The sensitivity of the brain to barbiturate during chronic administration and withdrawal of barbitone sodium in the rat

1. The sensitivity of the central nervous system to barbiturate was determined in rats during the chronic administration of barbitone sodium and after its withdrawal.

2. The brain barbiturate concentration determined on awakening from a hypnotic dose administered intraperitoneally was found to increase throughout the period of barbitone administration.

3. A similar gradual development of central nervous system tolerance was indicated by measuring the duration of anaesthesia following an intraventricular injection of pentobarbitone.

4. The change in sensitivity of the brain which occurred during the period of barbitone administration was not demonstrable from the measurement of sleeping time following intraperitoneal injection of barbitone or pentobarbitone.

5. After withdrawal, the sensitivity of the brain to barbiturate gradually returned to normal.

6. It was concluded that the hypersensitivity to pentobarbitone, but not to barbitone, which develops after withdrawal of barbitone sodium is due to a decreased drug-metabolizing capacity.

     

Potentiation of barbiturate hypnosis by probenecid: Differential effect in tolerant animals

Earlier observations that the chronic intracerebroventricular injection of phenobarbital caused a gradual attenuation in the duration of loss of righting reflex (tolerance) and that the development of tolerance was independent of barbiturate efflux from the brain have been extended by examining the effect of probenecid on this phenomenon. Probenecid (200 mg/kg, i.p.) delayed the efflux of phenobarbital from the brain; the half-life of the barbiturate after intracerebroventricular injection increased from 7.3 to 17.6min. In both tolerant and naive animals, probenecid prolonged the duration of phenobarbital hypnosis from 14.4 to 26.4 min in naive rats and from 2.1 to 25.5 min in tolerant rats. Thus, evidence of tolerance was abolished by probenecid pretreatment.The possibility that the sedative effects of probenecid were responsible for the potentiation of barbiturate hypnosis was examined by measurement of spontaneous locomotor activity. Both tolerant and nontolerant rats were equally sedated by probenecid. Since tolerant animals recovered earlier, additive depressant effects of the two drugs cannot adequately account for the unequal potentiation of hypnosis.Probenecid pretreatment also prolonged hypnosis produced by intracerebroventricular injection of barbital or intraperitoneal hexobarbital. The possibility that probenecid decreased the metabolism of hexobarbital was examined by measurement of hexobarbital oxidation and p-nitroanisole O-demethylase in liver microsomal preparations. This possibility was eliminated since neither enzyme activity was altered by probenecid concentrations below 1.0 mM.     

Chronic ethanol tolerance as a result of free-choice drinking in alcohol-preferring rats of the WHP line

The development of tolerance to alcohol with chronic consumption is an important criterion for an animal model of alcoholism and may be an important component of the genetic predisposition to alcoholism. The aim of this study was to determine whether the selectively bred Warsaw High Preferring (WHP) line of alcohol-preferring rats would develop behavioral and metabolic tolerance during the free-choice drinking of ethanol. Chronic tolerance to ethanol-induced sedation was tested. The loss of righting reflex (LRR) paradigm was used to record sleep duration in WHP rats. Ethanol (EtOH)-naive WHP rats received a single intraperitoneal (i.p.) injection of 5.0 g ethanol/kg body weight (b.w.), and sleep duration was measured. Subsequently, rats had access to a 10% ethanol solution under a free-choice condition with water and food for 12 weeks. After 12 weeks of the free-choice intake of ethanol, the rats received another single i.p. injection of 5.0 g ethanol/kg b.w., and sleep duration was reassessed. The blood alcohol content (BAC) for each rat was determined after an i.p. injection of 5 g/kg of ethanol in naive rats and again after chronic alcohol drinking at the time of recovery of the righting reflex (RR). The results showed that the mean ethanol intake was 9.14 g/kg/24 h, and both sleep duration and BAC were decreased after chronic ethanol intake. In conclusion, WHP rats exposed to alcohol by free-choice drinking across 12 weeks exhibited increased alcohol elimination rates. Studies have demonstrated that WHP rats after chronic free-choice drinking (12 weeks) of alcohol develop metabolic tolerance. Behavioral tolerance to ethanol was demonstrated by reduced sleep duration, but this decrease in sleep duration was not significant.     

Prevention and reversal of tolerance to barbiturates by intraventricular injection of hemicholinium-3.

Intracerebroventricular (i.c.v.) injection of phenobarbital, 800 mug, or intraperitoneal (i.p.) injection of hexobarbital, 100 mg/kg, into rats resulted in a loss of righting reflex lasting 15.4 +/- 0.2 min and 20.7 +/- 0.7 min, respectively. A 40-60% reduction in this response was obtained following administration of phenobarbital either i.c.v. (800 mug 4 times daily) or i.p. (80 mg/kg/day) for 4 days. Although these treatments also increased hepatic mixed function oxidase activity, this enzyme induction was shown to be unrelated to the development of tolerance to loss of righting reflex. I.c.v. injection of hemicholinium-3 (HC-3) in doses which reduce brain acetylcholine levels (4-20 mug) profoundly affected tolerance to the central depressant effect of the barbiturates. Thus, depending upon the time of administration, HC-3 either retarded or prevented development of this tolerance. Moreover, if tolerance was allowed to progress normally, administration of HC-3 on day 4 or 5 returned the duration of the loss of righting reflex toward normal values. HC-3 did not influence either the duration of this response in non-tolerant rats or the induction of the hepatic mixed function oxidase activity. These results suggest that brain ACh plays an important role in the development and maintenance of tolerance to the central depressant effects of barbiturates.     

Barbiturate tolerance and dependence: effects on synaptosomal sodium transport and membrane fluidity

DBA mice were fed lab chow containing phenobarbital for seven or eight days. Upon withdrawal of the phenobarbital diet, dependence was evidenced by appearance of hypothermia, handling-induced convulsions and lethal seizures. Functional tolerance was determined by injecting phenobarbital into mice treated with the phenobarbital diet or a pair-fed control diet and measuring the brain concentration of phenobarbital at the time of loss of righting reflex and the time of regaining righting reflex. Both measures demonstrated that chronic consumption of phenobarbital resulted in functional tolerance. When the diet was withdrawn for two days, tolerance was no longer present, indicating a rapid reversal of the adaptive changes. The veratridine-stimulated uptake of 24Na by isolated brain synaptosomes was used as a measure of membrane function. Sodium uptake was inhibited in vitro by pentobarbital and ethanol, and the inhibitory effects of these drugs were attenuated by chronic in vivo phenobarbital treatment. The fluidity of brain synaptic plasma membranes was estimated by the fluorescence polarization of the fluorescent probe molecules 1-(4-trimethylammonium phenyl)-6-phenyl-1,3,5-hexatriene and 1,6-diphenyl-1,3,5-hexatriene. Synaptic membranes from mice treated chronically with phenobarbital did not differ from those of control mice with regard to either the baseline fluorescence polarization of the probes or the decrease in fluorescence polarization produced by in vitro exposure to phenobarbital or ethanol. Taken together, these results indicate that although chronic phenobarbital ingestion resulted in tolerance and dependence (studied in vivo), and adaptation of sodium channels (studied in vitro), there was no evidence that these changes were due to alterations in the membrane physical properties.     

A study of the factors affecting the sleeping time following intracerebroventricular administration of pentobarbitone sodium: Effect of prior administration of centrally active drugs

1 Injection of pentobarbitone sodium into a lateral cerebral ventricle of rats produced a loss of righting reflex. The duration of anaesthesia was dose-dependent.

2 The optimum dose of pentobarbitone to allow study of the factors affecting the sleeping time was considered to be 650 μg injected in 25 μl water.

3 In a study of the effect of age and sex on the sleeping time, the youngest rats used (88 g body weight) were found to be the most sensitive to barbiturate. Female rats were more sensitive than male animals.

4 The duration of anaesthesia was not affected by induction or inhibition of hepatic drug-metabolizing enzyme activity.

5 Prior administration (acute) of central nervous system depressant drugs shortened the latent period and prolonged the duration of sleep. Prior administration of stimulant drugs antagonized the effect of pentobarbitone.

6 Animals withdrawn following chronic administration of a number of drugs, barbitone, barbitone/bemegride mixture, Mandrax (methaqualone: diphenhydramine; 10: 1), chlordiazepoxide, nitrazepam, chlorpromazine or ethanol, exhibited a significant tolerance to intracerebroventricularly administered pentobarbitone.

7 Withdrawal of amphetamine, morphine, methyprylon or diazepam did not result in tolerance to intracerebroventricularly administered pentobarbitone.

8 Chronic administration of all drugs except amphetamine and morphine induced a tolerance to intraperitoneally administered hexobarbitone (100 mg/kg).

9 The usefulness of sleeping time determination following intracerebroventricular administration of pentobarbitone as an assessment of central nervous system excitability is discussed. It is concluded that this method gives a valid indication of the sensitivity of the central nervous system to barbiturate and of the level of excitability in general. The method is particularly applicable in situations where the activity of hepatic drug-metabolizing enzyme activity may be altered.

     

BLOOD PRESSURE OVERSHOOT UNDER PENTOBARBITONE ANAESTHESIA FOLLOWING A SINGLE DOSE OF CLONIDINE IN RATS*

Withdrawal of chronic antihypertensive therapy with clonidine is known to produce a blood pressure overshoot. It has been reported that the same may occur after a single dose of clonidine. A single, intramuscular dose of clonidine (0.05 mg/kg) produced an overshoot in blood pressure, on the day following administration, in normotensive rats anaesthetized with sodium pentobarbitone. No rebound elevation of mean arterial pressure or of heart rate occurred in conscious, normotensive, spontaneously hypertensive or renal hypertensive rats following this dose of clonidine, nor did it occur in rats anaesthetized with ether. It is suggested that the overshoot phenomenon in rats under barbiturate anaesthesia may involve an interaction between an effect of clonidine and the barbiturate.     

Effect of acetaldehyde on acute tolerance and ethanol consumption in drinker and nondrinker rats

OBJECTIVE: Acetaldehyde (AcH) has been shown to have aversive or reinforcing actions in relation to ethanol consumption. We have previously observed that a pharmacological dose of AcH (50-150 mg/kg) administered intraperitoneally (i.p.) produced a dose-dependent flavor aversion in low-ethanol drinker (UChA) rats, whereas high-ethanol drinker (UChB) rats appeared to be insensitive to AcH. Both strains of rats differ innately in their brain aldehyde dehydrogenase (ALDH) activity and in their capacity to develop acute tolerance to ethanol. The present study evaluates the effects of AcH, in UChA and UChB rats, on rats' behavior, their voluntary ethanol consumption and the development of acute functional tolerance to motor impairment induced by a dose of ethanol. METHOD: Subjects were rats selectively bred for high (UChB; n = 48) and low (UChA; n = 40) voluntary ethanol consumption. Rats were treated with either saline or doses of AcH (50 or 100 mg/kg, i.p.), and examined for effects on motor activity, on voluntary alcohol consumption with free access to a 10% alcohol solution and on acute tolerance to motor impairment induced by an ethanol dose (2.3 g/kg, i.p.), using the tilting plane test. RESULTS: AcH, 50 or 100 mg/kg, caused a dose-dependent loss of the righting reflex in UChA rats, whereas in UChB rats with same dose, a slight excitement was observed. There was significant increase of voluntary ethanol consumption in UChB rats (p < .001) 17 hours after the AcH injection, compared with saline-treated and control rats; in UChA rats, no change in voluntary ethanol consumption was produced. AcH produced a faster acute tolerance-to-ethanol development in UChB rats (p < .001) as compared with saline-treated and control rats, and no change in acute tolerance in UChA rats. Acetaldehyde injection did not change total mitochondrial ALDH2 activity. CONCLUSIONS: These results show that, 17 hours later, treatment of rats with pharmacological doses of acetaldehyde alters the voluntary ethanol consumption and acute tolerance development in UChB but not UChA rats. One of the factors involved may be a different sensitivity to AcH in these rat strains.     

Acute tolerance in inbred and selected lines of mice

Mice of the C57Bl and C3H strains regained their righting reflex at higher brain ethanol levels than those at which they had lost their righting reflex, indicating that these animals developed acute tolerance. DBA mice did not develop acute tolerance. DBA mice "slept" significantly longer than C57Bl mice, but all mice lost their righting reflex at similar brain ethanol levels. Mice of SS and LS lines also showed no evidence for developing acute tolerance but differed significantly in brain ethanol levels upon loss of righting reflex. Both acute tolerance development and initial brain sensitivity to ethanol seem to determine duration of ethanol "sleep time" in mice.     

The effects of long-term, low-dose diazepam treatment on the guinea pig righting reflex and medial vestibular nucleus neuronal activity

Guinea pigs received a 2 mg/kg IP injection of diazepam, or an equivalent volume of vehicle, daily for 28–60 days. To determine whether tolerance developed to the ataxic effects of diazepam on the righting reflex, daily righting reflex latency (RRL) measurements were made before and 20, 30, and 40 min following the diazepam or vehicle injection for 28 days. Analyses of the RRLs for individual animals indicated that a significant decrease in RRL over time (indicating tolerance) occurred in only one out of nine animals receiving diazepam and in none of the vehicle animals. Medial vestibular nucleus (MVN) neurons in brain stem slices from animals receiving chronic diazepam treatment had a significantly higher average firing rate than those from vehicle controls. These results suggest that: a) long-term treatment with single 2 mg/kg daily IP injections of diazepam does not result in tolerance to diazepam's ataxic effects on the righting reflex in the majority of animals; b) this form of diazepam treatment may, nonetheless, induce a hyperactivity of brain stem MVN neurons that may be consistent with the occurrence of a withdrawal syndrome.     

Initial sensitivity and acute tolerance to ethanol in the P and NP lines of rats

We recently reported that selectively bred, alcohol-preferring (P) and alcohol-nonpreferring (NP) rats differ in sensitivity to a single sedative-hypnotic dose of ethanol, as measured by performance in the jump test. The present study examines the contributions of initial sensitivity and acute tolerance development to this difference. Initial sensitivity, assessed by brain alcohol content upon loss of the aerial righting reflex, was not significantly different between P and NP groups given 3 g ethanol/kg body weight intraperitoneally. Acute tolerance was indexed from blood alcohol concentrations (BAC) upon recovery of jumping performance following two successive ethanol doses. Practiced P and NP rats were required to jump 35 cm to a descending platform following the IP injection of 2.0 g ethanol/kg. The NP group took signiificantly longer (74 min) than the P (33 min) group whereupon BAC₁ of NP rats (234 mg%) was significantly lower than that of P rats (250 mg%). A second injection (1.0 g/kg) was given immediately after the animals reached the 35 cm criterion. Again, NP rats took significantly longer (124 min) than P rats (52 min) to jump 35 cm and BAC₂ of NP animals was lower (295 mg%) than that of P rats (343 mg%). The difference between BAC₂ and BAC₁, the measure of tolerance development, was significantly larger for P rats (90 mg%) than for NP rats (61 mg%). No significant differences in blood ethanol elimination weree observed between the groups. The data indicate no difference in initial sensitivity between P and NP animals but that P rats develop acute tolerance more rapidly and/or to a greater degree than do NP rats. The results are consistent with a relationship in these selectively bred lines of rats between alcohol preference and the development of acute tolerance.     

A model for the rapid development of dispositional and functional tolerance to barbiturates

The s.c. implantation of a 75 mg pentobarbital pellet in the back of a conscious mouse resulted in a much more rapid development of tolerance to barbiturates than that produced in mice receiving daily i.p. injections of 75 mg/kg sodium pentobarbital. Acceleration in tolerance development by pentobarbital pellet implantation was evidenced by a decrease in sleeping time after the challenge with either sodium pentobarbital or sodium barbital. The degree of hepatic microsomal drug enzyme induction after pentobarbital pellet implantation also was found to be significantly higher than that produced by the injection technique. Further studies demonstrated that the threshold for pentylenetetrazol-induced seizures was significantly reduced compared to that of the sodium pentobarbital daily injected and control groups. These studies provide an animal model for studying the mechanism of barbiturate tolerance and dependence.     

Effect of muscimol on ethanol-induced central nervous system depression

In male Sprague-Dawley rats acute ethanol (1.0 and 2.0 g/kg) produced impairment of motor coordination and induced hypnosis (4.0 g/kg). Muscimol (1.25 mg/kg, IP) prior to ethanol administration enhanced motor impairment as measured by the aerial righting reflex. The rate of ethanol disappearance from the blood was unaltered by muscimol. Functional tolerance to the effect of ethanol on sleep time was produced by a 24 hr ethanol inhalation procedure. Animals tested 48 hr after ethanol inhalation exhibited a reduced sleep time from ethanol (4.0 g/kg). Muscimol (1.75 mg/kg) was administered along with ethanol 48 hr following 1 day of ethanol inhalation. Although the animals exhibited tolerance to ethanol-induced hypnosis, they did not manifest tolerance to the effect of muscimol.     

Effect of age on the pharmacodynamics of phenobarbital and ethanol in rats

The purpose of this investigation was to determine the effect of age on the sensitivity of the central nervous system (CNS) to the depressant action of phenobarbital and ethanol. For this purpose, one or the other of these drugs was administered by slow iv infusion to male rats of various ages until the animals lost their righting reflex. The drug concentrations at that time in serum, brain, and cerebrospinal fluid were determined. The results obtained in studies on 1, 9, and 18-month-old Sprague-Dawley rats and on 7, 16, and 24-month-old Fischer-344 rats showed that phenobarbital concentrations at the pharmacologic end-point decreased with increasing age, indicative of an increased sensitivity of older animals to the CNS depressant effect of the barbiturate. Similar studies with ethanol on Sprague-Dawley rats (only) showed substantially higher drug concentrations at all sampling sites in 5-week-old animals than in 9- and 12-month-old animals at the onset of loss of righting reflex, but no significant differences between the 9- and 12-month-old groups. This investigation, which was designed to exclude or account for pharmacokinetic variables and to avoid confounding secondary effects, such as hypothermia and development of acute functional tolerance, showed a substantial increase in CNS sensitivity to phenobarbital and ethanol with increasing age in rats between the age of 1 and 9 months, and a less pronounced increase (phenobarbital) or no significant change (ethanol) in rats between 9 and 18 months of age.     

Determination of halothane-induced sleeping time in the rat: effect of prior administration of centrally active drugs.

A method is described for the determination of halothane-induced sleeping time in the rat. 2 The sleeping time exhibited a diurnal variation which was due, at least in part, to a change in the sensitivity of the central nervous system (CNS) to the anaesthetic. 3 Tolerance to halothane did not develop in rats repeatedly exposed to the anaesthetic over a period of over 48 hours. 4 Repeated sleeping time determinations have been used to follow changes in the sensitivity of the CNS to the anaesthetic occurring with time. 5 A tolerance to halothane was induced by pretreatment of rats with doses of amylobarbitone, pentobarbitone or meprobamate sufficient to keep animals anaesthetized for approximately 12 hours. This tolerance was followed by a period of halothane-hypersensitivity. 6 Halothane-tolerant animals awakened with higher brain halothane concentrations and were also tolerant to intracerebroventricularly administered pentobarbitone. 7 Halothane-hypertensive rats awakened with lower brain halothane concentrations and were also hypersensitivity to intracerebroventricularly administered pentobarbitone. 8 The possibility that the induction of cross-tolerance to halothane may be indicative of a drug's potential to produce dependence is discussed.     

ACUTE TOLERANCE TO DIAZEPAM INDUCED BY BENZODIAZEPINES

It was observed that the effectiveness of diazepam in causing sleep, as defined by the loss of righting reflex, was significantly decreased after a single exposure to either diazepam or lorazepam. RO 15-1788, a benzodiazepine antagonist, in contrast did not induce tolerance to diazepam. The mechanism for this acute tolerance is unclear. The rapidity in its development may exclude metabolic tolerance while alterations in brain sensitivity to diazepam remain a possibility.     

Developmental alterations of ethanol sensitivity in selectively bred high and low alcohol sensitive rats.

Initial sensitivity and acute tolerance to ethanol have been implicated as risk factors in the development of alcoholism in humans. These behaviors were investigated in rats selectively bred for differences in hypnotic sensitivity following their first dose of ethanol in two different experiments. In Experiment 1, developmental profiles of the association between initial sensitivity and acute tolerance induced by a single exposure to ethanol were examined using male and female high, low, and control alcohol sensitive (HAS, LAS, and CAS) rats. Dose-response curves were constructed for duration of the loss of the righting reflex and for blood ethanol concentration (BEC) at the regain of the righting reflex. Animals were tested with a single ethanol dose ranging from 1.5 to 5.0 g/kg at either 15, 25, 40, 70, 120, or 180 days of age (DOA). For each group, acute tolerance to ethanol was estimated by the slope of the regression line using dose of ethanol and mean BEC at regain. In general, all rat lines showed an increase in hypnotic sensitivity to ethanol with age. To a large degree, the lower sensitivity observed in 15 and 25 DOA HAS and LAS rats was associated with an increase in the development of acute ethanol tolerance relative to older rats. Divergence of the LAS and CAS lines was evident by 25 DOA and remained stable with advancing age. However, HAS rats did not differ significantly from CAS rats until 40 DOA, after which the magnitude of the difference continued to increase with age. In Experiment 2, rats were treated with alcohol at 25, 70, or 180 DOA. Rats at 70 or 180 DOA required less ethanol to disrupt their motor coordination on a rotating dowel (rotarod). Blood ethanol levels were determined at the loss and subsequent regain of the ability to negotiate the rotarod. Total duration of inability to negotiate the rotarod also was recorded. HAS rats were less able to remain on a rotarod while under the influence of alcohol relative to LAS and CAS rats regardless of age. However, no evidence of acute tolerance was observed in this experiment and, in fact, there was evidence of reverse tolerance in that all animals had lower BEC values at regain of ability than they did at loss.     

Tolerance to the antinociceptive effect of morphine in the spinal rat

Tolerance and withdrawal were studied in spinal and intact rats receiving morphine hydrochloride (10–20 mg/kg, i.p.) every 12 hr for 10 days. All rats developed tolerance to morphine-induced antinociception measured by the tail-flick method. Tolerance was not reversed by d,l-5-hydroxytryptophan (200 mg/kg, i.p.). Naloxone (1–2 mg/kg) induced signs of withdrawal both in spinal and intact rats. Thus, functional changes in the aminergic systems and in brain and brainstem structures appear not to be necessary for tolerance to morphine-induced antinociception and for dependence on morphine. The experiment does not support the hypothesis that conditioning to environmental stimuli and changes in cognitive functions play a major role in tolerance development in the rat.     

Anaesthesia effects on in vivo acetylcholine transmission; comparisons of radioenzymatic and HPLC assays

The effect of general anaesthesia on extracellular levels of acetylcholine (ACh) in the caudate-putamen of freely moving rats was studied by microdialysis. ACh concentrations were determined in the same perfusate samples by radioenzymatic and HPLC/electrochemical procedures in order to compare the assays. The concentration of ACh in perfusate samples was estimated to be 0.30 microM in conscious unrestrained rats. However, when these rats were administered chloral hydrate (400 mg/kg i.p.), the level of ACh was decreased immediately by 50%, attaining a value of 0.06 microM within 20-40 min following the injection. Upon recovery of the righting reflex, ACh levels were once again re-elevated. The levels of choline (Ch), the precursor of ACh, were unaffected by anaesthesia. It was apparent that the level of consciousness (i.e. awake vs. anaesthetized) is an important factor determining ACh overflow. Radioenzymatic and HPLC assays proved to give identical results for the analysis of ACh and Ch.     

Comparison of anaesthetic and kinetic properties of thiobutabarbital, butabarbital and hexobarbital after intravenous threshold doses in the male rat

Due to the exceptionally long duration of action of thiobutbarbital the anaesthetic properties of this barbiturate was reinvestigated with an intravenous threshold technique using butabarbital and hexobarbital as references. Adult male rats were used. The criterion of anaesthesia was a burst suppression in the EEG of 1 sec. or more (the "silent second" = SS). The dose which induced the criterion was used as a threshold. The barbiturates were infused with different rates to obtain dose rate curves. After induction of the threshold criterion the animals were either killed and different tissue concentrations were analyzed with a HPLC method or allowed to survive and duration of SS and duration of loss of righting reflex were recorded. With hexobarbital, duration of SS and of loss of righting reflex increased significantly with increasing dose rate. With increasing rates of thiobutabarbital and butabarbital there was in both cases a stepwise increase in duration of SS. At sacrifice, after induction of SS with slow rates brain concentrations of both thiobutabarbital and butabarbital were lower than values recorded after higher rates. The change between the two concentrations was abrupt and occurred at a rate of 20 mg/kg/min. with thiobutabarbital and at the rate of 1.25 mg/kg/min. with butabarbital. This phenomenon was the reverse of acute tolerance which was recorded with hexobarbital and can thus be denoted acute supersensitivity. A kinetic analysis of serum, muscle and fat indicated considerable differences between the barbiturates. As indicated by mortality figures the induction of acute supersensitivity could be potentially dangerous.