Dr. P. Warren

Professor, Faculty of Medicine, University of Manitoba

Pliny the Elder (28-79 AD) recommended for tuberculosis:

Such potions were often combined with copious bloodletting to deplete the humours. In time bleeding was justified as anti-phlogistic therapy to remove the cause of fever.

Tuberculosis was also treated for years by moving the patient to a different climate. In the early years to a warm climate- the poet and physician John Keates traveled to Italy where he died. In the mid 19th century the fashion changed and patients were sent to cold, usually mountain climates where they were placed outside in fresh frosty air to rest; the sunlight was thought to help. In these institutions, sanatoria, prolonged periods were spent lying in bed to rest the lungs. In Manitoba our first sanatorium was opened at Ninette 1910, later others were built in the North for aboriginal patients. Other measures included good diet. Osler (1882) recommended whisky for breakfast as well as red wine. Other remedies included creosote in capsules, cod-liver oil and arsenic. Direct injection into the lung of antiseptics such as iodine was tried. For bone and joint, TB sea bathing was used.

Rheumatic fever was known to be associated with heart disease and lead to heart failure manifest by shortness of breath and edema, called dropsy. William Withering (1741-1799) in 1785 published An Account of the Foxglove and some of its Medical Uses with Practical Remarks on Dropsy and Other Diseases. He gave his reasons for publishing his research in the preface:

Withering's evidence may seem crudely assembled today but he distinguishes himself from quacks by using the science known to him to uncover the truth. He went on:

He gives his personal experience of 156 outpatient and 7 inpatient case histories and a number of cases from correspondents. From all this he concluded when to use Foxglove, Digitalis purpurea, and how to use it safely. He drew several inferences from his observations and his 9th Inference was "That it has a power over the motion of the heart, to a degree yet unobserved in any other medicine, and that this power may be converted to salutary ends". He was correct and the synthetic derivative of his drug, digoxin, is still in frequent use today for heart disease.

The treatment of rheumatic fever was based on the theory that natural remedies would be found where the diseases arose. Rheumatic fever arose from without- a "miasmatic" origin. MacLagan published his work on his treatment in The Lancet in 1876 in the article "The Treatment of acute Rheumatism by Salicin:"

The bark contained the bitter principle called salicin.

Before treating a patient, MacLagan took a large dose himself to ensure that it was safe. Salicin had been extracted by Leroux in 1827 and was known to be good for fevers. In due course, Acetyl Salicylate was synthesized in 1899 and Bayer patented this compound commonly called Aspirin and it has been the most popular drug of all time. Aspirin was effective at controlling the symptoms of rheumatic fever but did not prevent the damage to the heart.

With the discovery of bacteria as the cause of many diseases and the realization that immune responses helped combat them. Paul Ehrlich (Germany, 1854-1915) investigated antibodies and then looked for agents that bound to microbes hoping that they might similarly negate them. He had the chemicals of the German dye industry to hand and knew that these could be used to stain bacteria and might also treat them. He studied arsenical compounds. In 1910 after he had tried 600 substances he found the compound Salvarsan that was found to control Syphilis. Domagk, Germany, (1895-1964) in 1935 found Prontosil - its active agent was a Sulphonamide. This was the first really effective antibacterial agent. Domagk was awarded the Nobel Prize but the Nazi government refused to let him accept it. These drugs are bacteriostatic i.e. they stop the bacteria dividing, leaving their destruction to the body's immune response.

In 1929, Alexander Fleming (1888-1955) England, described how a mould Penicillium had destroyed Staphylococcal colonies in culture. He did little work with the discovery but it was realized that this could be an approach to destroying bacteria. In 1939, Howard Florey and Ernst Chain at Oxford produced pure Penicillin from the mould and in 1940 they "cured" 4 streptococcus infected mice while 4 controls died. They then tried penicillin on humans testing it on a policeman who was dying of Staphylococcal septicemia, he responded but they ran out of penicillin, despite recycling it from his urine, and he died. The great value of such a drug was recognized, but wartime Britain did not have the resources to produce it. So that in 1941 Penicillin was given to the USA for production. Penicillin was found to be highly effective against Staphylococcus and Streptococcus in particular but in time resistant organisms emerged. Sulphonamides had been used for rheumatic fever and these were compared with penicillin. Penicillin was highly effective at clearing the Streptococcus from the throat and preventing rheumatic fever. So once you had rheumatic fever once, you were placed on penicillin for years.

After the value of Penicillin was recognized there was a wide search for other moulds that might produce antibiotics. Selman Waksman (1888-1973), USA, a soil microbiologist identified several antibiotics but all were toxic until in 1940 he isolated the Streptomycin from Streptomyces griseus. It had activity against several bacteria including the Tubercle bacilli. This was first shown to be very effective in curing tuberculosis-infected guinea pigs and it began to be used on patients in the USA. Because it was in short supply in 1948, the British Medical Research Council designed a trial of Streptomycin using randomized assignment of treatment. All patients got the routine bed rest and dietary treatment but half, chosen randomly, were injected with streptomycin. There was no informed consent obtained and the use of controls was considered to be ethical for the benefits and risks were unknown. Randomization produced two groups that had similar conditions and removed personal responsibility from the clinician caring for the patient. This study is considered to be the model for all subsequent drug studies: the birth of Evidence Based Therapy.

Results were judged by radiological assessment or death by 6 months

But relapses then developed due to drug resistance.

In due course, similar studies showed that three drugs, Streptomycin, Isoniazid, and PAS were needed for tuberculosis and that treatment had to be given over a long time; at least 6 months. For many years because bed rest in sanatoria had been for years drug therapy was given in hospital partly to reduce spread of the infection. In the 1960's, tuberculosis was decimating the Inuit people; the Canadian government took a harsh, paternalistic approach, and moved them to sanatoria in the South. Thorough treatment and isolation controlled the epidemic successfully and it was viewed as a triumph of modern medicine, but there was a considerable social cost and disruption of family and cultural life.

Drug resistance could become a very real problem and lead to a resurgence of this great foe of mankind.