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TOXIC EFFECTS OF BUSULPHAN
1
854 " interpretation " areas of the temporal-lobe cortex, which might be peculiar to man, since memories of baser sexual and oral gratifications were never evoked. Nevertheless, the fact that resection of the anterior horn of the temporal lobe did not usually impair memory showed that the permanent engram did not reside in the cortical mantle. It was here that the astute interpretation of chance clinical finding played a further part in elucidating the memory mechanism. Two epileptic patients subjected to a more radical operation which removed the hippocampal gyrus did experience a peculiar type of memory loss; both of them (an engineer and a glove cutter) retained the basic skills of their trade but each was unable to retain imme- diate facts once their attention was distracted. Recent memory was also impaired (Wilder Penfield was remem- bered and a contemporary girl-friend forgotten). Penfield’s inspired speculation that the contralateral hippocampal zone (" that area of the brain rolled up like a rug beneath the ventricle ") must also be damaged has since been confirmed. At least one or two aspects of memory localisation now seem clearer. The interpretation areas of the temporal cortex can scan the past and interpret the present by recall from the bilateral hippocampal zones which retain the sequential record of experience. Dr. Penfield was too wise and too modest to strain the interpretation of his findings further, but they remain milestones in the frustrating and fascinating search for memory and where it lies in the brain. TOXIC EFFECTS OF BUSULPHAN THE toxic drugs used in the treatment of malignant disease have some serious adverse effects in common, and treatment is often continued until one of these effects appears. Bone-marrow depression affecting some or all of the blood-cell series has been reported with each of them, and agranulocytosis brings the risk of infection, commonly by a fungus. Rashes are frequent, and several cytotoxic drugs produce alopecia. Reactions in the gastrointestinal tract and liver are also common. Moreover, all these drugs are known to be teratogenic. Busulphan can produce any of these toxic effects, and also a peculiar addisonian- like pigmentation in patients receiving it for a long time. Porphyria cutanea tarda may be initiated or precipitated by busulphan.1 Amenorrhoea has been reported in women of childbearing age, but it does not seem to be dose- dependent.2 Another side-effect of busulphan given for chronic granulocytic leuksemia is diffuse pulmonary fibrosis, first described by Oliner et al.3 and confirmed by others.4 Although this was originally thought to be a form of "interstitial fibrosis ", Heard and Cooke describe a case in which the alveoli were filled by organising fibrin and the fibrous tissue seemed to be intra-alveolar rather than interstitia1. 5 Thus, the changes resembled those which may appear in the lungs of patients given hexametho- nium,6 7 which has certain structural similarities to busulphan. Heard and Cooke studied at necropsy the lungs of 14 patients with chronic granulocytic leukxmia 1. Kyle, R. A., Dameshek, W. Blood, 1963, 22, 776. 2. Netter-Lambert, A., Bourignac, M.-Cl., Netter, A. Presse méd. 1963, 71, 2285. 3. Oliner, H., Schwartz, R., Rubio, F., Dameshek, W. Am. J. Med. 1961, 31, 134. 4. Leake, E., Smith, W. G., Woodliff, H. J. Lancet, 1963, ii, 432. 5. Heard, B. E., Cooke, R. A. Thorax, 1968, 23, 187. 6. Doniach, I., Morrison, B., Steiner, R. E. Br. Heart J. 1954, 16, 101. 7. Heard, B. E. J. Path. Bact. 1962, 83, 159. treated with busulphan, and fibrinous oedema changing to fibrous tissue was found in 6. Only 1 out of 7 control patients with leukxmia not receiving busulphan had these changes. The alveoli of busulphan-treated patients con- tained large atypical cells which resembled cells found by other workers in other tissues, including bronchial epi- thelium, uterine cervical epithelium, and lymph-nodes. Although the mechanism of production of these lung changes are not known, Heard and Cooke suggest they should be called intra-alveolar fibrosis rather than inter- stitial fibrosis. The histological picture is impressive, but the lesions seldom seem to cause much respiratory embar- rassment. The drug need rarely be withdrawn, therefore- only when the intra-alveolar fibrosis produces severe disability. APRIL 27 REGULATIONS 1 which the Minister of Health laid before Parliament on April 1 concern the certificates of opinion and the notices of termination required by the Abortion Act when it comes into operation on April 27.2 The Regulations need explanation on certain points. Before the Bill was passed, the debate in the Commons and elsewhere indicated that the aims of notification would be: to provide information for statistical analysis; and to deter unscrupulous doctors from performing abortions purely for money, by compelling them to justify their action with certified reasons. In the Regulations now proposed the first (the statistical) object may have been given more thought than the record of reasons. The Regulations demand little of the recommending doctors: they must simply " ring " one of the four groups of possible indications approved by the Act. For his part, the doctor who actually does the abortion must supply, for scrutiny at the Ministry of Health, for possible transmission to the Registrar General, and conceivably for exposure to the police, certain information about the pregnant woman, not all of it seemingly vital. For one thing, what if the patient forbids her doctor to disclose her name and address-or gives them falsely? A more confidential (though not necessarily more accurate) account might be afforded by the doctor’s own records, not to be transmitted unless the need was more than routine. Must the woman’s N.H.S. number be part of the contract-and her maiden name ? The questions to be asked about existing children do not seem to take full account of everyone who might be judged, under the terms of the Act, a child. The time set by the Regulations for the certificates to be completed is short. For example, if a general practi- tioner sees a woman who has attempted suicide, and he believes that pregnancy is largely responsible for her illness, will he have time to ensure that schedule 1 is completed within 24 hours ? A young girl may be advanced in pregnancy before her trouble is understood: if termination is then advised, can schedule 1 be com- pleted in time ? Such situations may not rank as out- right emergencies, but they could be urgent all the same. The 7-day limit on schedule 2 may also create difficulties, because many gynxcologists visit some of their hospitals only once a week. The Regulations require them to complete schedule 2 at the time of operation: they may not be able to do it all at that time; and a proposed later sterilisation may not fall within the limit. 1. See Lancet, April 13, 1968, p. 825. 2. See ibid. March 30, 1968, p. 678.
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Transcript of TOXIC EFFECTS OF BUSULPHAN
854
" interpretation " areas of the temporal-lobe cortex, which
might be peculiar to man, since memories of baser sexualand oral gratifications were never evoked. Nevertheless,the fact that resection of the anterior horn of the temporallobe did not usually impair memory showed that thepermanent engram did not reside in the cortical mantle.It was here that the astute interpretation of chance clinicalfinding played a further part in elucidating the memorymechanism. Two epileptic patients subjected to a moreradical operation which removed the hippocampal gyrusdid experience a peculiar type of memory loss; both ofthem (an engineer and a glove cutter) retained the basicskills of their trade but each was unable to retain imme-diate facts once their attention was distracted. Recent
memory was also impaired (Wilder Penfield was remem-bered and a contemporary girl-friend forgotten). Penfield’sinspired speculation that the contralateral hippocampalzone (" that area of the brain rolled up like a rug beneaththe ventricle ") must also be damaged has since beenconfirmed.At least one or two aspects of memory localisation now
seem clearer. The interpretation areas of the temporalcortex can scan the past and interpret the present byrecall from the bilateral hippocampal zones which retainthe sequential record of experience. Dr. Penfield was toowise and too modest to strain the interpretation of hisfindings further, but they remain milestones in the
frustrating and fascinating search for memory and whereit lies in the brain.
TOXIC EFFECTS OF BUSULPHAN
THE toxic drugs used in the treatment of malignantdisease have some serious adverse effects in common, andtreatment is often continued until one of these effects
appears. Bone-marrow depression affecting some or all ofthe blood-cell series has been reported with each of them,and agranulocytosis brings the risk of infection, commonlyby a fungus. Rashes are frequent, and several cytotoxicdrugs produce alopecia. Reactions in the gastrointestinaltract and liver are also common. Moreover, all thesedrugs are known to be teratogenic. Busulphan can produceany of these toxic effects, and also a peculiar addisonian-like pigmentation in patients receiving it for a long time.Porphyria cutanea tarda may be initiated or precipitatedby busulphan.1 Amenorrhoea has been reported in womenof childbearing age, but it does not seem to be dose-
dependent.2Another side-effect of busulphan given for chronic
granulocytic leuksemia is diffuse pulmonary fibrosis, firstdescribed by Oliner et al.3 and confirmed by others.4Although this was originally thought to be a form of"interstitial fibrosis ", Heard and Cooke describe a casein which the alveoli were filled by organising fibrin andthe fibrous tissue seemed to be intra-alveolar rather thaninterstitia1. 5 Thus, the changes resembled those whichmay appear in the lungs of patients given hexametho-nium,6 7 which has certain structural similarities to
busulphan. Heard and Cooke studied at necropsy the
lungs of 14 patients with chronic granulocytic leukxmia1. Kyle, R. A., Dameshek, W. Blood, 1963, 22, 776.2. Netter-Lambert, A., Bourignac, M.-Cl., Netter, A. Presse méd. 1963,
71, 2285.3. Oliner, H., Schwartz, R., Rubio, F., Dameshek, W. Am. J. Med. 1961,
31, 134.4. Leake, E., Smith, W. G., Woodliff, H. J. Lancet, 1963, ii, 432.5. Heard, B. E., Cooke, R. A. Thorax, 1968, 23, 187.6. Doniach, I., Morrison, B., Steiner, R. E. Br. Heart J. 1954, 16, 101.7. Heard, B. E. J. Path. Bact. 1962, 83, 159.
treated with busulphan, and fibrinous oedema changing tofibrous tissue was found in 6. Only 1 out of 7 controlpatients with leukxmia not receiving busulphan had thesechanges. The alveoli of busulphan-treated patients con-tained large atypical cells which resembled cells foundby other workers in other tissues, including bronchial epi-thelium, uterine cervical epithelium, and lymph-nodes.
Although the mechanism of production of these lungchanges are not known, Heard and Cooke suggest theyshould be called intra-alveolar fibrosis rather than inter-stitial fibrosis. The histological picture is impressive, butthe lesions seldom seem to cause much respiratory embar-rassment. The drug need rarely be withdrawn, therefore-only when the intra-alveolar fibrosis produces severe
disability.
APRIL 27
REGULATIONS 1 which the Minister of Health laid beforeParliament on April 1 concern the certificates of opinionand the notices of termination required by the AbortionAct when it comes into operation on April 27.2 TheRegulations need explanation on certain points. Beforethe Bill was passed, the debate in the Commons andelsewhere indicated that the aims of notification wouldbe: to provide information for statistical analysis; and todeter unscrupulous doctors from performing abortionspurely for money, by compelling them to justify theiraction with certified reasons. In the Regulations nowproposed the first (the statistical) object may have beengiven more thought than the record of reasons.The Regulations demand little of the recommending
doctors: they must simply " ring " one of the four groupsof possible indications approved by the Act. For his
part, the doctor who actually does the abortion mustsupply, for scrutiny at the Ministry of Health, for possibletransmission to the Registrar General, and conceivablyfor exposure to the police, certain information about thepregnant woman, not all of it seemingly vital. For one
thing, what if the patient forbids her doctor to discloseher name and address-or gives them falsely? A moreconfidential (though not necessarily more accurate)account might be afforded by the doctor’s own records,not to be transmitted unless the need was more thanroutine. Must the woman’s N.H.S. number be part ofthe contract-and her maiden name ? The questionsto be asked about existing children do not seem to takefull account of everyone who might be judged, under theterms of the Act, a child.The time set by the Regulations for the certificates to
be completed is short. For example, if a general practi-tioner sees a woman who has attempted suicide, and hebelieves that pregnancy is largely responsible for her
illness, will he have time to ensure that schedule 1 is
completed within 24 hours ? A young girl may beadvanced in pregnancy before her trouble is understood:if termination is then advised, can schedule 1 be com-
pleted in time ? Such situations may not rank as out-right emergencies, but they could be urgent all the same.The 7-day limit on schedule 2 may also create difficulties,because many gynxcologists visit some of their hospitalsonly once a week. The Regulations require them to
complete schedule 2 at the time of operation: they maynot be able to do it all at that time; and a proposed latersterilisation may not fall within the limit.
1. See Lancet, April 13, 1968, p. 825.2. See ibid. March 30, 1968, p. 678.
