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FEWER N.H.S. PRESCRIPTIONS?
156 A clinical investigation of dihydrostreptomycin in tuberculosis was undertaken by Feldman, Hinshaw, and their group at the Mayo Clinic6 during 1948. They had -previously shown that in experimental tuberculosis in guineapigs, due to a human strain (H 37 Rv), dihydro-
streptomycin is as effective as the parent substance in prolonging the survival-rate of the infected 7 animals and in limiting the spread of the infection. Their clinical material was limited to only 14 cases, but they were convinced that the activity of the dihydro compound was similar to that of streptomycin. They were also impressed with the diminished toxicity of dihydrostreptomycin. Thus they could administer it to patients in doses of 2-3 g. daily for sixty days or longer with little danger of producing vestibular dysfunction. They also observed that the drug is tolerated by some patients who are highly sensitive to streptomycin. The Mayo Clinic workers did, however, note that in cases of tuberculous meningitis intrathecal therapy produced irritation of the cord and a block in the cerebrospinal fluid. Some irritation at the site of intramuscular injection was observed in some patients, but was no worse than that after the injection of streptomycin. Another 12 cases of pulmonary tuberculosis treated with dihydrostreptomycin 4 are reported by Hobson and colleagues. They also confirm the diminished neurotoxicity of the drug in man and consider that the therapeutic results are as good as. those obtained with streptomycin. These preliminary clinical reports are encouraging, though they need to be confirmed on a larger series of cases. There seems to be no doubt about the diminished neurotoxicity of dihydrostreptomycin and its ability to replace streptomycin in hypersensitive patients. It might therefore be preferable to streptomycin for patients who require large doses or long courses. We still know little about the therapeutic effectiveness of streptomycin in small doses-the precise ratio of the toxic dose to the optimal therapeutic dose has not yet been established. It is thus important that experience should be gained on the effectiveness of dihydrostreptomycin in dosages that are well tolerated for long
periods. ADRENALINE AND ITS NEAR RELATIONS
IT has long been known that adrenaline is the active substance obtained from extracts of the suprarenal medulla. The lœvo-isomer is the one found in the gland and this has much greater pharmacological activity than the dextro compound. Commercial l-adrenaline is now usually prepared synthetically, and to maintain stability it is essential to have it in acid solution and advantageous to include a stabiliser such as sodium or
potassium metabisulphite. The chemical mediator (or mediators) liberated by nerves has not yet been identified with The evidence of experiments with isolated frogs’ hearts and perfused rabbits’ ears has supported the view that this substance is adrenaline. But the findings with other mammalian tissues suggest that adrenaline is not the only substance liberated. It is not yet known how adrenaline is formed in the body but information is accumulating. A second phenolic hydroxyl group may be introduced into the tyrosine thus molecule, dihydroxyphenylalanine; forming decarboxylation then occurs yielding hydroxytyramine, and the introduction of the OH group into the side-chain follows to form the primary sympathomimetic amine, The last stage of adrenaline formation noradrenaline. is the N-methylation of noradrenaline. Since adrenaline occurs as the lcevo-isomer in the adrenal medulla, one
adrenergic certainty.
6. Feldman, W. H., Karlson, A. G., Hinshaw, H. C. Ibid, p. 494. 7. Hinshaw, H. C., Feldman, W. H., Carr, D. T., Brown, H. A. Ibid, p. 525.
might expect that if there were other similar natural compounds they would also occur as the 1-iso-mers. The production of l-noradrenaline last year has made it possible to compare this substance with sympathin liberated by, or contained in, adrenergic nerves. In an
adrenal tumour about ten times as much l-noradrenaline as l-adrenaline has been detected, and it may be that noradrenaline as well as adrenaline is present in the normal adrenal medulla. So far as we know, adrenaline (which may also be called methyl-noradrenaline) and noradrenaline are only absorbed adequately when given by injection, and even then absorption is slow. The instability of these substances is said to be due to the presence of the ihree-oii differs from that of groups. The molecule of adrenaline in the absence of two hydroxyl groups and the presence of an extra methyl group in the sidechain, both of which differences tend to make ephedrine stable. Hence ephedrine is effective when given by mouth and its action lasts longer than that of adrenaline. A stage further in stability is reached when the three-OH groups of the adrenaline molecule are omitted, the N-methyl group is lost (as in noradrenaline) and the extra methyl group is added (as in ephedrine). The resulting compound-amphetamine or’Benzedrine’is volatile and may be inhaled to produce vasoconstriction in the nose. Both amphetamine and ephedrine are derivatives of isopropylamine, and are not inactivated by tissue amine oxidase. Returning again to the adrenaline molecule, noradrenaline results if the N-methyl group is lost. But if the N-methyl group is - replaced by aN-isopropyl group, , Aleudrine’ or isopropylnoradrenaline is produced. This compound, when tested on animals, is vasodepressor in all doses but produces the typical tachycardia. Its therapeutic importance lies in the fact that it is many times stronger than adrenaline as a bronchodilator and can be administered by mouth.
ephedrine
FEWER N.H.S. PRESCRIPTIONS?
IN Middlesex the number of National Health Service grew steadily, at the rate of about 100,000 a month, from 511,031 in July to 915,931 in November. Then last month the total receded by nearly 42,000 to 874,077. Some may attribute the decline to the season. Or it may be that doctors are now giving fewer and larger prescriptions, or that patients, weary of waiting in surgeries, are sometimes buying medicines themselves or going without. But it is possible that initial curiosity and desire to test the new service is becoming exhausted. The experience of one county in one month is not proof that demand has reached or passed its peak ; but it may be a hint. BETTERMENT
prescriptions
IT will be remembered that the Spens Committees made their recommendations in terms of the 1939 value "We leave to others," they said, "the of money. of the necessary adjustment to present conproblem ditions, but we would observe in this connexion that such adjustment should have direct regard not only to estimates of the change in the value of money but to increases which have in fact taken place since 1939 in The British Medical incomes in other professions." Association has now received a report from an expert who argues that if the professional classes’ cost-of-living figure in 1938 is taken as 100, the appropriate figure for today is 185. He points out that it has risen by 35 points since 1946 when the Ministry of Health decided that 20% should be added for betterment. Reasons for an increase will be put forward by a deputation from the Joint Committee of Consultants and Specialists and the General Medical Services Committee.
streptomycin is as effective as the parent substance in prolonging the survival-rate of the infected 7 animals and in limiting the spread of the infection. Their clinical material was limited to only 14 cases, but they were convinced that the activity of the dihydro compound was similar to that of streptomycin. They were also impressed with the diminished toxicity of dihydrostreptomycin. Thus they could administer it to patients in doses of 2-3 g. daily for sixty days or longer with little danger of producing vestibular dysfunction. They also observed that the drug is tolerated by some patients who are highly sensitive to streptomycin. The Mayo Clinic workers did, however, note that in cases of tuberculous meningitis intrathecal therapy produced irritation of the cord and a block in the cerebrospinal fluid. Some irritation at the site of intramuscular injection was observed in some patients, but was no worse than that after the injection of streptomycin. Another 12 cases of pulmonary tuberculosis treated with dihydrostreptomycin 4 are reported by Hobson and colleagues. They also confirm the diminished neurotoxicity of the drug in man and consider that the therapeutic results are as good as. those obtained with streptomycin. These preliminary clinical reports are encouraging, though they need to be confirmed on a larger series of cases. There seems to be no doubt about the diminished neurotoxicity of dihydrostreptomycin and its ability to replace streptomycin in hypersensitive patients. It might therefore be preferable to streptomycin for patients who require large doses or long courses. We still know little about the therapeutic effectiveness of streptomycin in small doses-the precise ratio of the toxic dose to the optimal therapeutic dose has not yet been established. It is thus important that experience should be gained on the effectiveness of dihydrostreptomycin in dosages that are well tolerated for long
periods. ADRENALINE AND ITS NEAR RELATIONS
IT has long been known that adrenaline is the active substance obtained from extracts of the suprarenal medulla. The lœvo-isomer is the one found in the gland and this has much greater pharmacological activity than the dextro compound. Commercial l-adrenaline is now usually prepared synthetically, and to maintain stability it is essential to have it in acid solution and advantageous to include a stabiliser such as sodium or
potassium metabisulphite. The chemical mediator (or mediators) liberated by nerves has not yet been identified with The evidence of experiments with isolated frogs’ hearts and perfused rabbits’ ears has supported the view that this substance is adrenaline. But the findings with other mammalian tissues suggest that adrenaline is not the only substance liberated. It is not yet known how adrenaline is formed in the body but information is accumulating. A second phenolic hydroxyl group may be introduced into the tyrosine thus molecule, dihydroxyphenylalanine; forming decarboxylation then occurs yielding hydroxytyramine, and the introduction of the OH group into the side-chain follows to form the primary sympathomimetic amine, The last stage of adrenaline formation noradrenaline. is the N-methylation of noradrenaline. Since adrenaline occurs as the lcevo-isomer in the adrenal medulla, one
adrenergic certainty.
6. Feldman, W. H., Karlson, A. G., Hinshaw, H. C. Ibid, p. 494. 7. Hinshaw, H. C., Feldman, W. H., Carr, D. T., Brown, H. A. Ibid, p. 525.
might expect that if there were other similar natural compounds they would also occur as the 1-iso-mers. The production of l-noradrenaline last year has made it possible to compare this substance with sympathin liberated by, or contained in, adrenergic nerves. In an
adrenal tumour about ten times as much l-noradrenaline as l-adrenaline has been detected, and it may be that noradrenaline as well as adrenaline is present in the normal adrenal medulla. So far as we know, adrenaline (which may also be called methyl-noradrenaline) and noradrenaline are only absorbed adequately when given by injection, and even then absorption is slow. The instability of these substances is said to be due to the presence of the ihree-oii differs from that of groups. The molecule of adrenaline in the absence of two hydroxyl groups and the presence of an extra methyl group in the sidechain, both of which differences tend to make ephedrine stable. Hence ephedrine is effective when given by mouth and its action lasts longer than that of adrenaline. A stage further in stability is reached when the three-OH groups of the adrenaline molecule are omitted, the N-methyl group is lost (as in noradrenaline) and the extra methyl group is added (as in ephedrine). The resulting compound-amphetamine or’Benzedrine’is volatile and may be inhaled to produce vasoconstriction in the nose. Both amphetamine and ephedrine are derivatives of isopropylamine, and are not inactivated by tissue amine oxidase. Returning again to the adrenaline molecule, noradrenaline results if the N-methyl group is lost. But if the N-methyl group is - replaced by aN-isopropyl group, , Aleudrine’ or isopropylnoradrenaline is produced. This compound, when tested on animals, is vasodepressor in all doses but produces the typical tachycardia. Its therapeutic importance lies in the fact that it is many times stronger than adrenaline as a bronchodilator and can be administered by mouth.
ephedrine
FEWER N.H.S. PRESCRIPTIONS?
IN Middlesex the number of National Health Service grew steadily, at the rate of about 100,000 a month, from 511,031 in July to 915,931 in November. Then last month the total receded by nearly 42,000 to 874,077. Some may attribute the decline to the season. Or it may be that doctors are now giving fewer and larger prescriptions, or that patients, weary of waiting in surgeries, are sometimes buying medicines themselves or going without. But it is possible that initial curiosity and desire to test the new service is becoming exhausted. The experience of one county in one month is not proof that demand has reached or passed its peak ; but it may be a hint. BETTERMENT
prescriptions
IT will be remembered that the Spens Committees made their recommendations in terms of the 1939 value "We leave to others," they said, "the of money. of the necessary adjustment to present conproblem ditions, but we would observe in this connexion that such adjustment should have direct regard not only to estimates of the change in the value of money but to increases which have in fact taken place since 1939 in The British Medical incomes in other professions." Association has now received a report from an expert who argues that if the professional classes’ cost-of-living figure in 1938 is taken as 100, the appropriate figure for today is 185. He points out that it has risen by 35 points since 1946 when the Ministry of Health decided that 20% should be added for betterment. Reasons for an increase will be put forward by a deputation from the Joint Committee of Consultants and Specialists and the General Medical Services Committee.