- Email: [email protected]
TREATMENT OF ADDER BITE
185
to
operate it in these
parlous times, when
in the Service are constrained by enfeebled resources and collapsing morale. "Hang on" is the wisest adviceand the hardest perhaps to follow-for the N.H.S. and for the nation, many of whose citizens are in more vulnerable shape than the doctors. If the doctors who call for strikes, however temporary, cannot find it in their hearts to refrain, as an example to national endeavour, then at least they must ponder what further damage they may be doing to a profession which has declined in public esteem, to their patients who have suffered much, and to their colleagues who have battled on, ill rewarded
-
and overworked, because they believed that this effort, for richer, for poorer, was part of a vow they made when they became doctors.
LIPOSOMES AS CARRIERS OF DRUGS
drugs might be wrapped up in tiny in the body selectively to certain and delivered packages cells, such as tumour cells, has long appealed to pharmacologists. Lately, liposomes have been used experimentally as carriers of drugs. They have an onion-like structure, being made up of concentric spherical layers of phospholipid and water. Since the liposomes have lipid and aqueous compartments they can be used to carry most drugs. They are versatile carriers since their size, THE notion that
and surface
be varied
will.
composition, charge For example, liposomes made up of phosphatidylcholinecontaining saturated-fatty-acid chains will be rather rigid at body temperature, whereas liposomes with other compositions are fluid. It is also possible to associate with the surface of a liposome a molecule, such as an antibody or lectin, that favours localisation at a particucan
at
lar site. For some years liposomes have been used as carriers of enzymes. Liposomes injected intravenously are preferentially removed by mononuclear phagocytic cells, mainly in the liver and spleen, and they can deliver penicillin and actinomycin D to these organs. In three patients with metastatic cancer there was some preferential uptake of labelled liposomes into malignant deposits.2 Antibodies against target cells have been used to encourage homing of liposomes and so too has desialylated fetuin, which is bound to parenchymal cells of the liver.3 Coating of liposomes with immunoglobulin has been proposed as a means of enhancing uptake of liposomes containing enzymes into phagocytic cells of patients with inherited enzyme deficiencies. Liposomes might also be used to deliver enzymes or drugs into different cellular compartments. Usually liposomes enter the lysosomal vacuolar system, where the lipid layers are digested and the contents released.12 4 .1 Negatively charged liposomes composed of lipid mixtures that are fluid at 37°C are incorporated into cell by fusion with the plasma membrane, so that they intro 1 Gregoriadis, G. FEBS Letters, 1973, 36, 292. 2 Gregoriadis, G., Swain, C P., Wills, E J, Tavill, A. S Lancet, 1974, i,
1313 3
G., Neerunjun, D. Biochem.
Biophys.
Res Comm
W
S.
K
OVER 150 years ago The Lancetl0 recorded three bites
by the adder, Vipera berus. One bite involved the author at St. Thomas’ Hospital. He took a frozen adder out of the freezing mixture and, not suspecting that it would quickly regain its native state, was bitten on the hand. The wound was immediately excised and "... not a single bad symptom followed the injury." Local measures such as this are not advocated by Reid" in a review of adder bites in Britain. Early symptoms of poisoning include local swelling and discolouration, vomiting, diarrhoea, and early collapse, which often resolves spontaneously. In severe poisoning, persistent or recurrent shock is the main feature. Deaths are rare-much less common than after bee or wasp stings. Nevertheless, deaths can occur, in adults as well as in children. There were several near-escapes among the severely poisoned, including personal experiences in doctors. Although the average doctor in Britain will never treat a patient for adder bite, this does not absolve him of responsibility. For the patient, an adder bite can be a matter of life or death and he is not interested in the rarity of the event. Guidelines both for first-aid and pre-hospital procedure and for hospital treatment of adder bite are summarised by Reid." Victims should be taken to hospital-preferably directly to the hospital designated to hold stocks of Zagreb antivenom (and also to have informed advice immediately available for clinicians and all concerned with adder bites). Most patients respond satisfactorily to simple symptomatic treatment but all patients should be carefully monitored, if possible in an intensive-care unit. Fatalities have occurred because on admission the patient was thought to have only slight poisoning. But it is important not to panic-there is abundant time to administer antivenom if it is indicated. The average time between bite and death was 34 hours. In 1957 a boy died from anaphylactic shock due to Pasteur antivenom." Understandably, many clinicians in Britain became reluctant to use antivenom. In 1969 Zagreb antivenom was made available; in a paper complementary to the clinical review, Theakston and Reid12 reported on its effectiveness in monkeys. In addition to saving life, the Zagreb antivenom greatly reduced the local effects even when administered as late as four hours after a triple-lethal dose of V. berus venom. The
7. G.,
M, Weissmann, G, Hoffstein, S, Awasthi, Y
5
TREATMENT OF ADDER BITE
1975, 65,
Bloomgarden, D., Kaplan, R., Cohen, C, Hoffstem, S, ColGotlilb, A, Nagle, D. Proc. natn Acad Sci., USA 1975, 72,
eissmann,
Biochemistry, 1976, 15, 452.
C, Srivastava,
contents
up.
6.
Gregoriadis, 537.
4
directly into the cytoplasmic compartment. Drug-containing liposomes have been shown to make drug-resistant tumour cells sensitive to actinomycin D.7 Preliminary reports also suggest that proteins such as insulin, when entrapped in liposomes, can be administered by the oral route and, protected from digestion, exert their physiological effects.899 All this work is still in the experimental stage, and the degree of selective uptake so far achieved is small. Nevertheless, a new approach to drug administration has been opened
duce their
all who work
8 9 10 11. 12
G., Mayhew, E Biochem. Soc. Trans. 1975, 3, 606. Poste, G., Papahadjopoulos, D. Nature, 1976, 261, 699 Patel, H. M, Ryman, B. E FEBS Letters, 1976, 62, 60. Dapergolas, G., Neerunjun, D., Gregoriadis, G. ibid. 1976, 63, 235 Lancet, 1824, iii, 161. Reid. H. A. Br. med J 1976, ii, 153. Theakston, R D. G., Reid, H A. Lancet, 1976, ii, 121
Papahadjopoulos, D., Poste,
186
conclusions are that Zagreb antivenom is indicated at all ages when life is endangered by shock. In addition, it should be considered in adult patients seen within two hours of the bite and already showing swelling extending up the bitten limb, with the object of reducing morbidity from local effects. Adults take longer than children to recover, two-thirds taking three or more weeks and a quarter taking one to nine months." During these months aches and intermittent swelling of the bitten limb may be disabling. Lessening the time for full recovery is more important for adults than it is for children. What are the dangers of antivenom therapy? Reactions of one kind or another are common, up to 48%,13 but immediate hypotensive reactions are much less common, about 3%. Zagreb antivenom is highly refined, making immediate reactions uncommon; for immediate antivenom reactions Reid" reports that adrenaline was invariably successful, provided it was promptly injected.
excess
ueciuie
iti
first six months
venniaLury capaciLy
uuserveu
III
Lite
sustained. These findings are not unexpected, but 23 of the group also had neural symptoms which have not previously been reported with isocyanates. 5 had immediate symptoms-euphoria, ataxia, and loss of consciousness. These and 9 others complained of headache, difficulty in concentration, poor memory, and confusion during the next three weeks. After four years, 13 men still complained of poor memory, personality change, irritability, and depression, and some of these symptoms were confirmed by psychowas not
metric testing. Normal industrial exposure is unlikely to be high enough to produce these symptoms, but the fact that they can occur after heavy exposure will be noted by those caring for isocyanate workers. The incident also draws attention to the need for special instruction of firemen about the hazards of fires in factories making and using substances with toxic products of combustion. Breathing apparatus seems to be the only safeguard against hazardous substances in the smoke.
ISOCYANATES IN THE FIRE ISOCYANATES are widely used in the synthesis of polyurethane, and their hazards have been known for at least twenty years. Polyurethane foam is one of the end-products, and the paint industry has been devising quick-drying polyurethane paints which depend on the presence of an isocyanate hardener or activator in the mix made for spraying. Toluene di-isocyanate (T.D.I.) is the most widely used of these compounds, but diphenyl methane di-isocyanate (M.D.I.), naphthalene di-iso-
(N.D.I.), and hexamethylene di-isocyanate also employed. Exposed workers may become sensitised and develop asthma-like symptoms which
cyanate
(H.D.I.)
are
re-exposure even to small amounts, and this sensitisation is commonest with T.D.I. and H.D.I., the more volatile members of the group. There is also an irritant effect on mucous membranes and skin. More rarely there may be irreversible lung damage, probably due to alveolitis, which shows itself in a permanent reduction in ventilatory capacity. In industry, the hazards are now generally recognised, the threshold limit value being 0-02 p.p.m. (For a potential sensitising agent there is no such thing as a safe limit, but this is a reasonably practicable level.) However, a further addition to recorded experience comes in two reports14 15 concerning a group of firemen who received a single severe exposure while dealing with recur on
fire in
polyurethane-foam factory, during which in large quantities from storage tanks. 35 firemen were exposed and most of them had symptoms at the time or in the ensuing three weeks. 15 complained of gastrointestinal symptoms, which were transient; but 31 had respiratory symptoms-initially, irritation of mucous membranes and subsequently tightness of the chest, cough, and breathlessness. These tended to improve ; but of 31 who were seen again after six months, 14 had persistent symptoms and said they were more susceptible to respiratory infections. Almost four years later, 20 men still had respiratory symptoms, but the a
T.D.I.
a
BILATERAL NEPHRECTOMY BEFORE TRANSPLANTATION
SOME transplant surgeons routinely remove both kidneys from patients on the waiting-list for renal transplantation. Now groups from Glasgow and Portland, Oregon, recommend a more conservative approach. In Glasgow’ 53 patients underwent bilateral nephrectomy, usually as a separate procedure from the transplantation.5 patients died as a result of the operation, and complications included hypotension, infection, and clotting of external shunts or arteriovenous fistulas. In the Portland series2 there were no operative deaths, but analysis of the results of subsequent transplantation revealed a significant advantage in terms of rejection and a possible one in terms of patient survival for the 49 patients without pre-transplant nephrectomy compared with the 27 who had had both kidneys removed. The rationale for nephrectomy is the avoidance of graft-hazarding urinary-tract infection: in Portland no patient with their old kidneys in place had graft-threatening sepsis, and in the Glasgow series 9 of the 17 nephrectomised pyelonephritic patients had one or more urinary infections. Some indications for bilateral nephrectomy remain, but the procedure is likely to become less of a routine in the light of these two reports.
spilled
13 Campbell, C. H Med. J. Aust. 1967, ii, 106. 14. Axford, A. T., McKerrow, C. B., Parry Jones, A., Le ind. Med. 1976, 33, 65. 15. Le Quesne, P. M., Axford, A. T., McKerrow, C. B.,
p.72
Quesne,
P. M.
A MEDICAL SCHOOL IN HULL
ANYONE advocating a scheme involving even modest Government expenditure today must be unbalanced, ridiculously optimistic, or convinced that his case is so strong that even penurious Britain cannot ignore it. The University of Hull clearly believes that its proposal for an early start on a medical school falls in the last category. The first formal case for a medical faculty in Hull was made in evidence to the Todd Commission in 1966,
Br. J. 1
Parry Jones,
A. ibid.
Calman, K C., Bell, P R. F., Bnggs, J. D., Hamilton, D N. H., Macpherson, S. G., Paton, A. M. Br J.Surg. 1976, 63, 512. 2. Bennett, W. M. J. Am. med. Ass. 1976, 235, 1703.
to
operate it in these
parlous times, when
in the Service are constrained by enfeebled resources and collapsing morale. "Hang on" is the wisest adviceand the hardest perhaps to follow-for the N.H.S. and for the nation, many of whose citizens are in more vulnerable shape than the doctors. If the doctors who call for strikes, however temporary, cannot find it in their hearts to refrain, as an example to national endeavour, then at least they must ponder what further damage they may be doing to a profession which has declined in public esteem, to their patients who have suffered much, and to their colleagues who have battled on, ill rewarded
-
and overworked, because they believed that this effort, for richer, for poorer, was part of a vow they made when they became doctors.
LIPOSOMES AS CARRIERS OF DRUGS
drugs might be wrapped up in tiny in the body selectively to certain and delivered packages cells, such as tumour cells, has long appealed to pharmacologists. Lately, liposomes have been used experimentally as carriers of drugs. They have an onion-like structure, being made up of concentric spherical layers of phospholipid and water. Since the liposomes have lipid and aqueous compartments they can be used to carry most drugs. They are versatile carriers since their size, THE notion that
and surface
be varied
will.
composition, charge For example, liposomes made up of phosphatidylcholinecontaining saturated-fatty-acid chains will be rather rigid at body temperature, whereas liposomes with other compositions are fluid. It is also possible to associate with the surface of a liposome a molecule, such as an antibody or lectin, that favours localisation at a particucan
at
lar site. For some years liposomes have been used as carriers of enzymes. Liposomes injected intravenously are preferentially removed by mononuclear phagocytic cells, mainly in the liver and spleen, and they can deliver penicillin and actinomycin D to these organs. In three patients with metastatic cancer there was some preferential uptake of labelled liposomes into malignant deposits.2 Antibodies against target cells have been used to encourage homing of liposomes and so too has desialylated fetuin, which is bound to parenchymal cells of the liver.3 Coating of liposomes with immunoglobulin has been proposed as a means of enhancing uptake of liposomes containing enzymes into phagocytic cells of patients with inherited enzyme deficiencies. Liposomes might also be used to deliver enzymes or drugs into different cellular compartments. Usually liposomes enter the lysosomal vacuolar system, where the lipid layers are digested and the contents released.12 4 .1 Negatively charged liposomes composed of lipid mixtures that are fluid at 37°C are incorporated into cell by fusion with the plasma membrane, so that they intro 1 Gregoriadis, G. FEBS Letters, 1973, 36, 292. 2 Gregoriadis, G., Swain, C P., Wills, E J, Tavill, A. S Lancet, 1974, i,
1313 3
G., Neerunjun, D. Biochem.
Biophys.
Res Comm
W
S.
K
OVER 150 years ago The Lancetl0 recorded three bites
by the adder, Vipera berus. One bite involved the author at St. Thomas’ Hospital. He took a frozen adder out of the freezing mixture and, not suspecting that it would quickly regain its native state, was bitten on the hand. The wound was immediately excised and "... not a single bad symptom followed the injury." Local measures such as this are not advocated by Reid" in a review of adder bites in Britain. Early symptoms of poisoning include local swelling and discolouration, vomiting, diarrhoea, and early collapse, which often resolves spontaneously. In severe poisoning, persistent or recurrent shock is the main feature. Deaths are rare-much less common than after bee or wasp stings. Nevertheless, deaths can occur, in adults as well as in children. There were several near-escapes among the severely poisoned, including personal experiences in doctors. Although the average doctor in Britain will never treat a patient for adder bite, this does not absolve him of responsibility. For the patient, an adder bite can be a matter of life or death and he is not interested in the rarity of the event. Guidelines both for first-aid and pre-hospital procedure and for hospital treatment of adder bite are summarised by Reid." Victims should be taken to hospital-preferably directly to the hospital designated to hold stocks of Zagreb antivenom (and also to have informed advice immediately available for clinicians and all concerned with adder bites). Most patients respond satisfactorily to simple symptomatic treatment but all patients should be carefully monitored, if possible in an intensive-care unit. Fatalities have occurred because on admission the patient was thought to have only slight poisoning. But it is important not to panic-there is abundant time to administer antivenom if it is indicated. The average time between bite and death was 34 hours. In 1957 a boy died from anaphylactic shock due to Pasteur antivenom." Understandably, many clinicians in Britain became reluctant to use antivenom. In 1969 Zagreb antivenom was made available; in a paper complementary to the clinical review, Theakston and Reid12 reported on its effectiveness in monkeys. In addition to saving life, the Zagreb antivenom greatly reduced the local effects even when administered as late as four hours after a triple-lethal dose of V. berus venom. The
7. G.,
M, Weissmann, G, Hoffstein, S, Awasthi, Y
5
TREATMENT OF ADDER BITE
1975, 65,
Bloomgarden, D., Kaplan, R., Cohen, C, Hoffstem, S, ColGotlilb, A, Nagle, D. Proc. natn Acad Sci., USA 1975, 72,
eissmann,
Biochemistry, 1976, 15, 452.
C, Srivastava,
contents
up.
6.
Gregoriadis, 537.
4
directly into the cytoplasmic compartment. Drug-containing liposomes have been shown to make drug-resistant tumour cells sensitive to actinomycin D.7 Preliminary reports also suggest that proteins such as insulin, when entrapped in liposomes, can be administered by the oral route and, protected from digestion, exert their physiological effects.899 All this work is still in the experimental stage, and the degree of selective uptake so far achieved is small. Nevertheless, a new approach to drug administration has been opened
duce their
all who work
8 9 10 11. 12
G., Mayhew, E Biochem. Soc. Trans. 1975, 3, 606. Poste, G., Papahadjopoulos, D. Nature, 1976, 261, 699 Patel, H. M, Ryman, B. E FEBS Letters, 1976, 62, 60. Dapergolas, G., Neerunjun, D., Gregoriadis, G. ibid. 1976, 63, 235 Lancet, 1824, iii, 161. Reid. H. A. Br. med J 1976, ii, 153. Theakston, R D. G., Reid, H A. Lancet, 1976, ii, 121
Papahadjopoulos, D., Poste,
186
conclusions are that Zagreb antivenom is indicated at all ages when life is endangered by shock. In addition, it should be considered in adult patients seen within two hours of the bite and already showing swelling extending up the bitten limb, with the object of reducing morbidity from local effects. Adults take longer than children to recover, two-thirds taking three or more weeks and a quarter taking one to nine months." During these months aches and intermittent swelling of the bitten limb may be disabling. Lessening the time for full recovery is more important for adults than it is for children. What are the dangers of antivenom therapy? Reactions of one kind or another are common, up to 48%,13 but immediate hypotensive reactions are much less common, about 3%. Zagreb antivenom is highly refined, making immediate reactions uncommon; for immediate antivenom reactions Reid" reports that adrenaline was invariably successful, provided it was promptly injected.
excess
ueciuie
iti
first six months
venniaLury capaciLy
uuserveu
III
Lite
sustained. These findings are not unexpected, but 23 of the group also had neural symptoms which have not previously been reported with isocyanates. 5 had immediate symptoms-euphoria, ataxia, and loss of consciousness. These and 9 others complained of headache, difficulty in concentration, poor memory, and confusion during the next three weeks. After four years, 13 men still complained of poor memory, personality change, irritability, and depression, and some of these symptoms were confirmed by psychowas not
metric testing. Normal industrial exposure is unlikely to be high enough to produce these symptoms, but the fact that they can occur after heavy exposure will be noted by those caring for isocyanate workers. The incident also draws attention to the need for special instruction of firemen about the hazards of fires in factories making and using substances with toxic products of combustion. Breathing apparatus seems to be the only safeguard against hazardous substances in the smoke.
ISOCYANATES IN THE FIRE ISOCYANATES are widely used in the synthesis of polyurethane, and their hazards have been known for at least twenty years. Polyurethane foam is one of the end-products, and the paint industry has been devising quick-drying polyurethane paints which depend on the presence of an isocyanate hardener or activator in the mix made for spraying. Toluene di-isocyanate (T.D.I.) is the most widely used of these compounds, but diphenyl methane di-isocyanate (M.D.I.), naphthalene di-iso-
(N.D.I.), and hexamethylene di-isocyanate also employed. Exposed workers may become sensitised and develop asthma-like symptoms which
cyanate
(H.D.I.)
are
re-exposure even to small amounts, and this sensitisation is commonest with T.D.I. and H.D.I., the more volatile members of the group. There is also an irritant effect on mucous membranes and skin. More rarely there may be irreversible lung damage, probably due to alveolitis, which shows itself in a permanent reduction in ventilatory capacity. In industry, the hazards are now generally recognised, the threshold limit value being 0-02 p.p.m. (For a potential sensitising agent there is no such thing as a safe limit, but this is a reasonably practicable level.) However, a further addition to recorded experience comes in two reports14 15 concerning a group of firemen who received a single severe exposure while dealing with recur on
fire in
polyurethane-foam factory, during which in large quantities from storage tanks. 35 firemen were exposed and most of them had symptoms at the time or in the ensuing three weeks. 15 complained of gastrointestinal symptoms, which were transient; but 31 had respiratory symptoms-initially, irritation of mucous membranes and subsequently tightness of the chest, cough, and breathlessness. These tended to improve ; but of 31 who were seen again after six months, 14 had persistent symptoms and said they were more susceptible to respiratory infections. Almost four years later, 20 men still had respiratory symptoms, but the a
T.D.I.
a
BILATERAL NEPHRECTOMY BEFORE TRANSPLANTATION
SOME transplant surgeons routinely remove both kidneys from patients on the waiting-list for renal transplantation. Now groups from Glasgow and Portland, Oregon, recommend a more conservative approach. In Glasgow’ 53 patients underwent bilateral nephrectomy, usually as a separate procedure from the transplantation.5 patients died as a result of the operation, and complications included hypotension, infection, and clotting of external shunts or arteriovenous fistulas. In the Portland series2 there were no operative deaths, but analysis of the results of subsequent transplantation revealed a significant advantage in terms of rejection and a possible one in terms of patient survival for the 49 patients without pre-transplant nephrectomy compared with the 27 who had had both kidneys removed. The rationale for nephrectomy is the avoidance of graft-hazarding urinary-tract infection: in Portland no patient with their old kidneys in place had graft-threatening sepsis, and in the Glasgow series 9 of the 17 nephrectomised pyelonephritic patients had one or more urinary infections. Some indications for bilateral nephrectomy remain, but the procedure is likely to become less of a routine in the light of these two reports.
spilled
13 Campbell, C. H Med. J. Aust. 1967, ii, 106. 14. Axford, A. T., McKerrow, C. B., Parry Jones, A., Le ind. Med. 1976, 33, 65. 15. Le Quesne, P. M., Axford, A. T., McKerrow, C. B.,
p.72
Quesne,
P. M.
A MEDICAL SCHOOL IN HULL
ANYONE advocating a scheme involving even modest Government expenditure today must be unbalanced, ridiculously optimistic, or convinced that his case is so strong that even penurious Britain cannot ignore it. The University of Hull clearly believes that its proposal for an early start on a medical school falls in the last category. The first formal case for a medical faculty in Hull was made in evidence to the Todd Commission in 1966,
Br. J. 1
Parry Jones,
A. ibid.
Calman, K C., Bell, P R. F., Bnggs, J. D., Hamilton, D N. H., Macpherson, S. G., Paton, A. M. Br J.Surg. 1976, 63, 512. 2. Bennett, W. M. J. Am. med. Ass. 1976, 235, 1703.