Brit. J. Anaesth.

(1971), 43, 637

RESPIRATORY AND HYPNOTIC EFFECTS OF NITRAZEPAM, DIAZEPAM

AND PENTOBARBITONE AND THEIR SOLVENTS IN THE RABBIT AND
THE MOUSE
BY

ELIZABETH G. BRADSHAW AND BARBARA J. PLEUVRY

SUMMARY

Nitrazepam and diazepam only cause significant depression of respiratory rate and loss
or righting reflex, in mice, at lethal doses. In sub-lethal doses they induce a stage of
deep but rousable sleep which is quite distinct from the intermittent dozing of control
mice and the comatose state of mice injected with pentobarbitone. However, the
respiratory effects of nitrazepam and diazepam in high doses in mice and low doses in
rabbits are modified by the presence of solvent. Furthermore the solvent itself causes a
loss of righting reflex in mice and the lethal dose of nitrazepam and diazepam is greatly
reduced when the drugs are administered in solvent.

Recently nitrazepam has been suggested as a
pre-operative medication for patients undergoing
minor surgery (Vega, 1964; Alder, 1965; Troch,
1965; Norris and Telfer, 1969) and it has also
been recommended as the pre-operative sedative
to be used in conjunction with neurolcptanalgcsia
to overcome the dysphoric effects of the butyro-
phenones, e.g. droperidol (Brichard and John-
stone, 1970).
Nitrazepam is being prescribed with increasing
frequency as a hypnotic and, compared with the
barbiturates, it has a remarkably good safety
record. No deaths have been reported which can
be attributed directly to nitrazepam. Matthew and
associates (1969) described 27 patients who had
taken overdoses of nitrazepam; 25 were fully
conscious and the duration of the drowsiness in
the remaining two lasted less than 12 hours. There
was no depression of respiration, and only a
transient fall in blood pressure; no active treat-
ment was required. Similar observations have been
made at the Manchester Royal Infirmary poisons
unit (Mawer, personal communication). Barbitu-
rates, on the other hand, were responsible for
nearly 2,000 deaths in 1964 alone (Ministry of
Health report, 1968) and overdose is characterized
by coma, respiratory depression and hypotension.
It has been advocated that barbiturates should
be used only in hospitals, whilst in general practice
nitrazepam is the hypnotic of choice (McQueen,
1969).
Experimental work with nitrazepam, in animals,
has centred round its hypnotic, sedative and
muscle-relaxant properties (Randall et al., 1965)
and little attention has been paid to the respiratory
effects of overdoses of nitrazepam. The present
study was designed to investigate the respiratory
effects of overdoses of nitrazepam in the mouse
and to compare the results with those obtained
with diazepam and pentobarbitone. Relationships
between behavioural and respiratory effects of the
three drugs were also compared in the mouse.
In view of the growing interest in the use of
nitrazepam and diazepam as adjuvants to anaes-
thesia, the effects of low doses of the two drugs^
injected intravenously, were examined in the
rabbit so that a more detailed investigation of the
respiratory effects of low doses could be made.
METHODS
Mice.
Groups of not less than 6 and not more than
24 albino mice of either sex and weighing between
25 and 35 g were used.
Respiratory rate was measured by placing the
mouse's snout into the barrel of a syringe con-
ELIZABETH G. BRADSHAW,* M.B., B . S ^ F.F.A.RX.S., D.A.J
BARBARA T. PLEUVRY, B.PHARM., M.SC., P U D . , M J . S . ;
Research Department of Anaesthesia and Pharmacology,
University of Manchester.
* Present address: Department of Anaesthetics,
Royal Infirmary, Glasgow, Q 4 .
 638
nected to a pressure transducer, the output of
which was recorded on a pen recorder. After the
injection of drug in test mice and solvent (or
suspending agent) in control mice, respiratory rate
was measured at 5-minute intervals for 2 hours
and thereafter at 15-minute intervals. The dura-
tion of ataxia and loss of righting reflex was also
determined. When these times exceeded 5 hours,
observations were only made at 30-minute inter-
vals and thus results in excess of 5 hours were
expressed in hours.
Drugs and solvents used.
Pentobarbitone was used either as the sodium
salt dissolved in 20 per cent propylene glycol and
10 per cent ethanol, in which it is readily soluble,
or as the acid (relatively non-water-soluble) sus-
pended in 1 per cent sodium carboxymethyl-
cellulose.
Nitrazepam was used either suspended in
methylcellulose or dissolved in the solvent
supplied by the manufacturer. The highest
concentration which could be prepared in this
solvent was 2 mg/ml.
Diazepam was used as the suspension described
above or as a solution in the commercially avail-
able solvent (5 mg/ml). This solvent differs only
slightly, by the addition of a trace of benzoic acid,
from that used for nitrazepam and thus solvent
control experiments were carried out utilizing the
solvent for nitrazepam alone.
AH injections in mice were made intra-
peritoneally.
Rabbits.
Groups of 5 male Californian red rabbits were
used.
Respiratory rate (RR) and respiratory minute
volume (RMV) were measured using the Krogh
spirometer. Nitrazepam and diazepam were dis-
solved in the solvent described above and injec-
tion made into the lateral ear vein.
Generally the results obtained for respiratory
measurements are expressed as percentage changes
from control values, but some absolute values have
been included so that they can be compared with
those obtained by other workers.
Significance was estimated using the Wilcoxon
test.
BRITISH JOURNAL OF ANAESTHESIA
RESULTS
Ataxia, sleep, loss of righting reflex and
determination of lethal doses in mice.
The results obtained using nitrazepam, diaze-
pam and pentobarbitone in solvent and suspension
are shown in table I.
In solvent the higher doses of all three drugs
caused a loss of righting reflex and ataxia, the
duration of both increasing with increasing dose.
In suspension, however, only pentobarbitone had
this effect. Nitrazepam and diazepam only induced
a sustained loss of righting reflex in doses which
also caused some fatalities. However, in sub-ledial
doses a state of sustained sleep occurred during
which the mice could be aroused by handling.
This sleep was quite distinct from that exhibited
by mice in the saline control group, who were
aroused by the slightest movement near the cage.
In the case of diazepam-treated mice, this sleep
was interrupted by brief periods during which
the righting reflex was lost.
The administration of high doses, particularly
of nitrazepam, required the injection of large
volumes of solvent. In the control group of mice
the injection of solvent volumes equivalent to 40
and 80 mg/kg nitrazepam (20-40 ml/kg) pro-
duced ataxia, loss of righting reflex and some
deaths.
The LD50 doses of the drugs and nitrazepam
solvent are shown in table II. The remarkable
reduction of the LD50 doses of nitrazepam and
diazepam when administered in solvent compared
with administration in suspension underline the
toxicity of the solvent when administered alone in
equivalent volumes.
Effect on the respiratory rate of the mouse.
The mean ( ± SD) pre-injection respiratory rate
of a group of 36 mice was 141 (±50.7) b.pjn.
Table III shows the percentage changes in respira-
tory rate induced by the three drugs. In their
respective solvents, nitrazepam and pentobarbi-
tone caused progressive depression of respiratory
rate with increasing dose. Diazepam in solvent
only caused significant (P<0.05) depression of
respiratory rate compared with saline controls in
doses which caused some fatalities (80 mg/kg).
The solvent for nitrazepam on its own, however,
caused an increase in respiratory rate significantly
greater than saline controls (P<0.05).
 EFFECTS OF NITRAZEPAM, DIAZEPAM AND PENTOBARBITONE 639

TABLE I
The effect of nitrazepam, diazepam and pentobarbitone in solvent or suspension, on the duration
of alaxia, sleep and loss of righting reflex in the mouse.
Mean duration (±SD)
Drug No. in Loss righting
(mg/kg) group Ataxia Rousable sleep reflex

Nitrazepam
5 solv. 11 86 ±66 min (10) 0 0
10 solv. 15 219 ±74 min (15) 0 32 min (2)
20 solv. 10 11.5±1.1 hr (9) 0 293 ±142 min (9)
40 solv. 7 Over 12 hr 0 240 min (3)
80 susp. 6 57 ±11 min (6) 0 0
160 susp. 10 6.5 ±1.7 hr (10) 136±47 min (10) 0
320 susp. 7 Over 12 hr 6.9 ± 0.6 hr (7) 0
640 susp. 7 Over 24 hr 132±53 min (7) 215 min (3)
Up to loss of
nghting reflex

Diazepam
10 solv 6 0 0 0
20 solv. 7 50±10 min (7) 0 0
40 solv. 9 186±66 min (9) 0 6 min (1)
80 solv. 8 Over 12 hr 0 48 min (3)
80 susp. 6 Over 12 hr Variable, mainly rousable sleep with
intermittent loss of righting reflex
120 susp. 6 Over 24 hr 0 Over 12 hr
Pentobarbitone*
20 solv. 6 20 ± 5 min (6) 0 12 min (1)
40 solv. 10 50 + 15 min (10) 0 24 ± 14 min (8)
60 solv. 6 100±16 min (6) 0 70± 15 min (6)
80 solv. 6 238 ±53 min (6) 0 159± 80 min (6)
120 solv. 17 8.5 ±0.8 hr (8) 0 7.0 ± 0.8 hr (8)
40 susp. 10 66 ±15 min (10) 0 23 ± 11 min (5)
60 susp. 12 75 ±32 min (12) 0 34 ± 19 min (12)
80 susp. 9 162 ±49 min (9) 0 98 ± 32 min (9)
120 susp. 12 6.6±1.1 hr (9) 0 279 ± 52 min (9)
* Pentobarbitone sodium in solvent and pentobarbituric acid in suspension.
(n) Number of experiments from which mean and SD was derived (i.e. number of surviving mice
exhibiting the parameter measured).
Note. SD were only calculated for groups of four or more results.

TABLE II than the change in respiratory rate obtained with

LD50 values in mice. controls injected with either carboxymethyl-
In solvent In suspension cellulose solution or talc suspended in carboxy-
Nitrazepam 37.5 640*
methylcellulose. The time course of the effects of
Diazepam 87 120 nitrazepam, 160, 320, 640 and 900 mg/kg suspen-
Pentobarbitone 124 141 sion on the respiratory rate of the mouse is shown
Nitrazepam solvent 26 ml/kg (equiv. 52 nitrazepam) in figure 1.
* 58 per cent mortality. Doses in mg/kg. The depression of rate induced by the two
higher doses, both of which caused fatalities over
In suspension pentobarbitone had qualitatively a 24-hour period, did not become significant until
similar effects as it did in solvent. Nitrazepam, 3-4 hours after injection and progressed gradually
however, caused an increase in respiratory rate in for the next 20 hours, at which time the mice
non-lethal doses, an increase significantly greater either died or made a slow recovery.
640 BRITISH JOURNAL OF ANAESTHESIA

TABLE III
Effects of nitrazepam, diazepam and pentobarbitone on the respiratory rate of the mouse.
In solvent; In suspension;
max. % change max. % change
Dose respiratory rate Dose respiratory rate
(mg/kg) (±SE) (mg/kg) (±SE)
Nitrazepam
5 - 8.5 ± 9.1 (8) 160 + 25.1± 3.8 (8)
10 -20.3± 5.7 (10) 320 + 19.2+ 4.0 (10)
20 -33.1 ± 6.2 (10) 640 -50.8** (12) 7*
40 -58.9± 9.8 (5) 3* 900 -68.0** (6) 6*
Diazepam
10 + 8.5 ± 2.5 (6) 80 -39.0± 6.8 (6) 1*
20 - 1 6 . 6 ± 5.9 (6) 120 -40.2 (3) 3*
40 -28.1 ±12.7 (7) 240 All died 6*
80 -20.5 ± 8.7 (6)
120 -69.7 (3) 3*
Pentobarbitone
Nasalt Acid
20 -21.4 ± 3.7 (9) 40 -19.8 ± 5.4 (10)
40 - 2 8 . 5 ± 2.3 (21) 60 -26.5 ± 5.2 (12)
60 -43.5 ± 4.5 (6) 80 -46.1 ± 4.9 (9)
80 - 6 6 . 4 ± 2.3 (6) 120 -79.5 ± 0.5 (9) 3*
120 -79.8 ± 2.0 (9) 8*
Controls
Saline -10.0 + 3.5 (
Na carboxymethylcellulose - 7.6 ± 1.8 (
Talc, suspended in above -18.5± 5.4 ( 6)
Nitrazepam solvent 20 ml/kg + 19.8± 6.5 ( 6)
(n) Number of experiments from which mean ± SE was derived (i.e. number of surviving
animals exhibiting the parameter measured).
• Number of fatalities in the group.
•• Mean changes measured 12 hours after injection (seefig.1).

FIG. 1
Time course of the effect of nitra-
zepam on the respiratory rate of the
mouse.
Nitrazepam was suspended in 1 per
cent sodium carboxymethylcellulose
and injected by the intraperitoneal
route.
# 160 mg/kg nitrazepam.
C 320 mg/kg nitrazepam.
• 640 mg/kg nitrazepam.*
• 900 mg/kg nitrazepam.*
* Mean values for survivors. After
24 hours all mice given 900 mg/kg
were dead and 7 of 12 mice given
640 mg/kg were dead.

Effects of nitrazepam and diazepam on the
respiration of the rabbit
In a group of 51 rabbits the mean ( ± SD) pre-
injection value for respiratory minute volume was
675 ( ± 161) ml/min and respiratory rate was 75
( ± 36) b.p.m.
The effect of nitrazepam 1-4 mg/kg i.v. and
diazepam 2-8 mg/kg i.v. on the minute volume
and respiratory rate of the rabbit are shown in
figure 2, together with the effects of equivalent
volumes of solvent injected into separate groups
of 5 control rabbits. Maximum changes are shown
EFFECTS OF NITRAZEPAM, DIAZEPAM AND PENTOBARBITONE 641

Diazepam Nitrazepam

RMV RR RMV RR

1
mg/kg mg/kg

-it -to

FIG. 2
Effect of diazepam and nitrazepam on the respiratory minute volume and respiratory rate of the
rabbit, compared with that of equivalent volumes of solvent.
# Maximum respiratory effect of the drug.
O Effect of solvent at the same time after injection.
Each point represents the mean of at least five experiments and all injections were intravenously
administered.
RMV, respiratory minute volume; RR, respiratory rate.

in the presence of drug, whilst the changes illus-
trated for the solvent were those obtained at the
same time period after injection that the maximum
effects of the drug occurred in test animals Thus
the effects of the solvent shown in the figure are
not necessarily maximum effects.
The increase in respiratory rate and minute
volume obtained with the highest volumes of
solvent were significantly greater than those
obtained with rabbits treated with saline ( P <
0.05).
DISCUSSION
The LD50 values obtained for nitrazepam and
diazepam injected intraperitoneally in mice varied
markedly with the formulation of the injection
(37.5 mg/kg and 87 mg/kg respectively in solvent
and 640 mg/kg and 120 mg/kg in suspension),
whereas that for pentobarbitonc did not (124
mg/kg in solvent and 141 mg/kg in suspension).
The LD50 value quoted in the literature for
nitrazepam injected intraperitoneally in mice is
275 mg/kg (Randall et al., 1965) and 220 mg/kg
for diazepam (Randall et al., 1961). Further
enquiry revealed that the drugs were administered
in suspension. The LD50 value obtained using a
suspension will vary with the particle size of the
drug and this may explain the discrepancy
between the results obtained by the authors and
those quoted in the literature. No LD50 values
for the two drugs dissolved in solvent could be
traced in the literature. Calesnick, Smith and
Beutner (1951) found the LD50 of pentobarbi-
tone sodium i.p. in mice to be 130 mg/kg; a
value close to that found by the authors (table
n).
The solvent used for nitrazepam and diazepam
has toxic effects in mice in the volumes used and
it is almost certain that the deaths which occurred
with nitrazepam in solvent can be attributed to
the solvent alone. The effects of the solvent were
less obvious with the diazepam solution as a more
concentrated solution could be prepared than that
for nitrazepam.
Further effects of the solvent were seen when
diazepam and nitrazepam in solvent were injected
intravenously in rabbits. The lower dose caused a
depression of minute volume and rate. However,
this did not increase progressively with dose and
a rise in minute volume and rate were obtained
with 8 mg/kg diazepam. This was most probably
related to the observation that equivalent volumes
of solvent induced a stimulation of respiration.
Pharmacological effects of both nitrazepam and
642
diazepam solvents have also been reported by
other workers. Parkes (1968) quoted work by
Lessin which showed that whereas intravenous
injection of diazepam 5 mg/kg in rabbits pro-
duced a brief rise in minute volume and a fall in
blood pressure, these effects were also seen after
the solvent alone. Vieth, Holm and Knopp (1968)
demonstrated that the solvent for nitrazepam
exerted its own effects on the central nervous
system, these being very similar to those of
ethanol.
It must be emphasized that the toxic effects of
the solvent reported in this study only occurred
with very high volumes of solvent. Frank and
Jhamandas (1970) found that solvent equivalent
to 8 mg/kg diazepam, when injected intraperi-
toneally in mice, had no effect on motor activity
and, in man, doses of solvent in excess of those
recommended for clinical use have no undesirable
pharmacological effects (Dundee and Haslett,
1970). However, the authors' experiments indicate
that the therapeutic indices of diazepam and nitra-
zepam in mice are considerably lower when the
drugs are administered in the existing solvent.
In this investigation nitrazepam and diazepam,
when administered without solvent, caused no
respiratory depression until lethal doses were
reached. This was in marked contrast to the bar-
biturates which caused significant respiratory
depression in doses considerably below the lethal
dose. Any respiratory effects of diazepam and
nitrazepam in rabbits were significantly modified
by the solvent. Parkes (1968) suggested that the
prolonged lower level of respiration induced by
diazepam in rabbits could be attributed to the
tranquillized state of the rabbits.
This view is supported by the demonstration
that in rabbits, diazepam does not affect the res-
piratory response to carbon dioxide (Parkes, 1968)
and preliminary studies of one of the authors
indicates that there is little change in the Pco2 of
arterialized blood in rabbits injected with
diazepam.
The stage of sustained, but rousable, sleep
reported in mice in this study parallels the clinical
experience obtained with overdoses of nitrazepam
in man (Matthew et al., 1969). A stage of rousable
sleep was not seen in any animal given pento-
barbitone and this may be explained by differ-
ences in the mechanisms by which pentobarbitone
BRITISH JOURNAL OF ANAESTHESIA
and nitrazepam produce hypnosis. It has been
suggested that nitrazepam induces sleep via a
selective depressant effect on limbic inputs and
the amygdala and hippocampus (Zbinden and
Randall, 1967). The barbiturates, however, have
a general depressant effect on the reticular forma-
tion (Jovet, 1961) which induces both sleep and
respiratory depression.
Since submission of this paper, Crankshaw and Raper
(1971) have examined the effects of solvents on the
potency of several drugs including diazepam and
nitrazepam. They have shown that the ED50 dose for
loss of righting reflex in mice is markedly influenced
by the character of the solvent, thus confirming some
of the findings reported by the authors.
ACKNOWLEDGEMENTS
We would like to thank Professor H. Schnieden and
Dr A. R. Hunter of the Departments of Pharmacology
and Anaesthesia, University of Manchester, for the
laboratory facilities.
Nitrazepam and diazepam powder was kindly sup-
plied by Roche Products Ltd, as was the nitrazepam
in solvent, which is not available in the United
Kingdom.
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Brichard. G., and Johnstone, M. (1970). The effect of
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Combined action of cardiotoxic drugs: a study on
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Crankshaw, D. P., and Raper, C. (1971). The effect of
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Dundee, J. W., and Haslett, W. H. K. (1970). The
benzodiazepines: a review of their actions and
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Frank, G. B., and Jhamandas, K. (1970). Effects of
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Jovet, M. (1961). The Nature of Sleep, Ciba Founda-
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Matthew, H., Proudfoot, A. T., Aitken, R. C B., Rae-
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McQueen, E. G. (1969). Management of unconscious
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Norris, W., and Telfer, A. B. M. (1969). Nitrazepam
in premedication. Brit. J. Anaesth., 41, 877.
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Knight, P. F., and Burgess, C G.), p. 1. Bristol:
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EFFECTS OF NITRAZEPAM, DIAZEPAM AND PENTOBARBITONE
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LES EFFETS RESPIRATOIRES ET
HYPNOTIQUES DE NITRAZEPAM, DIAZEPAM
ET PENTOBARBITONE ET LEURS SOLVANTS
CHEZ LE LAPIN ET LA SOURIS
SOMMAIRE
Nitrazepam et diazepam ne causent une depression
significative du taint respiratoire et une perte du
reflexe de redressement, qu'uniquement aux doses
lethalcs chez la souris. Aux doses sublithales ces
substances provoquent une phase de sommeil profond
mais reversible, qui se distingue de l'assoupissement
intermittent chez les souris-controles et de l'itat
comateux des animaux injectes avec pentobarbitone.
Mais les effets respiratoires de nitrazepam et diazepam
en doses ilevees chez la souris et en petit dosage chez
le lapin sont modifies par la presence du solvant.
Celui-ci seul cause en outre une perte du reflexe de
643
redressement chez la souris et la dose lethale de
nitrazepam et diazepam est sensiblement moins grande
lorsque les medicaments sont administres en solvant.
RESPIRATORISCHE UND SCHLAFMnTEL
WIRKUNGEN VON NITRAZEPAM, DIAZEPAM
UND PENTOBARBITAL UND EHRER
LOSUNGSMITTEL AM KANINCHEN UND AN
DER MAUS
ZU SAMMENF A SSUNG
Nitrazepam und Diazepam bewirken nur eine signifi-
kante Depression der Atemfrequenz und einen Verlust
des Aufnchtreflexes bei der Maus in letalen Dosen.
In subletalen Dosen fuhren sie zu einem tiefen, aber
storbaren Schlaf, der sich deutlich von dem inter-
mittierenden Dammern der Kontrollmause sowie von
dem komatosen Zustand der Mause mit Pentobarbital
unterschied. Die respiratorischen Wirkungen von Nitra-
zepam und Diazepam in hohen Dosen an MSusen und
in niedrigen Dosen an Kanninchen werden jedoch
durch die Gegenwart eines Losungsmittels beeinflufit.
Ferner kann das Losungsmittel allein schon
zu einem Verlust des Aufnchtreflexes bei der Maus
fuhren. Die letale Dosis von Nitrazepam und Diazepam
wird deutlich verringert, wenn die Drogen in Losung
verabreicht werden.
EFECTOS RESPIRATORIOS E HIPNOTICOS
DE NITRAZEPAM, DIAZEPAM Y
PENTOBARBITONA Y DE SUS SOLVENTES
EN EL CONEJO Y EN EL RATON
RESUMEN
El nitrazepam y diazepam provocan unicamente a dosis
letales en ratones una depresion significativa de la
frecuencia respiratoria y pirdida del reflejo de endere-
zamiento. A dosis subletales inducen un estadio de
sueno profundo pero despertable que es bien diferente
del sopor intermitente de los ratones de control y el
estado comatoso de ratones inyectados con pentobar-
bitona. Sin embargo, los efectos respiratorios del nitra-
zepam y diazepam a dosis elevadas en ratones y a dosis
bajas en conejos son modificados por la presencia de un
solvente. Por otra parte, el solvente mismo provoca una
perdida del reflejo de enderezamiento en ratones y la
dosis letal de nitrazepam y diazepam queda muy
reducida cuando estos medicamentos son administrados
en un solvente.