Postgrad Med J: first published as 10.1136/pgmj.22.246.118 on 1 April 1946. Downloaded from 118 POST-GRADUATE MEDICAL JOURNAL April, I946 If the patient is allowed fluid by mouth, it 4. If the apparatus does not appear to be work- should be given by the feeder between times of ing, the clips should be clamped, the appa- aspiration. ratus disconnected from the gastric tube and Aspiration is performed at regular intervals some water injected down the tube to make either every hour or half-hour according to sure that it is patent. instructions. The aspirated material must always be saved The Time for Removal of the Tube: The tube is for inspection. removed under the Doctor's instructions. In 2. Continuous Suction: A study of the diagram cases of intestinal obstruction this is usually (Fig. 2) will explain the work of the apparatus, after the patient has had one bowel action, and and attention must be to the has passed flatus on at least two occasions. particular paid After operations on the stomach, the tube is following points:- removed when the aspirated contents appear I. The reservoir A must never be allowed to clear contain bile. become empty. and 2. The end of the tubing in bottle B must be Vomiting: If a patient who is undergoing gastro- below the level of the water. intestinal suction vomits, it indicates that there 3. The clips D and E must be clamped before is some fault in the procedure, and is a reflection and during the changing of the bottles A and on the management of the suction. Every B. They are then released to re-commence effort should be made to discover and correct the suction. fault.
RECENT DEVELOPMENTS IN WOUND ANTISEPTICS By H. E. DALE copyright. During recent years a considerable amount of appear that it was selected primarily for this work has been carried out with the object of reason as the bacteriostatic powers of acriflavine, finding a non-toxic antiseptic which would be neutral acriflavine (or euflavine) and proflavine effective against all the bacteria likely to be present against various organisms are approximately the in wounds. From I939 onwards sulphonamides, same. In I934 acriflavine was shown to be a especially sulphanilamide, have been used exten- mixture of the hydrochlorides of 2 : 8-diamino- local in the and chloride and 2 8-diamino- sively by application prevention Io-methylacridinium http://pmj.bmj.com/ control of wound infection, and they are undoubt- acridine, and neutral acriflavine a mixture of edly effective bacteriostatic agents. Their action 2: 8-diamino-io-methylacridinium chloride and. is, however, inhibited by pus and necrotic tissue, 2: 8-diaminoacridine hydrochloride. Proflavine is and they are ineffective against some organisms. however, not a mixture but a simple salt-- Penicillin has and will be used extensively, and 2 : 8-diaminoacridine sulphate. It is the precursorl may well replace many antiseptics, but it is not of acriflavine and neutral acriflavine and is therefore. effective against gram-negative organisms such as simpler to manufacture.
Ps. pyocyanea and Proteus and supplies are at In I936 Albert Linnell and others began' on October 2, 2021 by guest. Protected present restricted. intensive investigations on the acridine series. They prepared all the possible aminoacridines and investigated the relation between chemical con- Acridines stitution and activity. They found that amino The acridines or flavines, as they have been groups in positions 2, 3, or 5 increased the activity called, were introduced by Browning in 1917, of the acridine molecule and gave compounds of and recent work on their properties and methods high bacteriostatic activity. 2: 7-diaminoacri- of application has brought to light many interesting dine and 5-aminoacridine were considered to be facts. For some time acriflavine was considered the best of the series. to be the most suitable acridine for use as an It is well known that chlorophenols are con- antiseptic, but in I94I proflavine sulphate was siderably more active than the parent phenol, included in the 4th Addendum to the British and experiments were also carried out to determine Pharmacopoeia. Acriflavine is much more soluble in the effect of introducing chlorine into amino- water than the other acridines, and it would acridines. New chloroacridines were prepared but Postgrad Med J: first published as 10.1136/pgmj.22.246.118 on 1 April 1946. Downloaded from Alpril, 2-946 WOUND ANTISEPTICS they were less active than the aminoacridines and More recently Albert et al. (i945) in a general possessed no therapeutic advantages. 2-chloro-5- survey of the acridine series have described three aminoacridine was found to be most active, but new drugs, I: 9-dimethyl-proflavine, 5-amino-I- also the most toxic and the 6- and 7-chloro-2- and aminoacridines methylacridine 2-nitro-5-aminoacridine. were quite inactive. Bacteriological tests showed that i : 9-dimethyl- Attention was again drawn to proflavine and proflavine is approximately five times as potent as the two new acridines 2: 7-diaminoacridine and proflavine against gram-positive and twice as 5-aminoacridine, when Russell and Falconer (I940) potent against gram-negative organisms without showed that buffered isotonic solutions of pro- any increase in toxicity. flavine sulphate with a pH approaching neutrality 5-amino-I-methylacridine is non-staining, less could safely be applied to the surface of a rabbit's toxic and more active than 5-aminoacridine. brain. They found that both acriflavine and The outstanding property of 2-nitro-5-amino- neutral acriflavine caused damage, but the newer acridine is its marked anti-streptococcal action compounds 2:7-diaminoacridine and 5-amino- suggesting a sphere of usefulness in the treatment acridine did not. The surprising fact that isotonic of haemolytic streptococcal infections and pro- solutions of proflavine could be applied to such phylactically in obstetrics. delicate tissues as brain tissues stimulated greater interest in this compound and also in the newer acridines 2: 7-diaminoacridine and 5-aminoacri- Relative dine. Clinical reports on the new acridines have Toxicity been published in this country and in Australia Selbie and McIntosh (I943), carried out experi- confirming their value as non-toxic antiseptics, mental work on the action of antiseptics on muscle but it is difficult to assess how these new compounds and connective tissue. The assessment of toxicity differ in their bacteriological action from proflavine. by this method was designed to avoid reactions It has been suggested that the divergence of opinion other than those arising from the toxicity of the on their relative toxicity to leucocytes and action substance to be tested, and to simulate as far as certain bacteria possible, in experimental animals, conditions likely against may be dependent upon copyright. the methods employed by different workers. to be found in wounds. A known quantity of the Generally, it can be said they do not differ very substance to be tested was dissolved in water, and much in their action from that of proflavine against o.I and 0.2 c.c. were injected into the thigh muscles most organisms. 5-aminoacridine, unlike most of mice. The mice were killed after 3 days and other acridine antiseptics, does not stain the skin it was found that any lesions were fully developed or fabrics. It is a yellow compound, but the by that time. Any visible reactions were noted yellow colour may be removed easily by washing and the injected muscles were examined histo- with water. As acridine stains are logically. Proflavine sulphate produced approxi- usually very mately the same degree of muscle necrosis and difficult to remove, this is a decided advantage. http://pmj.bmj.com/ Solutions of proflavine sulphate deposit on exposure connective tissue reaction as 2 : 7-diaminoacridine to but solutions of hvdrochloride and 5-aminoacridine hydrochloride, light, 5-aminoacridine hydro- but the acridine bases were chloride are stable. 2 7-diaminoacridine hydro- considerably more chloride and proflavine sulphate are stated to be toxic than their acid salts, producing more necrosis .ess toxic than 5-aminoacridine hydrochloride and and considerable cellular reaction. The toxicity also possibly effective against Ps. and of bases in pharmaceutical preparations was also Proteus. pyocyanea determined and it was shown that many had a Berry (I941) investigated the bacteriostatic high degree of tissue toxicity. This work is not on October 2, 2021 by guest. Protected values of the two components of acriflavine against yet completed, but experiments carried out so far various organisms and found that mixtures pos- show how important it is to examine the bases sessed no greater bacteriostatic power than either used in ointments and other pharmaceutical pre- compound. He suggested that the neutral hydro- parations for their toxicity to tissues before use. chloride of 2 : 8-diaminoacridine, i.e. proflavine monohydrochloride, would be the best acridine to use. Method of Application Albert (I943) described several salts of proflavine, The acridines, until recently, were only applied the more important being the monohydrochloride to wounds in solution in water or saline, but it and neutral sulphate, orange to red powders has now been shown that proflavine can safely be giving solutions which are nearly neutral. They applied in powder form to infected wounds, may replace the more acid proflavine sulphate provided small amounts only are employed. Sup- which is usually employed. purating wounds have been successfully treated Postgrad Med J: first published as 10.1136/pgmj.22.246.118 on 1 April 1946. Downloaded from POST-GRADUATE MEDICAL JOURNAL April, I946 with proflavine powder in amounts up to 0.5 gm., but in fresh wounds too much proflavine may Prollavine-Sulphathiazole (Flavazole) cause some necrosis of healthy tissue. Recent investigations have shown that several Since no one drug has proved effective against sulphonamides are sufficiently acidic to unite all the organisms likely to be found in wounds it with various aminoacridines to form definite seemed likely that the best results would be compounds of the salt type, and Proflavine- achieved with a mixture of two or more drugs SulPhathiazole (Flavazole), has been submitted which complemented each other in their action. to bacteriological, pharmacological and clinical McIntosh and Selbie (I944) suggested a mixture of investigation. 99 parts sulphathiazole and one part proflavine ?z¶aole has a solubility in water and normal sulphate known as S.P. Powder which has been saline of about 1-2,500, 1-250 in alcohol and is extensively employed by the Army Medical readily soluble in glycerin and acetone. The Department for application to wounds. The saturated solution is neutral or slightly alkaline proflavine is stated to enhance the anti-staphylo- (pH 7.0-7.4). coccal action of the sulphathiazole and at the same time affords protection against gram-negative Results organisms such as Ps. pyocyanea, Proteus and Bacteriological coliform bacilli. For the local treatment of The action of Flavazole against certain gram- wounds S.P. Powder is applied in the same manner negative organisms indicated that it was in some as sulphanilamide and has given very good respects superior to either sulphathiazole or pro- results. flavine sulphate respectively, of to mixtures of the two. Further bactericidal tests carried out by McIntosh, et al. (I945), confirmed that Flavazole was at least as efficient as either sulphathiazole or Sulphonamides proflavine sulphate against all the organisms tested. With the introduction of the sulphonamides a Compared with sulphathiazole, Flavazole was three demand arose for ointments and creams. hundred to six hundred times more active against
quickly copyright. most of these was a Cl. welchii and Cl. oedematiens, eight to sixteen The popular sulphanilamide times more active Ps. and cream with a water miscible base containing the against pyocyanea, antiseptic detergent cetyl trimethyl ammonium sixteen to one hundred and twenty times more bromide (CTAB). This was known as the Glasgow active against Proteus. Compared with proflavine No. 9 cream and was officially recommended in sulphate, Flavazole was of equal value against M.R.C. War Memorandum, No. io, "The Medical most organisms, but was more active against Use of Sulphonamides" for the first-aid treatment Ps. pyocyanea and Proteus. of burns and scalds of slight and moderate severity. to the variation of the of Toxicity Owing great solubility http://pmj.bmj.com/ sulphanilamide with temperature, difficulty has The maximum tolerated dose of Flavazole given been experienced in the preparation of satisfactory by intramuscular injection into mice was 30 mg. creams with water miscible bases, particularly on for a 20 gm. mouse, whereas the maximum tolerated a manufacturing scale, and it is of interest to note dose of proflavine sulphate was 1.5 mg. The local that the formula of sulphanilamide cream has toxicity to muscle tissue of the two drugs had recently been altered to contain equal parts of approximately the same relationship, but the sulphathiazole and sulphanilamide as described difference was less by the intraperitoneal route, in the National War Formulary addendum which was probably due to the low solubility on October 2, 2021 by guest. Protected I945. 2,500) of Flavazole. Sulphanilamide creams made with bases con- (I: taining water gradually crystallise and the product Results tends to develop a gritty texture. To overcome Pharmacological this a considerable amount of work has been Tests carried out against anaerobic infections in carried out and it has been demonstrated that mice showed that Flavazole lost none of the sulphanilamide and sulphathiazole may be com- therapeutic value of its components against bined to give a sulphanilamide-sulphathiazole Cl. welchii and Cl. septicum infections. The follow- compound. This preparation does not appear to ing table shows the average days survived by the offer any bacteriological advantages over its com- mice expressed as a percentage of three days when ponents, but on account of its physical properties the experiments were terminated. The drugs were and low solubility offers advantages in the pro- injected at the site of infection one hour after duction of water-containing creams which are free intramuscular inoculation of a washed suspension of from tendency to develop crystals. organisms in 2.5 per cent calcium chloride solution. Postgrad Med J: first published as 10.1136/pgmj.22.246.118 on 1 April 1946. Downloaded from April, I946 HISTORY OF MEDICINE SECTION 121 EFFICIENCY OF WOUND ANTISEPTICS following the application of Compound Flavazole (Expressed in percentage survival rate) Powder, though complete elimination of bacteria Dose Cl. welchii Cl. septicum was difficult owing to the unhealthy state of the Flavazole .. o1 mg. 90 90 tissues. Infection was, however, reduced and Sulphathiazole .. 40 mg. 7 90 healing was promoted. Proflavine .. o.5 mg. 60 70 Penicillin .. 50 units 1oo 60 Method of Application Control Mice .. o o After a thorough cleansing of the wound, Com- Clinical pound Flavazole Powder should be dusted over Results the surface either from a sifter envelope or by The published clinical results on Flavazole are means of an insufflator. On a clean, fresh wound, on over a hundred cases and the Flavazole was the amount applied should be just enough to give used as a compound powder containing 2 per cent a slight dusting or frosting on the surface equivalent Flavazole and 98 per cent Sulphathiazole. It to 0.5 gm. for an area of 4 square niches. In old has also been employed as a saturated aqueous or suppurating wounds, more may be used. This solution (I : 2,500). Further clinical trials are in treatment may be repeated daily without undue progress. The cases treated were mainly open danger of unfavourable reactions. wounds which could be accurately observed It is interesting to note that penicillin may be clinically and bacteriologically. Many cases had mixed with Compound Flavazole Powder without been very heavily infected for a prolonged period, any reduction in its activity, and that this addition and treatment was successful in 50 per cent of enhances the activity of the powder, particularly cases, the success being estimated by the take of skin against staphylococci. grafts or healing after various plastic operations. Flavazole can also be used as a saturated solution In a number of cartilage grafts and rotation in water or normal saline for the irrigation of flaps in which no known infection was present, infected wounds, as a bladder lavage, and as an healing was achieved by first intention in every antiseptic eyewash. Undiluted Flavazole must not case. In a few cases where Flavazole Compound be used on wounds. copyright. Powder was used twice daily, a dermatitis resulted. REFERENCES This cleared rapidly on discontinuing for ALBERT, A. (I943), Pharm. J., 2, 87. forty- ALBERT, A., and LINNELL, W. H. (1936), J. chem. Soc., 88. eight to seventy-two hours, and did not recur when ALBERT, A., RUBBO, S. D., GOLDACRE, R. J., DAVEY, M. E., and smaller doses were used. STONE, J. D. (I945), Brit. J. exp. Path., 26, i6o. BERRY, H. (I941), Quart. J. Pharm., 14, I49. Pressure sores presented a very serious problem BROWNING, C. H., GULBRANSEN, R., KENNAWAY, E. L., and THORNTON, L. H. D. (19I7), Brit. med. J., 1, 73. because of the loss of nerve supply and likelihood MCINTOSH, J., and SELBIE, F. R. (I944), Lancet, 1, 66. of contamination. In nine sores MCINTOSH, J., ROBINSON, R. H. M., SELBIE, F. R., REIDY, J. P., pressure heavily ELLIOTT BLAKE, H., and GUTTMANN, L. (I945), Lancet, infected with pyogenic cocci and gram-negative 2, 97. RUSSELL, D. S., and FALCONER, M. A. (I940), Brit. J. Surg., 28,472. bacilli, there was a great reduction of infection SELBIE, F. R., and MCINTOSH, J. (I943), J. Path. Bact., 55,477. http://pmj.bmj.com/ HISTORY OF MEDICINE SECTION PRESERVING MINERAL WATERS A letter of I735 from Stephen Hales, F.R.S.
The fashion for "taking the waters" was at its Kennedy published a fascinating biography of on October 2, 2021 by guest. Protected height in the mid-eighteenth century, and many Hales in 1929, in which may be read the full story English spas were popular then. The following of his many avocations, which included the letter written in 1735 is printed by courtesy of demonstration and measurement of blood-pressure the President and Council of the Royal College and the construction of novel ventilating machines of Surgeons of England, to whom the original for prisons and ships. Stephen Hales was a most belongs. It discloses an early attempt at bottling original physiologist and a pioneer of public natural waters for the benefit of people living at hygiene in that low period of English science and a distance from the wells. The artificial aeration medicine which lies between the days of Sydenham of water had not yet been made practicable, and and Boyle and those of Priestley and the Hunters. commercial bottling did not begin till the very The letter is addressed to Robert Nisbit or Nesbitt, end of the eighteenth century. This letter was who lived from about 1700 till 1761, a fashionable written by the Rev. Stephen Hales, the versatile London physician of scientific bent. As a student parson of Teddington, whose long life (I677-I76I) at Leyden Nesbitt formed a close friendship with was given to scientific work. Dr. A. E. Clark- the great Dutch anatomist Bernard Albinus;