During the 1950's, heart condition had risen to epidemic figures. According to the World Health Organisation, finding a way to control these conditions was an utmost priority. In the United States alone, deaths caused by cardiovascular diseases were at 307.4 per 100,000 persons (CDC, 1999). The lead role for the development of beta-blockers was credited to Sir James Black. He described that "Heart disease had become a serious epidemic" and that "Patients were suffering from angina pectoris... many were dying from heart attack". However, in order for Black to invent beta blockers, several key discoveries had to be made, in order that for the rational design of the drug.
The interest in the cardiovascular system only increased when (W. Harvey 1628) investigated the circulation of blood which quashed the central dogma that had been around for over one thousand years. In this paper, he illuminated the true function and structure of the heart. In 1706, a French professor named Raymond de Vieussens successfully described the chambers and vessels of the heart. Blood pressure was first measure by (S Hales, 1733), and in 1903 a Dutch physiologist developed the electrocardiograph. Control of the vascular system by the nervous system was proven successful by (deCyon and Ludwig, 1866) who showed that arterial hypotension and bradycardia was caused by excitation of the aortic depresser nerve. Hormonal control of the circulation was suggested by (Goldblatt et al. 1934) who were able to show that by impairing perfusion of the kidney, led to arterial hypertension. Renin was discovered by (Tigerstedt and Bergman, 1898) and forty years later (Braun-Menendez et al. 1939; Page, 1940) identified that angiotensin was a direct product of Renin. This discovery that a hormone had a direct effect on the vascular system opened many channels of research.
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One key hormone that already had been discovered was adrenaline. It was first discovered by Japanese chemists, Jokichi Takamine and Keizo Uenaka in 1900. In 1901, they successfully isolated the hormone, taken from sheep and oxen adrenal glands (Yamashima, 2003). A few years later Stolz and Dakin synthesised adrenaline in 1904 (Bennett, 1999). The discovery and subsequent research into the effects of adrenaline on the heart is focal, because without it, Black would not have been able to deduce what hormone(s) was/were the leading cause(s) of vasoconstriction. Another muse for Black was Dr. Claude Beck, an American heart surgeon considered the leading heart surgeon of the time. Beck had discovered that to ease the pressure on the heart, only a small increase of oxygen in the blood was necessary. Beck was trying to find from a non-cardiac source a way to increase blood flow. Black took a different approach, instead of following Beck's idea he attempted to decrease the heart's demand for oxygen. Black also had other individuals who, through their own scientific discoveries had helped him achieve his goal.
Two other particular key individuals were Paul Ehrlich and John Newport Langley. Paul Ehrlich was a German Scientist in the 19th -20th Century and is considered the father of modern chemistry. Amongst his research into the cure for syphilis and the work he did that led to the discovery of the Blood-Brain barrier; his one major theory was that of the "magic bullet". In 1897 he proposed that living cells have side chains that link with a particular toxin. He then reasoned that a compound could be made to selectively target the organism that is causing the disease, therefore creating a "magic bullet" that only destroys the organism targeted. He theorised that under threat, a cell could create new side chains and these broke off, thus creating antibodies that circulate around the body (TCHF, 2001). However, this concept was not fully realized until the invention of monoclonal antibodies. John Newport Langley also theorised that chemicals and cells had receptors (Langley 1905; Maehle 2004). However, accepting this theory was delayed due to conflicting ideologies of drug action, and to uncertainties about the concept. Due to this delay, (Prüll et al 2002) believed that the concept did not come into fruition until "Raymond Ahlquist made his distinction...between a- and Β-adrenoceptors". Black himself credited Ahlquist, that without him "My own work... would not have been started but for the existence of Ahlquist's theory" (Black, 1976).
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However, according to historian, John Parascandola, the receptor theory did not spread through to other pharmacologists until A.J Clarke did quantitive research in the 1920s and 1930's on the interaction between receptors and drugs (Albert A, 1965; Parascandola, 1959; A J Clark, 1982). Clark moved from Cambridge University to UCL in 1919, and began his research on the neurotransmitter acetylcholine. This research was the central aspect which began the receptor theory. In 1926, he moved to Edinburgh, where he showed that there was competition for a common receptor between quaternary ammonium salts and acetylcholine. (Clark & Raventos, 1937). Clark used mathematics to evaluate pharmacological data. He successfully showed that there was for many drugs, a relationship between biological effects and drug concentrations which corresponded to a hyperbolic curve. He concluded that the curve expressed the symmetry between the amount of receptors on a cell and the drug it was interacting with; and that response from the drug was "directly proportional to the number of receptors occupied" (Prüll et al 2002). This theory coincided with the 3-D structure of the cell which was investigated during the same period. This research did not become important till after the Second World War when E.J Ariëns (1954) and R.P Stephenson (1956) adapted the theory of occupancy to explain the efficacy and the affinity. Additionally, partial agonist theory was introduced by Stephenson, which signified a compound with high affinity but more importantly, low efficacy. This made a significant difference between the affinity of a drug, and its potency once it was linked; a conception which soon after became significant in beta blocking.
Receptor theory therefore comes from a range of scientific fields, including immunology, mathematical design on pharmacological data, work done chemically on metabolism and the physiology of the nervous system (Prüll et al 2002). The sympathetic nervous system also provided a key role, because beta-blockers emerged from research on the sympathetic nervous system and studies on the interactions between the cell and drugs/hormones (A Woodbridge, 1981). This link between the sympathetic nervous system and drug interaction had been illuminated by (Langley 1905), but rather than use the term "receptor", he used "receptive substance (Maehle 2004).He argued that drugs, such as adrenaline, in the cell, bind to receptive molecules, and that there were two classes of these:"inhibitory" and "motor". (Dale 1906) verified this by showing that ergot alkaloids blocked the excitatory actions of adrenaline and other similar-structured compounds in the majority of tissues, their inhibitory effects were not.
Raymond Ahlquist was the catalyst that provided Black with the solution. Ahlquist's paper published in 1948, originally started as an investigation to lighten period pains by reducing the strength of the contractions of the uterine muscle by using a sympathomimetic amine. He found that in different tissue the potency presented itself in two orders. This led him to believe that there were more than "excitatory" and "inhibitory" receptors, concluding that there were two different receptors, named "alpha and beta". Stimulation of beta receptors responded by vasodilation and uterine and bronchial muscle relaxation, and stimulation of a receptors led to smooth muscle contraction and vasoconstriction. Conversely to other tissues observed, in the heart, excitatory responses resulted were responsible not by a, but by beta receptors. The paper was not published until 1948; however the "Journal of Pharmacology and Experimental Therapeutics" rejected its publication because Ulf von Euler in 1946 found that the primary neurotransmitter was noradrenaline and not adrenaline. W F Hamilton, who at the time was the editor of the "American Journal of Physiology", was a colleague and also a friend of Ahlquist published it (Black, 1976).
For ten years it was ignored by Black, who described his academic attitude at the time "to have had a powerful effect in delaying the introduction of the idea of receptors into pharmacological teaching" (Black, 1976). In 1958, Powell and Slater described the pharmacological properties of their new compound DCI- dichloroisoproterenol. DCI was similar to isoprenaline, in which its primary function was bronchodilation. However, it had antagonising effects on the heart (Powell & Slater, 1958). It was published (ironically) by the same journal that had rejected Ahlquist's dual receptor theory "Journal of Pharmacology and Experimental Therapeutics". The term "beta-blocker" was coined by M Perkins and N Moran, who argued that the activity of DCI belonged to the "beta-adregenic" type that Ahlquist was responsible," calling it beta-adrenergic blocking drug", which was later shortened to the name we know. (Moran & Perkins, 1958). Chance also played a big role in Black's realisation of drug development. Firstly, it was not serendipitous that Moran had realised that DCI was an example of a new type of bio-active compound. (Fitzgerald, 2000) showed that upon hearing Slater and Powell's paper, Moran was looking at the effects of catecholamines. Black had just joined ICI, when he read the report by Moran and believed it was possible to construct an analogue dichloroisoproterenol. Clinicians (Pritchard and Cruickshank 1994) said "that the major contribution of Black was to appreciate the possible clinical value of developing compounds to inhibit the sympathetic nerves to the heart, and then to persuade, and then lead a team of scientists at ICI to translate the idea into reality".
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Black decided to treat angina, rather by reducing oxygen demand from the heart instead of increasing oxygen supply. He read "Drills Pharmacology" in which Ahlquist's paper gave him a solution, advocating blocking the receptors that control heart rate increase. In 1956 the project started with searching with substances that provoke the effects of noradrenaline and adrenaline on the heart. He obtained a sample of DCI and used it on a guinea pigs hearts that were still beating. However, the test showed that DCI had stimulating properties, and so he designed an innovative in vitro assay (Black, 1996). This assay looked at the effects on the papillary muscle. From the results, he believed that development of DCI was the correct direction.
To find compounds that block the sympathetic responses by the heart, he developed screening processes on whole animals and isolated tissues. DCI was selected as the key compound, his team tried to analyse and improve on its chemical structure. In 1960, Stephenson attached another phenyl ring replacing two chlorine atoms, reasoning that this would enhance the inhibition of DCI. This compound was called Pronethalol. It was shown to perform just as well in the papillary muscle test. (A M Barrett, 1972). However Black felt that it was not a good enough candidate for clinical trials. He wanted it to be longer lasting, penetrating the CNS less and resisted catecholamine. It wasn't until compound 45,520 that a breakthrough came.
It had an advanced therapeutic index and twenty times activity than pronethalol. Black wrote that this new compound "was blocking the peripheral vasodilation of isoprenaline but failing to block the cardiac responses. Thus the increased cardiac output delivered to undilated vessels now produced a pressor response". (ICI CPR, 1962). It was given the name Inderal (trade name Propranalol) and was showing very good sign of accomplishment. Black was able to alter Ahlquist's theory into a more complex issue with a larger number of subdivisions. It proposed that it would be possible to construct other drugs with a higher selectivity than pronethalol. Black alluded that it would be possible to treat peptic ulcers this way, as he saw them as parallels of angina (Gerskowitch, Hull, & Shankley, 1988).
Toxicity tests had already shown in 1963, that in mice thymic tumours had appeared in 120 days, 45,520 mice showed no sign of tumour development. However, after a set of small sized clinical trials, pronethalol was launched in November. It showed positive results with certain arrhythmias and angina, and only prescribed for critical conditions (Vos, 1991). This timeline of discovery to marketing seems rapid, mainly due to two reasons: the drug was marketed before Thalidomide had come into its notorious reputation, and secondly due to ICI having close contact with British cardiologists, red tape and paperwork could be cut through and rushed. Another matter was the tenfold rise in clinics from four to forty five in four years (Vos, 1991). This increase allowed a larger number of data to be collected in a short time. Following this, Black became indifferent with the development of beta-blockers. This was due to his lack of interest of the stage of development but also largely, due to his attraction to blocking receptors responsible for histamine in the gut (A Woodbridge, 1981). Black departed for Sk&F's new research and development programme to work on the Β-receptors of histamine (Finucane, 1989). Further development of beta-blockers were built on the data that Black acquired during the time he was employed at ICI. However, their goal now was to remain ahead of the market, as they were now facing competition from other companies. From Propranolol, came Tenormin alongside being marketed as the world's most successful heart drug, generating sales to the value of £500 million worldwide (K Holland, 1987), helping to engrain the receptor theory amongst other pharmaceutical companies and more importantly among the scientific community.
Sir James Black played a vital role not only in the expansion of beta-blockers but also with the development of H2-antagonists. By the year 1987, beta blockers had become the standard for treatment in angina, cardiac arrhythmias and hypertension (K Holland, 1987). Following his departure from the two companies, both had the scientific advantage over their competitors in their particular field but also provided a path for other companies to follow suit. Black was able to flourish in his accomplishments not only because of the ideological standards of the respective companies, but also due to proficient colleagues whose skills complemented his. The physiology and the pathophysiology of cardiovascular disease had been so researched rigorously up until this point that advances in treatment were almost expected. The increased understanding of the disease enabled Black to quickly establish his goals in terms of chemistry and biological function. Stringent clinical standards had not come into effect until after the aftermath of the thalidomide catastrophe, which enabled the drug companies in comparison to today's standards of practice, to rapidly go from idea to product in an exceptionally quick duration. The finish of the Second World War gave drug companies an idea of where they stood in the global market and their ability not only to affect outcomes of war, but also the capacity to change the academic community and their scientific discoveries into the global market and into profit.
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