Making British Cortisone: Glaxo and the development of Corticosteroids in Britain in the 1950s–1960s

Following the announcement in 1949 in the USA that cortisone offered rheumatoid arthritis sufferers effective treatment for their crippling disease, the Ministry of Health came under considerable pressure from the medical profession and the public to make cortisone available in Britain. The Ministry, therefore, urged British companies to start manufacturing cortisone. Among the several pharmaceutical firms responding to the Ministry’s request, Glaxo’s expertise in the field of vitamins gave them a head start. This paper describes the varied and flexible strategy that enabled Glaxo to maintain this head start, and the scientific and technical capabilities which the company subsequently built up, enabling them to dominate the market for corticosteroids in Britain.Among the drugs to emerge out of the Glaxo project to manufacture cortisone, which began in 1950 and later became a wider R&D programme on steroids, was the topical steroid Betnovate, launched in 1963, which remains a best-seller today. However, although it led to successful new products, Glaxo’s programme had limitations. The paper identifies a missed opportunity, in the shape of the biosynthetic route to steroid drugs, often considered as a milestone in the development of the new biotechnology. Whether or not this missed opportunity proved costly to the company is uncertain. However, it illustrates the role of technological path-dependence, and the importance of the integration between different scientific disciplines, in this case chemistry and biology, in pharmaceutical innovation.     

From paper chromatography to drug discovery: Zaffaroni.

A paper chromatography assay for adrenocortical steroids, published just as cortisone's therapeutic value in arthritis was announced, had far-reaching consequences. Its use by Upjohn scientists led to the first synthesis of cortisone. Interest in the assay also led the author to an association with Syntex S.A. in Mexico, which he was instrumental in transforming from a small chemical company into the large pharmaceutical firm, Syntex Corporation, having its base of operations in the United States. The major events of this history are described, showing how steroid product development helped establish Syntex and later played a role in the founding of ALZA Corporation.     

合成生物技术生产甾体激素中间体的研究展望

甾体类药物是销售额仅次于抗生素的世界第二大类药物,不同的甾体药物分子结构均由甾体激素中间体衍生而来。甾体激素中间体的传统生产方法包括植物提取皂素法和化学全合成法,其对环境有害,反应产物结构不唯一且成本较高,不利于工业化生产。目前主要的生产工艺是利用微生物对特殊原料进行转化的半合成法,但会遇到微生物酶转化率低、发酵周期长等问题。合成生物学的出现为构建利用糖为唯一碳源生产甾体激素中间体的人工细胞提供了理论上的可行性和可靠的技术支持。重点综述了合成生物技术在甾体激素中间体生产中的应用,以有利于工业发酵的酿酒酵母、分枝杆菌等为底盘细胞,通过引入外源合成功能模块,实现胆甾醇、雄烯二酮等甾体激素中间体的生物合成,并对合成生物技术在医药生产方式转变中的应用进行了展望,以期推动甾体类药物生物制造技术的进步。     

The cortisone era: aspects of its impact. Some contributions of the Merck Laboratories.

The announcement in 1949, by Hench at the Mayo Clinic, that cortisone had a dramatic beneficial effect on bed-ridden patients suffering from rheumatoid arthritis ushered in the cortisone era. This medical landmark was made possible by the prior steroid research of distinguished chemists and biologists in several countries. The first partial synthesis of cortisone by Sarett was the culmination of a worldwide chemical effort. This work ultimately enabled the process research department at Merck, under the direction of Max Tishler, to perform the 37-step conversion of deoxycholic acid to cortisone on a scale that made the initial clinical trials possible. In spite of the enormity of the project, and the fact that neither of two closely related analogs of cortisone had shown any interesting biological activity. Merck elected to embark on this synthetically challenging project. The clinical results reported in 1949, combined with the complexity of the partial synthesis, stimulated highly innovative research to discover new routes to cortisone and to cortisol, the active hormone. This research, particularly in the pharmaceutical industry in the United States, Mexico, and Europe, demonstrated, among other things, the value of microbial transformations in synthetic sequences. The recognition that the chronic administration of cortisol produces several unexpected side effects stimulated an intensive effort in many countries to discover an analog with an improved therapeutic index. This led to more novel chemistry and many analogs were discovered that proved to be more potent than cortisol. Prednisolone, discovered at the Schering Corporation, was the first compound that combined a high level of anti-inflammatory activity with reduced salt retention. Derek Barton contributed greatly to steroid research during the 1950s by applying creative structural thinking to systematize a host of seemingly unrelated chemical and biological observations. The cortisone era had a profound impact on drug discovery also, since it led to the logical application of steric and electronic concepts to medicinal chemistry. Last, but not least, the cortisone era taught medicinal chemists many important lessons about drug-receptor interactions.     

Steroids and "the pill": early steroid research at Searle.

The announcement from the Mayo Clinic in 1949 of the dramatic effectiveness of cortisone in the treatment of rheumatoid arthritis stimulated tremendous interest in steroid chemistry, endocrinology, and related areas of medicine. Shortly thereafter, G. D. Searle & Co. initiated a major effort in steroid research, the objective of which was to discover better steroid drugs than those available at that time or steroids that could be used for conditions for which no compounds were previously available. This effort was remarkably successful and resulted in the introduction of several important pioneering drugs. These included norethandrolone, marketed in 1956 as Nilevar, the first anabolic agent with a favorable separation between protein building and virilization, and spironolactone, introduced in 1959 as Aldactone, the first steroid antialdosterone antihypertensive agent. Of special importance was the research that culminated in the discovery of Enovid. This substance, a combination of the progestin norethynodrel and the estrogen mestranol was first approved in 1957 for the treatment of a variety of disorders associated with the menstrual cycle. The era of oral contraception began in May 1960, when Enovid was approved by the Food and Drug Administration for ovulation inhibition, and was immediately thereafter introduced for such use.     

Transformation of steroids by actinobacteria: a review

Development of pharmaceutical industry is currently aimed at introducing biotechnological processes on a large-scale and thereby replacing multiple-stage chemical syntheses. Actinobacteria are efficient biocatalysts of many processes involving steroid bioconversion, which hold considerable importance for the synthesis of hormonal drugs. The potential to catalyze the conversion of a broad spectrum of steroid substrates makes it possible to expect efficient utilization of these microorganisms in development of new technologies of manufacturing steroid pharmaceutical substances. The review is a first attempt to systematize data on the potential of actinobacteria to catalyze diverse reactions of steroid transformation (such as hydroxylation, introduction and reduction of double bonds, oxidation of steroid alcohols, reduction of ketones, side chain de-esterification and degradation, etc.), with emphasis on processes of practical biotechnological importance and progress in steroid bioconversion over the last ten years.     

Better prepared than synthesized: Adolf Butenandt, Schering Ag and the transformation of sex steroids into drugs (1930-1946)

This paper follows the trajectory of sex steroids in 1930s Germany as a way to investigate the system of research which characterized the development of these drugs. Analyzing the changing relationship between the pharmaceutical company Schering and the Kaiser Wilhelm Institute für Biochemie headed by Nobel Prize winner Adolf Butenandt, the paper highlights the circulation of materials, information and money as much as the role of patents in shaping the study of sex steroids. Semi-synthetic analogs and metabolic pathways thus emerged as shared bio-industrial assets. This collaborative work participated in a more general 'internalization' of biology, which took place in pharmaceutical firms during the 1920s and 1930s as a strategy to standardize and develop biologicals. The construction of the hormone market was also based on Schering's collaboration with a selected group of clinicians who worked out the wide-range of indications associated with these 'natural' drugs. The paper finally shows how the wartime scientific and industrial mobilization in Nazi Germany marginalized the study of sex steroids and led to the dismantling of the KWIB-Schering network.     

Transformation of steroids by actinobacteria: A review

Development of pharmaceutical industry is currently aimed at introducing biotechnological processes on a large-scale and thereby replacing multiple-stage chemical syntheses. Actinobacteria are efficient biocatalysts of many processes involving steroid bioconversion, which hold considerable importance for the synthesis of hormonal drugs. The potential to catalyze the conversion of a broad spectrum of steroid substrates makes it possible to expect efficient utilization of these microorganisms in development of new technologies of manufacturing steroid pharmaceutical substances. The review is a first attempt to systematize data on the potential of actinobacteria to catalyze diverse reactions of steroid transformation (such as hydroxylation, introduction and reduction of double bonds, oxidation of steroid alcohols, reduction of ketones, side chain de-esterification and degradation, etc.), with emphasis on processes of practical biotechnological importance and progress in steroid bioconversion over the last ten years.     

赣州市结核病防治规划实施情况分析

目的详细了解赣州市结核病防治规划实施情况,为今后结核病防治工作提供依据。方法由赣州市疾病预防控制中心执行卫生部统一制定下发的《全国结核病防治规划(2001-2010年)终期评估方案》和《终期评估调查表》,进行单位自查与市级组织检查验收。通过验收的《终期评估调查表》全部录入计算机,进行资料分析。结果《规划》期间全市投入用于结核病防治的各种费用总计4 517.04万元。登记活动性肺结核63 427例,其中涂阳患者33 339例(初阳27 621例、复阳5 718例),涂阴27 408例,完成初治涂阳任务指标平均达到99.64%,治愈率平均达到91.11%。结论经实施《全国结核病防治规划(2001-2010年)》,赣州市结核病的防控措施无论是软件还是硬件都得以完善,并且病人及时得到发现与有效治疗。     

科学典故在组织胚胎学教学中的应用

人体组织胚胎学是一门医学形态学课程,也是医学生进入人体奥秘大门的一把重要钥匙,但形态结构中繁多的记忆内容常常让学生感到学习枯燥,因而更需要授课教师通过不同形式的教学策略引导学生领会其中的乐趣和科学意义。在众多的教学方法和教学手段中,适当引用教学内容相关的科学典故和科学名人,能在潜移默化中培养学生的学习兴趣,理解相关的理论知识,改善教学效果。本文作者整理了一些组织胚胎学教学内容相关的科学典故及其在教学中的应用,供同行交流和医学生参考学习。     

Effect of substrate and small doses of cortisone on the induction of Tryptophan 2,3-dioxygenase (author's transl)]

A number of enzymes are induced by steroid hormones. In this paper the reaction of tryptophan 2,3-dioxygenase is further analyzed. In particular we show in which way the substrate and low doses of cortisone cause an induction. 1) For the induction of tryptophan 2,3-dioxygenase in adrenalectomized rats by 2.5 mg cortisone/kg, the presence of the substrate is necessary as well. Under these conditions an induction of the enzyme can already be registered in the presence of 12.5 mg L-tryptophan/kg. 2) In animals treated before with cortisone, the enzyme maximum appears 30 min after L-tryptophan injection, The enhancement of enzyme activity in animals which are treated with 2.5 mg cortisone/kg before is blocked by actidione only until 30 min after L-tryptophan injection. 3) Experiments with antibodies in animals treated with a low dosis of cortisone show that L-tryptophan acts mainly via enzyme degradation or the saturation with the coenzyme hematin, respectively.     

Capillary electrophoresis with UV detection and mass spectrometry in method development for profiling metabolites of steroid hormone metabolism

The aim of this study was to develop a method for comprehensive profiling of metabolites involved in mammalian steroid metabolism. The study was performed using the partial filling micellar electrokinetic chromatography (PF-MEKC) technique for determination of endogenous low-hydrophilic steroids. The detection techniques in capillary electrophoresis were UV absorption and electrospray mass spectrometry (ESI-MS). Thirteen steroids were included in the method development, and the selected were metabolites involved in major pathways of steroid biosynthesis. Although only eight of them could be separated and detected with UV, they could be identified by ESI-MS using selected ion monitoring (SIM) technique. Tandem MS spectra were also collected. UV detection was more sensitive than MS due to better separation of compounds and the selective signal sensitivity. The lowest limits of detection were 10-100ng/mL for cortisone, corticosterone, hydrocortisone and testosterone. The other steroids could be detected at 500-1000ng/mL. The identification of cortisone, corticosterone, hydrocortisone, estrogen and testosterone were made in patient urine samples and their concentrations were 1-40mug/L.     

Purchaser-provider: the international dimension.

Purchaser-provider systems in health care are being implemented in several countries and are under consideration in many more. These new arrangements are described for the United Kingdom, Finland, New Zealand, and Australia, and in each case responsibility for funding, purchasing, providing, and ownership is identified. The four systems, along with managed care organisations in the United States, are also compared with regard to several important features. There is a fundamental similarity between these purchaser-provider arrangements but several key differences are well worth systematic study. This is a major challenge for academic bodies in Britain and other countries, and the opportunity to learn from each other should not be missed.     

Better prepared than synthesized: Adolf Butenandt, Schering Ag and the transformation of sex steroids into drugs (1930–1946)

This paper follows the trajectory of sex steroids in 1930s Germany as a way to investigate the system of research which characterized the development of these drugs. Analyzing the changing relationship between the pharmaceutical company Schering and the Kaiser Wilhelm Institute für Biochemie headed by Nobel Prize winner Adolf Butenandt, the paper highlights the circulation of materials, information and money as much as the role of patents in shaping the study of sex steroids. Semi-synthetic analogs and metabolic pathways thus emerged as shared bio-industrial assets. This collaborative work participated in a more general ‘internalization’ of biology, which took place in pharmaceutical firms during the 1920s and 1930s as a strategy to standardize and develop biologicals. The construction of the hormone market was also based on Schering’s collaboration with a selected group of clinicians who worked out the wide-range of indications associated with these ‘natural’ drugs. The paper finally shows how the wartime scientific and industrial mobilization in Nazi Germany marginalized the study of sex steroids and led to the dismantling of the KWIB–Schering network.     

Acne conglobata; use of cortisone and corticotropin in therapy

Six patients with acne conglobata were treated with cortisone and adrenocorticotropic hormone. Definite immediate improvement was observed in all of them. In three cases control of the disease was maintained on relatively low doses of steroid. In one case there was response to superficial x-ray therapy after the acute phase of the disease had subsided in response to steroids. Resistance to steroid therapy apparently developed in one patient after approximately 18 months of treatment. One patient responded to treatment and then remained well (for two months when last observed) although steroids and all other treatment were discontinued. The combined use of antibiotics and steroids in the patients treated gave the best results.     

Morphofunctional Differentiation in the Liver

The influence of endotoxin and cortisone on the function of hepatic cells was studied in relation to the effect of partial hepatectomy on their activity. The overall rate of clearance of carbon (K) suffered a diminution within the first few hours after surgery but carbon uptake per unit weight tissue was elevated as a result of hepatic resection. The K values were increased by endotoxin (100°g i.p.) alone or together with cortisone (1 mg i.p.) but the hormone alone lowered the clearance rates in high doses (5 mg i.p.). Treatment with either substance increased liver weight over and above the control level in early phases of regeneration and lowered it in the later phases. The actions of cortisone and endotoxin were not additive on either process. As regards the influence of cellular cycle on hormonally modified gene activity, refractoriness to the hypertrophic effect of cortisone (5 mg i.p. a dose which lowered the K value at all times) developed soon after hepatic resection and continued for at least 36 h after surgery. These and other results indicate that the RE cells remain susceptible to external influences throughout the regenerative cycle and do not passively follow the behaviour pattern of parenchyma. An active contribution of RE cells is further supported by the observation that regeneration was accompanied by a progressive increase in spleen weight. Furthermore, because uptake and binding of cortisone to 'specific' receptors progressed at least as well as in control mice at all these time periods, the refractoriness to cortisone action must lie at some stage beyond uptake, processing or association of steroid with the appropriate receptor. These data indicate the necessity to consider the behaviour of individual cell types in order to comprehend the integrated responses observed during growth, development and differentiation in the liver.     

Dramaturgical study of meetings between general practitioners and representatives of pharmaceutical companies

ObjectivesTo examine the interaction between general practitioners and pharmaceutical company representatives.DesignQualitative study of 13 consecutive meetings between general practitioner and pharmaceutical representatives. A dramaturgical model was used to inform analysis of the transcribed verbal interactions.SettingPractice in south west England.Participants13 pharmaceutical company representatives and one general practitioner.ResultsThe encounters were acted out in six scenes. Scene 1 was initiated by the pharmaceutical representative, who acknowledged the relative status of the two players. Scene 2 provided the opportunity for the representative to check the general practitioner''s knowledge about the product. Scene 3 was used to propose clinical and cost benefits associated with the product. During scene 4, the general practitioner took centre stage and challenged aspects of this information. Scene 5 involved a recovery strategy as the representative fought to regain equilibrium. In the final scene, the representative tried to ensure future contacts.ConclusionEncounters between general practitioners and pharmaceutical representatives follow a consistent format that is implicitly understood by each player. It is naive to suppose that pharmaceutical representatives are passive resources for drug information. General practitioners might benefit from someone who can provide unbiased information about prescribing in a manner that is supportive and sympathetic to the demands of practice.

What is already known on this topic

Pharmaceutical representatives influence physicians'' prescribing in ways that are often unacknowledged by the physicians themselvesMeetings with pharmaceutical representatives are associated with increased prescribing costs and less rational prescribing

What this study adds

Meetings between pharmaceutical representatives and general practitioners follow a consistent format that is implicitly understood by each playerGeneral practitioners may cooperate because representatives make them feel valued     

Long-acting contraceptive agents: design of the WHO Chemical Synthesis Programme

The great demand for improved long-acting injectable steroid contraceptives, particularly in developing countries, and the relative lack of interest from the pharmaceutical industry to develop such products stimulated WHO to launch a synthetic and screening programme to find improved, safe and acceptable injectable preparations. More than 210 esters of norethisterone (17 alpha-ethynyl-17 beta-hydroxyestr-4-en-3-one) and levonorgestrel (D-(-)-13 beta-ethyl-17 alpha-ethynyl-17 beta-hydroxygon-4-en-3-one) have been prepared in university-based research laboratories situated mainly in developing countries, and then screened by NICHHD in animal models. The following three compounds, levonorgestrel butanoate, cyclopropylcarboxylate and cyclobutylcarboxylate, proved to be particularly long-acting when administered as microcrystalline suspensions. The overall strategy of this research and development programme is described.     

Review of neonatal screening programme for phenylketonuria.

OBJECTIVE--To review the neonatal screening programme during 1984-8. DESIGN--Analysis of data from screening laboratories and paediatricians. SUBJECTS--All live births in United Kingdom. MAIN OUTCOME MEASURES--Structure of programme; number of infants tested and number with phenylketonuria; number of infants missed; ages at testing and treatment. RESULTS--The proportion of infants tested approached 100%. The incidence of phenylketonuria was 11.7/100,000 births (445 subjects): 273 had classic phenylketonuria and three had defects of cofactor metabolism. One child with phenylketonuria was known to have been missed compared with three in 1979-83 and six in 1974-8. Seven subjects had been missed over the 15 years due to negative test results. All seven had been tested with the bacterial inhibition assay, although only 53% of infants had been so tested; the difference between the expected and observed proportion was significant (Fisher''s exact test, p = 0.017). Eleven infants with classic phenylketonuria were not tested by 14 days of age and 23 (8%) did not start treatment until after 20 days, an improvement compared with 36 (15%) in 1979-83. There were, however, wide regional variations (0% to 27% treated after 20 days). CONCLUSION--The screening programme achieves high coverage and effectiveness, although some children are still missed. A national practice for screening may help reduce regional variations.     

The Pricing of Breakthrough Drugs: Theory and Policy Implications

Pharmaceutical sales exceed $850 billion a year, of which 84% are accounted for by brand drugs. Drug prices are the focus of an ongoing heated debate. While some argue that pharmaceutical companies exploit monopolistic power granted by patent protection to set prices that are “too high”, others claim that these prices are necessary to motivate the high R&D investments required in the pharmaceutical industry. This paper employs a recently documented utility function of health and wealth to derive the theoretically optimal pricing of monopolistic breakthrough drugs. This model provides a framework for a quantitative discussion of drug price regulation. We show that mild price regulation can substantially increase consumer surplus and the number of patients who purchase the drug, while having only a marginal effect on the revenues of the pharmaceutical company.