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Prolonged Penicillin Action
872
Iatrogenic Epilepsy
of the effect on animals of agenised flour holds great promise ; for the signs of intoxication with this substance closely resemble those of epilepsy in man. SILVER and his colleagues5 have shown that dogs with signs of intoxication have electro-encephalograms very similar to those found in epilepsy ; and these authors6 also report that thiopentorle or’Trimetha" dione’ effectively controls " agene convulsions. At least three groups of workers are now trying to isolate the toxic principle in agenised flour. Its isolation would help indirectly in the search for new anticonvulsants ; and it would help to decide once and for all whether flour prepared in this way is harmless to man.
OFTEN a careful history and physical examination fail to reveal the cause of epileptic attacks ; and for diagnosis it may be necessary to observe the mode of onset and the pattern of the fit. Fits have long been induced artificially, both for this purpose and to test susceptibility. Three methods have beenused: hyperventilation, hydration, and the exhibition of a convulsant drug in doses that would not cause convulsions in non-epileptic’ subjects. Hyperventilation is rarely successful; while hydration, though more effective, is also more unpleasant, and the time of the resulting fit is uncertain. Convulsants have the drawback that doses which are sub convulsive to normal subjects may also fail to produce a clinical convulsion Penicillin Action in an epileptic. With the introduction of electroTo reduce the unpleasantness of penicillin treatment encephalography these diagnostic tests have been and extend its usefulness to ambulant patients, made less severe; for hyperventilation may cause three have been devised : delayed absorption ; plans characteristic electrical changes without a clinical and oral administration. Lately, excretion ; delayed attack. it has been that in staphylococcal or too, suggested American workers have now carried " activation infections of moderate severity intrastreptococcal electro-encephalography a stage further. Two aims muscular of units of 100,000-200,000 injections underlie their studies : first to devise a test that is in solution 8-12 hours penicillin aqueous every pathognomonic of epilepsy, if possible distinguishing be effective, because the bacteriostatic action of may penibetween " idiopathic " and " acquired " epilepsy ; for some time after it can cfflin persists apparently and secondly, with acquired epilepsy to demonstrate no longer be detected in the blood. 8 In the early days the focus in the brain from which the attack originates. of penicillin therapy, the retarding effect of applying So far the most successful attempts to solve these two problems have been made with similar techniques. an ice-bag to the site of injection was tried, but this was soon superseded by the preparations which delay A convulsant, leptazol, is slowly injected intraabsorption. The method most commonly used up tog venously in doses up to a maximum of 400 mg. ; the present has been that of ROMANSKY and RITTMAN, when electrical changes appear in the record, the which consists in the intramuscular injection of injection of leptazol is stopped and replaced by calcium penicillin in beeswax and peanut oil. Although phenobarbitone or some other anticonvulsant. With at the time of its introduction this was a great advance this technique KAUFMAN and his co-workers1 in in prolonging penicillin blood-levels, it has some disMassachusetts have demonstrated the focus in 45% of advantages. The beeswax is not always completely 97 cases of post-traumatic epilepsy ; and by repeating absorbed, and both the beeswax and the peanut oil the test this figure was increased to 56%. With reactions and cause soreness occasionally idiopathic epilepsy, however, the 2results are less at the site of give rise toWith injection. preparation reactions satisfactory : CURE and JASPER at Montreal have been found in about this of 10% patients. Fluidity report that in half of a small group of idiopathic of the at room temperature has been preparation epileptics with normal or borderline encephalograms, difficult to attain, but newer preparations are much leptazol produced electrical and clinical seizures ; in this It now seems that the need respect. but after a similar injection 4 out of 27 non-epileptics improved for beeswax can be removed by combining penicillin with normal electro-encephalograms had epileptic aluminium or with procaine, to form relatively changes in the record. Leptazol appears to be with salts. The retarding effect of aluminium insoluble valuable in demonstrating the presence of an epileptoon the absorption of injected substances may also be genic focus ; but in diagnosing the doubtful case of made use of by suspending crystalline penicillin in a idiopathic epilepsy it is apparently no more helpful gel consisting of aluminium stearate in peanut or than hyperventilation and hydration. Rhythmic and BOGER and FLIPPIN 10 find this more sesame photic stimulation, which has lately been described effectiveoil, than combining penicillin and aluminium in by GREY WALTER,may prove a suitable alternative ; the same molecule. By suspending procaine penicillin but the clinical value of this technique cannot yet in such a gel they obtained measurable amounts of be gauged. antibiotic activity in the plasma for 4-6 days after a Artificially induced fits are equally important in single injection of 300,000 units. the selection of anticonvulsant drugs. Tc, investigate Procaine penicillin G, which was introduced 11 in the stream of new and modified drugs with suspected the United States last year, is a crystalline substance anticonvulsant activity, the pharmacologist would
Prolonged
"
.
like to produce in the laboratory a test situation in which success correlates highly with clinical efficacy ; but so far idiopathic epilepsy has not been simulated
experimentally.
However, MELLANBY’S4 discovery
Marshall, C., Walker, A. E. Arch. Neurol. Psychiat. 1947, 58, 533. 2. Cure, C., Jasper, H. Ibid, 1948, 59, 691. 3. Walter, V. J., Walter, W. G. Electroencephalography clin. Neurophysiol. 1949, 1, 567. 4. Mellanby, E. Brit. med. J. 1946, ii, 885. 1. Kaufman, C.,
Silver, M. L., Monahan, E. P., Klein, J. R., Pollock, G. H. Arch. Neurol. Psychiat. 1949, 60, 405. 6. Silver, M. L., Monahan, E. P., Klein, J. R. Proc. Soc. exp. Biol., N.Y. 1947, 66, 410. 7. Altmeier, W. A. Ann. Surg. 1948, 128, 708. 8. Tillett, W. S., Cambier, M. J.. McCormack, J. E. Bull. N.Y. Acad. Med. 1944, 20, 142. Jawetz, E. Arch. intern. Med. 1946, 77, 1. Zubrod, C. G. Bull. Johns Hopk. Hosp. 1947, 81, 400. 9. Romansky, M. J., Rittman, G. E. Science, 1944, 100, 196. 10. Boger, W. P., Flippin, H. F. J. Amer. med. Ass. 1949, 139, 1131. 11. Salivar, C. J., Hedger, F. H., Brown, E. V. J. Amer. chem. Soc. 1948, 70, 1287. Sullivan, N. P., Symmes, A. T., Miller, H. C., Rhodehamel, H. W. jun. Science, 1948, 107, 169. 5.
873 a molecule of procaine base molecule of sodium penicillin ; its potency is about 940 units per ml. Little has so far been published on its use in this country. Six months ago Jorms and SHOOTER 12 reported the effect of a single daily injection of 1 ml. of procaine penicillin in peanut oil which contained 300,000 units of penicillin. EMERY and his colleagues 13 gave procaine penicillin in peanut oil daily to 50 children and concluded that the penicillin blood-levels after 24 hours were extremely variable and that this was not an ideal preparation for administering penicillin by daily injections in children. In this issue YourrG and his colleagues have studied the effects of three preparations of procaine penicillin : (1) in peanut oil, (2) in water, and (3) in peanut oil with aluminium stearate. Their object was to find a depot preparation which would ensure a blood-level of 0-06 unit per ml. or over 24 hours after a single small injection. They chose three classes of subjects for this investigation : healthy members of the staff of their department; ward patients with a variety of diseases (excluding any cases with impaired renal function) ; and ambulant patients with gonorrhoea attending the venereal-diseases clinic. In all, 185 people received the procaine penicillin G ; preparations containing crystals 5-20 microns in diameter were
prepared by combining with
preferred
to
the
as p-aminohippuric acid and, more recently, caronamide.15 The necessity for the intravenous injection of the former severely limits its use ; the latter can be given by mouth but may cause transient albuminuria and nausea in the advocated dose of 4 g. 4-hourly and is still something of an unknown quantity. The particular value of caronamide as an adjunct to penicillin therapy is that it not only prolongs the action of penicillin but increases the bloodlevels attainable with a given dose, which is especially useful in conditions where very resistant bacteria are entrenched in tissues with a poor blood-supply, as in bacterial endocarditis.1-6 Where such very high bloodlevels are not required it seems that procaine penicillin in an aluminium stearate gel will prove to be the least toxic and most effective preparation for prolonging penicillin action.
drugs
The
Jones, P. F., Shooter, R. A. Brit. med. J. 1948, ii, 933. Emery J. L., Stewart, S. M., Stone, D. G. H. Ibid, 1949, i, 845. Robinson, J. A., Hirsh, H. L., Milloff, B., Dowling, H. F. J. Lab. clin. Med. 1948, 33, 1232.
Amending
Bill
THE Minister of Health has now laid before Parlialong-awaited Bill for amending the National Health Service Acts of 1946 and 1947. As it was largely the promise of this Bill, and of its safeguards, that last year induced the medical profession to accept the new service, the text is certain to be closely scrutinised. Let it be said at once that the Minister has fully kept faith ; for all the promises made a year ago are here translated into legal form. Clause 10 makes it impossible to change by regulation the general practitioner’s remuneration and to make it " consist wholly or mainly of a fixed salary which has no reference to the number of patients for whom he has undertaken to provide ... services," while clause 11 forbids " any requirement that all specialists employed for the purpose of hospital and specialist services shall be employed whole-time." Besides these clauses, and those concerned with partnership agreements, the Bill contains a number of additions and changes thought necessary in the light of experience of the working of the Acts. In clarifying the position of partnerships, the Bill deals first with partners who before the appointed day had entered into agreements providing for the sale and purchase of further shares in their practice. When these transactions take place, the partner from whom the share is transferred will straightway receive the share of the compensation attributable to the portion transferred. The position of mixed partnerships (where some of the partners have joined the service and others have not) is also clarified, and appropriate methods are provided for transferring the share of a retiring or deceased partner to the remaining partners. As there may be practices where, if the new provisions had appeared in the original Act, one or more of the partners would not have decided’ to stay out of the service, it is now to be enacted that= any such doctor will, for the first two months after the passing of this Bill, have a renewed option to join the service and receive compensation for the goodwill of his practice. Turning to disciplinary machinery, the ment his
coarse-particle preparations (60 µ)
which were found.to clog the needle and syringe. With a dose of 600,000 units of this penicillin preparation all subjects had a blood-level of 0.06 unit per ml. or over at 20 and 24 hours. The oily preparation than the aqueous suspenno better results produced sion. However, when aluminium stearate was incorporated in the oily preparation, 64 out of 65 cases showed a blood-level of 0-06 unit per ml. or over at 24 hours after only 300,000 units. The aluminium stearate, 14 which is a water repellant, seems particularly effective in delaying the action of procaine penicillin. In 8 patients who received a single injection of 2,000,000 units of procaine penicillin in oil with aluminium stearate, the blood-levels ranged from 1 to 2 units per ml. at 24 hours, followed by a gradual daily decline to zero on the 6th to 8th day. Also in this issue WrLSON and others report on the use of procaine penicillin in babies. They used procaine penicillin G in peanut oil in which over 60% of particles were 15-50 µ in diameter. They found this preparation was suitable for babies and young children, and selected 10 patients from each of the following groups for trial : premature infants ; infants aged 1-5 days ; infants aged 7-15 days ; children aged 1-12 months; children aged 1½-3 years ; children aged 4-9 years. The first three groups were all healthy, while the remainder were mostly recovering from acute infections. The dose of procaine penicillin was graded from 60,000 units in the youngest to 300,000 units in the oldest group, one injection only being given. In babies 100,000 units produced therapeutic blood-levels for at least 24 hours, and in the newborn these levels were maintained for considerably longer, owing, it is - suggested, to the period of physiological dehydration following birth. In the older children 150,000-300,000 units produced 12. 13. 14.
blood-levels lasting for at least 24 hours in 23 out of 29 patients. A different method of tackling the problem is by the inhibition of penicillin excretion in the urine by such
therapeutic
a
’
.
15.
Leading article, Lancet, 1948, i, 70. Eiber, H. B., Alture-Werber, E.
16. Loewe, L., 494.
Science, 1947, 106,
Iatrogenic Epilepsy
of the effect on animals of agenised flour holds great promise ; for the signs of intoxication with this substance closely resemble those of epilepsy in man. SILVER and his colleagues5 have shown that dogs with signs of intoxication have electro-encephalograms very similar to those found in epilepsy ; and these authors6 also report that thiopentorle or’Trimetha" dione’ effectively controls " agene convulsions. At least three groups of workers are now trying to isolate the toxic principle in agenised flour. Its isolation would help indirectly in the search for new anticonvulsants ; and it would help to decide once and for all whether flour prepared in this way is harmless to man.
OFTEN a careful history and physical examination fail to reveal the cause of epileptic attacks ; and for diagnosis it may be necessary to observe the mode of onset and the pattern of the fit. Fits have long been induced artificially, both for this purpose and to test susceptibility. Three methods have beenused: hyperventilation, hydration, and the exhibition of a convulsant drug in doses that would not cause convulsions in non-epileptic’ subjects. Hyperventilation is rarely successful; while hydration, though more effective, is also more unpleasant, and the time of the resulting fit is uncertain. Convulsants have the drawback that doses which are sub convulsive to normal subjects may also fail to produce a clinical convulsion Penicillin Action in an epileptic. With the introduction of electroTo reduce the unpleasantness of penicillin treatment encephalography these diagnostic tests have been and extend its usefulness to ambulant patients, made less severe; for hyperventilation may cause three have been devised : delayed absorption ; plans characteristic electrical changes without a clinical and oral administration. Lately, excretion ; delayed attack. it has been that in staphylococcal or too, suggested American workers have now carried " activation infections of moderate severity intrastreptococcal electro-encephalography a stage further. Two aims muscular of units of 100,000-200,000 injections underlie their studies : first to devise a test that is in solution 8-12 hours penicillin aqueous every pathognomonic of epilepsy, if possible distinguishing be effective, because the bacteriostatic action of may penibetween " idiopathic " and " acquired " epilepsy ; for some time after it can cfflin persists apparently and secondly, with acquired epilepsy to demonstrate no longer be detected in the blood. 8 In the early days the focus in the brain from which the attack originates. of penicillin therapy, the retarding effect of applying So far the most successful attempts to solve these two problems have been made with similar techniques. an ice-bag to the site of injection was tried, but this was soon superseded by the preparations which delay A convulsant, leptazol, is slowly injected intraabsorption. The method most commonly used up tog venously in doses up to a maximum of 400 mg. ; the present has been that of ROMANSKY and RITTMAN, when electrical changes appear in the record, the which consists in the intramuscular injection of injection of leptazol is stopped and replaced by calcium penicillin in beeswax and peanut oil. Although phenobarbitone or some other anticonvulsant. With at the time of its introduction this was a great advance this technique KAUFMAN and his co-workers1 in in prolonging penicillin blood-levels, it has some disMassachusetts have demonstrated the focus in 45% of advantages. The beeswax is not always completely 97 cases of post-traumatic epilepsy ; and by repeating absorbed, and both the beeswax and the peanut oil the test this figure was increased to 56%. With reactions and cause soreness occasionally idiopathic epilepsy, however, the 2results are less at the site of give rise toWith injection. preparation reactions satisfactory : CURE and JASPER at Montreal have been found in about this of 10% patients. Fluidity report that in half of a small group of idiopathic of the at room temperature has been preparation epileptics with normal or borderline encephalograms, difficult to attain, but newer preparations are much leptazol produced electrical and clinical seizures ; in this It now seems that the need respect. but after a similar injection 4 out of 27 non-epileptics improved for beeswax can be removed by combining penicillin with normal electro-encephalograms had epileptic aluminium or with procaine, to form relatively changes in the record. Leptazol appears to be with salts. The retarding effect of aluminium insoluble valuable in demonstrating the presence of an epileptoon the absorption of injected substances may also be genic focus ; but in diagnosing the doubtful case of made use of by suspending crystalline penicillin in a idiopathic epilepsy it is apparently no more helpful gel consisting of aluminium stearate in peanut or than hyperventilation and hydration. Rhythmic and BOGER and FLIPPIN 10 find this more sesame photic stimulation, which has lately been described effectiveoil, than combining penicillin and aluminium in by GREY WALTER,may prove a suitable alternative ; the same molecule. By suspending procaine penicillin but the clinical value of this technique cannot yet in such a gel they obtained measurable amounts of be gauged. antibiotic activity in the plasma for 4-6 days after a Artificially induced fits are equally important in single injection of 300,000 units. the selection of anticonvulsant drugs. Tc, investigate Procaine penicillin G, which was introduced 11 in the stream of new and modified drugs with suspected the United States last year, is a crystalline substance anticonvulsant activity, the pharmacologist would
Prolonged
"
.
like to produce in the laboratory a test situation in which success correlates highly with clinical efficacy ; but so far idiopathic epilepsy has not been simulated
experimentally.
However, MELLANBY’S4 discovery
Marshall, C., Walker, A. E. Arch. Neurol. Psychiat. 1947, 58, 533. 2. Cure, C., Jasper, H. Ibid, 1948, 59, 691. 3. Walter, V. J., Walter, W. G. Electroencephalography clin. Neurophysiol. 1949, 1, 567. 4. Mellanby, E. Brit. med. J. 1946, ii, 885. 1. Kaufman, C.,
Silver, M. L., Monahan, E. P., Klein, J. R., Pollock, G. H. Arch. Neurol. Psychiat. 1949, 60, 405. 6. Silver, M. L., Monahan, E. P., Klein, J. R. Proc. Soc. exp. Biol., N.Y. 1947, 66, 410. 7. Altmeier, W. A. Ann. Surg. 1948, 128, 708. 8. Tillett, W. S., Cambier, M. J.. McCormack, J. E. Bull. N.Y. Acad. Med. 1944, 20, 142. Jawetz, E. Arch. intern. Med. 1946, 77, 1. Zubrod, C. G. Bull. Johns Hopk. Hosp. 1947, 81, 400. 9. Romansky, M. J., Rittman, G. E. Science, 1944, 100, 196. 10. Boger, W. P., Flippin, H. F. J. Amer. med. Ass. 1949, 139, 1131. 11. Salivar, C. J., Hedger, F. H., Brown, E. V. J. Amer. chem. Soc. 1948, 70, 1287. Sullivan, N. P., Symmes, A. T., Miller, H. C., Rhodehamel, H. W. jun. Science, 1948, 107, 169. 5.
873 a molecule of procaine base molecule of sodium penicillin ; its potency is about 940 units per ml. Little has so far been published on its use in this country. Six months ago Jorms and SHOOTER 12 reported the effect of a single daily injection of 1 ml. of procaine penicillin in peanut oil which contained 300,000 units of penicillin. EMERY and his colleagues 13 gave procaine penicillin in peanut oil daily to 50 children and concluded that the penicillin blood-levels after 24 hours were extremely variable and that this was not an ideal preparation for administering penicillin by daily injections in children. In this issue YourrG and his colleagues have studied the effects of three preparations of procaine penicillin : (1) in peanut oil, (2) in water, and (3) in peanut oil with aluminium stearate. Their object was to find a depot preparation which would ensure a blood-level of 0-06 unit per ml. or over 24 hours after a single small injection. They chose three classes of subjects for this investigation : healthy members of the staff of their department; ward patients with a variety of diseases (excluding any cases with impaired renal function) ; and ambulant patients with gonorrhoea attending the venereal-diseases clinic. In all, 185 people received the procaine penicillin G ; preparations containing crystals 5-20 microns in diameter were
prepared by combining with
preferred
to
the
as p-aminohippuric acid and, more recently, caronamide.15 The necessity for the intravenous injection of the former severely limits its use ; the latter can be given by mouth but may cause transient albuminuria and nausea in the advocated dose of 4 g. 4-hourly and is still something of an unknown quantity. The particular value of caronamide as an adjunct to penicillin therapy is that it not only prolongs the action of penicillin but increases the bloodlevels attainable with a given dose, which is especially useful in conditions where very resistant bacteria are entrenched in tissues with a poor blood-supply, as in bacterial endocarditis.1-6 Where such very high bloodlevels are not required it seems that procaine penicillin in an aluminium stearate gel will prove to be the least toxic and most effective preparation for prolonging penicillin action.
drugs
The
Jones, P. F., Shooter, R. A. Brit. med. J. 1948, ii, 933. Emery J. L., Stewart, S. M., Stone, D. G. H. Ibid, 1949, i, 845. Robinson, J. A., Hirsh, H. L., Milloff, B., Dowling, H. F. J. Lab. clin. Med. 1948, 33, 1232.
Amending
Bill
THE Minister of Health has now laid before Parlialong-awaited Bill for amending the National Health Service Acts of 1946 and 1947. As it was largely the promise of this Bill, and of its safeguards, that last year induced the medical profession to accept the new service, the text is certain to be closely scrutinised. Let it be said at once that the Minister has fully kept faith ; for all the promises made a year ago are here translated into legal form. Clause 10 makes it impossible to change by regulation the general practitioner’s remuneration and to make it " consist wholly or mainly of a fixed salary which has no reference to the number of patients for whom he has undertaken to provide ... services," while clause 11 forbids " any requirement that all specialists employed for the purpose of hospital and specialist services shall be employed whole-time." Besides these clauses, and those concerned with partnership agreements, the Bill contains a number of additions and changes thought necessary in the light of experience of the working of the Acts. In clarifying the position of partnerships, the Bill deals first with partners who before the appointed day had entered into agreements providing for the sale and purchase of further shares in their practice. When these transactions take place, the partner from whom the share is transferred will straightway receive the share of the compensation attributable to the portion transferred. The position of mixed partnerships (where some of the partners have joined the service and others have not) is also clarified, and appropriate methods are provided for transferring the share of a retiring or deceased partner to the remaining partners. As there may be practices where, if the new provisions had appeared in the original Act, one or more of the partners would not have decided’ to stay out of the service, it is now to be enacted that= any such doctor will, for the first two months after the passing of this Bill, have a renewed option to join the service and receive compensation for the goodwill of his practice. Turning to disciplinary machinery, the ment his
coarse-particle preparations (60 µ)
which were found.to clog the needle and syringe. With a dose of 600,000 units of this penicillin preparation all subjects had a blood-level of 0.06 unit per ml. or over at 20 and 24 hours. The oily preparation than the aqueous suspenno better results produced sion. However, when aluminium stearate was incorporated in the oily preparation, 64 out of 65 cases showed a blood-level of 0-06 unit per ml. or over at 24 hours after only 300,000 units. The aluminium stearate, 14 which is a water repellant, seems particularly effective in delaying the action of procaine penicillin. In 8 patients who received a single injection of 2,000,000 units of procaine penicillin in oil with aluminium stearate, the blood-levels ranged from 1 to 2 units per ml. at 24 hours, followed by a gradual daily decline to zero on the 6th to 8th day. Also in this issue WrLSON and others report on the use of procaine penicillin in babies. They used procaine penicillin G in peanut oil in which over 60% of particles were 15-50 µ in diameter. They found this preparation was suitable for babies and young children, and selected 10 patients from each of the following groups for trial : premature infants ; infants aged 1-5 days ; infants aged 7-15 days ; children aged 1-12 months; children aged 1½-3 years ; children aged 4-9 years. The first three groups were all healthy, while the remainder were mostly recovering from acute infections. The dose of procaine penicillin was graded from 60,000 units in the youngest to 300,000 units in the oldest group, one injection only being given. In babies 100,000 units produced therapeutic blood-levels for at least 24 hours, and in the newborn these levels were maintained for considerably longer, owing, it is - suggested, to the period of physiological dehydration following birth. In the older children 150,000-300,000 units produced 12. 13. 14.
blood-levels lasting for at least 24 hours in 23 out of 29 patients. A different method of tackling the problem is by the inhibition of penicillin excretion in the urine by such
therapeutic
a
’
.
15.
Leading article, Lancet, 1948, i, 70. Eiber, H. B., Alture-Werber, E.
16. Loewe, L., 494.
Science, 1947, 106,