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Roger Altounyan and the discovery of cromolyn (sodium cromoglycate)

2005; Elsevier BV; Volume: 115; Issue: 4 Linguagem: Inglês

10.1016/j.jaci.2004.12.011

1097-6825

J. B. L. Howell,

Synthesis and Reactions of Organic Compounds

The discovery of cortisone in 1949 provided the first effective drug treatment of the inflammatory processes underlying asthma. Sadly, this benefit came with the risk of side effects so serious that doctors were often reluctant to use them. A safe nonsteroidal drug was urgently needed. Fifteen years later, a young British doctor of Armenian origin, Roger Ernest Collingwood Altounyan (Fig 1), discovered such a drug.1Edwards A.M. Howell J.B.L. The chromones: history, chemistry and clinical development. A tribute to the work of Dr REC Altounyan.Clin Exp Allergy. 2000; 30: 756-774Crossref PubMed Scopus (67) Google Scholar, 2Dingle J.R. Roger The life and distinguished achievements of Dr Roger Altounyan. Wild Reagents Publishing, Haymore Thatch, Devon (United Kingdom)2003Google ScholarThe AltounyansRoger was the third generation of doctors in his family. His Armenian grandfather, born in Turkey in 1854 and educated by American missionaries, was sent to Columbia University, New York, to graduate in Medicine. He returned to Turkey and married an Irish nurse. They escaped the genocide of the Armenians and established a private hospital in Aleppo, generally recognized as the best in the Middle East. Later, T. E. Lawrence (of Arabia) became a frequent visitor.Their son Ernest, born in England and educated at the famous public (private) school Rugby, graduated in Medicine at Cambridge University and the Middlesex Hospital, London. He would often spend vacations at the family home of a school friend at Coniston in the Lake District of Northwest England. In 1915, Ernest married the eldest of his friend's 3 sisters, winning her hand in competition with a neighbor, Arthur Ransome, who became distinguished as an author and also as Moscow correspondent of the Manchester Guardian newspaper in the period of the Revolution. He became a friend of Lenin and married his secretary, Evgenia, returning to the United Kingdom in 1925 and settling near Lake Coniston.Ernest and Dora Altounyan had 5 children; their only son, Roger, was born in 1922. The children loved sailing their 2 boats on Lake Coniston when not at boarding school or Aleppo. In 1930, Arthur Ransome, still a family friend, wrote a story for the children based loosely on their exploits, which he entitled “Swallows and Amazons,” the names of the 2 sailing boats.3Ransome A. Swallows and amazons. Jonathan Cape Ltd, London1930Google Scholar This became one of the most successful children's stories in the English language and is still widely read today. The hero is named Roger!War service in the Royal Air ForceRoger was very unhappy at his English public school, partly because he was greatly troubled by extensive atopic eczema. He planned to be a doctor and return to Aleppo to help run the family hospital, but while there in 1939, war with Germany was declared. Ernest Altounyan, who had won the Military Cross for gallantry in the First World War, enlisted in the British Army, but Roger was rejected as too young. By concealing his true age (and his atopic eczema), he joined the Royal Air Force and was sent for training as a fighter pilot in Rhodesia.On his return in 1941, he was retrained as a bomber pilot, but being an outstanding pilot, he became an instructor and then an instructor of instructors. His story might have ended here had he been less able: as an operational bomber pilot, his life expectancy would have been a matter of weeks. He was awarded the Air Force Cross for his work in the dangerous task of developing new techniques of low-level night flying over reservoirs in the Welsh mountains, probably used later in the Dam Buster raids.After the war, like his father, Roger studied medicine at Cambridge and the Middlesex Hospital, London. He had his first attack of asthma (nocturnal) when he was a clinical student and subsequently had recurrent attacks. He soon appreciated at first hand the paucity of knowledge and limited treatment of the condition. He graduated in 1952 and went immediately to Aleppo to work in the hospital, but by 1955, foreigners were unwelcome, and the Altounyans were forced to close their hospital and leave.Appointment at Bengers LtdRoger returned to the United Kingdom, and being unable to gain a hospital post for postgraduate training, in January 1956, he joined the research department of Bengers Ltd, a minor UK pharmaceutical company best known for its predigested protein food supplement!It also marketed a preparation of inhaled isoproterenol. Despite no experience in research, he was given the task of showing that an intramuscular injection of an iron-dextran preparation in rapidly growing piglets would prevent anemia and accelerate their growth. Although it prevented anemia, it had no measurable effect on growth, and he felt blamed for this commercially negative result.He initiated another project—the liquefaction of the tenacious sputum of chronic bronchitic patients by inhaled proteolytic enzymes—but this had to be withdrawn when it provoked asthmatic attacks in some bronchitic patients. Although he had warned of this complication and had tried to delay the launch, it went ahead. He was gaining, unfairly, a reputation for unreliability that was to be a major disadvantage later.A better bronchodilator?Roger discovered that the medical research department was seeking a better bronchodilator by means of molecular modification of the Middle Eastern drug khellin, which was known to relax smooth muscle. Some of the new compounds protected guinea pigs from fatal bronchoconstriction induced either by inhalation of histamine or methacholine or by inhalation of an aerosol of egg albumin in sensitized animals. However, he noted that prior inhalation of one compound partially protected antigen-challenged guinea pigs, even though it had no bronchodilator properties. The significance of this observation had been overlooked until Roger saw that this unique property had the potential of being a prophylactic treatment for allergic asthma. Unfortunately, the research director was only interested in bronchodilators. Roger knew that human asthma and bronchospasm induced in guinea pigs had different features (eg, antihistamines did not help his asthma) and was convinced that the experimental compounds needed to be tested in human asthma. He therefore persuaded the chemists to give him some to try on asthma that he would induce in himself.He carried out these tests while conducting thrice-weekly follow-up clinics for patients with chronic asthma and chronic nonspecific lung disease at the local chest hospital.At the start of each clinic, he would induce an asthmatic attack in himself either by inhaling histamine or methacholine or an aerosol of an extract of guinea pig hair, to which he was sensitive, measuring its progress and severity on the basis of FEV1. He then tested the ability of new compounds to prevent or reverse these attacks by inhaling them either before or after the challenge. Most new compounds had little effect, but prior inhalation of one intensely bitter, short-acting compound with no bronchodilator properties did significantly reduce his asthmatic reaction. Incidentally, it was ineffective in protecting guinea pigs. This was sufficient to convince him that if a more acceptable, more potent, and longer-lasting compound could be synthesized, it could be a unique prophylactic treatment for asthma and totally different in mechanism (and side effects) from corticosteroids. In the course of these studies, he discovered a great deal about bronchial pharmacology.4Altounyan R.E.C. Variation of drug action on airway obstruction in man.Thorax. 1964; 19: 406-415Crossref PubMed Scopus (77) Google ScholarBetween July 1957 and eventual success 8 years later, he must have induced about a thousand asthmatic attacks in himself. Some were frighteningly severe: he often allowed the FEV1 to fall to less than 0.5 L before aborting the attack with isoproterenol.Several of the new compounds provided limited protection against antigen challenge, but none were sufficiently potent, acceptable, or both to be therapeutically useful. But as the work continued, he began to see a structure-activity relationship to guide the development of new compounds.In 1961, a new research director decided that the work was getting nowhere and stopped the project. After 5 years of frustration punctuated by disappointment and failures, most people would have given up, but Roger remained determined to pursue his idea and persuaded his colleagues to make new compounds secretly, although now they could not be tested for safety.In 1963, a new compound, chemically a chromone, was synthesized, which provided virtually 100% protection for many hours and was only slightly bitter. He showed also that protection diminished rapidly if the compound was inhaled even minutes after antigen challenge. There were now 2 questions to be answered: Although the compound clearly protected against inhaled antigen, would it work in natural clinical asthma? How should it be administered? To ensure that the drug was in place before any putative inhaled antigen, a volunteer patient with severe allergic asthma inhaled an aerosol of the new compound continuously for 60 hours. The result was unequivocal and devastating: it had absolutely no effect.Roger retested it on himself: this time it provided no protection. He then discovered that a new batch of the compound had been made in an apparently identical way, but no one could explain what had happened. It was 18 months later that Roger wondered whether the compound might have contained some highly active contaminant. A chemist colleague speculated that 2 molecules of the chromone might have united to form a small quantity of a highly active bis-chromone. In the autumn of 1964, they synthesized several bis-chromones, which Roger tested, and in February 1965, he found that one of them, compound 670 (FPL 670), provided virtually complete protection against antigen challenge, lasting for many hours (Fig 2). This compound was named disodium cromoglycate in the United Kingdom and cromolyn in the United States.Fig 2The original data of the protection provided by FPL 670 (cromolyn) when inhaled before antigen challenge, February 1965. JBL Howell, 11-11-04.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Clinical effectiveness of cromolynUncontrolled studies in himself and some volunteer patients soon confirmed the beneficial effect of cromolyn in clinical asthma, but the degree of benefit did not always correlate with improvement in lung function measurements. By this time, a new research director had decided to back the project and approved the next step: a formal double-blind, placebo-controlled trial. In the autumn of 1965, a 6-week trial was carried out in 10 severely asthmatic patients requiring oral prednisolone in worryingly high doses. The results were highly significant: clinical improvement occurred only in the treatment period compared with the placebo.5Howell J.B.L. Altounyan R.E.C. A double-blind trial of disodium cromoglycate in the treatment of allergic bronchial asthma.Lancet. 1967; 2: 539-542Abstract PubMed Google ScholarThe optimum dose of cromolyn in Roger, 20 mg every 6 hours, was difficult to achieve with a pressurized metered-dose inhaler. He therefore resurrected a device he had invented for the inhalation of proteolytic enzymes, the Spinhaler, the idea for which had come from the vibration of the propeller of his Spitfire. Smaller doses of cromolyn were later found to be effective in most patients, and a pressurized metered-dose inhaler was introduced, but some patients required the larger dose achieved by the Spinhaler.Clinical studies in many countries confirmed the efficacy of cromolyn, and it rapidly became a mainline treatment for asthma throughout the world. The first study to quantify its effectiveness in a large group of asthmatic patients was the MRC/Brompton Hospital study6Brompton Hospital/Medical Research Council Collaborative TrialLong-term study of disodium cromoglycate in treatment of severe extrinsic or intrinsic bronchial asthma in adults.BMJ. 1972; 2: 383-388Crossref PubMed Scopus (56) Google Scholar: it maintained 67% of the patients in clinical well-being for one year compared with only 16% receiving placebo.Subsequently, more than 3000 publications reported on its effectiveness and confirmed its exceptional safety. Although many contributed to its development, cromolyn clearly owes its existence to the vision, courage, and determination of one exceptional man: Roger Altounyan. He had a great idea and pursued it relentlessly and fearlessly until it became a reality.Twenty more years of testingHe did not stop with the discovery of cromolyn. Over the next 20 years, he continued to study new compounds in the same way on himself, with the aim of discovering more effective and also orally active preparations. As his lung function deteriorated, he was advised, even instructed, not to conduct further challenge studies on himself, but characteristically, he ignored this. Even when it was arranged that he should spend the UK winter months in the summers of Australia, he arranged for new compounds to be sent to him unofficially because he knew that he was the most reliable test bed on which to try them.After increasing disability, for which he eventually required ambulatory oxygen, Roger died in December 1987 at the age of 65 years. We can only speculate how much the repeated bronchial challenges over nearly 30 years contributed to the progression of his illness. The discovery of cortisone in 1949 provided the first effective drug treatment of the inflammatory processes underlying asthma. Sadly, this benefit came with the risk of side effects so serious that doctors were often reluctant to use them. A safe nonsteroidal drug was urgently needed. Fifteen years later, a young British doctor of Armenian origin, Roger Ernest Collingwood Altounyan (Fig 1), discovered such a drug.1Edwards A.M. Howell J.B.L. The chromones: history, chemistry and clinical development. A tribute to the work of Dr REC Altounyan.Clin Exp Allergy. 2000; 30: 756-774Crossref PubMed Scopus (67) Google Scholar, 2Dingle J.R. Roger The life and distinguished achievements of Dr Roger Altounyan. Wild Reagents Publishing, Haymore Thatch, Devon (United Kingdom)2003Google Scholar The AltounyansRoger was the third generation of doctors in his family. His Armenian grandfather, born in Turkey in 1854 and educated by American missionaries, was sent to Columbia University, New York, to graduate in Medicine. He returned to Turkey and married an Irish nurse. They escaped the genocide of the Armenians and established a private hospital in Aleppo, generally recognized as the best in the Middle East. Later, T. E. Lawrence (of Arabia) became a frequent visitor.Their son Ernest, born in England and educated at the famous public (private) school Rugby, graduated in Medicine at Cambridge University and the Middlesex Hospital, London. He would often spend vacations at the family home of a school friend at Coniston in the Lake District of Northwest England. In 1915, Ernest married the eldest of his friend's 3 sisters, winning her hand in competition with a neighbor, Arthur Ransome, who became distinguished as an author and also as Moscow correspondent of the Manchester Guardian newspaper in the period of the Revolution. He became a friend of Lenin and married his secretary, Evgenia, returning to the United Kingdom in 1925 and settling near Lake Coniston.Ernest and Dora Altounyan had 5 children; their only son, Roger, was born in 1922. The children loved sailing their 2 boats on Lake Coniston when not at boarding school or Aleppo. In 1930, Arthur Ransome, still a family friend, wrote a story for the children based loosely on their exploits, which he entitled “Swallows and Amazons,” the names of the 2 sailing boats.3Ransome A. Swallows and amazons. Jonathan Cape Ltd, London1930Google Scholar This became one of the most successful children's stories in the English language and is still widely read today. The hero is named Roger! Roger was the third generation of doctors in his family. His Armenian grandfather, born in Turkey in 1854 and educated by American missionaries, was sent to Columbia University, New York, to graduate in Medicine. He returned to Turkey and married an Irish nurse. They escaped the genocide of the Armenians and established a private hospital in Aleppo, generally recognized as the best in the Middle East. Later, T. E. Lawrence (of Arabia) became a frequent visitor. Their son Ernest, born in England and educated at the famous public (private) school Rugby, graduated in Medicine at Cambridge University and the Middlesex Hospital, London. He would often spend vacations at the family home of a school friend at Coniston in the Lake District of Northwest England. In 1915, Ernest married the eldest of his friend's 3 sisters, winning her hand in competition with a neighbor, Arthur Ransome, who became distinguished as an author and also as Moscow correspondent of the Manchester Guardian newspaper in the period of the Revolution. He became a friend of Lenin and married his secretary, Evgenia, returning to the United Kingdom in 1925 and settling near Lake Coniston. Ernest and Dora Altounyan had 5 children; their only son, Roger, was born in 1922. The children loved sailing their 2 boats on Lake Coniston when not at boarding school or Aleppo. In 1930, Arthur Ransome, still a family friend, wrote a story for the children based loosely on their exploits, which he entitled “Swallows and Amazons,” the names of the 2 sailing boats.3Ransome A. Swallows and amazons. Jonathan Cape Ltd, London1930Google Scholar This became one of the most successful children's stories in the English language and is still widely read today. The hero is named Roger! War service in the Royal Air ForceRoger was very unhappy at his English public school, partly because he was greatly troubled by extensive atopic eczema. He planned to be a doctor and return to Aleppo to help run the family hospital, but while there in 1939, war with Germany was declared. Ernest Altounyan, who had won the Military Cross for gallantry in the First World War, enlisted in the British Army, but Roger was rejected as too young. By concealing his true age (and his atopic eczema), he joined the Royal Air Force and was sent for training as a fighter pilot in Rhodesia.On his return in 1941, he was retrained as a bomber pilot, but being an outstanding pilot, he became an instructor and then an instructor of instructors. His story might have ended here had he been less able: as an operational bomber pilot, his life expectancy would have been a matter of weeks. He was awarded the Air Force Cross for his work in the dangerous task of developing new techniques of low-level night flying over reservoirs in the Welsh mountains, probably used later in the Dam Buster raids.After the war, like his father, Roger studied medicine at Cambridge and the Middlesex Hospital, London. He had his first attack of asthma (nocturnal) when he was a clinical student and subsequently had recurrent attacks. He soon appreciated at first hand the paucity of knowledge and limited treatment of the condition. He graduated in 1952 and went immediately to Aleppo to work in the hospital, but by 1955, foreigners were unwelcome, and the Altounyans were forced to close their hospital and leave. Roger was very unhappy at his English public school, partly because he was greatly troubled by extensive atopic eczema. He planned to be a doctor and return to Aleppo to help run the family hospital, but while there in 1939, war with Germany was declared. Ernest Altounyan, who had won the Military Cross for gallantry in the First World War, enlisted in the British Army, but Roger was rejected as too young. By concealing his true age (and his atopic eczema), he joined the Royal Air Force and was sent for training as a fighter pilot in Rhodesia. On his return in 1941, he was retrained as a bomber pilot, but being an outstanding pilot, he became an instructor and then an instructor of instructors. His story might have ended here had he been less able: as an operational bomber pilot, his life expectancy would have been a matter of weeks. He was awarded the Air Force Cross for his work in the dangerous task of developing new techniques of low-level night flying over reservoirs in the Welsh mountains, probably used later in the Dam Buster raids. After the war, like his father, Roger studied medicine at Cambridge and the Middlesex Hospital, London. He had his first attack of asthma (nocturnal) when he was a clinical student and subsequently had recurrent attacks. He soon appreciated at first hand the paucity of knowledge and limited treatment of the condition. He graduated in 1952 and went immediately to Aleppo to work in the hospital, but by 1955, foreigners were unwelcome, and the Altounyans were forced to close their hospital and leave. Appointment at Bengers LtdRoger returned to the United Kingdom, and being unable to gain a hospital post for postgraduate training, in January 1956, he joined the research department of Bengers Ltd, a minor UK pharmaceutical company best known for its predigested protein food supplement!It also marketed a preparation of inhaled isoproterenol. Despite no experience in research, he was given the task of showing that an intramuscular injection of an iron-dextran preparation in rapidly growing piglets would prevent anemia and accelerate their growth. Although it prevented anemia, it had no measurable effect on growth, and he felt blamed for this commercially negative result.He initiated another project—the liquefaction of the tenacious sputum of chronic bronchitic patients by inhaled proteolytic enzymes—but this had to be withdrawn when it provoked asthmatic attacks in some bronchitic patients. Although he had warned of this complication and had tried to delay the launch, it went ahead. He was gaining, unfairly, a reputation for unreliability that was to be a major disadvantage later. Roger returned to the United Kingdom, and being unable to gain a hospital post for postgraduate training, in January 1956, he joined the research department of Bengers Ltd, a minor UK pharmaceutical company best known for its predigested protein food supplement! It also marketed a preparation of inhaled isoproterenol. Despite no experience in research, he was given the task of showing that an intramuscular injection of an iron-dextran preparation in rapidly growing piglets would prevent anemia and accelerate their growth. Although it prevented anemia, it had no measurable effect on growth, and he felt blamed for this commercially negative result. He initiated another project—the liquefaction of the tenacious sputum of chronic bronchitic patients by inhaled proteolytic enzymes—but this had to be withdrawn when it provoked asthmatic attacks in some bronchitic patients. Although he had warned of this complication and had tried to delay the launch, it went ahead. He was gaining, unfairly, a reputation for unreliability that was to be a major disadvantage later. A better bronchodilator?Roger discovered that the medical research department was seeking a better bronchodilator by means of molecular modification of the Middle Eastern drug khellin, which was known to relax smooth muscle. Some of the new compounds protected guinea pigs from fatal bronchoconstriction induced either by inhalation of histamine or methacholine or by inhalation of an aerosol of egg albumin in sensitized animals. However, he noted that prior inhalation of one compound partially protected antigen-challenged guinea pigs, even though it had no bronchodilator properties. The significance of this observation had been overlooked until Roger saw that this unique property had the potential of being a prophylactic treatment for allergic asthma. Unfortunately, the research director was only interested in bronchodilators. Roger knew that human asthma and bronchospasm induced in guinea pigs had different features (eg, antihistamines did not help his asthma) and was convinced that the experimental compounds needed to be tested in human asthma. He therefore persuaded the chemists to give him some to try on asthma that he would induce in himself.He carried out these tests while conducting thrice-weekly follow-up clinics for patients with chronic asthma and chronic nonspecific lung disease at the local chest hospital.At the start of each clinic, he would induce an asthmatic attack in himself either by inhaling histamine or methacholine or an aerosol of an extract of guinea pig hair, to which he was sensitive, measuring its progress and severity on the basis of FEV1. He then tested the ability of new compounds to prevent or reverse these attacks by inhaling them either before or after the challenge. Most new compounds had little effect, but prior inhalation of one intensely bitter, short-acting compound with no bronchodilator properties did significantly reduce his asthmatic reaction. Incidentally, it was ineffective in protecting guinea pigs. This was sufficient to convince him that if a more acceptable, more potent, and longer-lasting compound could be synthesized, it could be a unique prophylactic treatment for asthma and totally different in mechanism (and side effects) from corticosteroids. In the course of these studies, he discovered a great deal about bronchial pharmacology.4Altounyan R.E.C. Variation of drug action on airway obstruction in man.Thorax. 1964; 19: 406-415Crossref PubMed Scopus (77) Google ScholarBetween July 1957 and eventual success 8 years later, he must have induced about a thousand asthmatic attacks in himself. Some were frighteningly severe: he often allowed the FEV1 to fall to less than 0.5 L before aborting the attack with isoproterenol.Several of the new compounds provided limited protection against antigen challenge, but none were sufficiently potent, acceptable, or both to be therapeutically useful. But as the work continued, he began to see a structure-activity relationship to guide the development of new compounds.In 1961, a new research director decided that the work was getting nowhere and stopped the project. After 5 years of frustration punctuated by disappointment and failures, most people would have given up, but Roger remained determined to pursue his idea and persuaded his colleagues to make new compounds secretly, although now they could not be tested for safety.In 1963, a new compound, chemically a chromone, was synthesized, which provided virtually 100% protection for many hours and was only slightly bitter. He showed also that protection diminished rapidly if the compound was inhaled even minutes after antigen challenge. There were now 2 questions to be answered: Although the compound clearly protected against inhaled antigen, would it work in natural clinical asthma? How should it be administered? To ensure that the drug was in place before any putative inhaled antigen, a volunteer patient with severe allergic asthma inhaled an aerosol of the new compound continuously for 60 hours. The result was unequivocal and devastating: it had absolutely no effect.Roger retested it on himself: this time it provided no protection. He then discovered that a new batch of the compound had been made in an apparently identical way, but no one could explain what had happened. It was 18 months later that Roger wondered whether the compound might have contained some highly active contaminant. A chemist colleague speculated that 2 molecules of the chromone might have united to form a small quantity of a highly active bis-chromone. In the autumn of 1964, they synthesized several bis-chromones, which Roger tested, and in February 1965, he found that one of them, compound 670 (FPL 670), provided virtually complete protection against antigen challenge, lasting for many hours (Fig 2). This compound was named disodium cromoglycate in the United Kingdom and cromolyn in the United States. Roger discovered that the medical research department was seeking a better bronchodilator by means of molecular modification of the Middle Eastern drug khellin, which was known to relax smooth muscle. Some of the new compounds protected guinea pigs from fatal bronchoconstriction induced either by inhalation of histamine or methacholine or by inhalation of an aerosol of egg albumin in sensitized animals. However, he noted that prior inhalation of one compound partially protected antigen-challenged guinea pigs, even though it had no bronchodilator properties. The significance of this observation had been overlooked until Roger saw that this unique property had the potential of being a prophylactic treatment for allergic asthma. Unfortunately, the research director was only interested in bronchodilators. Roger knew that human asthma and bronchospasm induced in guinea pigs had different features (eg, antihistamines did not help his asthma) and was convinced that the experimental compounds needed to be tested in human asthma. He therefore persuaded the chemists to give him some to try on asthma that he would induce in himself. He carried out these tests while conducting thrice-weekly follow-up clinics for patients with chronic asthma and chronic nonspecific lung disease at the local chest hospital. At the start of each clinic, he would induce an asthmatic attack in himself either by inhaling histamine or methacholine or an aerosol of an extract of guinea pig hair, to which he was sensitive, measuring its progress and severity on the basis of FEV1. He then tested the ability of new compounds to prevent or reverse these attacks by inhaling them either before or after the challenge. Most new compounds had little effect, but prior inhalation of one intensely bitter, short-acting compound with no bronchodilator properties did significantly reduce his asthmatic reaction. Incidentally, it was ineffective in protecting guinea pigs. This was sufficient to convince him that if a more acceptable, more potent, and longer-lasting compound could be synthesized, it could be a unique prophylactic treatment for asthma and totally different in mechanism (and side effects) from corticosteroids. In the course of these studies, he discovered a great deal about bronchial pharmacology.4Altounyan R.E.C. Variation of drug action on airway obstruction in man.Thorax. 1964; 19: 406-415Crossref PubMed Scopus (77) Google Scholar Between July 1957 and eventual success 8 years later, he must have induced about a thousand asthmatic attacks in himself. Some were frighteningly severe: he often allowed the FEV1 to fall to less than 0.5 L before aborting the attack with isoproterenol. Several of the new compounds provided limited protection against antigen challenge, but none were sufficiently potent, acceptable, or both to be therapeutically useful. But as the work continued, he began to see a structure-activity relationship to guide the development of new compounds. In 1961, a new research director decided that the work was getting nowhere and stopped the project. After 5 years of frustration punctuated by disappointment and failures, most people would have given up, but Roger remained determined to pursue his idea and persuaded his colleagues to make new compounds secretly, although now they could not be tested for safety. In 1963, a new compound, chemically a chromone, was synthesized, which provided virtually 100% protection for many hours and was only slightly bitter. He showed also that protection diminished rapidly if the compound was inhaled even minutes after antigen challenge. There were now 2 questions to be answered: Although the compound clearly protected against inhaled antigen, would it work in natural clinical asthma? How should it be administered? To ensure that the drug was in place before any putative inhaled antigen, a volunteer patient with severe allergic asthma inhaled an aerosol of the new compound continuously for 60 hours. The result was unequivocal and devastating: it had absolutely no effect. Roger retested it on himself: this time it provided no protection. He then discovered that a new batch of the compound had been made in an apparently identical way, but no one could explain what had happened. It was 18 months later that Roger wondered whether the compound might have contained some highly active contaminant. A chemist colleague speculated that 2 molecules of the chromone might have united to form a small quantity of a highly active bis-chromone. In the autumn of 1964, they synthesized several bis-chromones, which Roger tested, and in February 1965, he found that one of them, compound 670 (FPL 670), provided virtually complete protection against antigen challenge, lasting for many hours (Fig 2). This compound was named disodium cromoglycate in the United Kingdom and cromolyn in the United States. Clinical effectiveness of cromolynUncontrolled studies in himself and some volunteer patients soon confirmed the beneficial effect of cromolyn in clinical asthma, but the degree of benefit did not always correlate with improvement in lung function measurements. By this time, a new research director had decided to back the project and approved the next step: a formal double-blind, placebo-controlled trial. In the autumn of 1965, a 6-week trial was carried out in 10 severely asthmatic patients requiring oral prednisolone in worryingly high doses. The results were highly significant: clinical improvement occurred only in the treatment period compared with the placebo.5Howell J.B.L. Altounyan R.E.C. A double-blind trial of disodium cromoglycate in the treatment of allergic bronchial asthma.Lancet. 1967; 2: 539-542Abstract PubMed Google ScholarThe optimum dose of cromolyn in Roger, 20 mg every 6 hours, was difficult to achieve with a pressurized metered-dose inhaler. He therefore resurrected a device he had invented for the inhalation of proteolytic enzymes, the Spinhaler, the idea for which had come from the vibration of the propeller of his Spitfire. Smaller doses of cromolyn were later found to be effective in most patients, and a pressurized metered-dose inhaler was introduced, but some patients required the larger dose achieved by the Spinhaler.Clinical studies in many countries confirmed the efficacy of cromolyn, and it rapidly became a mainline treatment for asthma throughout the world. The first study to quantify its effectiveness in a large group of asthmatic patients was the MRC/Brompton Hospital study6Brompton Hospital/Medical Research Council Collaborative TrialLong-term study of disodium cromoglycate in treatment of severe extrinsic or intrinsic bronchial asthma in adults.BMJ. 1972; 2: 383-388Crossref PubMed Scopus (56) Google Scholar: it maintained 67% of the patients in clinical well-being for one year compared with only 16% receiving placebo.Subsequently, more than 3000 publications reported on its effectiveness and confirmed its exceptional safety. Although many contributed to its development, cromolyn clearly owes its existence to the vision, courage, and determination of one exceptional man: Roger Altounyan. He had a great idea and pursued it relentlessly and fearlessly until it became a reality. Uncontrolled studies in himself and some volunteer patients soon confirmed the beneficial effect of cromolyn in clinical asthma, but the degree of benefit did not always correlate with improvement in lung function measurements. By this time, a new research director had decided to back the project and approved the next step: a formal double-blind, placebo-controlled trial. In the autumn of 1965, a 6-week trial was carried out in 10 severely asthmatic patients requiring oral prednisolone in worryingly high doses. The results were highly significant: clinical improvement occurred only in the treatment period compared with the placebo.5Howell J.B.L. Altounyan R.E.C. A double-blind trial of disodium cromoglycate in the treatment of allergic bronchial asthma.Lancet. 1967; 2: 539-542Abstract PubMed Google Scholar The optimum dose of cromolyn in Roger, 20 mg every 6 hours, was difficult to achieve with a pressurized metered-dose inhaler. He therefore resurrected a device he had invented for the inhalation of proteolytic enzymes, the Spinhaler, the idea for which had come from the vibration of the propeller of his Spitfire. Smaller doses of cromolyn were later found to be effective in most patients, and a pressurized metered-dose inhaler was introduced, but some patients required the larger dose achieved by the Spinhaler. Clinical studies in many countries confirmed the efficacy of cromolyn, and it rapidly became a mainline treatment for asthma throughout the world. The first study to quantify its effectiveness in a large group of asthmatic patients was the MRC/Brompton Hospital study6Brompton Hospital/Medical Research Council Collaborative TrialLong-term study of disodium cromoglycate in treatment of severe extrinsic or intrinsic bronchial asthma in adults.BMJ. 1972; 2: 383-388Crossref PubMed Scopus (56) Google Scholar: it maintained 67% of the patients in clinical well-being for one year compared with only 16% receiving placebo. Subsequently, more than 3000 publications reported on its effectiveness and confirmed its exceptional safety. Although many contributed to its development, cromolyn clearly owes its existence to the vision, courage, and determination of one exceptional man: Roger Altounyan. He had a great idea and pursued it relentlessly and fearlessly until it became a reality. Twenty more years of testingHe did not stop with the discovery of cromolyn. Over the next 20 years, he continued to study new compounds in the same way on himself, with the aim of discovering more effective and also orally active preparations. As his lung function deteriorated, he was advised, even instructed, not to conduct further challenge studies on himself, but characteristically, he ignored this. Even when it was arranged that he should spend the UK winter months in the summers of Australia, he arranged for new compounds to be sent to him unofficially because he knew that he was the most reliable test bed on which to try them.After increasing disability, for which he eventually required ambulatory oxygen, Roger died in December 1987 at the age of 65 years. We can only speculate how much the repeated bronchial challenges over nearly 30 years contributed to the progression of his illness. He did not stop with the discovery of cromolyn. Over the next 20 years, he continued to study new compounds in the same way on himself, with the aim of discovering more effective and also orally active preparations. As his lung function deteriorated, he was advised, even instructed, not to conduct further challenge studies on himself, but characteristically, he ignored this. Even when it was arranged that he should spend the UK winter months in the summers of Australia, he arranged for new compounds to be sent to him unofficially because he knew that he was the most reliable test bed on which to try them. After increasing disability, for which he eventually required ambulatory oxygen, Roger died in December 1987 at the age of 65 years. We can only speculate how much the repeated bronchial challenges over nearly 30 years contributed to the progression of his illness.