Sedative effects of PK 9084 and PK 8165, alone and in combination with chlordiazepoxide

1 The sedative effects in rats of two phenylquinolines, PK 9084 and PK 8165 (5-50 mg/kg), were examined in a holeboard: both when given alone and when given in conjunction with chlordiazepoxide (5 mg/kg). 2 Both phenylquinolines produced significant dose-related decreases in locomotor activity and rearing, with an ED50 about twice that for chlordiazepoxide. 3 When the phenylquinolines were combined with chlordiazepoxide the degree of sedation was equal to that seen with either drug given alone, whichever produced the greater sedation; the sedative effects of the two drugs were never additive. 4 PK 9084 (10 and 50 mg kg) significantly reduced rectal temperature, as did chlordiazepoxide (5 mg/kg), but there was no addition nor interaction of their effects. 5 Both phenylquinolines also reduced exploratory head-dipping, as did chlordiazepoxide, but in combination they antagonized each other's effects. 6 The classification of the phenylquinolines as non-sedative anxiolytics, acting as agonists at the benzodiazepine receptors needs revision.     

Effects of PK 8165, a partial benzodiazepine receptor agonist, on cholecystokinin-induced activation of hippocampal pyramidal neurons: a microiontophoretic study in the rat

Benzodiazepines (BZD) have been reported to suppress cholecystokinin-8S (CCK-8S)-induced activation. PK 8165, a ligand of BZD receptors, is an anxiolytic devoid of sedative and anticonvulsant effects. PK 8165, applied microiontophoretically or administered i.v. at low doses, suppressed CCK-8S-induced activation of hippocampal pyramidal neurons, whereas, at high doses it antagonized the effect of microiontophoretic applications of flurazepam. These results indicate that PK 8165 acts as a mixed agonist-antagonist at BZD receptors and suggest that the suppression of CCK-8S-induced activation by BZD might be related to their anxiolytic property rather than to their sedative or anticonvulsant activity.     

Evaluation of the sedative properties of PK 8165 (pipequaline), a benzodiazepine partial agonist, in normal subjects

The sedative properties of two doses (50 and 150 mg) of a benzodiazepine partial agonist, PK 8165 (pipequaline), were compared to diazepam 10 mg and placebo in 12 normal volunteers. The assessment, performed before drug intake and 2 and 5 hours after drug intake, included a battery of visual analogue scales and standardized computerized tests (labyrinths, series of digits, colour test, and Zazzo test). Results showed that, at low dose, PK 8165 is not only devoid of any sedative effect but presents psychostimulating properties. In contrast, diazepam 2 hours after intake and PK 8165 150 mg, 5 hours after drug intake induced a significant decrease in performance compared to placebo. This study suggests that small doses of PK 8165 merits further development as an anxiolytic/psychostimulating drug devoid of sedative properties.     

Controlled double-blind trial of camazepam,a new benzodiazepine derivative,versus chlordiazepoxide

Summary 31 in-patients with anxiety entered at random in a double-blind clinical trial of chlordiazepoxide and camazepam, a benzodiazepine derivative. They were assessed by three different rating scales. Statistical evaluation of the results showed similar psychopharmacological activity of both drugs. It is concluded that camazepam is suitable for treatment of mild and severe anxiety states.The study was supported by a grant from the Consiglio Nazionale delle Ricerche (C. N. R.)     

The effects of a new benzodiazepine derivative,ID-540, on the averaged photopalpebral reflex in man

The effects of 7-chloro-5-(2-fluorophenyl)-1-methyl-1 H, 1·4-benzodiazepin-2(3 H)-one (ID-540), a recently introduced benzodiazepine derivative, on the averaged photopalpebral reflex (PPR), subjective symptoms, and serum levels of ID-540 and its principal metabolite, N-desmethyl-ID-540, following an oral dose of 0.5 mg or placebo were investigated in six male Japanese students in a double-blind, crossover design. The peak latencies of PPR showed a statistically significant prolongation, with maximum level at 3h after administration, which recovered to the initial level within 4h. The amplitude of PPR failed to show a definite response to the drug. The serum concentration of ID-540 reached a peak level 2–3h after administration, and then decreased at 4h. N-Desmethyl-ID-540 exhibited a slow, gradual rise in serum. The latencies of PPR were positively correlated with the serum level of ID-540 but not with the N-desmethyl-ID-540. It is concluded that the PPR test may be a useful method for predicting the clinical effects of psychotropic drugs.To whom requests for offprints should be sent     

The effect of urapidil on responses to phenylephrine,angiotensin and isoprenaline in man

Summary Intravenous urapidil, 40 mg bolus followed by an infusion of 18 mg·h^–1 for 2 h was administered to 6 female non-patient volunteers. Randomised cumulative dose response curves to angiotensin, phenylephrine and isoprenaline were performed before and commencing 30 min after the start of the infusion of urapidil. Urapidil significantly reduced supine systolic blood pressure, 118.5 mm Hg to 105.3. The diastolic blood pressure was not significantly reduced, heart rate was not affected. Urapidil did not affect the responses to angiotensin or isoprenaline. Urapidil inhibited the pressor response to phenylephrine. The dose required to increase systolic blood pressure by 20 mm Hg increased from 156.9 g·min^–1 before to 685 g·min^–1 during urapidil; Dose ratio from individual values of 4.58. Urapidil concentrations were not significantly different before and after each agonist infusion. It is concluded that urapidil has ₁-adrenoceptor blocking activity in man without any non specific vasodilator action and that it is devoid of beta adrenoceptor blocking action.     

Bronchial and cardiovascular responses to inhaled reproterol in asthmatics: a double-blind placebo controlled dose-response study.

Reproterol is a synthetic selective beta-adrenoceptor agonist with a xanthine side chain. The bronchial and cardiovascular responses to inhaled reproterol were studied in 14 asthmatics. The study was placebo controlled and double-blind, comparing doubling doses of reproterol from 500 micrograms-8 mg. The peak improvement in FEV1 showed a non-linear dose-response, with an initial plateau at the 1 mg dose producing a mean increase in FEV1 of 17%, but significant further improvement at the 8 mg dose, producing a mean improvement of 29% in FEV1. The time taken for improvement in airways obstruction to start shortened with increasing doses. The duration of bronchodilation was dose-dependent, with the 8 mg dose showing a significantly longer duration of action than the lower doses. The time to drop below 75% of the maximum achieved bronchodilation was 125 min, and was independent of the dose. There were no significant changes in pulse or blood pressure at any dose. The study shows that reproterol is a well tolerated selective beta 2-adrenoceptor agonist whose duration of action and peak effect can be significantly increased by increasing the dose to 8 mg, without producing more unwanted effects.     

The effects of alcohol on psychological funtions in normal volunteers after 8 days' treatment with pipequaline (PK 8165), diazepam or placebo

Summary The effects of daily administration for 8 days of 50 mg pipequaline, 10 mg diazepam and placebo were assessed in a double-blind cross-over study with 12 healthy volunteers. This study also tested for an interaction between the drugs and alcohol on the eighth day. Subjective ratings, psychomotor and memory performance were evaluated.Diazepam produced the typical pattern of changes, namely impairments in psychomotor performance and reductions in the retention of newly memorised information.In contrast, the effects of pipequaline were relatively minor. In general, neither drug potentiated the effects of alcohol on performance, only isolated instances of non-additive interactions occurring. Subjective reports revealed that whereas both active drugs increased feelings of calmness, this result was accomplished by pipequaline with considerably less drowsiness, no euphoria and a general absence of the adverse side effects of diazepam.     

Effects of T-82, a new quinoline derivative, on cholinesterase activity and extracellular acetylcholine concentration in rat brain

The effects of T-82 (2-[2-(1-benzylpiperidin-4-yl)ethyl]-2,3-dihydro-9-methoxy-1H-pyrrolo [3,4-b]quinolin-1-one hemifumarate), a new quinoline derivative, on acetylcholinesterase (AChE) activity and acetylcholine (ACh) release were compared with those of the well-known cholinesterase inhibitors tacrine and E2020. T-82, tacrine and E2020 all concentration-dependently inhibited AChE in rat brain homogenate (IC50 = 109.4, 84.2 and 11.8 nM, respectively). In addition, although tacrine strongly inhibited butyrylcholinesterase (BuChE), T-82 and E2020 showed only weak activity on BuChE in human plasma. In ex vivo experiments, intraperitoneal administration of T-82 at a dose of 30 mg/kg inhibited AChE activity in the hippocampus, frontal cortex and parietal cortex of rats. The effect of T-82 on the extracellular ACh concentration in rat brain was measured using in vivo microdialysis. T-82 at doses of 10 and 30 mg/kg, i.p. increased the extracellular ACh concentration in the hippocampus and striatum in a dose-dependent manner. These findings suggest that T-82 activates the central cholinergic system by selectively inhibiting AChE activity, while weakly affecting peripheral BuChE activity, and that T-82 increases the extracellular ACh concentration in the brain, which is followed by inhibited AChE activity.     

Biochemical evidence that 2-phenyl-4[(4-piperidinyl) ethyl]quinoline, a quinoline derivative with pure anticonflict properties, is a partial agonist of benzodiazepine receptors

The atypical profile of 2-phenyl-4[2-(4-piperidinyl) ethyl]quinoline (PK 8165), a quinoline derivative with pure anticonflict properties, seems to be due to the fact that this compound is a partial agonist of benzodiazepine receptors. The drug PK 8165 is a competitive inhibitor of benzodiazepine binding sites with a Hill coefficient near unity. Opposite to 3-methyl-6-(3-trifluoromethylphenyl)2,4-triazolo(4,5-b)pyridazine (CL 218,872) it was unable to discriminate between BZ1 and BZ2 receptors in sections of brain. However, modulation by gamma-aminobutyric acid (GABA) and the effect of photolabelling by flunitrazepam on the affinity of PK 8165 indicated that GABA or photolabelling shifts of PK 8165 were between full agonists and antagonists. By itself PK 8165 was unable to modify the levels of cGMP in the cerebellum, but potentiated the lowering of levels of cGMP by diazepam and did not present antagonistic properties of this effect.     

Alcohol Expectancy Questionnaire tension reduction scale as a predictor of alcohol consumption in a stressful situation

This study was designed as an experimental investigation of the validity of the tension reduction subscale of the Alcohol Expectancy Questionnaire (AEQ) (Brown, Goldman, Inn, & Anderson, 1980). Subjects completed the AEQ in group testing. At a later time, they were placed in a moderate-stress or nonstress control situation, and given the opportunity to consume alcohol or a nonalcoholic beverage. The tension reduction scale did not predict whether they drank or not, nor did it predict the amount of alcohol consumed. Results suggest caution in interpreting the tension reduction scale scores, and that further study of the validity of the tension reduction and other AEQ scales is necessary.     

Pharmacologic profiles of GA0113, a novel quinoline derivative angiotensin II AT1-receptor antagonist.

GA0113 is a newly developed angiotensin II (Ang II) AT1-receptor antagonist having a quinoline moiety. This study was undertaken to clarify the pharmacologic profile of GA0113. In vitro profiles of GA0113 for Ang II receptors were examined in a receptor-binding assay and an Ang II-induced vasoconstriction study. Antihypertensive effects after single or repeated oral administrations were examined in conscious renal hypertensive (RH) or spontaneous hypertensive (SH) rats. Blood pressure (BP) and heart rate were measured by the tail-cuff method. GA0113 interacted with AT1 receptors in a competitive manner, but showed an insurmountable antagonistic action in Ang II-induced vasoconstriction. In RH rats, GA0113 (0.01-1 mg/kg) reduced BP with ED25 values of 0.015 mg/kg, and required 0.1 mg/kg for 24-h BP control. Repeated administration of GA0113 in SH rats (0.03-0.1 mg/kg) showed moderate onset and gradually potentiated reduction of BP, which reached a plateau after day 4 of treatment without alteration in heart rate. There was no tolerance of the hypotensive action or rebound phenomenon after cessation of the treatment. In pharmacokinetic studies, GA0113 shows excellent oral bioavailability (94%) and a long circulating half-life (12 h) in rats. These findings indicate that GA013 may serve as a highly potent and effective antihypertensive agent in humans. GA0113, with its unique chemical structure and pharmacologic and pharmacokinetic profiles may provide new possibilities in hypertension therapy.     

Pharmacokinetics and pharmacodynamics of the ergot derivative,transdihydrolisuride, in man

Summary Plasma levels and urinary excretion of the dopamine agonist, transdihydrolisuride (TDHL), were measured by radioimmunoassay in healthy male volunteers given TDHL 50 µg i.v. and oral doses of 200, 400 and 800 µg. Plasma prolactin was also measured by radioimmunoassay. Following i.v. injection, the concentration of TDHL declined with a half-life of 37±19 min. The total clearance was 38±27 ml/min/kg and the apparent volume of distribution was 1.3±0.4 l/kg. The bioavailability of oral TDHL was proportional to the dose; after 200, 400 and 800 µg the bioavailability was 20±25%, 31±24% and 48±26%. TDHL was almost totally metabolized and less than 0.5% of the dose was excreted unchanged in urine in 24 h. Plasma prolactin levels were depressed by 66±15%, 75±11% and 80±7% after TDHL 200 µg, 400 µg and 800 µg. The effect lasted for more than 12 h after the lowest dose and for more than 24 h after 400 and 800 µg. Side effects, mainly nausea and headache, only occurred at the two highest dose levels.     

Skin conductance responses to hypercapnia in man during a cycle of addiction to morphine

Summary Skin conductance changes during periods of stress induced by hypercapnia were studied during a cycle of addiction to morphine. Conductance changes were found to be dose dependent in both tolerant and non-tolerant states. The effects of morphine on skin conductance changes induced by hypercapnia were similar to those effects previously observed on changes induced by electric shock.     

The role of postcessation factors in tobacco abstinence: stressful events and coping responses

Postcessation factors of stressful events and coping responses used when tempted to smoke, were examined to determine their contribution to relapse among ex-smokers. Subjects from smoking cessation clinics (N = 150) were contacted at three months after quitting. Questionnaires that measured: (a) current smoking behavior, (b) stressful events that occurred since quitting, and (c) coping responses used when tempted to smoke, were administered. Results indicated that abstinent subjects reported fewer work-related stressful events than both partially or totally relapsed subjects. Abstinent subjects used more problem-focused coping responses and fewer emotion-focused coping responses than partially and totally relapsed subjects. It was concluded that work-related stressful events, as well as the use of problem-focused coping responses when tempted to smoke, play important roles in determining smoking behavior during the immediate postcessation period.     

The effectiveness of intramuscular biperiden in acute akathisia: a double-blind, randomized, placebo-controlled study

Neuroleptic-induced acute akathisia (NIA) is a distressing condition and an important clinical problem because it is associated with treatment noncompliance and suicidal or impulsive behavior. Anticholinergics are among the treatment options; however, a review of the literature fails to identify a double-blind, randomized, placebo-controlled study of these medications in NIA. In a randomized, double-blind, placebo-controlled design, we studied the effectiveness of intramuscular biperiden (n = 15) or isotonic saline (n = 15) in the treatment of NIA diagnosed with the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria. Injections were repeated up to 3 times unless akathisia was completely treated (scored 0 for global akathisia with the Barnes Akathisia Rating Scale). Patients were assessed for akathisia, other movement disorders, and psychiatric symptoms at baseline and 3 times after the first injection at 2-hour intervals. Response was defined as at least a 2-point decline in the global akathisia score. The numbers of responders in the 2 groups were not significantly different (7 and 5 in the biperiden and placebo groups, respectively). The courses of individual items on the Barnes Akathisia Rating Scale were also similar. Our results suggest that intramuscular biperiden should not be considered as a first-line treatment of NIA.