Abstract: In mice tested for 60 min in photometer-activity boxes, an increased locomotor activity (+50% to +100%) was observed after administration of cocaine (4 mg/kg i.p.). Such hyperactivity was markedly enhanced by all benzodiazepines studied (flurazepam excepted), at doses which did not modify spontaneous motility: chlordiazepoxide (1 mg/kg), diazepam (1 to 2 mg/kg), clobazam (1 mg/kg), oxazepam (0.25 mg/kg), nitrazepam (0.03 to 0.25 mg/kg), flunitrazepam (0.015 mg/kg), clonazepam (0.004 mg/kg) and lorazepam (0.004 mg/kg). These doses are very low, e.g., 8 to 20 times lower than those required to antagonize the locomotor stimulation caused by cocaine. The increase of cocaine-induced hypermotility elicited by nitrazepam (0.125 mg/kg i.p.) was reduced or suppressed by impairing gamma-aminobutyric acid (GABA)-ergic transmission with picrotoxin (0.25 mg/kg) or by blocking α or β adrenergic receptors with prazosin (1 mg/kg i.p.) or propranolol (4 mg/kg i.p.), respectively. At these doses neither picrotoxin, prazosin, nor propranolol modified the spontaneous locomotor activity or the hyperactivity induced by cocaine alone. These results suggest that benzodiazepines may exert their facilitatory activity on cocaine-induced hyperactivity by interfering with some central catecholaminergic processes either directly or through the involvement of a GABA-ergic link.

Abstract: Nicolaus, B.J.R.: Chemistry and pharmacology of nootropics. Drug Dev. Res. 2: 463–474, 1982. The paper discusses the chemistry and pharmacology of the nootropics, reviewing the new chemical entities to recently emerge and in particular the five-membered heterocyclic lactams belonging to the pyrrolidinone class, such as piracetam and oxiracetam. These gammalactams are related to the folded conformation of GABA, which seems to play a role in the uptake mechanisms—that is, in the transport of GABA across the membrances into differnt nervous tissue elements. The classification of nootropics is discussed, taking into consideration the six main criteria recently suggested, which are: no direct vasoactivity, no change in basic rhythm of EEG activity, blood brain barrier passage, positive metabolic activity in humans and animals, low incidence of side-effects, and objective demonstration of clinivicacy. A critical analysis is made of the various pharmacological and biochemical models employed to screen the nootropics, including a new approach based on the impaired learning rate of spontaneously hypertensive rats with cerebrovascular lesions. The activity of the new GABA-derivative nootropic called oxiracetam is also described and compared with the forerunner of the class, piracetam.

Abstract: The antihistaminic effect of terfenadine was studied in the isolated guinea pig ileum, histamine skin wheals in guinea pigs and monkeys, and i.v. histamine-induced death in guinea pigs. In the guinea pig ileum, terfenadine, 1 × 10−7 M, shifted the histamine dose-response curve to the right in a parallel fashion without affecting the dose-response curve of acetylcholine and barium chloride. However, as the dose of terfenadine was increased (3.16 × 10−7 and 1 × 10−6 M) the histamine dose-response curves were displaced to the right with a depression of the maximum response and a reduction of the slope. Thus an unsurmountable type of antagonism was observed. Acetylcholine was also antagonized in a similar fashion by these two concentrations. In contrast, terfenadine appeared to displace the barium chloride dose-response curve to the right in a parallel fashion. At 0.4 and 0.8 mg/kg p.o., terfenadine shifted the histamine skin wheal dose-response curves to the right in a parallel fashion, but at 1.6 to 6.4 mg/kg, terfenadine antagonized the histamine wheal dose-response curves with a depression of the maximum and the slope of the curve. These results were also similar to those of cyproheptadine but were different from those of chlorpheniramine, which produced parallel shifts. In monkeys, terfenadine produced a substantially greater effect on the histamine wheal than did chlorpheniramine (both administered at 30 mg/kg p.o.). Terfenadine also completely protected against i.v. histamine-induced death in guinea pigs. Terfenadine produced no atropine-like effect against pilocarpine-induced salivation in rabbits, no demonstrable histamine H2 antagonism, no antiserotonin activity, no α or β antagonism, and no untoward cardiovascular effects. Most significantly, terfenadine had no overt central nervous system (CNS) effects in mice, rats, guinea pigs, or monkeys; whereas chlorpheniramine produced tremors and convulsions in mice and monkeys when tested at much lower doses than those used for terfenadine. It is concluded that terfenadine is an effective and specific antihistaminic compound with the potential advantage of a lack of CNS sedative effects.

Abstract: SK&F 82526 is a potent renal vasodilator in dogs, monkeys, and hypertensive rats. It is orally active and has a specificity for the renal vasculature greater than dopamine. Its activity is owing, at least in part, to stimulation of renal dopamine receptors and has no effect on α- or β-adrenergic receptors. This compound should be valuable in further examining the importance of renal blood flow in essential hypertension.

Abstract: Thirteen known H1-antagonists were studied in a series of pharmacological in vivo tests in rats. Antihistamine activity, oral absorption, and duration of action were determined in the compound 48/80 test. The dissociation between the activity in the compound 48/80 test and in the other tests was used as a measured of antihistaminic specificity. Properties common to several H1-antagonists were: antimuscarinic (diphenhydramine, promethazine, mequitazine, azatadine, cyproheptadine, chlorphenriamine, clemastine, pyrilamine) and anti-serotonin activity (mianserin, pizotifen, cyproheptadine, prometazine, diphenhydramine, pyrilamine). Sedative effects of H1-antagonists were not detected by the pharmacological tests used here. Astemizole, ketotifen, and terfenadine were found to be very specific H1-antagonists. For ketotifen and terfenadine, oral activity (1/5 and 1/25 of astemizole, respectively) and oral absorption (1/50 and 1/7 respectively) were poor, and the duration of action (4 and 6 hr, respectively) was relatively short. Astemizole was as potent orally as it was subcutaneously (ED50 = 0.11 mg/kg) and appeared to have a duration of action as long as 24 hr.

Abstract: Buchsbaum, M.S., J. Cappelletti, R. Coppola, F. Regal, A. C. King, and D. P. van Kammen: New methods to determine the CNS effects of antigeriatric compounds: EEG topography and glucose use. Drug Dev. Res. 2:489–496, 1982. It has previously been possible to measure regional glucose use in the cerebral cortex in animals only with autoradiographic techniques. With the advent of position emission tomography (PET) using (18F-2DG) 18F-2-deoxyglucose, it is now possible to assess local glucose uptake in μmol/100 g tissue/min in normal volunteers or patients. The PET technique is complex and costly and cannot be repeated frequently because of the radiation dosage. However, local glucose use is closely tied to cerebral blood flow, and studies have related blood flow to EEG frequency measures. In this study, we have simultaneously investigated local glucose metabolism using 18F-2DG with PET and EEG frequency with 16-lead topographic mapping in six normal controls. Subjects sat in an acoustically treated darkened room with eyes closed for 10 min prior to, and 30 min following injection of 3–5 mCi 18F-2DG. Following uptake, seven to eight horizontal scans parallel to the canthomeatal line were made. EEG recordings are made beginning 1 min after injection of the isotope and continuing for 30 min with 12 standard 10/20 system points on the left hemisphere and midline, and 4 additional points between existing posterior leads. Ten-second EEG epochs are edited for artifacts and then analyzed by fast Fourier transform techniques. Using a cross-sectional whole-head atlas, a standardized, approximately equal-area two-dimensional representation of a lateral view of the brain was developed and 10/20 system scalp coordinates were projected onto it. EEG power estimates are interpolated for all points on this brain map. Using digital techniques, a 1-cm-thick cortical strip is peeled off each PET, slice and conformed to the lateral brain view, and values between strips are interpolated. The result is two simultaneously obtained electrophysiologic and metabolic lateral views of brain function displayed in gray-scale values represented by dot density. In some subjects with eyes closed, alpha power is high in low glucose-use regions, such as the occiput. Temporal regions appear low both in glucose use and in most power bands. Parallels between alpha distribution and glucose use are illustrated.

Abstract: Male rats were trained to emit responses on one lever after they were injected with pentylenetetrazol and a different lever when injected with saline in order to obtain food reinforcement. It was shown that the pentylenetetrazol action, which served as a cue for appropriate response selection, was predictive of anxiogenic activity. This cue was blocked by anxiolytic drugs in a dose-dependent manner but not by anticonvulsant or depressant drugs. This procedure was shown to reliably predict elicitation of anxiogenicity or its blockade.

Abstract: Epilepsy is a collection of seizure disorders which afflicts approximately 2 million Americans, and is equally common worldwide [Lennox and Lennox, 19601. Present antiepileptic drugs provide some control for only about 70-80%, and complete control for not more than 50%, of the affected population [Coatworth, 19711. Perhaps the most significant advance in the treatment of epilepsy came with the introduction of phenobarbital in 1912 [Hauptmann, 19121, but this is rivaled by the enthusiastic acceptance of phenytoin (diphenylhydantoin) in 1938, after animal studies and limited clinical trials suggested its therapeutic efficacy [Memtt and Putnam, 1938a,b]. Unfortunately, the decades that followed the introduction of phenytoin have witnessed application of the “law of diminishing returns”; that is, expanded programs have produced smaller increments of control in the remaining uncontrolled population. It has become increasingly evident that significant progress toward complete control will continue to elude society as long as the molecular bases of antiepileptic drug action remain unresolved. It is toward this latter goal that many of the recent structure-activity relationship (SAR) investigations have been directed. The purpose of this review is (1) to document the progress of anticonvulsant SAR in terms of qualitative and quantitative developments, and (2) to discuss the probable causes of failure in such research.

Abstract: Both learned helplessness and stress produce deficits in escape/avoidance behavior. The yoked control paradigm was used to compare these two phenomena, with pairs of animals exposed to the same amount of shock—in one case controllable (stress) and in the other uncontrollable (learned helplessness). Stressed animals demonstrated a transient (one day) elevation in serotonin levels in the septal synaptosomal pellet. On the other hand, animals subjected to uncontrollable footshock sustained a significant decrease in septal synaptosomal serotonin for five days. Similar differences were found in the anterior cortex, but not in the posterior cortex or hippocampus. This work demonstrates the importance of using appropriate controls in neurochemical and pharmacologic research with learned helplessness.

Abstract: Alpha-2 agonists by an effect on alpha-2 adrenoreceptors in the stomach (and probably in the brain also) suppress vagal nerve acetylcholine release thereby inhibiting gastric motility and secretion and inhibiting the development of gastric lesions in rats in the stress-, reserpine-, and cysteamine-induced ulcer models. Since the effects of the alpha-2 agonists are consistently inhibited by alpha-2 blocking agents, their effects appear to be selectively mediated via the alpha-2 receptor. It seems appropriate therefore that the role of the alpha-2 receptors be recognized in studies of gastric function and ulcer development.

Abstract: Normotensive rats of the Sprague-Dawley strain were administered either the centrally acting hypotensive drug clonidine (0.16 mg/kg IP) or the peripherally acting hypotensive drug hydralazine (1.25 mg/kg IP) to induce reliable hypotension (blood pressure reductions of 60–90 mm Hg), as measured by a tail cuff procedure. The opiate antagonist, naloxone (10–20 mg/kg IP), reversed clonidine but not hydralazine hypotension. Naloxone also failed to reverse hydralazine's hypotensive action in rats made hypertensive by renal ligation. Naloxone's reversal of clonidine (0.01 mg/kg IV) hypotension was confirmed in experiments in which blood pressure was measured through direct cannulation of the carotid artery. It is suggested that naloxone's antagonism of clonidine hypotension is located at a central nervous system site, and that clonidine hypotension may be mediated through an interaction with the brain opiate systems.

Abstract: The analgesic effect of morphine in a mouse writhing assay was enhanced by the simultaneous administration of fluoxetine, an inhibitor of serotonin uptake. Fluoxetine reduced the ED50 for morphine and extended the duration of morphine analgesia. The potentiation of morphine analgesia was particularly striking in mice made tolerant by repeated morphine injections. Potentiation of morphine by fluoxetine was also observed in a rat tail jerk test for analgesia. The acute lethality of morphine in rats and mice was altered by fluoxetine, yet the therapeutic index of morphine (ratio of LD50 to ED50) was unchanged. The decrease in blood pO2 produced by morphine at doses of 1 and 4 mg/kg in rats was attenuated by fluoxetine, which by itself increased blood pO2. These findings strengthen earlier evidence for an involvement of serotoninergic neurons in the analgesic effects of morphine and support the idea that enhanced serotoninergic function might be a useful means of enhancing morphine's actions in clinical therapy.

Abstract: Considerable evidence suggests that angiotensin interacts with the central nervous system (CNS) to increase blood pressure and alter peripheral hydration. Blood-borne angiotensin may affect circumventricular organs resulting in increased water intake and vasopressin release. In addition, current literature documents the presence of a complete renin-angiotensin system (RAS) in the brain. Angiotensin, presumably of central origin, increases sodium excretion; an effect opposite to blood-borne peptide. This effect, along with increased water turnover, could dilute body fluids. The relative activities of the peripheral (renal) and central RASs thus may be of considerable importance in both normal and pathophysiological control of blood pressure and hydration. Indeed, some models of spontaneous hypertension in rats are associated with an altered brain RAS; central administration of converting enzyme inhibitors or angiotensin receptor antagonists returns elevated blood pressure toward normal.

Abstract: Reisberg, B., S.H. Ferris, M.K. Schneck, J. Corwin, P. Mir, E. Friedman, K.A. Sherman, M. McCarthy, and R.T. Bartus: Piracetam in the treatment of cognitive impairment in the elderly. Drug Dev. Res. 2: 475–480, 1982. Piracetam (Nootropil, 2-oxopyrrolidone acetamide) has been extensively investigated for the treatment of cognitive impairment. Initial studies on normal subjects and patients with mild or moderate cognitive decline have been somewhat encoruaging. Accordingly, we conducted a further evaluation of the effects of piracetam in the treatment of elderly outpatients 60 to 85 years of age with mild to moderate memory impairment consistent with a diagnosis of Primary Degenerative Dementia (PDD). In our first study, we examined the effects of piracetam in 20 patients. All patients received 7.2 g of piracetam and placebo for 4 weeks in accordance with a double-blind, randomized treatment order, crossover design with 1-week washout periods prior to each crossover period. Hence, the total study period for each patient was 10 weeks (1-4-1-4). An analysis of 43 psychometric measures revealed significant improvement (P < 0.05) in only three measures, all favoring the treatment condition. Recent findings support a rationale for examining the effects of piracetam in conjunction with cholinergic precursors in patients with cognitive decline. In our second study we conducted a 1-week open trial of 1.6 g of piracetam t.i.d. in conjunction with 3 g of choline cholride t.i.d. in 15 patients. Four patients were rated as clinically improved. These “responders” were all subjects with moderate cognitive impairment. The responders showed much higher RBC choline levels than the nonresponders, both at baseline and during treatment. We conclude that the present evidence indicates that the effects of piracetam treatment alone in elderly outpatients with mild to moderate congnitive decline are subtle and not of proven clinical significance. However, studies of longer duration and of piracetam in combination with other agents may eventually show genuine clinical utility.

Abstract: Seven aromatic bisguanylhydrazones and two related compounds were screened against Trypanosoma brucei (EATRO 110M) in mice. The four most active were then screened against T. congolense (TREU 1183) in mice and rats. Eradication of parasitemia through 28 (T. brucei) or 42 days (T. congolense) resulting from a single dose of drug administered IP either 4 or 24 hours (respectively) after infection was used as the criterion of activity. 1,3-Diacetylbenzene bisguanylhydrazone dihydrochloride cleared T. congolense from 50% of the animals (ED50) at a dose of approximately 10 mg/kg and from mice infected with T. brucei at approximately 15 mg/kg. This drug was also active when given 5 days after infection with T. congolense (ED50 ≅ 15 mg/kg). The isomorphous pyridine derivative, 2,6-diacetylpyridine bisguanylhydrazone dihydrochloride, was active against T. brucei in mice (ED50 ≅ 8 mg/kg), but noncurative against T. congolense. At therapeutic doses of these two compounds, reversal and clearance of parasitemia was often not observed for 2–4 days, suggesting a delayed mode of action. Moreover, 1–2 days after drug treatment, the infectivity of parasites obtained from treated animals was significantly reduced, if not abolished. These findings indicate that more intensive screening of aromatic bisguanylhydrazones against various species of trypanosomes is warranted.

Abstract: The present study was undertaken to confirm and extend previous observations on the use of morphine-induced Straub tail and rotarod performance in mice as a means of assessing the efficacy of a compound as a muscle relaxant and its potential for depressant side-effects, respectively. The ratio of the rotarod to Straub tail ED50s was calculated as an index of specificity. Our results generally confirmed previous reports in the case of diazepam, chlordiazepoxide and dantrolene. Additionally, the recently introduced muscle relaxants, cyclobenzaprine, baclofen, and DS 103-282 were found effective in blocking Straub tail and their reported clinical specificity was reflected by the specificity observed in the mouse tests. DS 103–282 was found to be the most potent and specific. It is concluded that muscle relaxants with specificity ratios significantly greater than 1.0 appear to have comparatively few depressant effects at therapeutic doses. The relatively simple methods used in the present study appear to be useful in the initial assessment of compounds as potential muscle relaxants.

Abstract: The effect of chronic intravenous infusion of desmethylimipramine (DMI), amitriptyline, mianserin, bupropion, alprazolam, or diazepam on the density of beta-adrenergic receptors in the rat cerebral cortex has been investigated in this study. DMI and amitriptyline significantly decreased the density of beta-adrenergic receptors. Mainserin, bupropion, alprazolam, and diazepam had no significant effect on the density of beta-adrenergic receptors. Results of this study indicate that mechanisms other than beta-adrenergic receptors may be involved in the antidepressant activity of these drugs.

Abstract: Clobazam, a 1,5-benzodiazepine, and diazepam, a 1,4-benzodiazepine, were tested for their influence on motor activity and exploratory behavior in mice in an automatized hole-board apparatus with two light beams (“Planche a trous”) and in a nonautomatized motility-exploration (MOTEX) device, designed by Weischer 1976. Clobazam at oral doses of 5 to 80 mg/kg caused a marked increase in locomotion (79% to 122%) under MOTEX conditions, whereas results with the hole-board device were inconsistent and misleading: Enhanced locomotion was represented as reduced motor activity in terms of light-beam crossings. Exploratory behavior was reduced by clobazam in both MOTEX and Planche a trous at ED50 values of 33 and 67 mg/kg orally (p.o.), respectively. Diazepam at oral doses of 1 to 10 mg/kg slightly but not significantly increased locomotion in MOTEX and reduced motor activity in the hold-board test (ED50 = 3.8 mg/kg). Exploratory behavior was inhibited under both conditions at ED50 values of 3.2 and 6.7 mg/kg p.o., respectively. The inability of a two light-beam system to properly examine locomotor activity (particularly when peripheral areas of the apparatus are favored by the animals) is considered the reason for misleading results obtained with clobazam in the hold-board test. The marked increase in locomotion induced by clobazam in a nonautomatized apparatus (MOTEX) is discussed in terms of disinhibitory effects in connection with the fact that clobazam does not induce amnesia in animals and man.

Abstract: The efficacy of a new eburnamenine derivative (RU 24722) on cerebral insufficiency was studied by evaluation of postischemic EEG recovery in the conscious gerbil. Ischemias of different durations were obtained by clamping both common carotids. This method required only brief anesthesia, thereby permitting the recording of EEG recovery in unanesthetized and unrestrained animals during the 24 hr following arterial occlusion. The EEG was analyzed by the Fast Fourier Transform. Mortality rate and clinical status were also evaluated. After a 5-min ischemia the initial return of EEG was characterized by very high amplitude slow waves (1–2 Hz) and the EEG became normal 24 hr after ischemia. No mortality was observed. After a 10-min ischemia the early recovery phase was characterized by a decrease in the power spectrum and a rebound of slow frequency waves after 2–4 hr. After 24 hr the EEG was not yet completely normal and 1 animal out of 10 died. A 15-min ischemia killed 50% of the animals, and the EEGs of the survivors were abnormal even after 24 hr. Treatment with RU 24722 (10 mg/kg/s.c.) significantly improved the electrocortical recovery of gerbils submitted to a 10-min ischemia. In this group the EEG was normalized 6 hr after ischemia in the same way as in the controls submitted to a 5-min ischemia. These findings suggest that RU 24722 may have a therapeutic effect in cerebral insufficiency.

Abstract: The anticonvulsant action of N-desmethylclobazam, the metabolite of clobazam, has been evaluated acutely in DBA/2 mice with audiogenic seizures and in baboons (Papio papio) with photosensitive epilepsy, and compared with the effect of clobazam. In mice, desmethylclobazam appears less potent than clobazam, in terms of the ED50 for abolition of the tonic or clonic phase of the seizure response, but it has a longer time course of action. In baboons, desmethylclobazam, 1 to 4 mg/kg i.v., has a protective action against photically-induced myoclonus comparable to that seen after similar doses of clobazam. After clobazam, 4 mg/kg, plasma clobazam concentration shows a rapid, approximately exponential, clearance (t1/2 = 2.0 to 2.5 hr), and plasma desmethylclobazam content increases progressively to a peak at 6 hr or later. Plasma concentrations of desmethylclobazam after clobazam injection rapidly exceed those associated with potent anticonvulsant action when desmethylclobazam itself is administered. It is concluded that in the baboon and probably also in man the metabolite desmethylclobazam is responsible for a substantial part of the antiepileptic effect of clobazam.

Abstract: A commonly used method of evaluating critical flicker fusion (CFF) threshold—the Leeds psychomotor tester—has been assessed with regard to the influence of pupil-size alteration on CFF measurements. Six healthy volunteers, (three males, three females) took part and were treated with saline, pilocarpine 2%, and homatropine 1% eye drops at intervals of one week according to a balanced crossover design. The regression of CFF threshold on pupil size, both measured up to 7 hr after treatment, was highly significant in all subjects. Increases of pupil size from 2 to 8 mm produced a rise in CFF threshold which varied between individuals but ranged from 2 to 9 Hz. In a separate study, the effect of clobazam 20 mg on binocular and monocular CFF, the latter both uncorrected and corrected for pupil size, was assessed over the 8-hr period after treatment. No significant changes in either measure of CFF were observed. On a separate study day the same four subjects submitted to mydriasis/miosis induced by homatropine followed by pilocarpine eye drops. This procedure showed that the use of an artificial pupil of 2 mm adequately corrected for pupil-size influences on CFF in all but one subject.

Abstract: The effects of increasing doses of cibenzoline (-2(2,2-diphenylcyclopropyl)-2-imidazoline, Cipralan), a new compound with antiarrhythmic properties, on systemic hemodynamics and regional myocardial performance were studied in anesthetized pigs. Doses of 0.5–2.0 mg kg−1 i.v. produced a 10–15% prolongation of the PP' interval, and a dose-dependent increase (up to 60%) in QRS width, with only minor changes in PQ and ST length. Stroke volume decreased dose dependently (20–35%) immediately after drug administration, due to a decrease in myocardial contractility and an increase in systemic vascular resistance. Renal blood flow was unchanged, despite the decrease in cardiac output. Coronary blood flow decreased, while myocardial O2 extraction was unchanged. Hence myocardial O2 consumption decreased parallel to the decrease in flow, a consequence of the lowered myocardial O2 demand. Studies with radioactively labeled microspheres revealed that the decrease in myocardial blood flow was equally distributed over the transmural layers.

Abstract: The pharmacodynamics and pharmacokinetics of the benzodiazepines are discussed and differences which may be important in the clinical situation are stressed. Clobazam, one of a new generation of benzodiazepines, is discussed in relation to the 1,4-benzodiazepines.

Abstract: The effects of the 1, 5-benzodiazepine derivative clobazam upon critical flicker fusion (CFF) values in normal subjects is reviewed. All studies reviewed were double-blind and placebo controlled. Single acute doses of 10 or 20 mg did not lead to significant CFF changes, whereas repeated doses of 20 mg clobazam a day for 4 days produced a significant elevation in CFF thresholds. Possible pharmacokinetic reasons for this CFF elevation after repeated doses are discussed. Equivalent investigations of clobazam at higher dose levels (30 to 60 mg) showed a similar difference in the effects of acute versus repeated doses; single acute doses led to significant CFF decrements, while repeated administrations led to similar clobazam and placebo CFF levels. The patterns of CFF changes with this 1,5-benzodiazepine anxiolytic agent seems to be different from the CFF changes generally reported with the 1,4-benzodiazepine anxiolytic agents (generally CFF reductions), and suggests possible central nervous system alerting affects after repeated administration at the lower dose levels.

Abstract: Antiserotoninergic effects of maprotiline and its hydroxy derivative oxaprotiline (Ba 49802 B), two selective inhibitors of NA uptake, and clinically active antidepressants were investigated in several functional tests and also in in vivo 3H-spiperone binding assay in the rat. In some tests comparisons with amitriptyline, mianserin, and fluoxetine, which are antidepressants of different qualities, were also done. After single doses up to 30 mg/kg neither maprotiline nor oxaprotiline inhibited L-5-HTP-induced head twitch in mice or tryptamineinduced paw clonus in the rat. Maprotiline, however, but not oxaprotiline, significantly reduced the hyperthermic response to LSD in rabbits and blocked to nearly 90% the 3H-spiperone labeled 5-HT receptors in the rat frontal cortex at a dose of 30 mg/kg. Moreover, maprotiline also reduced the response of mice to L-5-HTP after daily administration of 25 mg/kg over 10 days. No change in the responsiveness of mice to L-5-HTP was observed after the same treatment with oxaprotiline. In agreement with other observations, mianserin and amitryptiline displayed clear-cut antiserotoninergic effects, whereas fluoxetine potentiated the effects of tryptamine and LSD. The results of this study indicate that, although chemically closely related, maprotiline and oxaprotiline distinctly differ in respect to their action on 5-HT receptors. Maprotiline exerts 5-HT receptor blocking effects that appear to increase upon repetitive administration in mice. Oxaprotiline, by contrast, is devoid of them. Comparative experimental and clinical investigations of maprotiline and oxaprotiline may, therefore, provide a clue as to the importance of 5-HT receptor blocking properties for antidepressant profile of action of drugs.

Abstract: The cardiac hypertrophy which develops in models of sustained hypertension in experimental animals cannot be prevented or reversed by all antihypertensive drugs. Clearly, blood pressure is only one of numerous factors which contribute to the development of hypertensive cardiomegaly. The ability of drugs to reduce cardiac hypertrophy depends primarily on their mode of action, rather than on the degree of blood pressure decrease. Vasodilators effectively control high blood pressure but enhance cardiac hypertrophy in rats. In currect experiments, minoxidil lowered blood pressure, but caused increases in heart weight and plasma-renin activity (PRA) in spontaneously hypertensive rats (SHR). In contrast, the calcium antagonist, nifedipine, reduced blood pressure or prevented its increase in SHR concurrently reducing heart wight and decreasing PRA. Moreever, nifedipine prevented salt-induced hypertension and heart hypertrophy in SD (sensitive)-Dahl rats. It is suggested that in contrast to the vasodilator minoxidil, nifedipine reduces the high renovascular resistance in hypertensives thus enhancing sodium and water elimination. Thus, the action of the calcium antagonist, nifedipine, involve both renal vasodilation and reduction of renin-angiotensin mediated renal vasoconstriction. In this way, the decreased volume load together with the decreased arterial afterload will contribute to the prevention or regression of hypertensive cardiac hypertrophy.

Abstract: Capel, 1.0., M.H. Pinnock, N.J. WIthey, D.C. Williams, and M.A. Patterson: The effec: of electrcslimulclion on barbiturale-induced sleeping times in ra!s. Drug Dev. Res. 2:073·079, 1982. Female ralS. anaesthetized with hexobarbital. regained their righting reflex more rapidly following,eleclrostimulation than sham-treated controls. The extent of the decreased sleep­ ing times in these animals varied according to the frequency (cycles per second) of the elec.rOSllmulation applied. The frequency which produced the largest decrease in sleeping lime was 10Hz. Determination of the activity of some microsomal enzymes indicated that the decreased sleeping time was not the result 01 increased hepatic enzyme activity. Animals which had received prior treatment with naloxone exhiblled increased sleeping times fol­ lowing barbiturate administration. but ltle effects of eleClros:imulatlon on the sleeping time at 10 Hz. was diminished, while lhe effect 01 eleclrOSlrmulaticn al hIgh frequency (500 Hz} was enhanced. Although repealed daily administration 01 hexobarbital progreSSively de­ creased sleeping times lor all the animals. electroslimulatlon decreased the sleeping :imes of the treated rats by a similar percentage of the control animals on each successive day. Electros:imulation at a frequency of 10 Hz produced a signilicanl decrease in serum cor­ ticosterone levels, whereas sao Hz resulted in an increase.

Abstract: To test the hypothesis that glucocorticoids modulate lung beta-adrenergic receptors as a mechanism for their therapeutic effect in asthma, we investigated the effects of adrenalectomy and glucocorticoid administration on rat lung beta-adrenergic receptors. The data demonstrate that, compared to untreated animals, adrenalectomized Sprague-Dawley rats treated with cortisol (80 mg/kg) for 5 days and nonoperated rats treated with methylprednisolone (100 mg/kg) for 5 days have a 30% increase in lung beta-adrenergic receptors, as measured by [3H]-dihydroalprenolol binding. These data support the hypothesis that pharmacological doses of glucocorticoids modulate lung beta-adrenergic receptors upwards. This mechanism may account, at least in part, for the therapeutic effect of these drugs in asthma.

Abstract: Clobazam is a 1, 5-benzodiazepine with significant activity in preclinical tests predictive of potential clinical antianxiety activity Clinical efficacy equivalent to diazepam has been established with minimal effects on psychomotor performance Clobazam has also been found to have a broad spectrum of anticonvulsant activity with acceptable toxicity and to be active in suppressing aggressive behavior in rodents This compound appears to have less of an effect on motor coordination, muscle tone, behavioral depression and hyporeflexia than standard reference compounds in various species as well as little or no apparent effect on memory and learning in animals and humans The major metabolite, desmethylclobazam, is also an anxiolytic candidate approximately 10 times less potent than diazepam and a potent anticonvulsant with a complete lack of sedation These compounds represent a new classification of pharmaceutical agents in which antianxiety and anticonvulsant effects can be achieved without sedative or depressive side effects