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CHLORAMPHENICOL IN EYE-DROPS CAUSING APLASTIC ANAEMIA AND LEUKAEMIA
Chloramphenicol was first generally used in the USA in 1948 and a Federal Food and Drug Act of 1949 certified its use as safe and efficient.
Within a year or two of its introduction medical papers began to appear, linking chloramphenicol to blood dyscrasias, which are any abnormal condition of the bone marrow, such as leukaemia or aplastic anaemia. The first paper I have on this problem of blood disorders as a side-effect is dated November, 1952 in a Special Survey by the US Federal Security Agency Food and Drug Administration, Washington D.C. This survey was a compilation and summary of several hundred case records reviewed in July and August of that year by a committee appointed by the National Research Council. The paper is headed “Chloramphenicol (Chloromycetin) in Relation to Blood Dyscrasias with Observations on Other Drugs”.
The many early papers confirming that chloramphenicol was a cause of blood dyscrasias seemed to have little or no effect on prescribing except that after a few years and countless reports of side-effects the drug was used a little more carefully and it was recommended for only a few very serious and potentially fatal infections against which it was more effective than alternatives. One paper notes that with the reduced routine prescribing of chloramphenicol, because of the very serious and often fatal side-effects of blood dyscrasias, the total number of cases of aplastic anaemia from all causes dropped by a noticeable amount in the USA.
A paper by J.Philip Loge M.D. in the Journal of the American Medical Association (JAMA) in July 1965 on Aplastic Anaemia Following Exposure to Benzene Hexachloride (Lindane) notes the “natural hesitancy on the part of physicians to report apparent associations of aplastic anaemia and drug or chemical exposures”. Dr Loge notes that at that time,1965, it was accepted that chloramphenicol caused aplastic anaemia but it had taken years for this to be accepted even though the cause and effect was obvious. Dr. Loge ends his paper with a quote from Alexander Gode, PhD demonstrating the hesitancy of the medical profession to admit the obvious “When a man with a bullet hole in his head is hanging from a rafter, it will be assumed he is dead. If someone, describing the sight, states in summary that he concluded he was dead, I can but admire his scientific caution, but smile anyway”.
A paper in The Lancet dated 16th August 1975, from a doctor Gurth Carpenter of Los Angeles, “Chloramphenicol Eye-Drops and Marrow Aplasia” observes that nearly a quarter of a century ago (early 1950s) he had many patients diagnosed with aplastic anaemia following the use of chloramphenicol eye drops. These patients included a pharmacist, a doctor’s wife, a physician’s son, a pathologist’s mother, a colleague’s nurse, a 37 year old diplomat and then some general patients. Dr. Carpenter notes the difficulty in obtaining an accurate history of exposures even from intelligent and informed patients.
The Martindale Extra Pharmacopoeia 1972, p1340, records a man aged 36 with aplastic anaemia following the use of chloramphenicol eye-drops every 2 days out of 3 for a period of 23 months. I found many cases where, on investigation, the medical profession had either dismissed a connection between a small exposure to a known causative agent and aplastic anaemia or put the condition down to an idiosyncratic reaction, individual susceptibility or genetic propensity. In WW2 the US troops in the Pacific were monitored for adverse reactions to antimalarial drugs as it was known these drugs caused blood dyscrasias. The resulting cases of aplastic anaemia proved to be dose-related and nothing to do with individual susceptibility or genetic propensity. The taking of a careful history by the medical profession is often non existent or generally very poor and private toxicology reports frequently confirm exposure to known causative agents which were never found by the medical profession.
At the present time there is some dispute between members of the medical profession in different countries about the incidence of blood dyscrasias and in particular aplastic anaemia caused by chloramphenicol eye-drops.
The July 8th issue of The Pharmaceutical Journal of the UK published a letter by consultant physician J. Barnard Walsh and registrar, Marie Doona, both from St. James’s Hospital in Dublin saying, because of the risk of aplastic anaemia with chloramphenicol eye drops they should not be used routinely. They found that systemic absorption does occur and the reaction can be idiosyncratic and that there is no safe dose. The letter quotes a 1993 Oregan USA report of the National Register of Drug Induced Ocular Side Effects which found 23 cases of blood dyscrasias following administration of chloramphenicol eye drops.
The Pharmaceutical Journal dated 2nd December, 1995 published a report “Further Support for Ocular Chloramphenicol”. Doctors from Hammersmith Hopital said that the risk of aplasia developing after systemic use of chloramphenicol is 13 times higher than in the general population but there is little evidence of a cause and effect connection and had found only 22 cases in 40 years. The Committee of Safety of Medicines was noted to have received only 11 reports of haematological reactions from 1966 to the date of the article. Two alternative safer drugs as effective as chloramphenicol, a combination of polymixin B and gramicidin, cost £5.36 at this time, compared with only 50p for chloramphenicol.
Professor G.C. de Gruchy in his book “Drug Induced Blood Disorders” 1972, notes that less than 10% of cases of drug induced blood disorders were reported by doctors. An article in The Pharmaceutical Journal of the UK in 1996 gave details of a survey of over 20,000 patients admitted to hospital and said that of those admitted because of an adverse drug reaction only 6.3% had been reported by doctors to the drug regulatory bodies under the “Yellow Card” system provided for this purpose.
The British National Formulary (BNF) published by the Royal Pharmaceutical Society of the UK and the BMA notes that, where chloramphenicol is used for infections other than the eye and ear, known side-effects are “aplastic anaemia and the resulting leukaemia”. Under chloramphenicol eye-drops it says it is well tolerated and that the recommendation it should be avoided because of increased risk of aplastic anaemia is not well founded. Under chloramphenicol for bacterial ear preparations it says avoid prolonged use. The BNF is the book doctors in the UK refer to when prescribing.
Answers to questions in Parliament on 11th January, 1989 on the causes of aplastic anaemia established that nearly 200 prescribed drugs, many toxic chemicals, pesticides etc and radiation are known causes. Chloramphenicol was named as a known cause. One answer from Roger Freeman, the government spokesman for health at the time said that all cases of aplastic anaemia were thoroughly investigated to find any possible cause. However, after investigating many cases and their possible causes I found that in all except one or two there had been no investigation as to the possible cause by anyone. In fact I found there were often attempts by the medical profession to dissuade patients from investigating the possible cause of their condition. My investigation of many cases followed circumstances surrounding my own case of severe aplastic anaemia diagnosed in April, 1986. On being diagnosed my consultant suggested to my wife (a UK State Registered Nurse) and myself that we should not “bandy my condition about”. A request for details of the chemicals I came into contact with at work at Yorkshire Water came with a letter attached saying “the labels had fallen off some drums of chemicals so those had been destroyed” and that “there was no cover-up”. It was therefore in my case not possible to investigate the cause thoroughly as the answers to the Parlimentary questions said was done in every case. My hospital records from Hammersmith Hospital note that no cause was found although I worked with a number of chemicals. The Hospital were not aware of the letter from my employers to me saying the list of chemicals they gave to investigate the cause of my condition was not complete.
I find these sorts of circumstances surrounded nearly every case where the sufferer or relatives has tried to investigate causes. In one case a sample of a suspected chemical ‘disappeared’ in transit several times in the same way that hospital notes often ‘disappear’ if you have a complaint and ask to look at them.
In the last few months one sufferer of a blood dyscrasia, not caused by chloramphenicol in this case but chemicals, found six other cases of aplastic anaemia following administration of chloramphenicol eye-drops. These were in children and young adults and some were severe. In one of these where the patient asked for their hospital notes it was discovered they had been ‘misplaced’. It was clear that until shown information chloramphenicol is a documented cause of aplastic anaemia none of these six, or their parents in the case of the infants, had any idea there might be a cause of their condition.
One of many similar references in medical papers and textbooks on the causes of aplastic anaemia, Bowman and Rand, Pharmacology says that “most cases are caused by drugs and chemicals” and “ionizing radiation has the same effect”. This publication, like others, notes that the reporting rates of aplastic anaemia caused by chloramphenicol varies, with figures of between 1 per 500 to 1 per 100,000 being quoted. It quotes chloramphenicol as a ‘high risk’ drug. The textbook Harrison’s Principals of Internal Medicine suggests the percentage of cases of aplastic anaemia found to be caused by drugs or other known agents depends on how hard the investigators look for a cause. These are my sentiments after investigating the causes in many cases A University of Texas paper of 1997 “Aplastic Anaemia Questions” notes that aplastic anaemia is known to be caused by drugs, including chloramphenicol, toxic chemicals and radiation in the same way that cancer is linked to these same agents. The leukaemia ‘atlas’ of cases for 1984 – 1986 for the UK found that during this period the official number of cases of leukaemia was 60% lower than the true numbers affected. This year, 2007, there are questions being asked in the UK Parliament as to why the leukaemia statistics of those affected in Scotland are being withheld. This followed much media coverage of the fact that the statistics were being withheld. Recent worldwide research in many countries including the UK has shown there is an increased risk of childhood leukaemia of around 25% (depending on distance from the plant) to those living near nuclear power plants. This was previously denied by governments although Professor Alex Elliot, in July 2006, said they were as convinced as any scientists could be, that nuclear sites were not responsible for higher rates of leukaemia or lymphoma, with the exceptions of Sellafield and Dounreay.
Looking at the information given here and many other similar textbooks, research papers and reports, there are questions which should be asked about the true numbers of people who develop non-malignant blood disorders resulting from the side-effects of chloramphenical eye-drops and also how many cases of leukaemia and other cancers are of the same cause but go unreported. The non-malignant blood disorders can often be mild and may even go undiagnosed but can still be precursor conditions to leukaemia and other cancers. This is demonstrated clearly with the atomic bomb victims, with over 3000 being added to the list in 2007 of those dying of radiation effects in Nagaski. The American Journal of Pathology 1949 on the atomic bomb victims gives details of the depression of the bone marrow caused by radiation. Later reports, until the present time, show that the nearer the victims were to the blasts the greater the bone marrow depression and the incidence of the resulting cancers is in direct relationship to the severity of the bone marrow depression. The side-effects of many prescribed drugs, including chloramphenicol have the same effects as radiation.
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