22 August 1970 Patients from the Tropics-Rowland BRiTISH 449

What has been said regarding persons working overseas Conclusions

but whose long-standing home is the United Kingdom applies Clearly the greatest hurdle to overcome is to discover that Br Med J: first published as 10.1136/bmj.3.5720.449 on 22 August 1970. Downloaded from to this third group of patients. Rapid air travel enables such the patient has been overseas, information which is not persons to reach this country during the incubation period of always volunteered. Acute illness should be managed as some serious infective disorders of which typhoid fever, outlined in this article and failure to make a diagnosis calls smallpox, and malaria are the most common, and many of for early assistance from one of the specialized hospitals. Less the patients seen suffering from these disorders have recently acute illness should be investigated as for permanent resi- left their country of origin. dents of this country, but failure to make a satisfactory diag- Acute illness should be managed as for group 1 patients; in nosis should suggest an expert opinion, again early rather those suffering less acute illness it is probably advisable to than late; this might be sought more often by general hospi- obtain further opinion either from a general hospital or from tals as well as by general practitioners. one specializing in tropical disorders. It is understandable that general hospitals should like to keep an "interesting Tropical Diseases Hospitals patient," though this is not always in the best interest of the Hospital for Tropical Diseases, 4 St. Pancras Way, London individual; they too might do better by obtaining expert N.W.1. Department of Tropical Medicine, Liverpool School of Tropical opinion and by obtaining it early rather than as a last resort Medicine, Pembroke Place, Liverpool 3. when all other investigations have proved negative. As there Tropical Diseases Unit, Eastern General Hospital, Edinburgh 6. are good and bad ways of handling an acute abdomen, a spontaneous pneumothorax, and a placenta praevia so there REFERENCES are good and bad ways of handling an amoebic liver abscess Maegraith, B. G., Transactions of the Royal Society of Tropical Medicine and Hygiene, 1969, 63, 689. or an infection with P. falciparum. Shute, P. G., and Maryon, M., British Medical Journal, 1969, 2, 781.

TODAY'S DRUGS

With the help of expert contributors we print in this section dose levels in gout, small doses (1-2 g. daily) lessening uric notes on drugs in common use. acid output and causing elevation of serum uric acid levels, larger dosage (5-6 g.) having the opposite effect. It should Non-steroid Anti-inflammatory Agents be said in passing that aspirin has little part to play in the treatment of acute gout. In the 1920s and even In larger dosage aspirin has a definite anti-inflammatory later it was fashionable to treat fevers and for with analgesic-antipyretic substances. As there were then no effect, this reason it is usually the first choice in the effective bactericidal or bacteriostatic agents all treatment of rheumatoid arthritis. Soluble aspirin is generally one could do http://www.bmj.com/ was to attempt to reduce pain, fever, and other unpleasant the most popular, but all preparations may cause gastro- symptoms. Today, in spite of a vast selection of antibiotics, intestinal complications and bleeding. Popular proprietary many inflammatory diseases cannot be rapidly cured but can preparations are Paynocil (glycinated aspirin), each tablet be symptomatically relieved; examples are virus pneumonias, containing 0.6 g. which dissolves on the tongue, Palaprin forte connective tissue disorders such as rheumatoid arthritis, rheu- (aloxiprin) each tablet containing 0.6 g. which may be matic fever and systemic lupus erythematosus, glandular fever, chewed, sucked, swallowed, or dispersed in water, Bufferin sarcoidosis, and gout. (aspirin buffered with magnesium carbonate and aluminium Patients with such disorders are often glycinate), enteric glad of symptomatic relief. Since the anti-inflammatory agents coated preparations, and several others. have also analgesic and This anti-inflammatory analgesic action has been shown by on 30 September 2021 by guest. Protected copyright. antipyretic properties they are Lim2 to be at extremely useful in this widely scattered group of inflamma- least in part peripheral. Unfortunately, the high tory disorders. dosage necessary to achieve the effect is often poorly Anti-inflammatory agents available are: tolerated, and dosage has to be reduced or the drug changed the salicylates- to something better tolerated. At high dose particularly aspirin in all its different forms; the levels compound pyrazolones-phenylbutazone and oxyphenbutazone; indo- preparaticns containing phenacetin, caffeine, or codeine are methacin; the anthranilates-mefenamic and flufenamic never used. acids; and ibuprofen. Though gold salts, chloroquine, and immunosuppressive agents- can be legitimately considered to be anti-inflammatory Pyrazolones long-term agents, they are not discussed here. Phenylbutazone and its metabolite oxyphenbutazone are effective long-acting, slowly metabolized, anti-inflammatory, Salicylates antipyretic, analgesic agents. They are only slowly broken down and are excreted in the urine largely as a number of Aspirin in its various forms is usually first choice in the water-soluble metabolites. They are firmly bound to plasma treatment of any inflammatory disorder, whether it be a com- protein, largely to albumin and alpha globulin, and for this mon cold, rheumatoid arthritis, or glandular fever. Sodium reason they exert an even, prolonged action, which is particu- salicylate has been largely given up in favour of aspirin as larly effective in the chronic arthropathies and in acute gout the latter drug relieves symptoms more effectively. Aspirin is (total daily dosage being 200-400 mg. in the former and rapidly absorbed from stomach and small intestine and begins 600 mg. in the latter condition). When treating acute gout the to ease pain within 15 minutes of ingestion. Used in low dos- dosage should be gradually reduced by 100 mg. daily as the age it is essentially an analgesic agent only; in larger dosage, attack comes under control. Though oedema, rashes, and such as 5 g. or more daily, it has a measurable anti-inflam- gastrointestinal complications are known to occur, the much matory effect also, as has been shown in patients with rheuma- rarer, though more dangerous, toxic effects are toid arthritis.' Similarly, it has different effects at different haematological-neutropenia, thrombocytopenia, or aplastic 450 22 August 1970 Non-steroid Anti-inflammatory Agents MEDICALBRITISHJOURNAL anaemia.3 For this reason blood counts should be done every est side effect is a dose-related one, an unpleasant swimmy or few weeks if the patient is on regular therapy, and immedi- muzzy sensation in the head or a true headache, sometimes Br Med J: first published as 10.1136/bmj.3.5720.449 on 22 August 1970. Downloaded from ately if suggestive symptoms arise, such as buccal ulceration, severe.10 unexplained pyrexia, sore throats, stomatitis, or odd ill feel- As with tinnitus in patients on salicylates and nausea with ings which cannot be accurately described. Buccal ulceration digitalis, this toxic effect is met by reduction of dosage. Dys- commonly occurs, however, without any changes in the blood pepsia, on the other hand, sometimes with gastrointestinal and is in most cases of nuisance value only. bleeding, is not dose related1' and may occur at any stage of Its even therapeutic action makes phenylbutazone particu- therapy on almost any dosage. Prepyloric ulceration may larly effective in disorders such as ankylosing spondylitis, occur'2 which radiologically may closely resemble a malignant where frequent aches and pains and constant stiffness is the condition; but such ulcers diminish and disappear, usually rule throughout the 24 hours, but the pyrazolones are also within four weeks of stopping the drug. useful in the treatment of osteoarthritis, rheumatoid arthritis, Indomethacin is available in 25 mg. capsules taken by Reiter's (Brodie's) disease, and a number of other rheumatic mouth with or after food, as an elixir 25 mg. per 5 ml. and in afflictions. In non-arthritic conditions, such as thrombo- suppository form (100 mg.). In many rheumatic disorders phlebitis, where pain and swelling play a part in the more pain is experienced at night and in the early morning disease the pyrazolones may also prove useful, and in non- than in the day, and painful morning stiffness is characteristic inflammatory conditions of bone such as metastatic malignant of rheumatoid arthritis, ankylosing spondylitis, some cases of and Paget's disease symptoms may be at least partly relieved periarthritis of the shoulder, and a number of other condi- in some cases. Both phenylbutazone and oxyphenbutazone tions. A 100 mg. suppository inserted late at night or three to may be given in suppository form (250 mg.) and the former four capsules (75-100 mg.) by mouth taken with food on retir- by intramuscular injections (600 mg.), but the oral route ing may help the patient through the night very effectively," usually proves the most satisfactory. Nifenazone has not the larger dose being tolerated since headaches rarely waken proved to be as effective as its predecessors.' the patient from sleep. The usual total daily dosage is two, A few more rare side effects may be noted. Thyroid three, or four capsules (50-100 mg.) taken with food. There is enlargement may very rarely occur, with clinical features of great individual variation in tolerance, some patients hypothyroidism, owing to blocking of iodine uptake by the experiencing headaches on 50 mg., others none on 200 mg. a thyroid gland. Enlargement of the salivary glands with day. Rashes are rare, purpura rarer still. Buccal ulceration dryness of the mouth may be erroneously thought to be due may sometimes occur, but in almost all cases without any to Sj6gren's syndrome rather than to the drug. Salt and fluid change in white cell count. Recently" there has been a report retention may occasionally precipitate cardiac failure in of corneal deposits, reversible on stopping the drug, and of patients with heart disease. decreased retinal sensitivity, as shown by decreased electro- As these drugs are largely bound to serum proteins competi- retinograms, altered thresholds of dark adaptation, and visual tion for binding may occur with other drugs. The sulpha field changes: in clinical practice, however, ocular side effects group, for example, may be displaced and so have increased appear to be very rare. Though the dose-related cerebral sen- antibacterial action.5 Similarly, the hypoglycaemic action of sations referred to earlier may limit the usefulness of the tolbutamide may be increased by concurrent administration of drug, as many patients cannot tolerate it at effective dose phenylbutazone; and the action of warfarin-98 bound to levels, indomethacin continues to be a useful and widely used albumin with only 2° of the total drug in the plasma biolog- anti-inflammatory, analgesic agent in a large number of http://www.bmj.com/ ically active-may be greatly potentiated, with a very real risk conditions. of serious haemorrhagic complications.6 For quite different reasons phenylbutazone enhances the hypoglycaemic action of Anthranilates acetohexamide.7 Care should be taken, then, in giving phenyl- butazone and oxyphenbutazone with other drugs. The whole Mefenamic and flufenamic acids are relatively mild anti- question of drug interreaction has been reviewed recently by inflammatory, analgesic, antipyretic agents used usually in the Prescott.8 rheumatic disorders where other drugs prove ineffective or The toxic effects of this useful group of drugs may have toxic. The recommended dosage of mefenamic acid is 500 mg. been over emphasized. In common with many new drugs, initially, then 250 mg. six-hourly by mouth. It causes on 30 September 2021 by guest. Protected copyright. phenylbutazone was at introduced higher dose levels than was diarrhoea in about 10-20'Y, of patients on continued dosage, therapeutically necessary, with the inevitable flood of reports and occasionally haemolytic anaemia; rashes or of toxic dyspepsia reactions in the world's literature. In a recent survey may occur but are not common. In patients on anticoagulants in the U.S.A.9 562 patients treated for 2-10 and averaging 4.1 the prothrombin time may be prolonged. Flufenamic acid is years an showed incidence of 7-5' adverse reactions on an given orally in a dose of 100 mg. four to six times a day. It average daily dosage of 148 mg. phenylbutazone. In only 4 also causes diarrhoea and more rarely dyspepsia. cases (0.7%) was it necessary to stop treatment, in one because of oedema, in three because of peptic ucleration. Ibuprofen This is a newcomer which succeeded ibufenac from the Indomethacin same laboratories. Ibufenac was withdrawn because of hepato- toxicity; this complication has not been noted with This is an effective anti-inflammatory, antipyretic, analgesic ibuprofen. Opinions vary as to its clinical merit, some agent in much the same conditions as phenylbutazone proves workers'5 finding it as effective as aspirin in full useful: acute gout, ankylosing spondylitis, rheumatoid arthri- dosage, others'6 no better than placebo, some'7 half way between. tis, osteoarthritis, Reiter's (Brodie's) disease, and also in General opinion seems to be that it is a weak, but febrile inflammatory disorders such as glandular fever, non-toxic, analgesic agent: its anti-inflammatory action has not been as wnere unpleasant symptoms may be relieved. Unlike the yet demonstrated in rheumatoid disease in man. The pyrazolones it has a relatively short duration of dosage action, advocated is 200 mg. three times daily. roughly 4-12 hours or more depending on the dose given. It is rapidly absorbed when given by mouth or rectum and is rapidly eliminated, largely in the urine: for this reason it Conclusions should be given very warily or not at all if there is any Though the steroids remain the most effective anti-inflam- impairment of renal function, and it is wise to estimate the matory agents available, their endocrine effects make blood urea before starting therapy. The commonest and earli- long- term therapy too complicated and dangerous in any except 22 August 1970 Today's Drugs M3DICB JOUUL 451 conservative dosage. Of the non-steroidal agents the Field, J. B., Ohta, M., Boyle, C., and Remer, A., New England Journal of Medicine, 1967, 277, 889. salicylates, phenylbutazone, and indomethacin remain the Prescott, L. F., Lancet, 1969, 2, 1239. most popular and probably the most effective. 9Sperling, I. L., Lancet, 1969, 2, 535. Br Med J: first published as 10.1136/bmj.3.5720.449 on 22 August 1970. Downloaded from 10 Hart, F. D., and Boardman, P. L., British Medical_Journal, 1963, 2, 965. Boardman, P. L., and Hart, F. D., Annals of the Rheumatic Diseases, 1967, 26, 127. 12 Taylor, R. T., Huskisson, E. C., Whitehouse, G. H., Hart, F. D., and REFERENCES Trapnell, D. H., British Medical Journal, 1968, 4, 734. Boardman, P. L., and Hart, F. D., British Medical Journal, 1967, 4, 264. 3Huskisson, E. C., Proceedings of the 12th International Congress of Lim, R. K. S., in Pain, edited by R. S. Knighton and P. R. Dumke, Rheumatology. Prague, No. 831. p. 117. London, Churchill, 1966. 14 Burns, C. A., American Journal of Ophthalmology, 1968, 66, 825. 3 Fowler, P. D., Annals of the Rheumatic Diseases, 1967, 26, 344. s5 Jasani, M. K., Downie, W. W., Samuels, B. M., and Buchanan, W. W., ' Hart, F. D., and Boardman, P. L., British Medicaljournal, 1964, 1, 1553. Annals of the Rheumatic Diseases, 1968, 27, 457. 5 Anton, A. H., Clinical and Pharmacological Therapeutics, 1968, 9, 561. 16 Boardman, P. L., Nuki, G., and Hart, F. D., Annals of the Rheumatic 6 Aggeler, P. M., O'Reilly, R. A., Leong, L., and Kowitz, P. E., New Diseases, 1967, 26, 560. England Journal of Medicine, 1967, 276, 496. 1 Chalmers, T. M., Annals of the Rheumatic Diseases, 1969, 28, 513.

ANY QUESTIONS? We publish below a selection of questions and answers of general interest.

Vitiligo tense, nervous, and sometimes hysterical large increase in the water content of the tissue. subject. It was occasionally seen in the last The water molecules seemed to be bound to the Q.-Why do lesions of vitiligo fluoresce war after unnerving incidents on active mucopolysaccharide molecules and to have been brilliantly in Wood's light? Can this be a clue service. It may also result from disease of retained without a corresponding increase in to the aetiology of vitiligo? electrolyte. Similar changes can be induced in the the nervous system as a limited form of sex skin of monkeys by administering oestrogen.7 A.-This question is based on a false torsion spasm, as a sequel to epidemic Thus the evidence from animal experiments premise-patches of vitiligo do not fluoresce encephalitis with or without Parkinsonism, or suggests that, in some instances, generalized in Wood's light but the contrast between the some other extrapyramidal syndrome. oedema may occur as part of the process of unpigmented and adjacent pigmented skin is The commonest cause, however, appears to adjustment to increased steroid levels. It has heightened and areas of slight hypopigmenta- be a minor subluxation in an osteoarthrotic already been suggested8 that the ground sub- cervical spine or even in a normal one. It stance of connective tissue may act as an "organ" tion not obvious in daylight or conventional for water storage in pregnancy, and that the artificial light are easily identifiable in Wood's occurs when a fixed position has been held unnaturally for prolonged periods, as in function of the mucopolysaccharides may be to light. This is particularly helpful when provide a buffer against a changing tissue water examining the skin of patients suspected of driving a car. A cold draught through the and electrolyte concentration in order to maintain epiloia. open window seems to play an aggravating the constancy of the internal environment. When part. The condition usually responds to the functional capacity of this "organ" is

analgesics, warmth, and gentle manipulation exceeded then generalized oedema can occur. In http://www.bmj.com/ and traction. pregnancy these changes are also enhanced by Sclerodermatous Plaques the lowered oncotic pressure of the plasma pro- teins8 thus enabling more rapid transfer of fluid Q.-Is it safe to try to remove small to the extravascular space. sclerodermatous plaques in the fingers with OUR EXPERT replies: Though oestrogen- ring or are induced changes in the mucopolysaccharides may blocks, they contraindicated in provide the explanation for the oedema of preg- this condition? Is the removal of plaques Notes and Comments nancy there are other factors operative which worth while, or are they more to likely recur? GeneraLized Oedema.-Dr. E. G. ROBERTSON encourage the formation of oedema.1 Exchange-

able on 30 September 2021 by guest. Protected copyright. A.-It is not easy to answer this question (Department of Obstetrics and Gynaecology, sodium values are increased in normal preg- Princess Mary Maternity Hospital, Newcastle nancy, and, despite controversy over the relation- without further information about the under- ship between sodium balance and pre-eclampsia, lying condition. upon Tyne) writes: With reference to the answer If the sclerodermatous to this question ("Any Questions?" 25 July p. the balance of evidence lies in favour of the plaques are due to fibrosis secondary to the 212), I would like to add some further comments conventional view that excessive storage of ischaemic changes of systemic sclerosis on about the relationships between generalized sodium takes place. Thomson et al.2 report-d that discoid lupus erythematosus the result of oedema and changes in mucopolysaccharides. whereas 35%' of normotensive patients developed local surgery may be disastrous and lead to Generalized oedema is found commonly in oedema in pregnancy 60 / of hypertensive sub- intractable ulceration requiring the amputa- normal pregnancyl as well as in association with jects and 85 % of those with proteinuria were tion of the digit. Painful plaques of calcinosis pre-eclampsia. The excess water stored in oedematous. Unless pre-eclampsia leads to in- generalized oedema is no doubt mainly extra- creased levels of oestrogen or a change in tissue cutis of fingers, whether due to systemic sensitivity sodium retention is probably the major sclerosis, or cellular, but as suggested by Hytten and dermatomyositis, of idiopathic Thomson2 it is not necessarily free fluid in the cause of oedema in these patients. The dimin- origin, can be removed easily without extracellular space. The ground substance of ished oncotic pressure of plasma proteins which dangerous trauma and with much sympto- connective tissue may be responsible for the Dr. Robertson has demonstrated also tends to matic relief of the pain with which these storage of water. There are widespread changes favour the accumulation of extracellular fluid. lesions are usually associated. Scleroder- in the nature of connective tissue in pregnancy. matous plaques due to other causes, includ- In a recently completed study3 evidence was ing scars, can be softened or diminished in found of progressive increases in skinfold com- REFERENCES size by intralesional corticosteroids like tri- pressibility with gestation which were greater in Thomson, A. M., Hytten. F. E., and Billewicz, amcinolone injected with a the presence of generalized oedema. W. Z., 7ournal of Obstetrics and Gynaecology pressure syringe. Gersh and Catchpole4 and Langgard5 have of the British Commonwealth, 1967, 74, 1. 2 Hvtten. F. E.. and Thomson, A. M., British suggested that changes in skin associated with Medical Bulletin, 1968, 24, 15. oedema may be caused by alterations in the com- s Robertson, E. G., Thesis for the Degree of M.D. Acute Torticollis ponent mucopolvsaccharides of ground substance. University of Newcastle upon Tyne. 1970. 4 Gersh, I., and Catchpole, H. R., Perspectives in Q.-What is the Langgard and Hvidberg6 showed that the admini- Biology and Medicine, 1960, 3, 282. aetiology of acute torti- stration of oestradiol could cause oedema in 5 Langg8rd, H. E., Danish Medical Bulletin, 1967, collis (acute wryneck), and does being in a mice, there being an increase in the tissue hexos- 14, 130. draught of cold 6 Langggrd, H. E., and Hvidberg, E., lournal of air play any part? amine and hyaluronic acid content. The long Reproduction and Fertility, 1969, Supplement chain mucopolysaccharide molecules appeared to 9. A.-Acute torticollis (wryneck) may be a undergo physical change (possibly polymerization) Rienits, K. G., Biochemical 7ournal, 1960, 74. 27. psychogenic tic-a 8 Robertson, E. G.. 7ournal of Reproduction and habit spasm-often in a which was accompanied by a disproportionately Fertility, 1969, Supplement 9.