Medical application of sulphonamides (1948)

carbon hydrogen nitrogen and hydrogen sulfur and oxygen nitrogen and hydrogen para amino benzene sulfonamide and certain derivatives of it are the sulfonamides used in medicine these derivatives are formed by substitution of amino or amide hydrogen the first one to be used clinically was the sulfonamide derivative of the dye stuff chrysoidine derma announced this to be curative in experimental streptococcal infections though virtually inactive in vitro french workers suggested this was due to sulfonomidocracoidine being broken down in the body with release of the active para aminobenzene sulfonamide commonly known as sulfonylamide which now largely replaced the dystop compound in clinical use since sulfanilamide proved to be inactive against pneumococcal infections efforts were made in the main baker research laboratories to find a sulfonamide which would be effective in the print of pneumonia many compounds were synthesized and tested of these a heterocyclic derivative of sulfanilamide two para aminobenzene sulfonamido pyridine was found to be active in experimental pneumococcal infections and of low toxicity the properties of this compound which had been given the laboratory number t693 by the discoverers ewins and philips were reported in the lancet for may the 28th 1938 a controlled clinical trial in acute primary pneumonia was made the results of this trial were reported in the lancet for july the second 1938 results of further trials in pneumonia and information regarding possible toxic effects were collected these being satisfactory the drug was generally released studies in a wider clinical field were made including the treatment of gonococcal and meningococcal infections soon the demand for the drug was worldwide in view of the eminence of war the discovery that an effective and relatively safe chemotherapeutic agent was available for the treatment of gonorrhea was to prove extremely opportune meanwhile investigations in the main baker research laboratories had been continuing because of the established value of m b 693 which was later to be termed sulfur pyridine attention had naturally been directed to further compounds of similar chemical constitution the next heterocyclic derivative to be synthesized was the corresponding thiozole compound which was designated m b 760 later termed sulfathiazole this compound was also discovered independently by swiss workers these achievements stimulated energetic research in other countries notably in the united states where further heterocyclic derivatives were synthesized during the early years of the war important contributions to the pharmacology of these compounds were also made sulfonamides inhibit the multiplication of susceptible organisms provided the drug is present in sufficient concentration for a long enough time this inhibitory action is reduced or abolished by parallel exits the bacteriostatic action of sulfanilamide and its derivatives is also inhibited by para aminobenzoic acid which is closely related in structure to sulfanilamide one theory of sulfonamide bacteriostasis which does not however fit all the known facts is that para aminobenzoic acid is an essential metabolite for certain bacteria and that sulfonamides compete with it sulfonamide sensitive organisms are those unable to synthesize sufficient para aminobenzoic acid sulfonamide insensitive organisms are those able to do so the amount of para aminobenzoic acid required to antagonize the bacteriostatic action of different sulfonamides is an index of their activity while the sulfonamides have little specificity on bacterial species they differ in degree of activity sulfonamide resistance can develop as a result of the use of sub-optimal concentrations but this does not imply resistance to a different antibacterial substance such as penicillin the presence of the drug in normal concentrations does not interfere with phagocytosis and other body defense mechanisms if the natural defenses are unequal to their task an infection may prove fatal despite the correct use of sulfonamide therapy in man and most animals sulfonamides are partly conjugated to an acetyl derivative this takes place mainly in the liver the acetal derivatives are inactive since for full activity a sulfonamide must have a free or unsubstituted amino group sulfonamides penetrate to all body fluids in varying degrees including the blood and tissue fluids cerebrospinal fluid and the milk which has no unturned effect on the infant they also pass into the fetal circulation without an effect on the fetus after absorption sulfonamides are excreted almost entirely by the kidney partly unchanged and partly as acetyl derivatives with these sulfonamides the extent of absorption from the intestinal tract after oral administration is only about five percent of the amount ingested while succinyl and parallel sulfathazole are virtually an active in vitro they are active in the interstellar tract this being ascribed to the partial hydrolysis they undergo hydrolysis to freeze sulfathiazole takes place too low in the interstellar tract for much absorption to occur for this reason the succinal sulfothazole and thermal sulfathiazo are the sulfonamides of choice in interstellar infections sulfonamides are used in the treatment of acute infections by the biogenic cocci sulfonamides also have an action on some gram-positive bacilli they have been used for example associated with antitoxin and surgery in the treatment of gas gangrene they tend to be less active on gram-negative bacilli but are however effective in chancroid due to hemophilus to create in urinary tract infections due to bacterium coli and acute bacillary dysentery sulfonamides have a retarding influence on the course of experimental tuberculosis infections in guinea pigs when they're given in very large doses they are however of no value for the treatment of human tuberculosis infections the compound 4 4 diamino diphenyl cell phone is a more active antibacterial agent than the sulfonamides but it is too toxic for clinical use various derivatives of this compound have been found to be more effective than sulfonamides in experimental tuberculosis infections these cell phones have been used clinically in the treatment of tuberculosis both systemically and by topical application to accessible lesions the results on the whole have been disappointing and the cell phones are rather toxic their research is still proceeding trials of the cell phones in leprosy have given much more promising results these compounds are proving effective in the lipromatose type of leprosy and in arresting eye damage sulfonamides are most effective in infections running an acute course which tend to be generalized successful therapy aims at a high loading dose followed by smaller doses at regular frequent intervals to maintain the blood concentration at a constant level no attempt should be made to obtain a higher blood level by restricting fluid intake four to six pints per day are essential the following tables of dosage are given as a guide to assist clinicians in judging the appropriate dose for an individual patient there are a number of variable factors which influence dosage final sulfonamides are primarily indicated in infections running an acute course they are also of value in sub-acute types of infection and may have a place in the management of certain chronic infections and conditions of infective origin for example in bacterium coli infections of the urinary tract sulfonamides are frequently effective in clearing up any acute and subacute attacks in chronic bacilluria however it may not be possible to eradicate the infection permanently in the absence of any discoverable underlying pathology but a very small dose of a sulfonamide taken daily or on alternate days for long periods will usually keep the urine sterile in some chronic dermatosis courses of sulfonamides in small dosage may be useful notably in dermatitis herpetiformis where the distressing symptoms are often relieved in a striking manner sulfur pyridine is the compound usually advised as it will sometimes control the disease when other sulfonamides fail the reason for the superiority of sulfur pyridine is not known sulfonamides have some prophylactic applications the dosage required for these is much less than that employed in active treatment examples of prophylaxis in surgical cases include prevention of urinary tract infection as in patients with an indwelling catheter and obstetric cases of a kind in which infection is liable to occur such as prolonged and instrumental deliveries examples of medical cases include the control of secondary bacterial infections in such conditions as measles pertussis and influenza the prevention of acute rheumatism after tonsillectomy and the prevention of recurrences in patients especially children who have had an attack of rheumatic fever has been widely studied the abnormally lengthened pr interval on the electrocardiogram indicates rheumatic carditis for the prevention of acute rheumatism the sulfonamide is administered for several months sulfonylamide was the compound originally used but it has been largely replaced by the heterocyclic derivatives sulfamerazine is perhaps the drug of choice since the infrequent administration is an advantage in these cases group prophylaxis is the systematic administration of a sulfonamide to control the spread of an infection in a community examples are the control of epidemics of cerebrospinal fever tonsillitis and respiratory infections and facility dysentery for the control of bacillary dysentery in mental hospitals and other institutions a small dosage of succinal sulfathazal or phthalal sulfathiazole is effective and virtually free from risk sulfonamides are used topically as well as systemically for the local treatment and prevention of accessible infections they are applied in the form of powders as various types of ointments and in solution solutions of sodium sulfide are sometimes used because they are neutral in reaction the value of sulfonamides for these purposes is limited by the inhibitory effect of fuss on their bacteriostatic action by their lack of effect on gram-negative bacilli and by the risk of local sensitization for these reasons better results are generally to be obtained from the use of one of the aromatic diamadines or a penicillin sulfur guanidine of which about 30 to 60 percent is absorbed was introduced for the treatment of the ciliary dysentery the succinyl sulfathiazole with both of which absorption is about five percent only are now largely used for this purpose the two latter sulfonamides are also used in surgery of the interstellar tract both before and after operation for the prophylaxis and treatment of peritonitis fecal festival and wound infection of patients undergoing such operations as a resection of the rectum and of the colon the operation the stages of which we see here for resection in cases of carcinoma of the colon carries a risk of peritonitis the mortality from which has been reduced by the use of these gut active sulfonamides for this purpose fell outside our sulfathazole is advised it is essential to use a very large dosage some surgeons use as much as four grams four hourly for the first 24 hours a reduced dosage must be continued for several days after the operation trial of feral sulfathiazole is justified in ulcerative colitis both acute and chronic while the results of treatment are difficult to assess in this disease the feral sulfathosal appears to give better results than any other sulfonamide though amitine is the standard specific for acute amoebic dysentery the succinyl sulfathiazole or thylal sulfothazole are used to control the secondary bacterial infections while this use of sulfonamides is adjuvant to specific therapy they are employed in veterinary medicine as the primary therapeutic measure in certain infections by coccidia as well as in various bacterial infections for oral administration which is the routine method the tablet should be crushed up to aid absorption they may be taken with water or milk about 20 grains each of sodium citrate and sodium bicarbonate may be added this will alkalinize the urine and so render the sulfonamides and their acetyl derivatives more soluble the mouth should afterwards be rinsed and the water swallowed as the powder tends to lodge in the buccal cavities in comatose states the drug may be given by nasal catheter or stomach tube but parenteral administration is generally to be preferred when oral administration is inadvisable or difficult for instance because of vomiting in severe infections all or part of the initial dose should be given parentally maintenance therapy being oral intravenous injection is the method of choice the intramuscular route provides an alternative before parenteral administration the sodium salts of the sulfonamides are used these yield solutions which are strongly alkaline and should never be given subcutaneously or intrathecally if the sodium sulfonamide is in the form of powder this is dissolved in the appropriate volume of sterile distilled water sodium salts of sulfonamides are often supplied in the form of concentrated solutions of 25 percent or 33 and a third percent and for intravenous injection it is essential that such solutions should be diluted to a concentration of from five percent to not more than ten percent stronger solutions would be more irritating should perivascular injection or leakage occur if the intramuscular root is used the injection must be deep the deltoid is not the most suitable cases of wrist drop have occurred from damage to the musculospiral nerve foot drop has resulted from damage to the sciatic nerve so that an intragluteal injection must be given in the upper outer quadrant of the buttock the vastus externus provides a very suitable site for intramuscular injections which is free from any danger of nerve injury for intramuscular injections the concentrated solution of thirty three and a third percent or twenty five percent is used when parental administration has to be continued repeated injections can be used but sodium sulfonamides may be added to the intravenous drip for patients receiving infusions of saline or dextrose the disadvantages and potential dangers of the alkaline sodium sulfonamides can be avoided by giving solution this is a neutral soluble derivative of sulfathiazole intravenous doses of from 5 milliliters to 25 milliliters may be given these correspond to one to five grams of sulfothiazole doses of five milliliters may also be given intramuscularly and are very well tolerated cyanosis was one of the first side effects observed in the early days of sulfonamide therapy it was found to be associated with the formation of self-hemoglobin or of methymoglobin cyanosis is mild and infrequent with the modern heterocyclic derivatives and when it occurs is due to metemoglobinemia vomiting when it occurs is central and not local in origin this together with various cerebral symptoms is most common with sulfur pyridine less so with sulfothiazole and relatively infrequent with sulfadiazine and its methyl derivatives sulfonamide rashes are usually due to the development of sensitization to the drug and may appear on about the ninth day they may be preceded by drug fever this is one reason why sulfonamide therapy topical or systemic is preferably limited to about five days if a patient has previously become sensitized instead of occurring on about the ninth day the rash may appear at once various forms of blood dysprasia have occurred during sulfonamide treatment and most of these also appear to be sensitization phenomena an early leukopenia unless rapidly progressive is of little significance in the rare cases where prolonged administration is necessary the frequent white cell counts should be carried out acute hemolytic anemia is a rare complication of sulfonamide therapy which appears early other even rarer complications being aplastic anemia and purpura the occurrence of hematuria usually indicates the deposition of crystals in the urinary tract the signs and symptoms of which include lumbar or abdominal pain oliguria and microscopic hematuria the treatment at this stage is withdrawal of the drug and the forcing of fluids but should the condition precede to complete inuria cystoscopy and eurotech catheterization will usually be required the possibility of crystal duria which may occur with any of the absorbed heterocyclic derivatives is reduced by the maintenance of a high fluid intake and an alkaline urine if in a saturated solution of a sulfonamide another is dissolved their solubilities are not decreased addition of a further quantity of the same sulfonamide would produce a supersaturated solution from which sudden crystallization may occur this principle of mixed sulfonamides may be utilized to reduce the risk of crystal urea investigations have shown that an appropriate mixture is one of sulfathazole sulfadiazine and self-amerizing in approximately equal proportions this is issued for oral administration under the name sulfur triad today the scope of antibacterial therapy is extended by certain antibiotics in some infections in which sulfonamide proved inadequate or ineffective penicillin has triumphed streptomycin has proved valuable and the search for new antibacterial agents goes on sulfonamide therapy however constituted the most important advance ever made in therapeutics and inaugurated a new era in the conquest of disease you