Chapter 18
APART FROM THOSE MEDICINES that cause problems such as dependence, there are also medicines that have been withdrawn from use or have had special precautions applied to their continued use because of a variety of other problems. Some have been found to damage the unborn child, some cause muscle damage, including heart damage, as the heart is a muscle, others may damage the liver or kidneys, or cause blindness or deafness, while yet others can cause death by affecting the blood or the brain.
Our regulatory authorities continually monitor reports of adverse drug reactions and act quickly when a potential problem becomes known. All new medicines are evaluated by the Committee on Safety of Medicines (CSM), a part of the Medicines and Healthcare products Regulatory Agency (MHRA). In the United Kingdom, this current system was set up following a drug disaster of immense proportions that occurred over 50 years ago.
As safe as houses
In 1956, a new sleeping pill was launched on to an unsuspecting world. This drug was claimed to be ‘outstandingly safe’ even in overdose. Doctors were pleased that at last they had something safer than the barbiturates to prescribe for their patients. The barbiturates were available for about a hundred years and had two major faults: they were highly addictive and they were very dangerous in overdose, particularly to children.
The new sleeping pill was developed by a German drug company called Chemie Grunenthal, and was available in several countries in Europe, as well as in many other countries worldwide, including Australia. In both Australia and the United Kingdom, the new drug was marketed by the Distiller’s Company, under licence from Chemie Grunenthal, using the brand name Distavan. It was marketed as a great advance by the medical sales representatives to every doctor, and these doctors duly prescribed it to soothe the stomach and calm the mind. Because it worked so well, doctors also happily prescribed it for pregnant women suffering from morning sickness as well as those needing a sleeping pill. The name of this new drug was thalidomide.
In November 1959, an Australian obstetrician and gynaecologist sent a letter to The Lancet about a number of babies with birth defects, stating that the only thing that the mothers of these children had in common was that they had all taken thalidomide during their pregnancy. This was the first warning of what was to follow. Thalidomide was eventually to become known as the most potent teratogen (a substance that induces developmental abnormalities in a foetus) ever synthesised by man.
Thalidomide was withdrawn from the market in December 1961, but in the five years it was available it caused immense damage. Eventually it became known that some 8,000 children in 46 countries, including 400 in the United Kingdom, were born affected in one way or other by this drug.
At the time of its withdrawal elsewhere, the drug was still awaiting approval by the Federal Drugs Agency in the United States. The FDA were worried about peripheral neuritis, a disabling and irreversible side effect of thalidomide affecting feeling in the fingers and toes, that had been known about for some years. So apart from a few free sample tablets, which had been given to a few doctors and passed on to their patients, thalidomide was not yet available to the general public in America. Needless to say, once the birth defects came to light, approval to market thalidomide in the USA was denied.
For every damaged child born alive, there were about twice as many infants born dead to mothers who had used thalidomide, the drug having caused so much damage to the babies’ internal organs that they had no hope of sustaining independent life outside the womb.
Some of the affected children who did survive only had mild effects, a missing or shortened finger or two, but many were horribly deformed. Some had no arms or legs, with perhaps a hand or finger protruding from their shoulders, or a foot or toes protruding from their hips. Some had flipper-like limbs, instead of arms and legs, a condition called phocomelia. Babies were born with ears missing and heard through an opening on the side of their head; some had no internal hearing organs in their head, as well as no ears. Some were born without eyes, some with a cleft lip or palate, some unable to raise their eyes or head to look at things. Some were born with deformed genitals or none at all. Some babies were born without an anus, and so could not pass bowel movements. There were many with multiple handicaps, with damaged internal organs and damaged brains.
Careful investigation of the damage done to each child showed that the damage was dependent on the stage of the child’s development in the womb, when the mother took the drug and the number of doses taken, which explained why such a wide range of problems were seen in the surviving babies. Between days 20 to 35 of the pregnancy, the drug affected the production of growth factors involved in the formation of blood vessels. However, beyond day 35 of the pregnancy, the mother was not affected by thalidomide and neither were those babies who had been exposed to the drug after day 35.
Animal testing performed during the drug’s development before its launch had not shown these effects as the testing was only done using rats, which are rodents. If monkeys, much more similar to humans, had been used in the testing as well, the damage would have been seen. It was only after the thalidomide tragedy that the regulation of new drugs became a priority.
In the UK, the Dunlop Committee was initially set up and later was replaced by the Committee on Safety of Medicines (CSM) in 1964, which was part of the Medicine Control Agency (MCA), the UK regulatory authority at that time. The USA already had the Federal Drugs Agency (FDA) in place to oversee all new and revised drugs before they were marketed. In April 2003, the Medicines and Healthcare products Regulatory Agency (MRHA) replaced the Medicines Control Agency and the Medicines Devices Agency. It is the MRHA that now licenses all new medicines and medical devices. The CSM continues as before, but now within the MRHA, advising on the licensing of new medicines, and on their safety once they are marketed in the UK.
Manufacturers are now required to supply a mass of information about any new medicine, the conditions it can be used to treat, the results of the clinical trials and data about its safety and any side effects or contra-indications that have come to light during the clinical trials. Only when the authorities are fully satisfied will the new medicine be issued with marketing authorisation, previously known as a Product Licence. Once a new medicine has been given a marketing authorisation number, it is allowed to be used by doctors, who can then prescribe it to their patients. All new drugs are intensively monitored for several years for side effects, contra-indications and drug interactions.
Thalidomide today
It may seem surprising, but thalidomide is still in use even today – but now only with very careful safeguards to protect against damage in the future. In America, it is now marketed under the brand name of Thalomid. In the United Kingdom, thalidomide is only available on a named-patient basis under specialist supervision, for use by men and post-menopausal women only. Strict conditions are imposed on its use; it may not be used at all to treat women of child-bearing potential, and male patients must use a barrier form of contraception, as the drug may be in the seminal fluid, or may have affected the sperm. Male patients may not donate sperm and patients of both sexes may not donate blood while taking thalidomide.
Thalidomide has been found to have both an anti-inflammatory and immunomodulatory affect, preventing the immune response flare-ups so common in auto-immune disorders. Thus it is now used in the management of the severe mouth and genital ulceration that can occur in Behçets disease or in association with HIV infection. Various serious skin disorders involving light-sensitive dermatoses, such as actinic prurigo and discoid lupus erythematosus, have also responded to treatment with thalidomide, where other treatments in the past have failed.
The drug has also been found to be effective in graft-versus-host disease, a complication that can occur after bone-marrow transplantation. In this disease, donor lymphocytes attack the recipient’s body, causing a chronic scleroderma-like condition, with thickening of the skin, resulting in waxy, ivory-coloured areas. This is steadily destructive, and has often, in the past, been fatal, despite treatment with massive doses of steroids and other immunosuppressants, whereas now treatment with thalidomide can deal with the condition very effectively.
Thalidomide has also been found to be a particularly useful treatment for certain cases of leprosy. Unfortunately, in various South American countries, a new generation of thalidomide children have been born as a result of this use. The drug was sourced from the USA and so the warnings about its effects on the foetus were in written English and not understood by the patients taking it to treat their leprosy.
A new role for thalidomide in the prevention of weight loss in some cancer patients is currently being studied to determine whether the results found relate to all cancers and whether the slowing of weight loss prolongs survival.
However, the peripheral neuritis that worried the FDA so long ago remains a major side effect, which can unfortunately be severe and irreversible. The debate continues.
Bendectin and Debendox doubts
Morning sickness in pregnancy is common, usually lasting for an hour or two each morning for a few weeks in early pregnancy. Unfortunately for some women, it can be severe and debilitating and, despite the name, can last all day, and sometimes for the whole of the pregnancy. An anti-nausea drug called Bendectin in America, and Debendox elsewhere in the world, which originally contained three ingredients, doxylamine, dicyclomine and pyridoxine, was used for several decades starting in the 1950s as a treatment for morning sickness in pregnancy.
Following on from the thalidomide tragedy, concerns arose from anecdotal reports of malformations in babies whose mothers had taken Debendox during pregnancy. Investigations over several years showed that one of the ingredients in this product, dicyclomine, might possibly cause problems. In 1977, dicyclomine was removed from the product in the USA, and then later in the UK, but still the rumours and reports continued.
Because of threatened litigation, the makers decided in 1983 to withdraw the product from the market. However, during the 27 years that it was available, the product had been used in some 33 million pregnancies. Both the CSM in the United Kingdom and the FDA in the USA reviewed the literature relating to all the studies done over the years. They concluded that, despite the lack of any scientific evidence of an increase in birth defects, the risk of teratogenicity could not be definitely excluded because of the particular combination of drugs contained in Debendox.
It was not until some years later that William McBride, a leading Australian gynaecologist who had earned much praise earlier in his career as one of the doctors who had revealed the dangers of thalidomide, admitted that he had faked research data in order to force Debendox off the market. He claimed that he did it ‘in the interests of humanity’.
Other tragic teratogens
Following the thalidomide tragedy, the CSM was very careful when new drugs were given marketing approval. When, in the 1980s, a new product to treat acne was launched, the British authorities insisted that it should only be prescribed by consultant dermatologists, and with very careful safeguards in place, because of possible birth defects it might cause. This new product was an oral retinoid, a vitamin A-like substance, called Roaccutane.
Some years later, in 1988, the FDA announced that they had received reports that over 600 babies had been born either mentally retarded or with severely deformed features after their mothers had taken the same product, called Accutane in the USA. America had escaped the thalidomide tragedy in the early 1960s, but not this time. Belatedly, the FDA now insisted that the Accutane product packaging must carry a picture of a deformed baby, to scare off pregnant women.
The British were only too aware of the threat of birth defects following thalidomide and so the CSM had insisted that the pack should carry clear warnings of the possible horrific side effects of this new drug. Today, all female patients are obliged to sign consent forms confirming that they are not pregnant before they can be given the drug. To exclude any possibility of pregnancy, it is mandatory that a pregnancy test be performed before treatment with this drug can be started and that effective contraception must be practised for one month before, then during and for one month after the 16-week course of treatment. Patients taking longer acting oral retinoids need to avoid conception for even longer periods, in some cases for up to two or three years.
Stilboestrol is a synthetic nonsteroidal oestrogen, which today is called diethylstilboestrol and used with careful safeguards in the palliative treatment of breast and prostate cancer. However, in the late 1940s and 50s, it was widely used, particularly in America, by pregnant women. It was not until the 1970s and 80s that it was realised that the children of these women were suffering side effects resulting from the medication taken by their mothers before they were even born. The female offspring of these mothers, who received stilboestrol while pregnant, developed cervical and vaginal abnormalities, including glandular growths and cancer. The male offspring similarly exposed in utero also developed genital abnormalities and abnormal spermatazoa.
The tale of the Dalkon Shield
The Dalkon Shield was an intra-uterine contraceptive device (IUD) introduced in the USA in the early 1970s. In the first year alone some 16,000 of them were fitted. Many doctors realised that this was a very useful alternative form of contraception. While the spread of cheap and effective contraception in the form of the contraceptive pill had been a great advance, it also had its problems: doctors were most concerned about the risk of thrombosis, as prolonged use of the pill led to a statistically significant increase in this risk. This was because the type of contraceptive pills that were available at the time contained a much higher dose of oestrogen than is the case now, over 30 years later.
Women who could not take the contraceptive pill for various reasons turned to alternative methods of contraception, one of which was the intra-uterine device. The Dalkon Shield was a new and supposedly improved type of IUD. Similar devices on the market at the time had a number of problems. For a start, they were less effective than the contraceptive pill. Doctors found that the devices then available were difficult to insert, and sometimes insertion was impossible in those women who had not yet had children. The devices also tended to be expelled from the womb, sometimes becoming lost even without the woman realising, which then put her at risk of an unwanted pregnancy.
The Dalkon Shield was designed to overcome these problems. It was a 3cm-long piece of plastic, a sort of diamond shape, like a kite, with three short blunt fins angled down each side. These were intended to act like the barbs on fish-hooks to provide a safe grip and prevent the device from slipping out through the cervix at the entrance to the womb. At the bottom end of the device, there was an eight cm length of cord, with a knot 3.5cm from the end.
This cord was there to enable the device to be removed and was to become the source of the problem. The device gripped so well that it needed a considerable force (of about 5kg) to extract it. So a strong multifilament cord was needed and such a cord was eventually developed. This multifilament cord could absorb fluid (and any bacteria in the fluid), which would pass along it, in the manner of paraffin along a lamp wick, a process called ‘wicking’.
The makers realised that this was a potential hazard, and so decided to enclose the cord in a black plastic sheath. The sheath was supposed to prevent the problem of wicking, but in fact it didn’t at all; what the coating did do was make the cord very stiff, which caused significant production problems. The makers then started to receive complaints from women who were fitted with the device. They complained that their partners could feel the stiff cord in its plastic sheath protruding from the cervix during intercourse. These ladies were not happy, and neither were their partners.
Nonetheless, by 1972, the Dalkon Shield was the best-selling IUD in America. However, there were more problems to come. Only a year later, following reports of seven septic spontaneous miscarriages, including one where the mother also died, a number of ectopic pregnancies, and one child who was born deformed, the Dalkon Shield was no longer marketed in America. The complaints and lawsuits that followed led to the makers paying out $6 million to one woman who had a near fatal miscarriage which resulted in a hysterectomy.
Even more money was paid out for many other out-of-court settlements. The device had been marketed around the world, including Britain, and although production had stopped in the mid 1970s, doctors still had stock on their hands in England, Australia and America and continued to fit them until 1979. It was not until 1982, following a victory in the American courts by a class action started by a group of British women, that the shields finally fell into total disuse.
Opren the awful
In 1980 in Britain, a new anti-inflammatory painkiller, Opren (benoxaprofen), was launched by Dista. Dista was a subsidiary of the American pharmaceutical company Eli Lilly, who later in the decade would launch the antidepressant drug Prozac. The launch of Opren was accompanied by the usual flurry of advertising in the medical and pharmaceutical press. It was a very effective painkiller for those with arthritis and was claimed to be even more effective than the existing non-steroidal anti-inflammatory drugs (NSAIDs) such as Brufen (ibuprofen) and Froben (flurbiprofen).
At a conference the following spring, some consultants were already warning that some of their elderly patients were showing signs of liver and kidney problems. The problem was that the elderly patients taking Opren had a reduced capacity to metabolise the drug, and reduced kidney function to excrete it, simply because they were old. As a result, they were being poisoned, more and more, day by day, as the drug built up in their bodies.
Opren was available in only one strength, while other similar drugs were available in two or more strengths. As the months went by, some patients taking the ‘one strength is suitable for all’ Opren developed jaundice, a sign of liver failure, and several of them died. Post-mortem examination of their livers showed it to be a drug-induced jaundice, and the one common drug taken by all the patients was Opren. By the spring of 1982, doctors began noticing strange symptoms caused by a build-up of the drug in their patients. Bald men grew hair, ladies grew whiskers, and nails grew very fast and then started to come loose, before falling off. This happened to about one in 20 patients.
One of the most common complaints, which affected at least half the patients, was of a burning sensation in the skin after only a few moments in direct sunlight, while longer exposure tended to result in blistering. Other skin disorders also occurred, such as pronounced reddening with lesions and the life-threatening Stevens-Johnson syndrome – in some patients great patches of their skin literally fell off. Many suffered gastro-intestinal disturbances, including peptic ulceration and bleeding. Some had blood disorders, as well as the jaundice, other liver and bile disorders, and even kidney failure as mentioned above, and they were all side effects of this one drug.
It was fortunate that these early reports of side effects came to light so soon after the launch of Opren, as this meant that other countries where the drug had not yet been launched were able to prevent its use. The FDA did grant a licence in the USA on 19th April 1982, where benoxaprofen was given the brand name Oraflex. But, within six months, the number of deaths across the world had risen to 61, and the drug was withdrawn globally in October that year.
In the 22 months that Opren was used in Britain it was estimated that, out of 4,000 patients who suffered side effects, some 100 patients died. Many patients continued to suffer long after stopping the drug, living in a twilight world behind closed curtains, to prevent the burning and blistering caused by exposure of their skin to sunlight, which continued long after they had stopped taking Opren.
Bute and blood
Phenylbutazone is a potent non-steroidal anti-inflammatory painkiller that has been in use for decades, and is still widely used in veterinary practice, where it is known as ‘Bute’. However, its use in humans is now severely restricted in the UK, being limited to the hospital treatment of ankylosing spondylitis (a form of arthritis mainly affecting the spine) specifically under the supervision of a specialist consultant.
This restriction to its use is due to occasional, but very serious, side effects that could be potentially fatal. Blood counts are needed both before and during treatment due to the risk of blood abnormalities, including aplastic anaemia, Stevens-Johnson syndrome, toxic epidermal necrolysis and pulmonary toxicity. The most serious of these are associated with bone marrow depression. In the 30 years between July 1963 and January 1993 the CSM received over 100 reports of blood disorders, of which over 40 were fatal, associated with the use of phenylbutazone.
Lasers no less
Indomethacin is an example of a similar, but much safer, drug still in use today. It is a very useful NSAID, particularly valuable in treating the excruciating pain of gout. The principal and most frequent side effect found with this type of drug, which has always limited its use, is that it can cause gastro-intestinal problems, including ulceration.
Over the last 30 years, the pharmaceutical industry has tried various strategies in an attempt to reduce this problem, such as formulating sustained release or modified release oral preparations or suppositories for rectal administration. In December 1982, a novel dosage form of indomethacin was launched: ‘Osmosin’ was a very special sort of sustained release tablet.
At the centre of one side of each pale blue tablet was a small hole, which the makers said was drilled by a laser. At that time, lasers were a new innovation to the general public, and had even been featured in the latest James Bond film. The idea behind the novel dosage form was that fluid from the gastro-intestinal tract, including the stomach, would be drawn into the tablet by osmosis (hence the brand name). Some of the drug within would dissolve into the fluid and would then be slowly expelled in solution through the laser-drilled hole, where it could be absorbed into the blood stream, without upsetting the stomach.
It sounded brilliant, but unfortunately in the same way as bread always seems to land butter side down, if the tablet landed hole side down, against the stomach or gut wall, the indomethacin would speed up the development of an ulcer in double-quick time. There were many cases of perforations of both the small and large bowel, and of haemorrhage too. Osmosin was withdrawn less than a year later in 1983 after some 650 reports of serious side effects and 20 deaths. However, this novel technology of osmosis was later successfully used with a number of other modified release medicines, using different types of drugs that did not cause gastric problems.
New but not improved
At the end of September 2004, another NSAID called Vioxx was taken off the market by its manufacturers, Merck. Vioxx (rofecoxib) was a cox-2 inhibitor, which acted more specifically on pain, while causing less upset to the stomach than older painkillers of this type. The older drugs worked by preventing two enzymes, cyclo-oxygenase 1 and 2 (cox-1 and cox-2, for short) from working, but while this resulted in stopping the pain, it could upset the stomach too. The newer cox-2 type of painkiller only stopped one enzyme working (cox-2), and this stopped the pain, without upsetting the stomach.
Vioxx was launched in the UK in 1999 and at the time of its withdrawal was prescribed for at least 400,000 people in Britain. Although Merck had known for at least four years that this drug had problems, it kept quiet as the drug’s global sales rose to $2.5 billion. When trial results published in 2000 showed an increased risk of heart attack by those taking rofecoxib, these were explained away by Merck, and the FDA took no action, even though it was sent further data about this problem.
This drug caused thousands of heart attacks and deaths worldwide before its withdrawal and no doubt will lead to many years of litigation. A few months after the withdrawal of Vioxx, doctors in the UK were told not to prescribe similar cox-2 inhibitor type drugs to patients with known coronary heart disease, following the realisation that all drugs of this type increase the risk of heart attack in such patients. It was estimated that coronary heart disease patients had a 34 per cent increased risk of heart attack when taking Vioxx.
Good old Aspirin
Aspirin was first marketed by the German drug company Bayer as long ago as 1899. Today we use it as a painkiller for headaches and rheumatics, and as an antipyretic to reduce fevers. People also take it in small daily doses to prevent heart attacks. So not only is it analgesic and antipyretic, but it is also anti-inflammatory and thins the blood as well.
In the mid 1980s, the British Committee on Safety of Medicines suddenly announced that Aspirin could no longer be given to children under 12 years of age. Aspirin tablets in the UK at that time came in two strengths: the adult 300mg tablets and the children’s 75mg tablets, known as ‘Junior Aspirin’. Research in America had suggested that a very rare illness called Reye’s syndrome, occasionally suffered by babies and children, was caused by Aspirin. This syndrome has already been mentioned in the chapters about foodstuffs and the noxious nursery, but in cases caused by other substances.
The illness usually occurred after the children had had a viral infection, such as influenza, chickenpox or gastro-enteritis, and the syndrome was devastating in its effects, attacking the liver by causing fatty degeneration, and affecting the brain too. Half the affected children died and those who survived were badly brain damaged. An Australian doctor, Ralph Reye, first reported this collection of symptoms as long ago as 1963 but it was not until 1982 that the surgeon-general in America ordered that Aspirin should not be given to children or teenagers. Within four years, the incidence of Reye’s syndrome in America had halved.
The British Committee on Safety of Medicines decided to investigate further and delayed action until a full review of the literature and further testing had been carried out. And so it was not until June 1986 that the use of Aspirin in children aged 12 or under was eventually restricted in the UK. Since then, the age below which Aspirin may not be used was raised from 12 to 16.
Aspirin should also not be taken by breastfeeding mothers because it then passes to the infant in the breast milk. There is only one application for which Aspirin is allowed in children, and that is in juvenile arthritis (Still’s Disease), and then it may only be prescribed for the child under the supervision of a specialist consultant.
The lower strength Aspirin (75mg) is no longer called ‘Junior Aspirin’ but is still very much in use, but now by older people as ‘a tablet a day keeps heart attacks away’. This strength is also used in stroke prevention and for its blood thinning qualities to prevent clots forming after cardiac bypass surgery.
Phenacetin has analgesic and antipyretic actions similar to Aspirin. This drug was used in headache tablets together with Aspirin, caffeine or codeine. In use since the end of the nineteenth century, it was withdrawn in the UK over 20 years ago because of adverse blood and kidney problems, which were associated with its prolonged use and large doses. Many years ago, Phensic tablets used to contain phenacetin, in addition to Aspirin and caffeine, but this product was reformulated following the withdrawal of phenacetin by the authorities, although the related brand name lives on.
Synergy at its worst
Bactrim, made by Roche, and Septrin, made by Wellcome, were two brands of the same medicine, a combination of a sulpha drug, sulphamethoxazole, and another antimicrobial chemical called trimethoprim. The two ingredients were said to act synergistically – that is they were claimed to be even more effective in combination than the simple additive effect of either taken alone. This combination was given the generic name of co-trimoxazole.
Twenty-five years ago, co-trimaxazole was widely prescribed for an assortment of infections including cystitis. However, it had some rare but very nasty side effects associated with its use. These included Stevens-Johnson syndrome (which had also happened with Opren and Bute), in which there was severe blistering of the skin and bleeding in the mucous membranes of the lips, eyes, mouth, nose and genitals. The skin could literally fall off in great patches. Other side effects could also occur, including various blood problems, particularly bone marrow depression and agranulocytosis, which especially affected the elderly. These devastating side effects were attributed to the sulpha drug component of the combination.
Since then it has been found that trimethoprim, the second component, is a very effective anti-bacterial agent in its own right, and today this is the treatment of choice for urinary tract infections, such as cystitis. It will come as no surprise that the use of co-trimoxazole today is now restricted to certain specific, very serious infections, while trimethoprim is considered so safe that it may soon be available from pharmacies without the need for a prescription.
Grey babies and other problems
Chloramphenicol is an antibiotic still in regular use today, in the form of drops for ear and eye infections and a lotion applied to the skin to treat acne. These uses are all diluted, external solutions. However, apart from these, it is now reserved for use only in life-threatening infections, such as meningitis and typhoid fever, when it is given by infusion (a drip). Its use is limited because, although it is a potent wide-spectrum antibiotic, it was associated with serious haematological side effects when given systemically.
The blood disorders associated with its systemic use include both reversible and irreversible aplastic anaemia (sometimes resulting in leukaemia), peripheral and optical neuritis, erythema multiforme (also mentioned with Opren), and ‘grey syndrome’ which occurs in small babies, resulting in abdominal distension, circulatory collapse and pallid cyanosis, which make the baby look grey. Chloramphenicol came into use in the early 1950s and these appalling side effects associated with its use became clear within a few years, leading to severe limitations in its use.
In France, also in the 1950s, a new drug called Stalinon, an organotin compound (mentioned in Chapter 2), was used by doctors to treat staphylococcal skin infections such as boils. Stalinon capsules caused massive poisoning, in which at least 100 patients were permanently affected, and 102 died, thought to be due to contamination of the medicine with a slightly different organotin substance. Further investigation later revealed that during the clinical trials – necessary to get government approval for the drug’s use – a much lower dose was used and so the toxicity had not been apparent.
Hexachlorophane is a disinfectant that was once widely used in soaps, creams and dusting powders, including products for nappy rash. However, during the 1970s, it was discovered that hexachlorophane could be absorbed, particularly through the skin of babies, in amounts sufficient to produce spongy lesions of the brain, which were sometimes fatal. It was also found to be teratogenic. Nurses who had used hand washes containing hexachlorophane while at work were later found to have given birth to deformed babies. Consequently, it may no longer be used at all in preparations designed to be used on babies. Limitations were also placed on its use in cosmetics and for personal hygiene products.
Along came Valium
In the 1930s, a Polish chemist discovered a new group of chemicals called the benzodiazepines, but it was not until 1961 that the first one went on the market. It was launched by the pharmaceutical manufacturer, Hoffman La Roche. Chlordiazepoxide, brand name Librium, was the first of many similar drugs. Hoffman La Roche launched Valium, or diazepam, the following year. Doctors had been searching for a safer type of tranquilliser, to use as an alternative to the barbiturates. The barbiturates had been available since the previous century and were known to be very dangerous, as they caused kidney damage and even fatalities in overdose.
Ten years after the launch of Valium there had not been a single fatality due to the benzodiazepines, and they were regarded as totally safe – the perfect tranquilliser – but by 1980 there were reports of problems. Some patients found that when they tried to stop taking their benzodiazepines, they suffered the most appalling withdrawal symptoms. They suffered personality changes, sudden rage and extreme mood swings, as well as anxiety, depression and agoraphobia. The first official warning did not come until January 1988 when the Committee on Safety of Medicines issued a report on the dangers posed. This was somewhat late in the day as many journalists had been writing articles in newspapers and magazines about the problems with benzodiazepines for several years previously.
Another drug of this type was Halcion, which became the world’s most widely prescribed sleeping pill. It was a short-acting benzodiazepine and so did not give patients a hangover the following morning, which was a problem with the older, longer-acting ones, such as nitrazepam. Halcion received much bad publicity when it was implicated in a number of murders in America, committed by people while under its influence. The British Department of Health banned the use of Halcion in October 1991.
By 1990, many sufferers, who blamed Valium, Ativan and other benzodiazepines for their condition, attempted to sue the makers of the various drugs. Eventually, there were 5,000 litigants in the group action which, fortunately for the manufacturers, failed. In 2002, Valium was discontinued in the UK, as usage of this more expensive branded version of diazepam had dropped to a very low level.
In the summer of 2003, the father of two French tennis prodigies was arrested in connection with the death of one of their opponents. It transpired that a number of rival tennis players had under-performed and complained of drowsiness while playing against them. Their father, Monsieur Fauviau, was arrested following a car crash that killed Alexandre Lagadere, a 25-year-old teacher. He died following a match against Maxime Fauviau. There was no alcohol in his blood, but a benzodiazepine called lorazepam was found to be present in his bloodstream, even though he had never been prescribed it or been seen to take it. Such is the ruthless and competitive world of sport these days that this father was prepared to drug his children’s opponents to enable them to succeed.
After Valium
Following the realisation in the 1980s that the benzodiazepines could cause problems when taken long term, the CSM advised that they should only be used for short-term relief of anxiety, or insomnia, and then only when it was severe and disabling or causing unacceptable distress to the patient. They advised that the benzodiazepines should no longer be used at all for mild anxiety or insomnia.
As an alternative to the benzodiazepines, doctors began to use very low doses of thioridazine for anxiety and distress, including treating the elderly who were suffering from confusion and dementia. Thioridazine, called thorazine in America, was a major tranquilliser and antipsychotic, in use since the early 1960s in Britain. When the doctors began using it in place of the benzodiazepines, it was used in a far wider population of patients than previously, especially in the elderly. This led to an increase in certain side effects, particularly those affecting the heart.
The cardiac problems caused a particular type of irregular heartbeat, or arrhythmia. This was due to prolongation of the QT interval of the heartbeat, which will cause even more problems later in this chapter. This was so serious that it led the CSM to advise that thioridazine should be reserved specifically for use as a second-line agent and only prescribed by consultants in the treatment of adults with schizophrenia, with stringent safeguards in place, to prevent heart problems in those taking it.
Before Prozac
Depression is a mental state characterised by extreme sadness. Sufferers may be agitated and restless or slow and retarded. Pessimism and despair, problems with sleep, appetite and concentration are all common symptoms. Treatment is with antidepressant drugs, cognitive behaviour therapy and/or psychotherapy. The main group of antidepressants, in use for the last 50 years, have been the tricyclics, mentioned in numerous murders throughout this book as well as in the chapter on treatment. However, these have been superseded in the last 20 years by the serotonin re-uptake inhibitors, which affect the levels of the neurotransmitter serotonin in the brain, and are far less sedative than the older tricyclics.
Zimelidine, brand name Zelmid, was an antidepressant introduced in the UK in 1982. It was a serotonin re-uptake inhibitor, a forerunner of the selective serotonin re-uptake inhibitors (SSRIs) such as Prozac and Seroxat that are used today. Zelmid was marketed as being very safe in overdose and as having fewer side effects than other antidepressants available at that time. However, it was withdrawn worldwide in September 1983 because of the risk of Guillain-Barré syndrome, which is more usually associated with viral infections.
This syndrome causes a rare form of damage to the peripheral nerves, which then become inflamed, leading to paralysis. The paralysis starts in the legs and spreads progressively upwards to the arms and on up to the face, to affect speech, swallowing and breathing. Total paralysis needs close monitoring in hospital, with intubation and ventilation, until the symptoms subside. Fortunately most people recover completely without any specific treatment.
Another antidepressant, nomifensine, whose brand name was Merital, worked by preventing the re-uptake of the neurotransmitters dopamine and noradrenaline in the brain, but had relatively little effect on serotonin. Its mode of action in depression was not fully understood; however, it worked well, had relatively few side effects and appeared to be safe in overdose. Unfortunately there were soon many cases of blood disorders including acute haemolytic anaemia, in which red blood cells are destroyed. Some patients also developed renal failure. Merital was withdrawn worldwide in January 1986, as the risks from these horrific side effects now far outweighed the benefits of treatment.
Slimming pills: too good to be true
Fenfluramine, as Ponderax, and dexfluramine, as Adifax, were marketed by the pharmaceutical industry for the treatment of obesity several decades ago. They were slimming pills, or in medical jargon, anorectics – drugs that reduce the appetite. They were chemically related to the stimulant amphetamine, but the usual dose of these anorectics tended to depress the central nervous system rather than stimulate it.
Immediately there were problems, including primary pulmonary hypertension, already known to be attributed to anorectic drugs and reported in the early 1980s. Both reversible and irreversible cases of this problem were reported, some of which were fatal. Drugs used to treat ordinary high blood pressure were ineffective in this type of hypertension. Investigations by the CSM in 1992 led to the advice that, as the condition appeared to be linked to the length of treatment, in future any course of treatment should not exceed three months. In 1997, the recommendations were revised for fenfluramine and dexfluramine to allow treament for up to 12 months, under certain conditions, but the use of another drug, phentermine, was still limited to three months.
Shortly after this revised recommendation, another report was published about an even more serious side effect. Twenty-four patients had developed damaged heart valves as a result of taking these slimming pills. By September 1997, the FDA in America had received a total of 144 reports, including the original 24, about valvular heart defects associated with fenfluramine or dexfluramine used alone or in combination with phentermine. None involved the use of phentermine alone.
Subsequently, all these drugs were withdrawn worldwide. As a consequence, the US authorities made recommendations regarding the screening of all patients who had received either fenfluramine or dexfluramine in order to detect any heart valve lesions and provide future care. Further studies suggested that prolonged exposure or higher than normal dosages appeared to increase the risk of heart valve damage. In a review of 53 cases of overdosage published in 1979, nine of these patients had died of cardiac and respiratory arrest.
In the USA, slimming pills containing these drugs were marketed under the brand names Phen-fen and Redux by a company called American Home Products. This company also sold its products to many other countries throughout the world. It was discovered during the FDA investigations, and the court cases which followed, that the manufacturers had been aware of these appalling side effects all along, but had chosen to cover them up. If they had been honest and told the FDA about the side effects, the drugs would have been withdrawn a lot sooner, or maybe not even marketed at all. Since then, they have paid out in excess of $17 billion in damages to the women they damaged, but no single individual employee of American Home Products has ever been prosecuted.
In 2007, a weight loss drug, Acomplia (rimonabant), widely available in Europe, including Britain, was banned from use in the USA when the FDA rejected a licence to market the drug. This followed research which indicated that the drug doubled the risk of suicidal thoughts and behaviour. Other drugs known to increase suicidal thoughts and behaviour, particularly in young people, are the anti-viral Tamiflu (oseltamivir), and the SSRI antidepressant Seroxat (paroxetine). Such drugs now carry warnings to alert prescribers that close monitoring is required.
New drugs, old problems
The pharmaceutical industry worldwide is always on the lookout for likely new drugs, particularly of the mood-altering kind. Whether drugs for schizophrenia, depression or dementia, there is a massive market to be tapped, and you can strike it lucky, like with Prozac. However, all drugs have side effects, some of which are worse than others. Sometimes even with potentially fatal side effects, a drug may still be allowed to be used, but with very careful supervision and monitoring, as we shall now see.
Clozapine, brand name Clozaril, is an atypical antipsychotic used in the treatment of schizophrenia, but it is reserved for use only in those patients who are unresponsive to, or intolerant of, the conventional antipsychotic drugs. This restriction is because of the risk of a fatal blood disorder, agranulocytosis, developing in patients using this drug. All patients taking it must be registered with a monitoring service run by the drug’s manufacturer.
The risk is so great that a white blood cell count and a differential blood count must be done before starting treatment, and then every week for the first 18 weeks, after which the counts can be reduced to every two weeks. Only after a year may they be reduced again, to every four weeks. Even after use of the drug has stopped the blood counts must continue for a further four weeks.
Another atypical antipsychotic, remoxipride, with the brand name Roxiam, caused aplastic anaemia. By November 1993, the CSM in Britain had received eight reports associated with this drug, five of which were in the UK. The patients, one of whom died, had only been taking remoxipride for between three and eight months. The drug subsequently remained available from the manufacturers for the compassionate treatment of psychosis in individual patients intolerant of other antipsychotics, but only with very careful monitoring.
The CSM recommended that it should not be given to patients with a history of blood disorders and that prospective patients should have blood counts before treatment commenced and then every week for the first six months, and monthly thereafter. Patients and their carers were advised to seek immediate medical attention if any bruising, bleeding, sore throat or fever developed. At the first sign of any blood disorder the treatment with remoxipride had to be stopped. Roxiam is no longer marketed.
Paraldehyde, a trimer of acetaldehyde, was used in the past as both a hypnotic and sedative, and for its antiepileptic effects. Unfortunately, it has a solvent action when in contact with plastics. And it tends to decompose on storage, particularly once opened. It is dangerous to use if it has a brownish colour or has the sharp vinegary smell of acetic acid, as these are both signs that it has begun to decompose. Deaths have occurred in the past due to the use of paraldehyde that had deteriorated during storage.
The administration of paraldehyde is problematic too, as both gastric and rectal administration may cause irritation, and there are even greater hazards when it is given by injection. Intramuscular injection is not only painful but also associated with tissue necrosis, nerve damage and sterile abscesses, while intravenous injection is extremely hazardous as it may cause many other problems such as haemorrhage, hypotension and circulatory collapse.
Needless to say, due to these hazards associated with its administration, its tendency to react with plastics – so that all-glass syringes need to be used – and the risks associated with its deterioration, it is not surprising that paraldehyde has largely been superseded by other more easily administered drugs.
Gas doing more harm than good
Halothane is an anaesthetic that would normally be administered together with oxygen, or with mixtures of nitrous oxide and oxygen. Unfortunately it sometimes damages the liver, an adverse drug effect first recognised many years ago. The liver is the body’s detoxification system so, if it is damaged, the consequences can be very serious. The first obvious sign of a problem is the development of jaundice, where the patient starts to turn yellow.
The CSM received 84 reports of liver damage associated with the use of halothane in the UK between 1978 and 1985, and so issued guidelines on the precautions to be taken by anaesthetists before using halothane. In 1997, these guidelines were reiterated after a further 15 cases of acute liver failure were reported, all of which required transplantation. An anaesthetic whose use results in the need for a liver transplant is not to be recommended.
Another gas needing precautions is oxygen. While oxygen is vital to our survival, too much can be disastrous. Premature babies used to be kept in a pure oxygen or high oxygen concentration atmosphere, within incubators, until it was realised that some became blind as a result. The blind singer-songwriter, Stevie Wonder, is one such victim. Nowadays, patients, including pre-term infants, receiving oxygen therapy do not breathe in pure oxygen, but instead breathe in air enriched with oxygen.
Too much sugar
Today we call it Type 2 diabetes, but this condition used to be called maturity onset diabetes because it tended to be diagnosed in middle-aged patients who had put on a lot of weight. This sort of diabetes can usually be treated with tablets rather than with insulin. Phenformin was such an oral hypoglycaemic drug – that is, it lowered blood sugar levels. It was in use in the UK from the mid 1960s until the late 1970s. It is still in use even today in Italy and Spain, but was discontinued in the United Kingdom due to an unacceptably high incidence of cases of lactic acidosis and coma, which were often fatal.
Phenformin was also implicated in reports concerning excessive cardiovascular mortality associated with its use. Buformin was a similar drug with similar problems, and it was also discontinued in the UK in the 1970s. However, a third drug of this type, called metformin, is still widely used in Britain and around the world to treat Type 2 diabetes, with relatively few problems. Metformin is also used with great success to treat the gynaecological condition called polycystic ovary disease.
Another oral hypoglycaemic medicine that was only on the market for a short time before being discontinued in Britain was troglitazone, brand name Romozin. Its withdrawal was due to severe liver reactions in certain patients, some of which were fatal. The average time before the onset of liver damage was only three months. The CSM was aware of more than 130 cases worldwide, including six deaths, by December 1997, although only one case had occurred in the UK. Drugs cost a great deal to develop, so in America the manufacturers and the FDA agreed a schedule of routine monitoring of liver function in November 1997 rather than withdrawing the product, but more and more cases occurred. The drug company recommended ever more intensive monitoring, but eventually they had to withdraw troglitazone worldwide in March 2000.
Stimulant dynamite
Phenolphthalein was a stimulant laxative in use from the early years of the twentieth century. It was available alone or as an ingredient of compound tablets which were composed of phenolphthalein, aloin, strychnine and belladonna. These tablets were described at the time as ‘a useful combination’; a more accurate comment would have been ‘dynamite’ – they were very good at what they were meant to do.
Some people may remember phenolphthalein from their schooldays, where they may have used it as an indicator in chemistry lessons: it is colourless in acid solutions but bright pink in alkaline solution, so if someone with alkaline urine took a laxative containing phenolphthalein, their urine would be coloured pink. About ten years ago, phenolphthalein was reclassified as a ‘prescription only medicine’ following animal tests in which rats and mice developed tumours after being fed very high doses of the drug.
This was a precaution as there does not appear to be any evidence of carcinogenicity in humans. However, action was taken in a number of countries because of concerns about the long-term safety. In the UK, all the ‘over the counter’ constipation remedies containing phenolphthalein were withdrawn, and although some of them were reformulated (most now contain senna instead), the rest of them were discontinued.
Beta-blockers
The general public have been aware of beta-blockers for many years because of their use in treating high blood pressure, heart problems and even anxiety, but like most other drugs, they have had a rocky road to success. The very first beta-blocker, nethalide, was never even marketed, as prolonged animal testing showed it to be carcinogenic.
Another of the early beta-blockers to be marketed in the 1960s was called practolol, brand name Eraldin. Shortly after its launch, serious adverse effects severely restricted its use. A series of severe side effects involved the eyes, ears, skin and mucous membranes. These led to blindness, deafness and numerous systemic effects resulting in painful joints and growths. By the end of 1974, nearly 200 reports had been received about the eye effects, and many other reports were filed related to the other side effects. Subsequently, use of practolol was restricted to the treatment of heart attack in hospital.
Another beta-blocker, propranolol, developed by the same manufacturer as practolol, was given the brand name Inderal, an anagram of Eraldin. Propranolol and many other beta-blockers have been used successfully for over 30 years without the dreadful problems that were seen with practolol.
Lipid lowering
Medication to lower cholesterol has been in the news a great deal over the last few years. The main group of drugs used to treat high cholesterol are called the ‘statins’. These drugs act by inhibiting an enzyme in the liver. Put simply, this reduces the total cholesterol in the body, as well as the low density lipoprotein (LDL) cholesterol concentration and the very low density lipoprotein (VLDL) concentrations in the plasma. See Appendix IV for further explanation. These drugs also tend to reduce the triglycerides while increasing the high density lipoprotein (HDL) cholesterol concentrations (the ‘good’ cholesterol), and so reducing risk of heart attack.
But all the statins and fibrates (another type of lipid-lowering drug) have caused some muscle problems to a greater or lesser extent.
Rhabdomyolysis is the name given to a rare side effect that leads to kidney failure, resulting in the destruction of muscle tissue together with blood problems. This initially causes weakness, then temporary paralysis progressing to total paralysis and death. There was a marked increase in such cases with one particular statin, cerivastatin, particularly when it was taken in combination with another lipid-lowering drug, gemfibrozil. This combination was commonly used in the USA but not in the UK. Since its initial authorisation and launch in the United Kingdom, there had been five reports of rhabdomyolysis reported to the CSM in Britain as well as many reports from other countries. So, in August 2001, Bayer plc, manufacturer of cerivastatin, brand name Lipobay, suspended marketing of the drug, first in the UK, and then worldwide.
In November 2004, the CSM advised that patients taking another drug of this type, simvastatin, should not drink grapefruit juice because grapefruit juice inactivated a liver enzyme important in metabolising this statin. Regular consumption of grapefruit juice could lead to high blood levels of simvastatin, resulting in life-threatening muscle toxicity. This advice about not drinking grapefruit juice has now been extended to all the ‘statins’. Eating a grapefruit for breakfast does not have this effect.
At about the same time, the CSM also advised patients taking the anticoagulant warfarin that they should not drink cranberry juice. This followed the second of two deaths of patients taking warfarin and drinking cranberry juice.
In both cases the problem is thought to be caused by something in the grapefruit and the cranberry juice that interferes with the way the body’s enzymes metabolise drugs.
Nothing but heartache
About ten years ago, astemizole, an antihistamine used to treat hay fever and sold under the brand name Hismanal, was discontinued in Britain. This was because of cardiac side effects similar to those of thioridazine, mentioned earlier, due to the prolongation of the QT interval. Initially, the reports of severe life-threatening cardiovascular effects were the result of cases of astemizole overdose. However, there then followed further reports, which showed that even a single tablet a day – the normal adult daily dose – was sufficient to cause problems in susceptible patients and that some patients with liver problems were also badly affected when taking it.
Terfenadine, better known as Triludan, was yet another antihistamine used to treat hay fever, but with a twice daily dosage. During the 1980s and 1990s, this was a best seller in Britain, both on prescription and, after a few years, over the counter. However, once it became available to purchase over the counter, it was then being taken by a much larger pool of patients than had been the case previously. All sorts of additional side effects, which had been largely unrecognised until then, emerged.
One of these side effects came from an interaction with grapefruit juice: if Triludan was taken together with grapefruit juice, the same problems that had caused astemizole to be discontinued in Britain appeared. Since then, a number of other drugs, including the cholesterol-lowering drug simvastatin described above, have also been found to interact negatively with grapefruit juice.
When taking terfenadine, patients already taking certain other drugs, or those with impaired liver function, found that their metabolism was impaired, even when taking normal doses, and this was found to be a risk factor in developing cardiac arrhythmias. Terfenadine is converted in the body to the active form fexofenadine, which does not have this effect, so Triludan was withdrawn and a new product, Telfast, containing fexofenadine, was launched instead.
It is interesting to note that another antihistamine, Piriton, chlorpheniramine, first marketed in 1954, still has massive sales today even though it is one of the older types of antihistamine, causes drowsiness and has a three times daily dosage.
Tummy troubles
Tummy upsets and mild food poisoning can seriously mar holidays, particularly in far-away places, where travellers are not used to the local water or the local bacteria. In 1976, a lady who was unable to get hold of a bottle of good old-fashioned Kaolin & Morphine Mixture, which she normally took for such upsets, used instead a product called Quixalin. It cured the tummy upset but had many other effects.
First her feet began tingling, then walking became difficult, and she became effectively blind, all due to the adverse effects of Quixalin. Many other people suffered similar effects from taking the same medicine. Quixalin, which contained a drug called halquinol, was manufactured by E. R. Squibb & Sons. The product was withdrawn from the UK market following reports about the neuropathy and optic atrophy associated with its active ingredient halquinol.
Another similar product containing a related substance, clioquinol, had been on the market since the 1930s, when it was originally used to treat dysentery and amoebiasis. In the 1960s and 70s, Entero-vioform, the brand name used for clioquinol, was regarded as a modern alternative to the old-fashioned remedy Kaolin & Morphine Mixture, which had been used for decades for diarrhoea and holiday tummy. Nowadays we use loperamide and oral rehydration mixtures to treat diarrhoea, but in the 1960s, loperamide had yet to be invented and clioquinol was the drug of choice.
Clioquinol was very popular in Japan in the 1960s, and in that country there developed an epidemic of SMON (sub-acute myelo-optic neuropathy), as the illness came to be called. SMON was associated with taking high, or even normal, oral doses of clioquinol, but for prolonged periods of time. The symptoms included great abdominal discomfort and diarrhoea, pins and needles in the legs, sometimes progressing to paraplegia (total paralysis). There was also loss of visual acuity, which sometimes led to irreversible blindness, sensory disturbances and a strange but characteristic green pigmentation to the tongue, urine and faeces.
There were more than 30,000 cases of blindness and/or paralysis in Japan alone, and thousands of deaths worldwide, all caused by this one drug. Cerebral disturbances including amnesia and confusion had also been reported as adverse drug reactions to clioquinol.
Although a few similar cases were reported from several other countries, it was felt that the epidemic in Japan may have been due to a genetic susceptibility in the Japanese. Nevertheless, the Ministry of Health and Welfare in Japan prohibited the production and sale of clioquinol in September 1970, and subsequently oral preparations of the drug were banned in the United Kingdom and in most other countries because of the severe neurotoxicity associated with taking the drug by mouth.
Clioquinol is a chemical that contains an atom of iodine in each molecule and so can, rarely, cause iodism in sensitive patients. The local application of creams or ointments containing clioquinol, which are still available today, can occasionally cause severe irritation. Its use in topical skin preparations can stain the skin and discolour fair hair as well as staining clothing yellow, because of the iodine content.
Another discontinued medicine, prescribed for digestive problems of a different kind, Prepulsid (cisapride) was a medicine that stimulated gastro-intestinal motility and was mainly used in cases of dyspepsia and reflux disease, and where gastro-intestinal motility is decreased, such as paralytic ileus. This is yet another example of a drug discontinued due to cardiac side effects, which caused prolongation of the QT interval.
Dialysis dementia
In the 1970s, early kidney dialysis patients suffered from ‘dialysis dementia’, which led to progressive brain damage and premature death. After much research it was found that aluminium, which was used to make parts of the dialysis machine, was binding on to a substance in the blood called transferrin as the patient’s blood passed through the machine, and when the blood passed back into the patient’s circulation the aluminium gained access to the brain, causing the horrible side effects of the treatment. Needless to say, the machines have long since been improved so that treatment nowadays no longer carries such a risk.
About ten years ago, there was a panic in the media because it was believed that high aluminium levels in the brains of elderly people might be the explanation for the onset of Alzheimer’s disease. Further research showed that this was not the case. The presence of aluminium was simply due to earlier researchers using an aluminium-containing stain on the tissue samples they had examined on microscope slides. These slides used the stained brain tissue of deceased patients so that the researchers could easily identify the characteristic plaques that form in the brains of dementia sufferers, but which are not present otherwise.
Quack cures
The heyday of quack medicines was probably the eighteenth century though, even now, in the twenty-first century, quack cancer cures are still being marketed and fortunes made from them.
Krebiozen was one such preparation, a supposed cancer cure that received a great deal of publicity, particularly in the USA during the 1960s. This substance was claimed to have been obtained from the blood of horses previously injected with extract of Actinomyces bovis. The claims were never substantiated and in 1966 the FDA acquired some of the product and had it analysed. The preparation was found to be an amino acid in powder form, nothing special at all, and so Krebiozen was totally discredited.
In the 1970s, a substance called laetrile became popular as an alternative remedy for cancer. Laetrile was derived from apricot kernels and consisted mainly of a substance called amygdalin, which contains cyanide. It was claimed that laetrile was preferentially hydrolysed by enzymes present in the cancer cells to produce benzaldehyde and hydrogen cyanide, which would then kill the cancer cells. Fine in theory, but amygdalin does not appear to be absorbed from the gastrointestinal tract, and both normal and malignant cells contain only traces of the particular enzymes required.
The instructions provided explained that laetrile was to be taken along with a special diet. This involved taking very high doses of an assortment of vitamins and pancreatic enzymes each day. No meat, no fish, no fowl, no dairy products and no animal protein were allowed; the diet was mainly massive quantities of fruit and vegetables. Laetrile was also claimed by some quacks to be ‘vitamin B17’. They claimed that a deficiency of this ‘vitamin’ could cause cancer but there is no evidence of this and, in fact, laetrile has no value whatsoever in human nutrition.
There were several reports of cyanide poisoning resulting from the use of laetrile, sadly including one of an 11-month-old baby who died after accidentally swallowing between one and five laetrile tablets, which contained up to 26mg of cyanide. Other reports of adverse effects were also associated with taking laetrile, especially by mouth. This quack cancer cure was banned from sale in Britain in the early 1980s.
Many other spurious ‘cures’, such as shark cartilage, based on the incorrect notion that sharks don’t get cancer, and other alternative cancer ‘cures’ can be found on various websites on the Internet. Unfortunately there is always someone willing to profit from the desperate.