Pharmacology of Anti-Anxiety
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Br. J. clin. Pharmac. (1979), 7, 7S-15S PHARMACOLOGY OF ANTI-ANXIETY DRUGS WITH SPECIAL REFERENCE TO CLOBAZAM STUART FIELDING Department of Pharmacology, Hoechst-Roussel Pharmaceuticals Inc., Somerville, New Jersey 08876, USA IRMGARD HOFFMANN Department of Pharmacology, Hoechst AG, Postfach 80 03 20, D-6230 Frankfurt/Main 80, Germany I In several studies clobazam exhibited a potency which ranges between that of chlordiazepoxide and diazepam. Its anxiolytic and anti-aggression effects are produced by doses usually ranging below those that cause disorders in motor activity. 2 This separation was demonstrable to an even greater degree with the desmethyl metabolite. The ac- tivity of the metabolite, however, was weaker than that of the original substance. 3 The advantage of clobazam compared with the 1,4 benzodiazepines lies mainly in the fact that motor activity is influenced only after very high doses, these doses being markedly above those re- quired to induce tranquilizing and anti-aggression activities. 4 Clobazam has no marked effect on the cardiovascular system, respiration or excretion. Introduction tests should be sensitive enough to detect the activity of reference agents within a reasonable dose range; (3) CLOBAZAM, a 1,5 benzodiazepine, has an animal the relative potency of reference agents in the animal profile of an anxiolytic agent without the strong test should compare favourably with their relative sedative and depressive side-effects of the older ben- potency in man; (4) tolerance should not develop to zodiazepines. Before we compare and contrast the measure presumed to reflect therapeutic activity. clobazam with the other anti-anxiety agents, it is (It should be pointed out that no one procedure will appropriate to consider the clinical term 'anxiety' and fulfil all these considerations; rather a profile of activity the criteria used on test procedures to measure it. in several test systems must be generated.) The definition of anxiety is hardly precise, con- For example, anticonvulsant procedures are most sisting of an intuitive combination of unpleasant important in screening for anxiolytic activity. The feelings and sensations and more or less objective prevention of pentylenetetrazol-induced seizures is one observations of disturbed breathing, increased heart anticonvulsant assay that shows a high degree of activity, vasomotor changes and musculo-skeletal dis- selectivity and sensitivity. It can be seen (Table 1) that turbances. Clinical anxiety represents a persistent the relative potency of clinically established anti- concern for something or someone which can vary in anxiety agents in preventing pentylenetetrazol-induced intensity from mild uneasiness to an overwhelming in- seizures parallels their clinical potency. This satisfies a capacitation. Pathological anxiety is characterized by criterion that permits good compound selection. Fur- its ability to interfere with normal function and manifests itself in somatic and emotional disorders, Table I Median effective dose for protection reduced productivity and a lessening of the quality of against pentylenetetrazol-induced seizures in rats life. Anxiety can also be considered a fearful response which has become associated, by conditioning, with Drug Median effective Unit dose in previously neutral stimuli. Even though definitions of dose (mg/kg man (mg) anxiety are unclear, we nevertheless agree on which orally) drugs are anti-anxiety drugs. Lorazepam 0.048 0.5-0.75 One is hard pressed to apply these clinical consid- Nitrazepam 0.25 5-10 erations literally to experimental animal models. Conse- Oxazepam 0.72 10-30 quently, more investigations resort to empirical test Diazepam 1.65 2-10 systems which are relatively uncomplicated and Chlordiazepoxide 2.41 5-25 display easily measured endpoints. In order for animal Sodium pentobarbital 3.32 50-100 tests to have predictive value the following criteria Clorazepate 3.54 3.75-15 should be met (Tedeschi, 1969): (1) tests should be Flurazepam 5.30 15-30 selective enough to differentiate false positives and to Meprobamate 36.9 200-400 distinguish side-effects from therapeutic activity; (2) From Lippa et al. (1978) 8S STUART FIELDING, IRMGARD HOFFMANN thermore it is well known that benzodiazepines good anti-anxiety agent without appreciable sedative antagonize the convulsions elicited by other agents and depressive side-effects (Barzaghi et al., 1973). The such as picrotoxin, bicuculline, isoniazid and strych- present paper describes these findings comparing this nine. Tolerance to the anti-strychnine and anti- drug with the reference agents chlordiazepoxide and bicuculline properties of diazepam, however, has been diazepam. The difference between clobazam and other reported by Lippa & Regan (1977) but not to the benzodiazepines structurally is that the N in the anti-pentylenetetrazol effects. One of the criteria for heterocyclic ring is in positions 1 and 5 rather than in predicting a compound to be active in attenuating positions 1 and 4. clinical anxiety is that tolerance should not develop to the measure presumed to reflect therapeutic activity. Thus, the anti-pentylenetetrazol effects seem to reflect Anticonvulsant profiles anxiolytic action, whereas effects in other convulsant procedures may reflect anticonvulsant properties. Anticonvulsant effects of clobazam, chlordiazepoxide The pharmacological screening procedures and diazepam were measured using pentylenetetrazol-, demonstrate quite clearly that the anti-anxiety drugs strychnine-, picrotoxin-, and nicotine-induced seizures, form a distinct class of compounds with a and electrically-induced tonic extensor seizures. characteristic profile of action. They are all muscle relaxants and anticonvulsants, inhibit aggressive Pentylenetetrazol behaviour, increase food intake and disinhibit response suppression due to punishment. They also produce Groups of mice were pretreated with the test com- sedation, hyporeflexia, hypothermia, ataxia, and pound 60 min before intravenous infusion of pen- potentiate anaesthesia. Generalisation of these findings tylenetetrazol 15 mg/ml. Three endpoints were suggests that a new compound with a similar profile observed: persistent convulsion; tonic extensor con- would also prove to be an effective anti-anxiety drug vulsions; and death. Anticonvulsant activity was con- when tested in humans. sidered to be present when the compound protected at Clobazam (Figure 1) (Rossi et al., 1969) least 50% of the animals from convulsion and death. demonstrated all the pharmacological properties of a Strychnine, picrotoxin and nicotine Groups of 10 mice were pretreated orally I h before OH30 subcutaneous injection of strychnine 0.75 mg/kg, N picrotoxin 12.5 mg/kg intraperitoneally or nicotine 5 mg/kg intravenously. Mice were observed for 1 h, and the number of animals exhibiting extensor convulsion CI N 0 was recorded. To be considered active, the compound had to protect at least 50% of mice from extensor convulsions. ED50 was calculated by the Lichfield-Wilcoxon method. Electroshock (mouse and rat) Figure 1 Clobazam: 7-chloro-1-methyl-5-phenyl- 1 H-1 ,5-benzodiazepine-2,4-(3H,5H)-dione. Three mice per group were treated orally with the test Table 2 Effect of clobazam on convulsions induced by various agents in mice Convulsions induced by ED50 (mg/kg orally)* Clobazam Diazepam Chlordiazepoxide Pentylenetetrazol (60 mg/kg intraperitoneally) 0.75 0.75 2.5 Strychnine (0.75 mg/kg subcutaneously) 16 21 86 Picrotoxin (12.5 mg/kg intraperitoneally) 26 Nicotine (5 mg/kg intravenously) 14 4.5 19 Electroshock (mice) 10 16 31 Electroshock (rat) 10 *Dose inhibiting tonic seizures in 50% of the animals (n = 10). COMPARATIVE PHARMACOLOGY OF CLOBAZAM 9S compound 60 min before electroshock of 0.25 mA for the method of Tedeschi et al. (1959) modified by Chen 0.3 s delivered through corneal electrodes. This tech- (1963). Subjects having a minimum of five fights nique results in convulsions (extensor) in 95% of the during the first trial were selected for treatment. A pair subjects. Significant activity was considered to be ob- exhibiting less than six fights during treatment were tained when two out of three subjects were protected considered to be significantly affected by the com- from these convulsions. Electroshock at 110 V for 0.4 pound. Eight pairs were used for each dose and s was delivered through temporal electrodes, and percentage protection calculated. resulted in clonic tonic seizures in rats. Anticonvulsant Table 3 shows the effect of clobazam on aggressive effects were measured by the degree of suppression of behaviour in mice. Clobazam inhibited isolation- seizure activity or diminution of the alteration of each induced aggressive behaviour with an ED50 = 10 phase of clonic or tonic attacks. mg/kg orally. This effect was a little more pronounced The anticonvulsant effects of clobazam are summarized in Table 2. These findings indicate that Table 3 Effect of clobazam on aggressive clobazam is equipotent to diazepam in antagonizing behaviour in mice pentylenetetrazol-, strychnine- and electroshock- induced seizures in mice, and approximately three Aggression ED50 (mg/kg, orally)* times less potent in the nicotine assay. In each case, induced by Clobazam Diazepam Chlordiazepoxide when compared with chlordiazepoxide, clobazam was more effective. Isolationt 1 0 14 As mentioned in the introduction, the lack of (4 weeks) tolerance by anti-anxiety agents in the pentylenete- Footshockt 2.6 0.16 14 trazol assay makes this procedure more sensitive to *Dose