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,
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,
