- Email: [email protected]
ACTION OF PSYCHOTROPIC DRUGS ON γ-AMINOBUTYRIC AND GLUTAMIC ACID IN RAT BRAIN
591
Unfortunately he died at the end of 1957, but the painful cedema of the hands and feet did not recur while he was receiving butazolidine, which was continued for about four months in all. In cases of this kind it may be worth trying butazolidine before emharking Colindale Hospital, London, N.W.9.
on vagotomy.
DIANA OWEN.
HÆMOPHILIA-LIKE STATES IN GIRLS SIR,—Iread with great interest the article by Professor Quick and Miss Hussey in your issue of June 21, and I want to emphasise the following findings. We, too, observed, with the late Prof. E. Frank, 2 cases of deficiency of antihxmophilic globulin (A.H.G.) (thromboplastinogen)
with
prolonged bleeding-time.
CASE I.—A
thirteen-year-old girl had
an
entirely negative
These findings suggest that in vascular haemophilia besides A.H.G.-deficiency there is a platelet defect as in the thrombasthenia described by Braunsteiner4 and by ourselves.5 In other words, these cases are combinations of thrombasthenia and haemophilia (thrombasthenia haemophilica). In these cases, the so-called Frank’s athrombia 6does exist-that is to say, the bleeding-time is prolonged because of defects in the aggregation and adhesiveness of platelets. The same defect of platelets has been observed by Payko and Erisilgil8 in a case of Christmas disease with prolonged bleeding-time. This finding confirms our observations. In my opinion, the third and fourth cases of Professor Quick are examples of the syndrome of thrombasthenia hsemophilica or athrombia hxmophilica.
family history. In childhood she had prolonged bleeding after minor cuts and bruised easily. She had severe epistaxis. The laboratory findings are summarised in the accompanying table.
Second Internal Clinic of Istanbul University, Guraba Hospital,
Istanbul, Turkey.
ORHAN NURI ULUTIN.
DIPLOMA OF CHILD HEALTH your educational number (Aug. 30) you do include the Royal Faculty of Physicians and of Glasgow amongst those bodies which grant a diploma of child health. Reference to the advertisement pages of the same number will confirm that it does.
SIR,-In
Surgeons
not
Royal Hospital for Sick Children, Glasgow, C.3.
ROBERT A. SHANKS.
ACTION OF PSYCHOTROPIC DRUGS ON &ggr;-AMINOBUTYRIC AND GLUTAMIC ACID IN RAT BRAIN SIR,-Recently one of us (C. de W.) recorded9 the results of an investigation into the inhibition of intermed-
iary metabolism by some diphenhydramine derivatives. Like the barbiturates, diphenhydramine reduces the oxygen consumption during oxidation of glucose (ratbrain slices).lo
A,H.G.-deficiency was noted, and A.H.G. was 5%. The case was a pseudohæmophilia B (vascular haemophilia or angiohæmophilia A). The cause of the prolonged bleeding-time was investigated and a platelet defect was observed under the electron microscope. The aggregation and adhesiveness, the formation of pseudopodia, and the spreading of hyalomere of platelets were absent or defective 12 (see fig.). CASE 2.-A year later, a second similar case (an eleven-yearold boy) was observed and the platelet defect was noted under the electron microscope.3 1. 2. 3.
Generally speaking, the alkyl-substituted derivatives have a similar but more pronounced effect. At the concentration used (0-002 M) the inhibition is antagonised by histamine. Another remarkable effect is seen in the action of these compounds on aminoacid metabolism. Paper chromatography showed that some of the compounds changed the level of at least two aminoacids which, to the best of our knowledge, were identified as glutamic acid and methionine. Of the compounds investi-
Frank, E., Ulutin, O. N. Bull. Soc. turq. Méd. 1957, 23, 301. Frank, E., Ulutin, O. N., Pecikyan, R. (in the press). Bilhan, N., Ulutin, O. N., Karaca, M., Sestakof, D. (in the press).
,
gated orphenadrine (&bgr;-dimethylaminoethyl 2-methylbenzhydrylether,Disipal’), gave the strongest effect-an elevenfold increase of glutamic acid and a more than seven-fold increase of " methionine ". Orphenadrine, the pharmacological properties of which are quite different 11from those of diphenhydrarnifte, is used in the treatment of parkinsonism12, but was recently found to have psychotropic activity13. These observations suggested that it might be useful to investigate the influence of psychotropic drugs on the aminoacid metabolism. Using the " collidine " filter-paper technique of Dent 14 the influence of orphenadrine on the aminoacid spectrum was reinvestigated (substrate: glucose 0-02 M, orphenadrine 0-002 M, buffer medium pH 7-2, weight of brain slices 80-100 mg.). We were able to prove that the designation of "
of the aminoacids mentioned above as methionine " was incorrect, and that after the experiment &ggr;-aminobutyric acid, as well as glutamic acid, was present in increased quantity. one
Braunsteiner, H., Fellinger, K., Pakesch, F. Klin. Wschr. 1953, 31, 21. Alatas, S., Ulutin, O. N. New Istan. contr. Clin. Sci. 1954, 3, 22. Frank, E., Ulutin, O. N., Karaca, M. ibid. 1956, 4, 62. Frank, E. Munch. med. Wschr. 1958, 100, 940. Paykoç, Z., Erişilgil, O. (unpublished observation). de Waart, C. Thesis, Vrije Universiteit, Amsterdam, 1958. de Waart, C. Acta physiol. pharmacol. Neerl. 1956, 5, 220; ibid. 1958 (in the press). 11. Bijisma, U. G., Harms, A. F., Funcke, A. B. H., Tersteege, H. M., Nauta, W. T. Arch. int. Pharmacodyn. 1956, 106, 332. 12. Gillhespy, R. O., Ratcliffe, A. H. Brit. med. J. 1955, ii, 352; Doshay, L. J., Constable, K. J. Amer. med. Ass. 1957, 163, 1352. 13. Scheurle, G. Dtsch. med. Wschr. 1957, 82, 2227. 14. Dent, C. E. Biochem. J. 1948, 43, 169. 4. 5. 6. 7. 8. 9. 10.
Defective pseudopodia formation and lack of spreading of hyalomere of platelet in a case of A.H.G.-deficiency with prolonged bleedingtime. (× 15,000.)
592 A
(a) Psychotropic drugs inhibit oxygen consumption of metabolising brain slices from 0 to 89% (molar concentrations as above). (b) If they affect aminoacid metabolism y-aminobutyric acid and glutamic acid are involved; in some cases only glutamic acid is present in larger concentration after the experiment. The results
so
far
are
compounds. As far as we know their influence on the aminoacid metabolism has not been investigated. During the past year y-aminobutyric acid has attracted the attention of several investigators. Its occurrence as free acid in relatively large amounts in the brain and its pharmacological
of these
preliminary investigation revealed that:
summarised in the accompanying table.
INHIBITION OF OXYGEN CONSUMPTION AND INCREASE IN AMINOACIDS
actions-e.g.
on
We would
central synapses-are very interesting."
not at
the
moment
suggest that the action o:
well-known psychotropic drugs could be explained by their influence on the y-aminobutyric-acid and glutamic-acid level in the brain alone, but we think it useful to continue our investigations in this direction and into the possibility of a biochemical classification" of psychotropic drugs. some
"
We
are
indebted
to
Mr. W. F. Kafoe for his valuable
help in the
experiments. Chemical
I
I
The inhibition of oxygen consumption tropic drugs is already known," but it is not
I
by some psychoa specific property
15. Pfeiffer, C. C., Jenney, E. H., Gallagher, W. Science, 1957, 126, 610 16. Bernsohn, J., Namajuska, I., Boshes, B. J. Neurochem. 1956, 1, 145.
Public Health Vaccination against Poliomyelitis THE Minister of Health has issued details of the Government’s plan for the extension of the poliomyelitis vaccination programme. This plan, based on the recommendations of the Joint Committee on Poliomyelitis Vaccine, with Lord Cohen of Birkenhead as chairman, falls broadly into three phases: 1. A drive to complete the vaccination of all those registered in the present priority groups and to raise the acceptance-rate among these groups as high as possible. The present groups are: (a) children aged 6 months to 15 years; (b) expectant mothers; (c) general practi-
tioners, hospital staff in contact with poliomyelitis patients, ambulance staff, and the families of these groups. 2. Vaccination of those born in 1933-42, thus raising the upper age limit from 15 to 25. 3. Vaccination of a wider range of hospital staff-namely, all who come in contact with patients-and medical students and the families of these groups. 4. Third injections. It is suggested that these should be offered to all who have already had two, in approximately the same order in which they were given their earlier injections, and that an offer should be made as soon as possible to those who were vaccinated in 1956.
Fluoridation
Laboratory,
Vrije Universiteit, Amsterdam. Laboratory for Chemical Physiology, Vrije Universiteit, Amsterdam. Research Department, Brocades, Amsterdam.
17.
W. TH. NAUTA. H. K. OOSTERHUIS C. DE WAART. M. J. E. ERNSTMG.
Purpura, D. P., Girado, M., Grundfest, H. Science, 1957, 125, 1200; Marrazzi, A. S., Ross Hart, E., Rodriguez, J. M. ibid. 1958, 127, 284; Roberts, E., Rothstein, M., Baxter, C. F. Proc. Soc. exp. Biol., N.Y. 1958, 97, 796; Kuriaki, K., Yakushiji, T., Noro, T., Shimizu, T., Saji, S. Nature; Lond. 1958, 181, 1336.
successful or defeated. As the result of a series of elections, the scheme ceased to command a majority on the council and the original decision to cooperate was reversed.2 The experience of New Zealand suggests that prejudiced opposition can be overcome by patient and vigorous instruction in the facts about fluoridation. In a programme of this kind, publicity should be given to experiences of local natural fluoridation of public water-supplies, such as that at Deeping St. James, in Kesteven, mentioned by the principal school medical officer for Lincolnshire in his annual report for 1957. In this area, the water has been naturally fluoridated at a constant level of 2’5 p.p.m. for no less than twenty years, and, " to quote the report, the markedly superior dental condition and oral hygiene of the children of Deeping St. James.., provide striking evidence in favour of fluoridation of othet water
supplies."
If the public could be convinced that countless peoplein these islands have been drinking naturally fluoridated water all their lives, with no ill effects, and that there is no essential difference between natural and artificial fluoridation, the opposition to this valuable preventive measure would at least be greatly weakened. 2. See
Lancet, July 26, 1958, p. 204.
Infectious Diseases in England and Wales
THE considered opinion of an international group of experts is given in a report from the World Health Organisation on the value of fluoridation of public water-supplies for the prevention of dental caries.1 This committee has no doubt about the efficacy, safety, or practicability of fluoridation: it draws attention to the mass of evidence that concentrations of 1 p.p.m. of fluorides, artificially or naturally present in drinking water, do no harm to health and go far to prevent decay of the teeth.
Unfortunately many members of the public do not see fluoridation in terms of compensating for a deficiency: they feel that something unnatural is being added, and they see possible danger to general health in drinking " doctored " water. The importance of such opposition was shown recently by the local decision to discontinue fluoridation of the watersupply at Andover-one of the places which were participating in the Ministry of Health’s test of the method. At Andover, as in some towns in New Zealand, fluoridation had become an acute political issue, on which candidates in local elections were 1. Expert Committee on Water Fluoridation; 1st Report. World Health Organisation Technical Report Series no. 146. Geneva: W.H.O. 1958 ; pp. 25. Obtainable from H.M. Stationery Office (P.O. Box 569, London, S.E.1). 1s. 9d.
*Not
including
late returns.
Unfortunately he died at the end of 1957, but the painful cedema of the hands and feet did not recur while he was receiving butazolidine, which was continued for about four months in all. In cases of this kind it may be worth trying butazolidine before emharking Colindale Hospital, London, N.W.9.
on vagotomy.
DIANA OWEN.
HÆMOPHILIA-LIKE STATES IN GIRLS SIR,—Iread with great interest the article by Professor Quick and Miss Hussey in your issue of June 21, and I want to emphasise the following findings. We, too, observed, with the late Prof. E. Frank, 2 cases of deficiency of antihxmophilic globulin (A.H.G.) (thromboplastinogen)
with
prolonged bleeding-time.
CASE I.—A
thirteen-year-old girl had
an
entirely negative
These findings suggest that in vascular haemophilia besides A.H.G.-deficiency there is a platelet defect as in the thrombasthenia described by Braunsteiner4 and by ourselves.5 In other words, these cases are combinations of thrombasthenia and haemophilia (thrombasthenia haemophilica). In these cases, the so-called Frank’s athrombia 6does exist-that is to say, the bleeding-time is prolonged because of defects in the aggregation and adhesiveness of platelets. The same defect of platelets has been observed by Payko and Erisilgil8 in a case of Christmas disease with prolonged bleeding-time. This finding confirms our observations. In my opinion, the third and fourth cases of Professor Quick are examples of the syndrome of thrombasthenia hsemophilica or athrombia hxmophilica.
family history. In childhood she had prolonged bleeding after minor cuts and bruised easily. She had severe epistaxis. The laboratory findings are summarised in the accompanying table.
Second Internal Clinic of Istanbul University, Guraba Hospital,
Istanbul, Turkey.
ORHAN NURI ULUTIN.
DIPLOMA OF CHILD HEALTH your educational number (Aug. 30) you do include the Royal Faculty of Physicians and of Glasgow amongst those bodies which grant a diploma of child health. Reference to the advertisement pages of the same number will confirm that it does.
SIR,-In
Surgeons
not
Royal Hospital for Sick Children, Glasgow, C.3.
ROBERT A. SHANKS.
ACTION OF PSYCHOTROPIC DRUGS ON &ggr;-AMINOBUTYRIC AND GLUTAMIC ACID IN RAT BRAIN SIR,-Recently one of us (C. de W.) recorded9 the results of an investigation into the inhibition of intermed-
iary metabolism by some diphenhydramine derivatives. Like the barbiturates, diphenhydramine reduces the oxygen consumption during oxidation of glucose (ratbrain slices).lo
A,H.G.-deficiency was noted, and A.H.G. was 5%. The case was a pseudohæmophilia B (vascular haemophilia or angiohæmophilia A). The cause of the prolonged bleeding-time was investigated and a platelet defect was observed under the electron microscope. The aggregation and adhesiveness, the formation of pseudopodia, and the spreading of hyalomere of platelets were absent or defective 12 (see fig.). CASE 2.-A year later, a second similar case (an eleven-yearold boy) was observed and the platelet defect was noted under the electron microscope.3 1. 2. 3.
Generally speaking, the alkyl-substituted derivatives have a similar but more pronounced effect. At the concentration used (0-002 M) the inhibition is antagonised by histamine. Another remarkable effect is seen in the action of these compounds on aminoacid metabolism. Paper chromatography showed that some of the compounds changed the level of at least two aminoacids which, to the best of our knowledge, were identified as glutamic acid and methionine. Of the compounds investi-
Frank, E., Ulutin, O. N. Bull. Soc. turq. Méd. 1957, 23, 301. Frank, E., Ulutin, O. N., Pecikyan, R. (in the press). Bilhan, N., Ulutin, O. N., Karaca, M., Sestakof, D. (in the press).
,
gated orphenadrine (&bgr;-dimethylaminoethyl 2-methylbenzhydrylether,Disipal’), gave the strongest effect-an elevenfold increase of glutamic acid and a more than seven-fold increase of " methionine ". Orphenadrine, the pharmacological properties of which are quite different 11from those of diphenhydrarnifte, is used in the treatment of parkinsonism12, but was recently found to have psychotropic activity13. These observations suggested that it might be useful to investigate the influence of psychotropic drugs on the aminoacid metabolism. Using the " collidine " filter-paper technique of Dent 14 the influence of orphenadrine on the aminoacid spectrum was reinvestigated (substrate: glucose 0-02 M, orphenadrine 0-002 M, buffer medium pH 7-2, weight of brain slices 80-100 mg.). We were able to prove that the designation of "
of the aminoacids mentioned above as methionine " was incorrect, and that after the experiment &ggr;-aminobutyric acid, as well as glutamic acid, was present in increased quantity. one
Braunsteiner, H., Fellinger, K., Pakesch, F. Klin. Wschr. 1953, 31, 21. Alatas, S., Ulutin, O. N. New Istan. contr. Clin. Sci. 1954, 3, 22. Frank, E., Ulutin, O. N., Karaca, M. ibid. 1956, 4, 62. Frank, E. Munch. med. Wschr. 1958, 100, 940. Paykoç, Z., Erişilgil, O. (unpublished observation). de Waart, C. Thesis, Vrije Universiteit, Amsterdam, 1958. de Waart, C. Acta physiol. pharmacol. Neerl. 1956, 5, 220; ibid. 1958 (in the press). 11. Bijisma, U. G., Harms, A. F., Funcke, A. B. H., Tersteege, H. M., Nauta, W. T. Arch. int. Pharmacodyn. 1956, 106, 332. 12. Gillhespy, R. O., Ratcliffe, A. H. Brit. med. J. 1955, ii, 352; Doshay, L. J., Constable, K. J. Amer. med. Ass. 1957, 163, 1352. 13. Scheurle, G. Dtsch. med. Wschr. 1957, 82, 2227. 14. Dent, C. E. Biochem. J. 1948, 43, 169. 4. 5. 6. 7. 8. 9. 10.
Defective pseudopodia formation and lack of spreading of hyalomere of platelet in a case of A.H.G.-deficiency with prolonged bleedingtime. (× 15,000.)
592 A
(a) Psychotropic drugs inhibit oxygen consumption of metabolising brain slices from 0 to 89% (molar concentrations as above). (b) If they affect aminoacid metabolism y-aminobutyric acid and glutamic acid are involved; in some cases only glutamic acid is present in larger concentration after the experiment. The results
so
far
are
compounds. As far as we know their influence on the aminoacid metabolism has not been investigated. During the past year y-aminobutyric acid has attracted the attention of several investigators. Its occurrence as free acid in relatively large amounts in the brain and its pharmacological
of these
preliminary investigation revealed that:
summarised in the accompanying table.
INHIBITION OF OXYGEN CONSUMPTION AND INCREASE IN AMINOACIDS
actions-e.g.
on
We would
central synapses-are very interesting."
not at
the
moment
suggest that the action o:
well-known psychotropic drugs could be explained by their influence on the y-aminobutyric-acid and glutamic-acid level in the brain alone, but we think it useful to continue our investigations in this direction and into the possibility of a biochemical classification" of psychotropic drugs. some
"
We
are
indebted
to
Mr. W. F. Kafoe for his valuable
help in the
experiments. Chemical
I
I
The inhibition of oxygen consumption tropic drugs is already known," but it is not
I
by some psychoa specific property
15. Pfeiffer, C. C., Jenney, E. H., Gallagher, W. Science, 1957, 126, 610 16. Bernsohn, J., Namajuska, I., Boshes, B. J. Neurochem. 1956, 1, 145.
Public Health Vaccination against Poliomyelitis THE Minister of Health has issued details of the Government’s plan for the extension of the poliomyelitis vaccination programme. This plan, based on the recommendations of the Joint Committee on Poliomyelitis Vaccine, with Lord Cohen of Birkenhead as chairman, falls broadly into three phases: 1. A drive to complete the vaccination of all those registered in the present priority groups and to raise the acceptance-rate among these groups as high as possible. The present groups are: (a) children aged 6 months to 15 years; (b) expectant mothers; (c) general practi-
tioners, hospital staff in contact with poliomyelitis patients, ambulance staff, and the families of these groups. 2. Vaccination of those born in 1933-42, thus raising the upper age limit from 15 to 25. 3. Vaccination of a wider range of hospital staff-namely, all who come in contact with patients-and medical students and the families of these groups. 4. Third injections. It is suggested that these should be offered to all who have already had two, in approximately the same order in which they were given their earlier injections, and that an offer should be made as soon as possible to those who were vaccinated in 1956.
Fluoridation
Laboratory,
Vrije Universiteit, Amsterdam. Laboratory for Chemical Physiology, Vrije Universiteit, Amsterdam. Research Department, Brocades, Amsterdam.
17.
W. TH. NAUTA. H. K. OOSTERHUIS C. DE WAART. M. J. E. ERNSTMG.
Purpura, D. P., Girado, M., Grundfest, H. Science, 1957, 125, 1200; Marrazzi, A. S., Ross Hart, E., Rodriguez, J. M. ibid. 1958, 127, 284; Roberts, E., Rothstein, M., Baxter, C. F. Proc. Soc. exp. Biol., N.Y. 1958, 97, 796; Kuriaki, K., Yakushiji, T., Noro, T., Shimizu, T., Saji, S. Nature; Lond. 1958, 181, 1336.
successful or defeated. As the result of a series of elections, the scheme ceased to command a majority on the council and the original decision to cooperate was reversed.2 The experience of New Zealand suggests that prejudiced opposition can be overcome by patient and vigorous instruction in the facts about fluoridation. In a programme of this kind, publicity should be given to experiences of local natural fluoridation of public water-supplies, such as that at Deeping St. James, in Kesteven, mentioned by the principal school medical officer for Lincolnshire in his annual report for 1957. In this area, the water has been naturally fluoridated at a constant level of 2’5 p.p.m. for no less than twenty years, and, " to quote the report, the markedly superior dental condition and oral hygiene of the children of Deeping St. James.., provide striking evidence in favour of fluoridation of othet water
supplies."
If the public could be convinced that countless peoplein these islands have been drinking naturally fluoridated water all their lives, with no ill effects, and that there is no essential difference between natural and artificial fluoridation, the opposition to this valuable preventive measure would at least be greatly weakened. 2. See
Lancet, July 26, 1958, p. 204.
Infectious Diseases in England and Wales
THE considered opinion of an international group of experts is given in a report from the World Health Organisation on the value of fluoridation of public water-supplies for the prevention of dental caries.1 This committee has no doubt about the efficacy, safety, or practicability of fluoridation: it draws attention to the mass of evidence that concentrations of 1 p.p.m. of fluorides, artificially or naturally present in drinking water, do no harm to health and go far to prevent decay of the teeth.
Unfortunately many members of the public do not see fluoridation in terms of compensating for a deficiency: they feel that something unnatural is being added, and they see possible danger to general health in drinking " doctored " water. The importance of such opposition was shown recently by the local decision to discontinue fluoridation of the watersupply at Andover-one of the places which were participating in the Ministry of Health’s test of the method. At Andover, as in some towns in New Zealand, fluoridation had become an acute political issue, on which candidates in local elections were 1. Expert Committee on Water Fluoridation; 1st Report. World Health Organisation Technical Report Series no. 146. Geneva: W.H.O. 1958 ; pp. 25. Obtainable from H.M. Stationery Office (P.O. Box 569, London, S.E.1). 1s. 9d.
*Not
including
late returns.