating from Danish animal husbandry. In 1932 the company had 26 preparations of this type in its range, many of them on the market for several years. These medicine substances included iron preparations and effervescent salts followed by sulfonamides, synthetic hormones and a substance to counteract motion sickness.

[A personal prescription book]. / En personlig receptbog.

The Danish Collection of the History of Pharmacy includes a unique record: Mrs. I.J. Valentiner's prescription book. The slim volume dates from the period 1906-1917 and contains a collection of 45 prescriptions for Mrs. Valentiner, whose husband was a land agent on a large estate, Frederikslund, on the island of Funen. Mrs. Valentiner's brother, Axel Bentsen, a physician in Northern Jutland during this period, wrote most of the prescriptions. Many of the prescriptions are dated within a few days of each other. The likely explanation is a practical one. When visiting his sister, Axel Bentsen probably provided her and her family with prescriptions for a broad spectrum of medicines such as analgesics, cough mixtures, laxatives and ointments, should they be needed. The record shows that various pharmacies were involved in making up 24 of the prescriptions in Mrs. Valentiner's prescription book until 1926, and the book was thus in use for 20 years.

[History of gold--with danish contribution to tuberculosis and rheumatoid arthritis]. / Guld i medicinens tjeneste--Med traek af dansk indsats ved tuberkulose og reumatoid artrit.

Gold has a long history as a therapeutic agent, first as gold particles and colloidal gold, then as a soluble salt made by the alchemists, and potable gold was recommended almost as a panacea against different diseases. Gold compounds were introduced in the treatment of tuberculosis, based initially on the reputation of Robert Koch, who found gold cyanide effective against Mycobacterium tuberculosis in cultures. Although several investigations of gold salts showed no convincing effect in experimental tuberculosis in guinea pigs, the idea of using gold compounds as chemotherapy was furthermore encouraged from the work of Paul Ehrlich with arsenicals. The enthusiasm and the craving desperately for a remedy for tuberculosis forced Danish physicians, in the mid-1920s to treat tuberculosis with Sanocrysin (gold sodium thiosulfate). Professor Holger Møllgaard, in collaboration with the clinicians the professors Knud Secher and Knud Faber, was the theoretical promoter of the project. He recommended sanocrysin-antiserum therapy, since sanocrysin caused serious reactions in tuberculosis animals, possible by releasing toxins from tubercle bacilli "killed" by sanocrysin. However the enthusiastic response to sanocrysin in Europe declined along by controlled trials and reports on toxicity in the 1930s. The belief that rheumatoid arthritis was a form of tuberculosis caused a renaissance in chrysotherapy. In France Jacques Forestier obtained encouraging results in the treatment of rheumatoid arthritis with myochrysine and other gold salts, and he pointed out the disease modifying effect of chrysotherapy. In Denmark Knud Secher, who was the clinical initiator of Sanocrysin therapy in tuberculosis, now became the founder of chrysotherapy in rheumatoid arthritis. Although new potential agents are now taking over in the treatment of arthritis, it is still believed, that there is a place for the chrysotherapy. However a new future for gold, in the form of nanoparticles, appears on the horizon, especially in the imaging, diagnostics and therapies of cancer.

[Ambroise Paré (1510-90)--and features of the history of surgery]. / Ambroise Paré (1510-1590)--Traek af kirurgfagets historie og dets medi- kamentelle aspekter.

For six centuries the barbers of Europe practiced surgery. In 1215 a papal edict forbade members of the clergy (physicians) from performing surgical procedures as contact with blood was felt to be contaminating to men of the church. Bloodletting and minor surgery was now turned over to the barber-surgeons and this was in agreement with the medical doctors who felt that these procedures were beneath their dignity. The barber-surgeons were sometimes called "doctors of the short robe" to distinguish them from the medical doctors and surgeons who were called "doctors of the long robe", although university status was hardly given to the surgeons. Ambroise Paré started as a barber-surgeon and his eminence was honoured by the long robe. It was his experience at the Hôtel Dieu that permitted him to serve as a surgeon to the French army and through his open mind Paré made many innovations during his career. Paré abolished the painful practise of cautery to stop bleeding and used ligatures and dressings instead. A multitude of subjects were included in his writings such as military surgery, aneurysm, hernia, obstetrics and plague, and through his techniques he guided the development of the gentle art of surgery. Paré became the founder of modern surgery, a restorative process that heals the body with minimal suffering.

[Early achievements of the Danish pharmaceutical industry--2. The minor and almost forgotten pharmaceutical companies]. / De mindre og naesten glemte laegemiddelindustrivirksomheder.

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.

[From willow bark to acetylsalicylic acid]. / Fra pilebark til acetylsalicylsyre.

Acetylsalicylic acid is one of the most widely used drugs in the world. Its ancestry the salicylates, including salicin and salicylic acid, are found in the bark and leaves of the willow and poplar trees. The ancient Sumerians and Egyptians, as well as Hippocrates, Celsus, Pliny the Elder, Dioscorides and Galen used these natural products as remedies for pain, fever and inflammation. In the Middle Ages these remedies were used for fever and rheumatism by Hildegard of Bingen and Henrik Harpestreng. The first "clinical trial" was reported by Edward Stone in 1763 with a successful treatment of malarial fever with the willow bark. In 1876 the antirheumatic effect of salicin was described by T. MacLagan, and that of salicylic acid by S. Stricker and L. Riess. Acetylsalicylic acid was synthesized by Charles Gerhardt in 1853 and in 1897 by Felix Hoffmann in the Bayer Company. The beneficial effect of acetylsalicylic acid (Aspirin) on pain and rheumatic fever was recognized by K. Witthauer and J. Wohlgemuth, and the mechanism of action was explained in 1971 by John Vane. Today the antithrombotic effect of acetylsalicylic acid and new aspects of ongoing research demonstrates a still living drug.

[Early achievements of the Danish pharmaceutical industry--1 Novo Nordisk]. / Dansk laegemiddelindustris første frugter--1. Novo Nordisk.

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 1 deals with products from Nordisk Insulinlaboratorium, founded in 1923, and Novo Terapeutisk Laboratorium, founded in 1925. The two companies were competitors for many years and became two of the world's leading insulin producers. In 1989 they joined forces, merging to become Novo Nordisk A/S, today one of the world's leading biotech companies. The article chronicles the earliest decades of development and progress in insulin production, illustrated with photos of several types of consumer packaging. In 1923 Nordisk Insulinlaboratorium marketed Insulin "Leo" tablets, from which patients had to make their own sterile solution for injection two to three times a day, because the solution was unstable. Ready-to-use solutions gradually came on the market, and formulations with prolonged duration, so-called protamin-insulins, were developed in the 1930s. Insulin "Leo" Retard was marketed in 1936, and its basic properties were maintained and further developed in step with research breakthroughs well into the 1980s. Novo Terapeutisk Laboratorium's first insulin was Insulin Novo in 1925, and at the same time one of the company founders developed Novo-sprøjten (the Novo Syringe) for individual dosage from a special ampoule. The syringe was further developed over the years and was the prototype for the NovoPen launched in 1985 as well as for later advanced dosage systems. Starting in 1938 Novo Terapeutisk Laboratorium marketed Zink-Protamin-Insulin Novo and products based on other insulin derivatives in the 1940s. The era concludes with Insulin Novo Lente from 1952 as well as suspensions of amorphous and crystalline zinc-insulin. Ever since, insulin treatments for diabetes have been the focus of intensive development throughout the global marketplace and continue to be so.

[Prescription of medicines by two medical officers in Jutland in 1797. An analysis of the prescription practice of C.D. Hahn, Physicus of Aarhus Diocese, and K.N. Carstensen, Physicus of Aalborg Diocese]. / Laegemiddelordinationer fra to jyske embedslaeger i 1797. En undersøgelse af ordinationspraksis for stiftsfysikus C.D. Hahn i Arhus og landfysikus K.N. Carstensen i Aalborg.

The concept of authorized medicines was introduced and defined by the Danish Government during the first half of the 17th century, thus establishing the basis for the sale of such medicines by pharmacists and their prescription by medical practitioners. The concept of authorized medicines was linked to the drug tariff in force until 1772 when the Pharmacopoea Danica was first published. The pharmacopoeia fixed the assortment of substances to be stocked by all pharmacies, including about 580 medicamenta simplicia, i.e. substances to be used as medicines or for the preparation of medicines, as well as 640 medicamenta composita, i.e. composite medicines already prepared. The pharmacopoeia helps us to understand the basis of medical therapy at that time, but it does not tell us which medicines were favoured in practice. However, two other sources prove valuable for that purpose. One of these is a large collection of patient records found in the archives of the Medical Museion of Copenhagen. These records were written by Christopher Detlev Hahn, medical officer in Aarhus from 1777 to 1817, and they include all his prescriptions to his patients. The other source is the prescription record from Aalborg Swan Pharmacy, kept in Jens Bang's House in Aalborg. It contains copies of prescriptions by Knud Nicolai Carstensen who was the medical officer in Aalborg from 1783 to 1802. We compared the prescription practice of these two doctors in the year 1797, studying 280 prescriptions by Hahn to 59 patients and 267 prescriptions by Carstensen to 137 patients. Both doctors used a large selection of the substances and preparations described in the pharmacopoeia, showing that they were familiar with that book, but usually they did not prescribe these substances and preparations as such. They individualized their treatment to suit each patient, composing medicines, whose ingredients, however, were mostly found in the pharmacopoeia. Medicines for internal use included drops, mixtures, electuaries, powders, teas and other herbs. Medicines for external use were usually ointments. In a number of cases Hahn prescribed pills, whereas Carstensen did not do so, although the production of pills at that time was common practice. Carstensen paid greater attention to the durability of the prescribed medicines than Hahn, probably because Carstensen's patients came from all of Northern Jutland. Therefore, it was important in his case that the keeping quality of the medicines permitted a time-consuming transport from pharmacy to patient and storage by the patient during the whole course of treatment. In contrast, most of Hahn's patients lived in Aarhus and surroundings. We compared the 22 substances used most frequently by Hahn and the 22 used most frequently by Carstensen. In both cases these included (in alphabetical order): bitter orange peel, camphor, cinchona, ether, peppermint, potassium carbonate, potassium tartrate and rhubarb roots. 60% of the substances in the preparations by either doctor were herbal drugs and 40% mineral or other chemical substances. Both Hahn and Carstensen favoured "evacuative" treatment, according to the theory of humoral pathology, using laxatives, diuretics and sudorifics. However, their choice of medicines differed, and, in contrast to Carstensen, Hahn also frequently prescribed emetics. The two doctors rarely prescribed the chemical substances recommended by the iatrochemists.

[Mercury--a major agent in the history of medicine and alchemy]. / Kviksølv--et centralt stof i medicinens og alkymiens historie.

From ancient time the history of mercury has been connected with that of the medicine and chemistry. Mercury therefore contributes to the history of science throughout times. Knowledge of cinnabar (HgS) is traced back to ancient Assyria and Egypt, but also to China. The Greek philosophers were the initiators of theoretical science. The idea of the four elements, earth, air, water and fire, was introduced mainly by Empedocles and Aristotle in the 5th and 4th century BC. The theory encouraged the hope of transmuting metal to gold. The early development of practical alchemy is obscure, but some hints are given in the encyclopedia compiled by Zosimos about 300 A.D. in Alexandria. It also includes the invention of equipment such as stills, furnaces and heating baths. Medical treatment is described by Pliny and Celsus, e.g. the use of cinnabar in trachoma and venereal diseases. When the Arabs learned Greek alchemy by the Nestorians, they introduced or improved chemical equipments and new chemicals were obtained such as sublimate (HgCl2), different salts, acids, alkaline carbonates and metal oxides. The first recorded account of animal experimentation on the toxicity of mercury comes from Rhazes (al-Razi) in the 9th century and in the 11th century Avicenna (Ibn Sina) had the foresight to recommend the use of mercury only as an external remedy, and quicksilver ointments were used by the Arabs in the treating of skin diseases. In the medieval west scientific experiments were forbidden since the interpretation of the world order should not be changed. Greek and Arabic medicine and alchemy were therefore authoritative and the breakthrough in scientific inventions first appeared after the introduction of the Renaissance. The Renaissance medicine included ancient medicine as well as "modern medicine", based on iatrochemistry, and this chemical approach was introduced by Paracelsus. The medicine included sulphur and salts or oxides of for instance mercury, copper, iron, antimony, bismuth and lead. Most important was mercury when the outbreak of syphilis appeared in Europe at the end of the 15th century. The Arabian quicksilver ointment was remembered and used for the treatment of syphilis, but the treatment also included pills and ointments of sublimate and calomel (Hg2Cl2). The breakthrough in science was the discovery of oxygen by Priestley in the late 18th century. Priestley heated the oxide of mercury and examined the gas and thereafter Lavoisier recognized that combustion involves oxidation. All this led to a new understanding of respiration and furthermore established the basis of modern chemistry. The apothecaries of the 19th and 20th century showed many colourful mercurials as calomel, sublimate, cinnober, oxides of mercury and mercury. Calomel pills were used in acute and chronic diseases and furthermore as a diuretic drug before the organomercurials appeared in the 1920s. Skin diseases were treated with ointments or plasters of the mercurials or quicksilver. Antiseptics were introduced by Semmelweis hand-washing with chlorinated water before deliveries in obstetrics and by Lister's antiseptic ritual with carbolic acid during surgical operations. Also organomercurial "antiseptics" were used but unfortunately these agents were bacteriostatic rather than bacteriocidal and allergic contact dermatitis has been observed. Today the problems are solved by sterilization and aseptic conditions. Penicillin appeared in the 1940s and chlorothiazide in 1957 and new effective agents have taken over in the treatment of diseases with mercurials.

[Pictures from the Dolphin Pharmacy in Copenhagen]. / Billeder fra Delfin Apoteket i København.

The development of the pharmacy in the 19th and 20th centuries is illustrated by education and activity in the Dolphin Pharmacy in Copenhagen. The career within chemistry and pharmacy started with an apprenticeship of 4 year in the pharmacies. The Dolphin Pharmacy was responsible for part of the examination, i.e. the examination of the preparation of medicine. Passing the examination the chemist's assistant was free to prepare and to dispense medicine. Graduation as a pharmaceutical candidate was necessary to obtain license. Lectures in chemistry, physics, pharmacy, botany and pharmacognosy were obtained at the University of Copenhagen and the Polytechnic, but no curriculum was available. A rational education was obtained later on by the establishment of the School of Pharmacy in 1892. The proprietor pharmacists of the Dolphin Pharmacy were excellent scientists who contributed to the development of pharmacy. Pictures of the pharmacy from about the 1930s show the manufacture of medicines on the basis of a prescription and a pharmacopoeia. Ointments containing zinc white, sulphur and tar were used for various skin diseases and for the tiresome cough; cough mixtures containing codeine or extract of ipecacuanha root were used. In the 1930s the medicine for injection was sterilized and the tablet machine was the breakthrough for a rational production in the pharmacy. However, at the end of the 1900s it was no more possible to compete with the pharmaceutical industry and all the production of medicine was taken over by the industry.

[On the history of injection]. / Traek af injektionens historie.

Although the effect of snake bites and poisoned arrows was known from ancient time, the development of the syringe and the needle lasted several centuries. Forms of intravenous injection and infusion are clearly documented in the 1650s. Sir Christopher Wren used a syringe made of animal bladder fixed to a goose quill to inject wine and opium into the veins of dogs. J.D. Major from Kiel and J.S. Elsholtz from Berlin probably were the first to deliberately administer intravenous injections to people in the 1660s. However, these early injections were not successful and injections did not come into fashion again until the latter part of the 1800s. Forerunners of subcutaneous administration were either the introduction of the drug under the epidermis by means of a vaccination-lancet or the application of a vesicant to remove the epidermis, after which the drug was applied to the denuded cutis. Lafargue, Lembert and Lesieur described these methods in the first half of the 1800s, and the methods continued to be of use in the second part of the century until the advent of subcutaneous injection. Alexander Wood of Edinburgh and Charles-Gabriel Pravaz from Lyon are known commonly as the inventors of the syringe for subcutaneous injection, but other pioneers such as Taylor, Washington and Rynd had already begun this form of administration. Increased use, safety and accuracy were accomplished by the progressive steps introduced by Wood, Pravaz and Luer. Thus, the syringe of Luer was fitted for aseptic heating, and a sharp needle readily perforated the skin. Sterilization by heating in an autoclave was developed by Pasteur, Chamberland and Koch, after managing aseptic conditions by the addition of preservatives such as carbolic acid. A safe method for the storage of sterile injectates was provided by Limousin's ampoule from 1886, and later by the introduction of multi-dose containers. The evolution of the syringe and its needle continues with the introduction of transdermal drug delivery by micron-scale needles and monitored drug delivery.

[History of opium poppy and morphine]. / Opiumsvalmuen og morfin gennem tiderne.

Opium has been known for millennia to relieve pain and its use for surgical analgesia has been recorded for several centuries. The Sumerian clay tablet (about 2100 BC) is considered to be the world's oldest recorded list of medical prescriptions. It is believed by some scholars that the opium poppy is referred to on the tablet. Some objects from the ancient Greek Minoan culture may also suggest the knowledge of the poppy. A goddess from about 1500 BC shows her hair adorned probably with poppy-capsules and her closed eyes disclose sedation. Also juglets probably imitating the poppy-capsules were found in that period in both Cyprus and Egypt. The first authentic reference to the milky juice of the poppy we find by Theophrastus at the beginning of the third century BC. In the first century the opium poppy and opium was known by Dioscorides, Pliny and Celsus and later on by Galen. Celsus suggests the use of opium before surgery and Dioscorides recommended patients should take mandrake (contains scopolamine and atropine) mixed with wine, before limb amputation. The Arabic physicians used opium very extensively and about 1000 AD it was recommended by Avicenna especially in diarrhoea and diseases of the eye. Polypharmacy, including a mixture of nonsensical medications were often used. Fortunately for both patients and physicians many of the preparations contained opium. The goal was a panacea for all diseases. A famous and expensive panacea was theriaca containing up to sixty drugs including opium. Simplified preparations of opium such as tinctura opii were used up to about 2000 in Denmark. In the early 1800s sciences developed and Sertürner isolated morphine from opium and was the founder of alkaloid research. A more safe and standardized effect was obtained by the pure opium. Several morphine-like drugs have been synthesized to minimize adverse effects and abuse potential. Opioid receptors were identified and characterized in binding assays and their localization examined. However, the complexity of the system including interaction with several neurons and transmitters indicate the goal of nonaddictive opiates to be elusive. Combination therapy, innovative delivery systems and long-acting formulations may improve clinical utility.