A single and multiple dose bioavailability study with carbamazepine 400 mg retard tablets with reference to enzyme autoinduction and circadian time differences

Both single and multiple dose bioequivalence studies are required to assess the quality of modified release formulations of drugs. In bioequivalence studies of drugs with enzyme autoinducing properties such as carbamazepine (CBZ), the standard multiple dose study design must be modified to guarantee equivalence of drug elimination. This problem was considered with regard to carbamazepine 400 retard AWD (test) whose bioavailability relative to a listed reference (Tegretal 400 retard) was studied in 2 randomized, open, crossover studies both with 18 healthy volunteers of Caucasian origin (20-36 years, 61.5-92 kg, 172-195 cm). The single dose study was done with 400 mg CBZ. Serum concentration time profiles of CBZ and its active metabolite CBZ-10,11-epoxide were determined until 144 h after administration. The multiple dose study was performed with 400 mg CBZ b.i.d. for 15 days (first 2 days: 200 mg b.i.d.) followed by a 7-day study with the alternative investigational product. 24-hour serum concentration time profiles of CBZ and its metabolite were measured on days 15 and 22 of the study. The quantitative drug analysis was done with an HPLC method the quality of which fulfilled the requirements of bioequivalence studies. Test was considered bioequivalent to reference with regard to the extent of absorption, if the 90% confidence intervals of the AUC0-infinity ratio (single dose) and AUC0-24h ratio (multiple dose) were within the range of 0.80-1.25, and with regard to rate of absorption if the 90% confidence intervals of the Cmax/AUC ratio (single dose) or AUCF0-24h ratio were within 0.70-1.43. The point estimators (90% confidence limits) of the AUC ratio (test/reference) of CBZ were 0.979 (0.94, 1.02) for the single and 1.01 (0.947, 1.076) for the multiple dose comparison. The point estimator (90% confidence limits) of the Cmax/AUC ratio was 0.989 (0.959, 1.020) and of the AUCF0-24h ratio 1.066 (0.937, 1.212). There were no circadian time differences in any pharmacokinetic parameter. In conclusion: Carbamazepine 400 retard AWD tablets were bioequivalent to reference with regard to extent and rate of absorption after both single and multiple dose administration.     

Deficits in D-fenfluramine-sensitive pool of brain 5-HT following withdrawal from chronic cocaine exposure

Recent head-twitch response (HTR) studies in mice have indicated that withdrawal from chronic cocaine exposure produces deficits in CNS conversion of L-tryptophan to 5-HT. In the present study, the ability of 5-HT releaser, d-fenfluramine, was utilized to induce the HTR in mice following abstinence from chronic cocaine exposure. d-Fenfluramine-induced HTR, is a 5-HT2A receptor-mediated phenomenon and its induction frequency can be regarded as an indirect but in vivo measure of basal brain 5-HT concentration. Thus, different groups of mice were injected with cocaine twice daily (0, 0.1, 0.5, 2.5, 5 or 10 mg/kg, i.p.) for either 7 or 13 days. At 24 h after last cocaine injection, the treated mice received d-fenfluramine (5 mg/kg, i.p.) and the induced HTR (mean+/-SEM) was recorded for the next 30 min. Cocaine attenuated the d-fenfluramine-induced HTR frequency by 30-37% in the 13-day regimen and significant effects were observed from 0.5 mg/kg dose. At 24 h withdrawal in the 7-day cocaine exposure group, the mean HTR frequencies were attenuated, however, they did not achieve statistical significance. Extended abstinence studies (i.e. 24, 48, 72 and 96 h postwithdrawal) from chronic cocaine exposure (0, 0.5 and 5 mg/kg/day for either 7 or 13 days) indicated that in the 7-day exposure group, significant reductions (26, 39 and 22%) in HTR frequency occurred at 48, 72 and 96 h following withdrawal from 0.5 mg/kg cocaine, whereas its 5 mg/kg dose failed to induce a significant effect. In the 13-day exposure group significant reductions in HTR frequency were observed at 24 h abstinence (27%) for the 0.5 mg/kg cocaine dose and at 24 and 48 h for the 5 mg/kg. Overall, these results indicate that abstinence from chronic exposure to cocaine produces enduring deficits in basal 5-HT concentration. Lastly, serotonergic function appears to be uniquely sensitive to chronic administration of low doses of cocaine.     

Opioid antagonist profile of SC nor-binaltorphimine in the formalin paw assay

The antinociceptive effects of mu and kappa agonists were examined after the systemic administration of the opioid antagonists nor-binaltorphimine (nor-BNI) and naloxone in the late response or tonic nociceptive phase of the mouse formalin assay. Initially, SC morphine (ED50, 0.97 mg/kg), racemic U-50488H (ED50, 0.79 mg/kg), (-)U-50488 (ED50, 0.41 mg/kg), and another agonist PD 117,302 (ED50, 0.28 mg/kg) were found to produce graded increases in the level of antinociception as measured by this procedure; naloxone, administered immediately before morphine and U-50488H, antagonized their antinociceptive actions. The effects of morphine and U-50488H then were evaluated 10 min to 96 h after the administration of nor-BNI. Subcutaneous nor-BNI at 30.0 mg/kg, but not at 3.0 or 10.0 mg/kg, attenuated the antinociceptive effects of morphine and U-50488H when the interval separating nor-BNI and the agonists was kept constant at 1 h. Time-course analysis of the effects of combinations of nor-BNI with morphine led to irregular findings: 10.0 mg/kg of nor-BNI lessened the effects of morphine (2.0 mg/kg) if the dosing interval was 10 min, whereas 30.0 mg/kg of nor-BNI attenuated the effects of morphine (2.0 mg/kg) if the dosing interval was 1 or 4 h; 10.0 mg/kg of nor-BNI also diminished the antinociceptive effects of U-50488H (1.7 mg/kg) only if the interval spacing the two drugs was 24 h. In comparison, a threefold higher dose of nor-BNI (30.0 mg/kg) reduced the effects of U-50488H (1.7 mg/kg) if the interval was 1 h or more. In these latter experiments, the antagonist effects of SC nor-BNI (30.0 mg/kg) were evident up to 96 h posttreatment. These results show that the mu opioid antagonist activity of nor-BNI is variable and that the kappa opioid antagonist selectivity of nor-BNI is a function of dose and treatment interval and is long-lasting even after systemic administration.     

Development of rapid tolerance to pentobarbital and cross-tolerance to ethanol on a motor performance test with intoxicated practice

Male Wistar rats given a single moderate dose (1.7 mg/kg, IP) of pentobarbital (PB), followed by six trials on the moving belt apparatus during the next hour, showed tolerance to the motor-impairing effects of a second dose of 17 mg/kg given 24 h later. A control group that received saline before the first test showed the usual initial sensitivity when tested with PB 24 h later. Three weeks later, the first group showed cross-tolerance to the effects of ethanol (1.7 g/kg, IP) on the same test, while the second group did not. These findings support the suggestion that rapid tolerance is closely similar to chronic tolerance and that the contribution of intoxicated practice results in a long-lasting component that applies to cross-tolerance to ethanol on the same test.     

Quality of life in children with congenital heart defects

PURPOSE: The antiepileptic effects of zonisamide (ZNS) have been well documented experimentally and clinically. The purpose of this study was to examine whether ZNS reduces cerebral damage after transient focal ischemia in rats. METHODS: Ischemia was induced by a transient occlusion of the left middle cerebral artery (MCA) with a 3-0 nylon monofilament for 90 min. Neurological evaluation was performed by measuring the event of neurological deficit of the contralateral forepaw and hindpaw at 10 min and 1 day after MCA occlusion (MCAo). Brain infarct size was determined by measuring triphenyltetrazonium chloride-negative stained area of the serial brain sections 1 day after MCAo. RESULTS: The pre- or postischemic treatment with ZNS [(10-100 mg/kg p.o.), 30 min before and 4 h after or 15 min and 4 h after the occlusion] markedly reduced cerebral damage in the ipsilateral hemisphere and the neurological deficit induced by transient ischemia. The reducing effect on the damage was observed in the cortical and subcortical regions. Preischemic treatment with carbamazepine (CBZ 60 mg/kg p.o. twice 30 min before and 4 h after MCAo) tended to reduce the cerebral damage and neurological deficit, but the lower dose (20 mg/kg p.o. twice) did not. Valproate (VPA 1,000 mg/kg p.o. twice) also had no effect. CONCLUSIONS: ZNS at the anticonvulsant dose, unlike CBZ and VPA, ameliorated the brain infarction and the event of neurological deficit after transient focal cerebral ischemia. These data suggest that ZNS has therapeutic potential in protecting against ischemic cerebral damage, such as stroke.     

Signalling initiated with CD4-TCR or TCR-TCR interactions: comparison of tyrosine phosphorylation patterns and CD45 effects

LY 300164 [7-acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo(4, 5H)-2,3-benzodiazepine], administered intraperitoneally up to 2 mg/kg, did not influence the threshold for electroconvulsions. In doses of 2.5-4 mg/kg, LY 300164 significantly raised the threshold. In subprotective doses against electroconvulsions, this excitatory amino acid receptor antagonist enhanced the protective activity of intraperitoneally given valproate, carbamazepine and diphenylhydantoin against maximal electroshock-induced convulsions in mice. The anticonvulsive action of phenobarbital was potentiated by LY 300164 only at 2 mg/kg. The non-N-methyl-D-aspartate receptor antagonist did not affect the plasma levels of the antiepileptic drugs, so a pharmacokinetic interaction is not probable. Combined treatment with LY 300164 (2 mg/kg) and the antiepileptics studied (providing 50% protection against maximal electroshock) did not impair the motor performance of mice, evaluated in the chimney test. Valproate, at its ED50 of 280 mg/kg against maximal electroshock, produced motor impairment. As shown in the passive avoidance task, combination of LY 300164 (2 mg/kg) with valproate or diphenylhydantoin resulted in impairment of long-term memory. Alone among the antiepileptics, valproate (280 mg/kg) and phenobarbital (28.5 mg/kg) disturbed long-term memory. The results suggest that blockade of glutamate-mediated events via non-NMDA receptors leads to enhancement of the anticonvulsive activity of conventional antiepileptics. Some combinations of LY 300164 with antiepileptic drugs were superior to these antiepileptics alone in terms of their lack of adverse effects.     

Lack of anticonvulsant tolerance to the neuroactive steroid pregnanolone in mice

GABA-potentiating neuroactive steroids such as pregnanolone have potent protective effects in the pentylenetetrazol seizure test. We sought to determine if tolerance develops to the anticonvulsant activity of pregnanolone with chronic administration. Mice were treated with two daily injections of a 2 x ED50 dose of pregnanolone (25 mg/kg, i.p.) for 7 days. On the day after the chronic treatment protocol, the dose-response relationship for protection in the pentylenetetrazol seizure test was obtained. The ED50 value after the chronic treatment protocol was not significantly different from that in naive mice (12 mg/kg), indicating that tolerance does not develop to the anticonvulsant activity of pregnanolone. In subsequent experiments, we extended the chronic treatment protocol to 14 days with three daily injections of pregnanolone (25 mg/kg, i.p.). Again, no tolerance was observed (ED50, 13 mg/kg). The anticonvulsant activity of pregnanolone was well correlated with plasma levels in both the naive and chronically (14 day) treated mice. The estimated plasma concentrations of pregnanolone representing threshold (10%) protection (125-150 ng/ml) and 50% protection (575-700 ng/ml) were similar in naive and chronically treated animals. In both chronically treated and naive animals, plasma levels of pregnanolone declined rapidly (t1/2, 16-19 min) and there was a corresponding reduction in the anticonvulsant activity. Our results with pregnanolone suggest that tolerance does not develop to the anticonvulsant activity of neuroactive steroids as it does with other GABA potentiating drugs such as benzodiazepines, supporting the potential clinical utility of neuroactive steroids in chronic seizure therapy.     

Transpositional activity of IS986 in Mycobacterium smegmatis

The aim of the present study was to determine if the calcium channel antagonist flunarizine would affect the time course of vestibular compensation for unilateral labyrinthectomy (UL) in guinea pigs. Animals received either a single IP injection of flunarizine 1 h pre-UL or a series of IP injections every 6 h for 24 h post-UL, starting at 6 h post-UL. Flunarizine was dissolved in 50-100% DMSO or suspended in 10% Tween-80 and administered at a dose of 10 mg/kg in the pre-UL condition and 10 or 20 mg/kg in the post-UL condition. All injections were 1 ml/kg in volume. Spontaneous nystagmus (SN), yaw head tilt (YHT), and roll head tilt (RHT) were measured using video analysis. When dissolved in DMSO and administered 1 h pre-UL, 10 mg/kg flunarizine had a small but significant effect on the rate of RHT compensation; otherwise, flunarizine had no significant effects on SN, YHT, or RHT when dissolved in DMSO. When suspended in Tween-80, 10 mg/kg flunarizine pre-UL resulted in a significant decrease in SN frequency and YHT relative to the control group, although the magnitude of the differences was small. When 20 mg/kg was given post-UL, both SN and YHT showed a small but significant change in the rate of compensation. No significant differences in RHT were observed. These results demonstrate that IP administration of flunarizine at a dose of 10-20 mg/kg IP has little effect on vestibular compensation compared to the effects obtained with low IM doses (0.8 mg/kg) of verapamil given 1 h pre-UL.     

EEG and clinical studies of the development of alumina cream epileptic focus in split-brain cats

Alumina cream epileptic focus was established in the right sensorimotor cortex in 20 split-brain cats (partial or complete). EEG and behavioral observations were made in a period ranging from 24 to 836 days. Four types of EEG changes after alumina cream injection were differentiated. These types could be related to the direct effects of brain damage and to development of epilepsy. Spikes and sharp waves and paroxysmal discharges (focal and multifocal) were observed in about 60% of the cats. Clinical seizures developed in about the same percentage of the animals. These values are below those reported for cats with intact interhemispheric commissures. Diphenylhydantoin (DPH) was given orally in a daily dose of up to 15 mg/kg body weight in 9 animals with developed epileptic EEG activity. Five of them had epileptic seizures. DPH was introduced not earlier than 1.5 months after intracortical alumina cream injection. The plasma level of DPH varied between 7-20 mug/ml. This dose produced chronic symptoms of intoxication. Neither EEG changes nor clinical seizures were entirely controlled by this drug. Additional doses of Relanium (diazepam), and phenobarbital were necessary to stop generalized seizures or status epilepticus.     

Clarithromycin-carbamazepine interaction: a case report

We report a clinically relevant interaction between a new macrolide antibiotic, clarithromycin, and carbamazepine (CBZ). In a patient receiving CBZ monotherapy, 10-day antibiotic treatment increased CBZ concentration despite concomitant CBZ dose reduction and doubled the CBZ concentration/dose ratio. Concentration of the CBZ epoxide (CBZ-E) metabolite was reduced, suggesting that the interaction occurs at a metabolic level.     

Comparison of [123I]beta-CIT and [123I]IPCIT as single-photon emission tomography radiotracers for the dopamine transporter in nonhuman primates

The aim of our randomized controlled study was to compare the neuromuscular characteristics of mivacurium and atracurium by evaluating the intubation conditions, intubation times, onset times and the duration of action of these two muscle relaxants using two different dosing principles. Forty-eight patients were included in this study. All patients were premedicated orally with 0.2 mg/kg diazepam. Anaesthesia was induced with 2.0 mg/kg propofol and 0.02 mg/kg alfentanil and maintained with 6 mg/kg/h propofol and 60% nitrous oxide in oxygen. Neuromuscular monitoring was carried out with supramaximal TOF-stimulation (2 HZ) of the ulnar nerve every 10 seconds and recording of the mechanomyogram (MMG) (Myograph 2000, Biometer) at the adductor pollicis muscle. The patients of group 1 (n = 12) received an intubation dose of 0.15 mg/kg mivacurium (2 x ED95) and the patients of group 2 (n = 12) received a priming dose of 0.015 mg/kg mivacurium (20% of ED95) followed by an intubation dose of only 0.07 mg/kg mivacurium (ED95) two minutes later. The patients of group 3 (n = 12) were intubated with 0.46 mg/kg atracurium (2 x ED95) and the patients of group 4 (n = 12) received a priming dose of 0.046 mg/kg atracurium (20% of ED95) and an intubation dose of 0.23 mg/kg atracurium (ED95) four minutes later. The patients were intubated under normocapnic conditions and following stabilisation of the palmar skin temperature after a 90% neuromuscular block (T1) had occurred. The intubation conditions were measured semiquantitatively using an intubation score.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of morphine-induced catalepsy, lethality, and analgesia by a benzodiazepine receptor agonist midazolam in the rat

Previously we have shown that intrathecal administration of midazolam can increase or decrease morphine-induced antinociception, depending upon relative concentration of these drugs by modulating spinal opioid receptors, and it also can inhibit morphine-induced tolerance and dependence in the rat. Now we report that midazolam also influences catalepsy, lethality, and analgesia induced by morphine in the rat. In the acute treatment, animals were first treated with saline or midazolam (0.03 to 30.0 mg/kg, b.wt., IP), and 30 min later with a second injection of saline or morphine (1.0 to 100.0 mg/kg, b.wt., SC). The catalepsy was measured 60 min after the second injection and lethality was checked after 24 h. Midazolam injection increased the morphine-induced catalepsy and lethality. In the chronic treatment, animals were injected with two injections daily for 11 days. The first injection consisted of saline or midazolam (0.03 to 3.0 mg/kg, b.wt., IP), and 30 min later with a second injection of saline or morphine (10.0 mg/kg, b.wt., IP) was given. Lethality, antinociception, and body weight were measured. Chronic morphine treatment also increased lethality in a dose-dependent manner. Chronic treatment with midazolam and morphine increased the antinociception on day 11, as measured in the tail-flick and hot-plate tests. Midazolam administration also prevented the morphine-induced weight loss. These results suggest a strong interaction between midazolam and morphine in altering catalepsy, lethality, and analgesia in rat.     

Attenuation of anticonvulsant effects of diazepam after chronic treatment with bicuculline

Changes in the GABAergic system after chronic treatment with bicuculline were examined in two strains of inbred rats, Fischer 344 (F344) and Lewis (LEW). Rats received an IP injection of either bicuculline (2 mg/kg) or vehicle once a day for 12 days. After this chronic treatment, the effects of diazepam (1 mg/kg, IP) and pentobarbital (20 mg/kg, IP) on bicuculline-induced convulsions were measured. Bicuculline was acutely infused into a tail vein at 0.0415 mg/min, and the infusion was terminated when rats showed seizure. Following the chronic bicuculline treatment, the anticonvulsant effect of diazepam, but not of pentobarbital, was significantly reduced as compared to its effect following chronic vehicle treatment in both strains. Both diazepam and pentobarbital showed a significant difference in anticonvulsant effects between strains (F344 > LEW). The hypnotic effects of muscimol, barbital, pentobarbital, and ethanol following chronic bicuculline treatment were examined. There was no significant difference in sleep time induced by these drugs between bicuculline- and vehicle-treated rats. These results suggest that the attenuation of diazepam's anticonvulsant effect after chronic bicuculline treatment may result from functional changes in benzodiazepine receptors and that the anticonvulsant effects of diazepam and pentobarbital may be influenced by genetic factors. Moreover, the hypnotic effects of several drugs tested are apparently not affected by chronic bicuculline treatment.     

Evaluation of the echinocandin antifungal MK-0991 (L-743,872): efficacies in mouse models of disseminated aspergillosis, candidiasis, and cryptococcosis

The in vivo activity of the Merck antifungal echinocandin drug candidate MK-0991 (L-743,872) was evaluated in mouse models of disseminated candidiasis, aspergillosis, and cryptococcosis. The echinocandins are potent inhibitors of 1,3-beta-D-glucan synthase. Two models of disseminated candidiasis were used. In a Candida albicans mouse survival model with both DBA/2N and CD-1 mice, estimates of the 50% effective doses (ED50s) of MK-0991 were 0.04 and 0.10 mg/kg of body weight/dose at 21 days after challenge, respectively. In a C. albicans target organ assay (TOA) with DBA/2N mice, MK-0991 at levels of > or =0.09 mg/kg/dose significantly reduced the numbers of C. albicans CFU/g of kidneys compared to the numbers in the kidneys of control mice from 1 to 28 days after challenge. Even when given as a single intraperitoneal dose either 30 min or 24 h after challenge, MK-0991 was effective and significantly reduced the numbers of C. albicans CFU/g of kidney compared to those in the controls. MK-0991 was >300-fold less active when it was administered orally than when it was administered parenterally. MK-0991 was efficacious in mouse TOAs against other C. albicans strains and Candida species including Candida tropicalis, Candida (Torulopsis) glabrata, Candida lusitaniae, Candida parapsilosis, and Candida krusei. MK-0991 was ineffective against disseminated Cryptococcus neoformans infections. In the model of disseminated aspergillosis in mice, MK-0991 at doses of > or =0.02 mg/kg/dose significantly prolonged the survival of DBA/2N mice, with estimates of the ED50 and ED90 of MK-0991 being 0.03 and 0.12 mg/kg/dose, respectively, at 28 days after challenge. MK-0991 is a potent, parenterally administered therapeutic agent against disseminated candidiasis and aspergillosis that warrants further investigation in human clinical trials.     

Effect of 5-fluoroindole-2-carboxylic acid (an antagonist of the NMDA receptor-associated glycine site) on the anticonvulsive activity of conventional antiepileptic drugs

5-Fluoroindole-2-carboxylic acid, an antagonist of the glycine site within the NMDA receptor complex, administered intraperitoneally in doses of 150 and 200 mg/kg, 120 min before electroconvulsions, significantly raised the convulsive threshold from 6.8 to 7.9 and 8.3 mA, respectively. At lower doses, it did not influence the threshold. However, lethality was observed 24h after administration of the threshold-elevating doses of this glycine site antagonist. 5-Fluoroindole-2-carboxylic acid (100 mg/kg), applied together with carbamazepine, valproate or phenobarbital, significantly reduced their ED50 values against maximal electroshock - from 13.9 to 7.5 mg/kg, from 291 to 242 mg/kg, and from 18.6 to 11.1 mg/kg, respectively. At the dose of 50 mg/kg, it also potentiated the protective activity of carbamazepine. However, 5-fluoroindole-2-carboxylic acid, up to 100 mg/kg, did not affect the anti-convulsive activity of diphenylhydantoin. When applied at doses equal to their ED50 values against maximal electroshock-induced convulsions, carbamazepine (13.9 mg/kg), phenobarbital (18.6 mg/kg) and valproate (291 mg/kg) did not affect the motor performance of mice in the chimney test. 5-Fluoroindole-2-carboxylic acid (100 mg/kg produced a significant motor impairment, at 50 mg/kg it did not affect the motor performance. The combined treatment of 5-fluoroindole-2-carboxylic acid (100 mg/kg) with carbamazepine, phenobarbital or valproate, providing a 50% protection against maximal electroshock, resulted in motor impairment. Only the combination of 5-fluoroindole-2-carboxylic acid (50 mg/kg) with carbamazepine (8.6 mg/kg) did not significantly influence this parameter. Almost all of the antiepileptic drugs studied, when administered at doses equal to their ED50 values against maximal electroshock, did not influence retention in the passive avoidance task, which is a measure of long-term memory. Only valproate (291 mg/kg) worsened long-term memory. The combined treatment of 5-fluoroindole-2-carboxylic acid (100 mg/kg) with carbamazepine or phenobarbital, providing a 50% protection against maximal electroshock, did not affect the retention. The combination of 5-fluoroindole-2-carboxylic acid (100 mg/kg) with valproate (242 mg/kg) caused a significant impairment of long-term memory and mortality of 50% of animals 24h following the administration. The results suggest that the blockade of the strychnine-insensitive glycine site may lead to an enhancement of the protective activity of some conventional antiepileptic drugs, which is associated with pronounced side-effects and lethality in some cases.     

Isoniazid-induced inhibition in the biotransformation of [14C] diphenylhydantoin in rat

The effect of isoniazid (0,10,20 and 40 mg/kg; i.v.) on the biliary and urinary excretion of [14C] diphenylhydantoin (DPH, 50 mg/kg; i.v.) was investigated in biliary-fistulated rats during the first 5 hours. Isoniazid cause a dose-dependent reduction in the total biliary excretion of 14 C without affecting its output in urine. After 5 h, maximal levels of radioactivity were recorded in the liver, followed by heart and brain. The glucuronides of DPH metabolites accounted for most of the 14C in 5 h pooled bile, less than 1% of the injected dose was excreted as unmetabolized DPH. Isoniazid administration caused the following significant dose-related changes in biliary excretion: (a) increased excretion of the unconjugated principal DPH metabolite, 5-(p-hydroxyphenyl)-5-phenylhydantion (HPPH); (b) decreased excretion of HPPH-glucuronide; and (c) increased excretion of the glucuronide conjugates of the polar metabolites of DPH. The results suggest that the isoniazid-induced elevation of DPH-derived 14C in blood and its marked accumulation in brain, heart and liver is due to inhibition of p-hydroxylation of DPH and the glucuronidation of HPPH.     

Influence of a potential anti-asthmatic drug, CR 2039, upon the anticonvulsive activity of conventional antiepileptics against maximal electroshock-induced seizures in mice

CR 2039 [[4-(1H-tetrazol-5-yl)-N-(4-(1H-tetrazol-5-yl]phenylbenza m ide], in doses of 10, 50, and 100 mg/kg i.p., significantly elevated the threshold for electroconvulsions, increasing the CS50 (current strength 50% in mA) values from 6.3 to 7.2, 7.5, and 7.6 mA, respectively. When combined with carbamazepine, diphenylhydantoin, or valproate, CR 2039 (5 and 10 mg/kg) potentiated the anticonvulsive action of these antiepileptics against maximal electroshock-induced convulsions which was reflected by significant decreases in the respective ED50s (in mg/kg). The protective efficacy of phenobarbital was not affected by the phenylbenzamide derivative. The potentiation of the anticonvulsive activity of three antiepileptics was not accompanied by increased adverse effects, evaluated in the chimney test (motor coordination) and passive avoidance task (long-term memory). Finally, CR 2039 (10 mg/kg) did not alter the plasma levels of the antiepileptic drugs studied which speaks against a pharmacokinetic mechanism in the observed results. It is concluded that CR 2039 may prove a safer anti-asthmatic drug for the use in epileptic patients than aminophylline which, either acutely or chronically, considerably impaired the anticonvulsive activity of conventional antiepileptics.     

Increased sensitivity to the locomotor depressant effect of a dopamine receptor antagonist during cocaine withdrawal in the rat

The effect of a dopamine receptor antagonist on locomotor activity was examined during withdrawal from either self-administered or experimenter-administered cocaine. In the self-administration experiment, the locomotor response to a challenge injection of cis-flupenthixol was assessed in photocell cages at 4 h after the cessation of a 12-h cocaine self-administration session. Rats which had self-administered cocaine, and were challenged with cis-flupenthixol (0.05 mg/kg), were found to be hypoactive relative to controls. In the experimenter-administered cocaine experiment, animals were given eight IP injections of 15 mg/kg cocaine over a 9.5-h period, for a total of 120 mg/kg. At 4, 8, and 24 h (tested in three separate groups of rats) after cessation of the eight injections, the locomotor response to a challenge injection of saline or cis-flupenthixol was tested. Cocaine-treated animals displayed a dose-dependent, heightened sensitivity to the locomotor depressant effects of 0.05 mg/kg and 0.2 mg/kg cis-flupenthixol 4 h post-cocaine, whereas they did not show increased sensitivity to 0.05 mg/kg cis-flupenthixol 8 or 24 h post-cocaine. However, cocaine-treated animals displayed a mild hypoactivity 8 h post-cocaine. In a separate group of animals, a dose-response experiment was performed which indicated that a dose of cis-flupenthixol as high as 0.2 mg/kg was required to produce locomotor depression in cocaine-naive rats. The results of this study support clinical observations of dopamine antagonist-precipitated motor dysfunction in abstinent cocaine abusers, and lend further support to the hypothesis that alterations in dopaminergic neurotransmission consequent to prolonged cocaine exposure are partly responsible for some of the symptoms of cocaine withdrawal.     

Predictive validity of the potentiated startle response as a behavioral model for anxiolytic drugs

The fear-potentiated startle (PSR) paradigm is a putative behavioral model for the determination of anxiolytic properties of drugs. The present study further investigated the predictive validity of the model. Predictive validity is high, when only drugs clinically used as anxiolytics attenuate PSR dose dependently. Results showed that startle potentiation decreased dose dependently after the administration of the anxiolytics CDP (2.5-10 mg/kg, IP) and alprazolam (1-3 mg/kg, IP). After administration of the clinically non-anxiolytic drugs amitriptyline (2.5-10 mg/kg, IP), carbamazepine (5-20 mg/kg, IP), fentanyl (0.0025-0.04 mg/kg, SC), naloxone (2.5-10 mg/kg, IP), nicotine (0.4-1.6 mg/kg, IP), alcohol (500-2000 mg/kg, IP), and d-amphetamine (0.6-2.4 mg/kg, IP), a dose-dependent decrease in startle potentiation was not found. The PSR correctly discriminated most of the drugs tested in clinically anxiolytic and clinically non-anxiolytic drugs. However, haloperidol behaved as a false positive, and results of nicotine and alcohol were at variance with results reported by others.     

Buspirone enhances immobility in the forced swim test in mice

We studied the effects of buspirone and 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) on duration of immobility in mice in the forced swim test. Buspirone [3-10 mg/kg, intraperitoneally (IP)] potently and dose dependently increased the duration of immobility in mice. In contrast, following a single dose of 8-OH-DPAT (1-3 mg/kg, IP), there was a dose-dependent decrease in the duration of immobility. Pretreatment with the 5-HT synthesis inhibitor p-chlorophenylalanine (200 mg/kg, IP, 3 days before further drug treatment) did not alter the effects of buspirone or 8-OH-DPAT. The increase in the duration of immobility induced by buspirone (3 mg/kg, IP) was blocked by NAN-190 [1-(2-methoxyphenyl)-4-(4-[2-phthalimido]butyl)-piperazine hydrobromide, 1 mg/kg, IP], a postsynaptic 5-HT1A receptor antagonist. However, the effect of 8-OH-DPAT (1 mg/kg, IP) was not blocked by NAN-190 (1 mg/kg, IP). The effect of buspirone (3 mg/kg, IP) was blocked by apomorphine (0.3 mg/kg, IP), a dopamine receptor agonist. Based on the results of this study, it is suggested that the effects of buspirone and of 8-OH-DPAT on immobility in the forced swim test may occur through different mechanisms.