Kew, angel's trumpet and artemisia - from dream plant and poison to herbal remedy.

@HealthMed Guides to plants have a large number of entries labelled as 'medicinal use' and 'poison'.

The ancient Greeks recognized this overlap, in using the same word for drug, poison and magic charm: pharmakon. This remains in current use in the word pharmacology - the study of drugs of all types.
The Temperate House at Kew Gardens, the largest surviving Victorian glasshouse in the world, has a tantalising display of medicinal plants, for most the scientific name the only clue to properties. Nearby there are two  examples of contrasting properties of plants.

Artemisia [in this case A. austriaca - Austrian wormwood] is there as scrawny, pale green, ground cover. This plant is thought to be named after 4th century BC  queen of Persia and botanical expert Artemisia, or after Artemis, sister of Apollo and Greek goddess of the wilderness, the hunt, fertility and both bringer and treater  of disease in women. This bitter herb is said to have been used by the ancient Greeks to treat parastic infestation by intestinal worms. A large number of medicinal properties are claimed for wormwood species. Artemisinin, the extract of Chinese Wormwood, is used as an anti-malarial however resistant strains of malaria are now being reported. Recent experimental evidence suggests that artemisinin may have anti-cancer effects through limiting proliferation and cause programmed cell death (apoptosis) in certain sub-types of cancer cell. Other research indicates that artemisinin may induce cancer cell resistance to other types of cancer treatment. Much more work is needed on effectiveness and safety of artemisia extracts in the clinic.

Angel's Trumpet [Brugmansia aurea] in contrast has more sinister properties. This tree, native to sub-tropical South America from Colombia to Ecuador, has delicate, orange, trumpet-shaped, hanging, lemon-scented flowers. All parts of the plant are considered poisonous through antagonism of muscarinic cholinergic receptors and other effects of tropane alkaloids, including the racemic mixture atropine, its laevo-stereoisomer hyoscyamine [M1-antagonist], and scopolamine. Actions include belladonna-like effects, hallucinations, sedation and pupil enlargement, which may be symmetrical or asymmetrical. Local shamans are reported still to use plant extracts to aid their ceremonies through inducing visual hallucinations. Historically it is believed that in the Americas extracts of this plant, combined with alcohol and tobacco, were used to induce sleep in slaves or wives before their immolation after the death of their king.

© DRJ Singer

The Tempest and Prospero's curse - magic, pleurisy, and other thoughts

@HealthMed In response to Caliban's cursing in 'The Tempest', Prospero rewards him with a threatening prophecy: 

'... tonight thou shalt have cramps, 

Side-stitches that shall pen thy breath up ...'

This is a plausible symptomatic description of the intermittent, breath-restricting pain caused by pleurisy [earlier known as pleuritis], a suggestion at least as early as 1886. In contrast, as used by Shakespeare, the word pleurisy denoted a plethora, or excess of blood. This use is thought to have arisen from the idea that the word pleurisy was derived from plus pluris. 
e.g  in Hamlet Act IV, Scene 7:  

"For goodness, growing to a plurisy
 Dies in his own too much."

Pleurisy, local pain and difficulty in breathing, usually arises from inflammation of the pleura - the membranes that lines the lungs and inner walls of the thoracic cage. These inflammatory processes lead to adhesion of the visceral to the parietal pleura.  

Dr Charles Buckmill, writing in 1860, was sceptical of the medical nature of Prospero's curse, seeing it as a blend, half health, half magical in character.

How could Prospero have predicted this would happen to Caliban? Were there poisons at the time [1610-11] that Prospero could have given to Caliban to cause reversible pleurisy? And how did doctors of Shakespeare’s day diagnose pleurisy? The pain of pleurisy is often knife like or cramp-like pain, and worse on inspiration. Pleuritic pain is typically altered by posture, eased in some positions, made worse in others.

These symptoms we now recognize as pleurisy were well-established in Tudor and early Jacobean times; and post-mortem examination was then in European medical centres a route to understanding (or misunderstanding) the nature of disease in retrospect.  The Hippocratic writers were already diagnosing pleuritis from a cluster of symptoms: pain in the side, fever, shivering, rapid breathing, difficulty in breathing when lying flat [orthopnoea] and cough productive of pomegranate-peel coloured or blood-stained sputum. From 300BC, discussion moved to the pathology of pleurisy, with a distinction between disease in the lung (e.g. Herophilus: modern pneumonia) and pleuritis as a disease of the membrane that lines the inner part of the ribs [membrana hypezocota] and resulting in increased pain on lying on the unaffected side [because lung movements than are greater at the site of pleural inflammation], or in some greater when lying on the affected part. 

Pleurisy results in abnormal lung sounds, which, if loud, would have been audible by a physician placing an ear against the chest [auscultation]. This medical diagnostic method is thought to have been used by Ancient Egyptian physicans. However the key early method of diagnosing pleurisy was ‘hardening of the pulse’.

On listening with a stethoscope, a pleural friction rub is heard. Laennec, the inventor in 1816 of the stethoscope, called this friction sound ‘frottement ascendant et descendant’ and ascribed it to emphysematous change in the lungs. Descriptions of the rub include - a scratchy sound similar to that of a door opening on a rusty hinge; or similar to the sound or two pieces of sandpaper rubbed together.  Laennec also used described ‘aegophony’ in pleurisy - a sound like the bleating cry of a goat. Laennec considered that pleurisy was typically associated with modest accumulation of fluid in the pleural cavity (pleural effusion). However with too much pleural fluid, lung sounds disappear, including pleural rubs.

Recognition of pleural effusion goes back to early Babylonian medicine.  Small lead tubes discovered in ancient Babylonian sites are considered to have been trochars – implements inserted through the chest wall to drain pleural fluid. With the benefit of modern imaging, it is now easy to be clear in life that both ‘wet’ and ‘dry’ forms of pleurisy may develop.

Contributors to the germ theory of disease range from Varro in 36BC, to microscope inventor Van Leeuwenhoek’s reports in the 17^th Century, and Semmelweiss and Pasteur in the 19^th Century. Modern medicine recognizes pleurisy, pleuritic pain and its other symptoms as part of a syndrome. Investigations aim to identify the cause of the pleurisy, which might include viral or bacterial infection, pulmonary embolism, immune-mediated disease, kidney failure and tumours. In addition pneumothorax may present wth pleuritic pain. Of note as early as the early 17^th Century, the Paduan Vincent Baronius recognized that patients with pneumonia can also develop pleurisy [pleuripneumony], a concept more widely disseminated by Morgagni a century later.

Back to Prospero’s curse. If not just author’s invention, here are some possible recurrent disorders symptoms of which Prospero could be predicting.

- Pleurisy is typical worse at night, when during attempts at sleep the sufferer may turn to adopt a posture likely to make pleurisy worse and thus awake in pain and breathless.

- Tuberculosis may not be fatal but may leave a patient with pleurisy.

- Malaria was endemic in Shakespeare’s day, including in Mediterranean islands such as Sicily. Attacks of malaria are known sometimes to present with cramping chest pains – and the anaemia of malaria could have made Caliban breathless, especially if were already anaemic. For example his inherited deformed appearance could have had a physical rather than imaginary basis. Thalassaemia – common in the Eastern Mediterranean setting of ‘The Tempest’ - may cause of chronic severe anaemia and is associated with facial deformity.  

- And familial Mediterranean fever (FMF), a genetic disorder common in the Mediterranean,  is a recurrent painful disorder of membranes, including the pleura. And FMF induced joint disease could contribute to a deformed appearance.

Prospero may thus simply have been reminding Caliban of previous or likely medical afflictions. Clearly the scientific details are modern, however these conditions were endemic at the time and present in the right geographical setting for the play.

More on history of pleurisy, stethoscopes and older treatments:

1. Hippocrates. Index of symptoms and diseases. vi. 33. Loeb edition. Translated by P. Potter. London, 1988. 

2. Shakespeare's doctor son-in-law John Hall describes use of scabious as a herbal remedy for ‘pains and stitches in the side’.

3. Laennec, R. T. H. (1819) De l’Auscultation Médiate ou Traité du Diagnostic des Maladies des Poumons et du Coeur. Paris: Brosson & Chaudé.

4. The cyclopaedia of practical medicine: comprising treatises on the nature and treatment of diseases ... Volume 1 Edited by Sir John Forbes, Alexander Tweedie, John Conolly. Publishers Whitaker et al, Paternoster Row, London 1833.

5. The medical knowledge of Shakespeare by Sir John Charles Buckmill MD, Longman, 1860.

6. TCM. Notes from a physician's notebook.  The Cincinnati Lancet. p75, January 16th, 1886.

7. Wilson, A. (2000) On the history of disease concepts: the case of pleurisy, History of Science, Volume 38 (3), 271 – 319. 
 

© DRJ Singer

Companion diagnostics - a new concept for safer medicines?

@HealthMed Diagnostics can be used in several ways: to establish the nature, subtype and severity of disease; to monitor wanted response to treatment with lifestyle, drugs and/or devices; to monitor for disease progression and for adverse effects of treatment. The term 'companion diagnostics' describes coupling diagnostic imaging or laboratory investigations with selection and monitoring of treatment. Although a logical idea, its use in the medical setting appears surprisingly recent.

In the late and 1980s and 1990s, reports of the use of combination diagnostics appear largely applying to veterinary and dental practice.

The partner term 'companion therapeutics' was used in a 2003 commentary on the FDA  "Draft Guidance for Industry: Pharmacogenomic Data Submission" issued on November 3, 2003, which noted that the [pharmaceutical and biotech] 'industry is now expected to accelerate its development of diagnostics and companion therapeutics towards the goal of personalized medicine'. Implicit in this evolution of a personalised approached to medicines is the recognition that diagnostics will not necessarily identify that a given patient may have a safe or effective treatment flagged as the result of testing.

An early example of a pharmacogenetic companion diagnostic is the UGT1A1 molecular assay for in vitro diagnostic use. This pharmacogenetic test was approved in 2005 by the FDA for use as a companion diagnostic to a specific drug therapy. The test was to be used to identify mutations in this gene in patients who may as a result be at increased risk of adverse reaction to the anti-cancer drug irinotecan. 

2006 and 2007 discussion of companion diagnostics pointed both to more efficient patient selection for clinical trials and a more profitable approach for drug developers. 

Current descriptions use narrower definitions of companion diagnostics as referring to tests to 'identify and detect genetic, protein, or gene expression markers to predict whether a drug works or causes adverse effect in patients'. However there is a long history of coupling tests with treatment choice and refinement, in every therapeutic area from cardiovascular disorders such as hypertension and raised cholesterol, to anaemia and treatment of lung, gastro-intestinal, renal and neurological disease.

To date there are only 75 publications in the PubMed research database with companion diagnostics as a key term, with a typical recent example from August 2011 in Nature Reviews on Clinical Oncology by La Thangue and Kerr applied to cancer chemotherapy: Predictive biomarkers: a paradigm shift towards personalized cancer medicine.

© DRJ Singer 

Ahead of their time

@HealthMed An example from this weekend's episode of the series 'Downton Abbey' of the challenges of historical accuracy in broadcast media. Set during the Great War, a keen enlister is turned down on medical grounds because of a heart murmur citing 'mitral valve prolapse' as the reason. This condition is often benign however was not recognised until the 1960s. The condition was first reported by John Barlow and colleagues in the American Heart Journal in Feb 1966 (Barlow's syndrome). The phrase 'mitral valve prolapse' was first used by Michael Criley and colleagues later that year in the July issue of the British Heart Journal.