1080
in the efferent lymph. However, except for a transient
disturbance immediately after irradiation, there was little
change in the morphology of the cells of the efferent
lymph.
Five preparations were stimulated antigenically 6-140
hours after the lymph-nodes had received 2000r. The
resulting increases in antibody titre and the characteristic
changes in the cellular composition of the lymph showed
that the immunological responsiveness of the nodes had
not been altered significantly by irradiation.
These results suggest that the functional capacity of the
lymphoid component of a lymph-node depends substantially on the entry of recirculating lymphocytes derived
from the pool of lymphocytes in the body rather than
on the primary production of lymphocytes within the
node.
We are indebted to Dr. R. D. Brock, of the Division of Plant
Industry, Commonwealth Scientific and Industrial Research Organisation, for making X-ray facilities available to us, and for his help
and advice during the irradiation procedures.
J. G. HALL
Department of Experimental
Pathology, John Curtin School
of Medical Research,
Australian National University,
Canberra, Australia
M.B.
B.V.SC.
Lond.
BEDE MORRIS
Sydney, D.PHIL. Oxon.
A NEW ADRENERGIC
BETA-RECEPTOR ANTAGONIST
PRONETHALOL was shown by Black and StephensonI
to be a specific adrenergic B-receptor antagonist which
was relatively free from sympathomimetic activity on the
cardiovascular system. Clinically, pronethalol has been
shown to be of potential value in the treatment of various
cardiac disorders .2-The clinical investigation of pronethalol has, however, been limited, partly by the presence
of undesirable side-effects in man, and partly because of a
particular toxic effect in mice. The side-effects in man
include lightheadedness and slight incoordination followed
by nausea and vomiting. These side-effects may be due
to a non-specific action of pronethalol on the central
nervous system, since in animals acute toxicity of central
nervous origin occurs with both the (+)- active and the
(Ň)Ň inactive isomers. Toxicity studies in animals
showed that pronethalol was free from chronic toxicity in
rats and dogs, but that mice developed lymphosarcomas
and reticulum-cell sarcomas, which were first seen in the
thymus. A large number of compounds have now been
made and tested in an effort to find one with a wider
therapeutic ratio than pronethalol and with no carcinogenic potential. Compound I.C.I. 45,520 (’ Inderal’) has
been found to satisfy these criteria.
I.C.I. 45,520 is 1-isopropylamino-3-(1-naphthyloxy)-2orooanol hvdrochloride:
1.
2.
3.
4.
5.
6.
7.
8.
Effect of I.C.I. 45,520 and pronethalol on increments in myocardial
tension produced by isoprenaline (results expressed as percentage
block of control responses).
Black, J. W., Stephenson, J. S. Lancet, 1962, ii, 311.
Stock, J. P. P., Dale, N. Brit. med. J. 1963, ii, 1230.
Dornhorst, A. C., Laurence, D. R. ibid. p. 1250.
Alleyne, G. A. O., Dickinson, C. J., Dornhorst, A. C., Fulton, R. M.,
Green, K. G., Hill, I. D., Hurst, P., Laurence, D. R., Pilkington, T.,
Prichard, B. N. S., Robinson, B., Rosenheim, M. L. ibid. p. 1266.
Payne, J. P., Senfield, R. M. ibid. 1964, i, 603.
Honey, M., Chamberlain, D. A., Howard, J. Circulation Res. (in the
press).
Johnstone, M. G. Brit. J. Anœsth. (in the press).
Paget, G. E. Brit. med. J. 1963, ii, 1266.
This new compound has
essentially the same pharmacopronethalol. The p-adrenergic
logical properties
the
of
two compounds has been comblocking activity
in
anaesthetised
dogs and on the isolated sinopared
atrial-node preparation of the guineapig. Dogs were
anaathetised with intravenous pentobarbitone; and increments in isometric tension, produced by intravenous
isoprenaline, were recorded from a strain-gauge arch
sutured to the left ventricle. The accompanying figure
shows the effects of increasing doses of pronethalol and of
I.C.I. 45,520 on the responses to isoprenaline. These
findings show that I.C.I. 45,520 is about ten times as
active in blocking the inotropic action of isoprenaline.
The effect of I.C.I. 45,520 and pronethalol on the chronotropic effect of adrenaline was investigated on an isolated
guineapig sinoatrial node preparation. The amounts of
pronethalol and I.C.I. 45,520 required to produce 50%
antagonism of a maximum increase in rate produced by
as
adrenaline (E.D...n)
were as
follows:
These results confirm that I.C.I. 45,520 is about ten
times more active than pronethalol.
Estimates of acute lethal toxicity were made in mice.
The L.D.5o was 30-40 mg. per kg. body-weight for male
mice and 40-50 mg. per kg. for female mice when the
drug was given intravenously. Under the same conditions,
the L.D.50 for pronethalol was 45-50 mg. per kg. bodyweight for male and female mice.
I.C.I. 45,520, 200 mg. per kg., was administered orally
to thirty male and thirty female mice for sixty-six weeks.
No tumours were found in the mice. In a comparable
series of experiments with pronethalol, thymic tumours
began to appear after ten weeks’ treatment.
Experience with this drug in man confirms that effective
P-blockade is achieved at about a tenth of the dose
needed for pronethalol, and at the effective blocking dose
there is no production of lightheadedness or incoordination.
In conclusion, I.C.I. 45,520 is an adrenergic B-receptor
antagonist which has a therapeutic ratio about ten times
greater than that of pronethalol. It has not caused thymic
tumours in mice, and in man does not produce the side-
1081
effects associated with pronethalol. The evidence suggests
that I.C.I. 45,520 should have extended clinical evaluation.
J. W. BLACK
M.B.
St. And.
A. F. CROWTHER
M.A.,
PH.D.
Cantab.
R. G. SHANKS
Imperial Chemical Industries, Ltd.,
Pharmaceuticals Division, Research
Department, Alderley Park, Cheshire
Medical Unit, St. George’s Hospital,
London, S.W.1
B.SC.,
M.D.
Belf.
L. H. SMITH
A. C. DORNHORST
M.D. Lond., F.R.C.P.
New Inventions
IMPROVED ALARM DEVICE FOR KOLFF
TWIN-COIL KIDNEY
DURING dialysis the hydrostatic pressure in the circuit of
the Kolff twin-coil artificial kidney must be watched continuously. In particular, if the pressure, which may fluctuate
unexpectedly, rises above 300 mm. Hg, the coil may burst.
Recently, an alarm device to warn against excessive coil
pressures was described by Bienenstock and Shaldon 1: the
electrical circuit was completed when a mercury column rose
above a pre-set level; an alarm bell rang and a relay switch
cut out the pump motor. Two 41/2 V batteries were used to
supply the circuit.
Bienenstock and Shaldon’s device is simple but has disadvantages. First, after the pump motor has been cut out, the
coil pressure falls and the electrical circuit is interrupted:
the pump motor re-starts and the pressure rises, whereupon the
pump is again cut out. Thus, the motor stops and starts
repeatedly until measures are taken to reduce the coil pressure.
Secondly, should a fault develop in the electrical circuit of
the alarm during dialysis, the pump continues to operate and
high pressures may be generated while the attendant medical
staff, unaware of the fault,. are relying on the alarm.
We have devised compact equipment which overcomes
these drawbacks, and which incorporates a mercury manometer to show the coil pressure whether or not the alarm is in
use (fig. 1). Circuit details are shown in fig. 2. The relay and
bell are supplied with 4 V d.c. from the a.c. mains through a
transformer and rectifier. thus disnensm? with batteries. One
1. Bienenstock, J., Shaldon, S. Lancet, 1963, ii, 815.
set of
relay
con-
controls the
bell and energising coil of the
relay itself; the
other
(heavy-
tacts
duty
contacts)
controls the
pump motor. A
diaphragm-type
pressure switch
has " normally
closed " contacts
in series with
the relay coil.
S, is the main
switch, and a
changeover
switch Sj2 enables the pump
to
motor
be
Fig. 2-Circuit details.
switched directly
on to the mains supply; pilot lights indicate whether the
motor is operating directly or through the alarm circuit.
Before the start of dialysis the pressure lead from the bubbletraps is connected with tubing (disposable recipient set extension tubing* is suitable) to the Luer mount at A in fig. 1.
When Sl is closed the bell rings, thus testing the alarm system.
Then the push switch S3 is pressed: the relay is energised and
the contacts change over, starting the pump motor and stopping the bell. If the pressure in the system rises high enough
(250 mm. Hg in this case) to separate the pressure switch
contacts, the relay opens, the bell rings, and the motor stops.
The motor cannot re-start until the pressure is lowered and
the push switch Sg is again pressed. The mode of operation
ensures that failure in the alarm-circuit supply or discontinuity
in the relay-energising circuit immediately shuts off the pump.
The device thus " fails safe ". In the event of such a failure,
however, dialysis may be continued by switching the pump
motor directly on to the mains supply through S2’ in the full
knowledge that the alarm is not in the circuit.
The alarm is particularly useful when high coil pressures
are deliberately used to augment ultrafiltration.
A. J. Low
Departments of Surgery
N. A. MATHESON
and Medical Physics,
M.B. Aberd., F.R.C.S., F.R.C.S.E.
University of Aberdeen
INSTRUMENT FOR EMERGENCY
LARYNGOTOMY
EMERGENCY tracheostomy for the relief of obstructive
laryngeal dyspnoea may be needed urgently to save life and
Yet ’any doctor may, at a moment’s
can be very difficult.
notice, be called on to undertake such an operation.
The easiest way of getting air into the lungs in a hurry is to
make a small cut in the skin over the larynx in the midline,
v
rtg. alarm equipment incorporating
a
mercury manometer.
and then open the membrane between the cricoid and thyroid
cartilages and slip in a small cannula. This can be left in for a
few hours until the patient can be taken to hospital, and, if
the obstruction is still present, a leisurely tracheostomy below
the first ring of the trachea can be carried out in an operatingtheatre and then the laryngotomy cannula can be removed.
The small combined instrument shown in the accompanying
figure comprises a knife and a laryngotomy cannula and can
be carried easily in the pocket or a bag, and in the casualty
department and certain wards of hospitals. Though not often
needed, it may enable a life to be saved by any doctor at any
*
Capon Heaton & Co. Ltd., Stirchley, Birmingham, 30.