AMAKOVE, DRWALAELIZABETH.  1993.  Effect of the chronic dose of diazepam on the intensity and characteristics of the precipitated abstinence syndrome in the dog. Sloan JW, Martin WR, Wala E.J Pharmacol Exp Ther. 1993 Jun;265(3):1152-62.. J Pharmacol Exp Ther. 1993 Jun;265(3):1152-62.. : Kisipan, M.L. Abstract
The ability of different chronic doses of diazepam to produce dependence was studied in groups of six dogs who received diazepam p.o. (0.05625, 0.225, 0.5625, 4.5, 9 or 36 mg/kg/day) every 8 hr. After 5 to 6 weeks of stabilization, the intensity of precipitated abstinence was measured by benzodiazepine-precipitated abstinence scores (BPAS) after the p.o. administration of graded doses of the benzodiazepine antagonist, flumazenil (0.66, 2, 6, 18, 36 and 72 mg/kg or a placebo). A modified Latin square design was used. Dogs receiving the two lowest stabilization doses of diazepam showed only liminal signs of precipitated abstinence even with 72 mg/kg of flumazenil. The intensity of the precipitated abstinence syndrome increased with the stabilization dose of diazepam. There was also a dose-related increase in BPAS for increasing doses of flumazenil for all doses of diazepam except the 9-mg/kg/day dose. Not only were quantitative differences observed in precipitated abstinence signs for different levels of diazepam dependence, but the pattern of abstinence signs differed also. Dogs dependent on high doses of diazepam were more sensitive to flumazenil than those dependent on lower doses. Furthermore, seizure activity was seen only in dogs dependent on 9 and 36 mg/kg/day of diazepam. BPAS increased linearly with plasma and brain total and free levels of the sum of diazepam and its metabolites (oxazepam and nordiazepam), but not with free plasma and brain levels of diazepam.


AMAKOVE, DRWALAELIZABETH.  1991.  Chronic administration of and dependence on halazepam, diazepam, and nordiazepam in the dog. Sloan JW, Martin WR, Wala E, Dickey KM. Drug Alcohol Depend. 1991 Oct;28(3):249-64.. Drug Alcohol Depend. 1991 Oct;28(3):249-64.. : Kisipan, M.L. Abstract
produced physical dependence which was revealed by a flumazenil precipitated abstinence syndrome and measured by the Nordiazepam Precipitated Abstinence Scale score (NPAS) (McNicholas et al., 1988; Sloan et al., 1990). This abstinence as measured by the NPAS score was more severe in diazepam- and halazepam-dependent than in nordiazepam-dependent dogs whereas the incidence of precipitated clonic seizures was greater in the diazepam- and nordiazepam-dependent than in the halazepam-dependent dogs. Pharmacokinetic studies showed that in the dog the major conversion of halazepam, like diazepam, was to nordiazepam and an oxazepam conjugate. Appreciable quantities of oxazepam, 3-OH halazepam and its conjugated metabolite were also identified in plasma. The NPAS score obtained in the halazepam-dependent dogs, however, was greater than the NPAS score obtained in nordiazepam-dependent dogs who had nordiazepam plasma levels over three times higher than those obtained in the halazepam-dependent dogs. Further, the precipitated abstinence observed in the halazepam-, diazepam- and nordiazepam-dependent dogs differed in qualitative as well as in quantitative aspects including marked differences in the time course of abstinence signs. These data argue that the different dependencies produced by halazepam, diazepam and nordiazepam are not due solely to either the parent compound or to a single metabolite but most likely to their combined effects.


AMAKOVE, DRWALAELIZABETH.  1990.  Precipitated abstinence in orally dosed benzodiazepine-dependent dogs. Martin WR, Sloan JW, Wala E.J Pharmacol Exp Ther. 1990 Nov;255(2):744-55.. J Pharmacol Exp Ther. 1990 Nov;255(2):744-55.. : Kisipan, M.L. Abstract
The ability of graded doses of flumazenil (2, 6, 18, 36 and 72 mg/kg) and a lactose placebo to precipitate abstinence was studied in dogs treated chronically with diazepam, nordiazepam, flunitrazepam, alprazolam, oxazepam, halazepam and lorazepam by oral dosing. A scale comprised of 10 precipitated abstinence signs, the Benzodiazepine Precipitated Abstinence Scale, was developed, which yielded linear flumazenil log-dose response lines with significant slopes in dogs dependent on diazepam, nordiazepam and flunitrazepam. The effects of 18, 36 and 72 mg/kg of flumazenil in otherwise drug naive dogs were studied. In naive dogs, the most prominent effect of flumazenil was to reduce activity. All benzodiazepines studied produced dependence that was characterized by signs of precipitated abstinence; however, the intensity and quality of abstinence varied from one benzodiazepine to another. Precipitated abstinence in dogs treated chronically with diazepam and flunitrazepam was characterized by a dose-related increase in clonic convulsions and Benzodiazepine Precipitated Abstinence Scale scores. This pattern differed from that seen in nordiazepam- and alprazolam-dependent dogs, which showed a comparable flumazenil dose-related increase in clonic convulsion but only a modest increase in Benzodiazepine Precipitated Abstinence Scale scores. Oxazepam and lorazepam produced dependence that was less intense than that seen with the other benzodiazepines. Plasma levels of the benzodiazepines and their metabolites were repeatedly determined after single doses and during addiction cycles. Nordiazepam accumulated in diazepam- and nordiazepam-dependent dogs and alpha-OH alprazolam accumulated in alprazolam-dependent dogs. Other drugs and metabolites did not. These observations suggest that: 1) different benzodiazepines or their metabolites produce different types of physical dependence, suggesting that they or their metabolites have different mechanisms and sites of action; 2) plasma cumulation of the benzodiazepines or their active metabolites is an important factor in the genesis of physical dependence; and 3) metabolism of benzodiazepines plays an important role in their dependence-producing capacity, and because of differences in the way species metabolize benzodiazepines, the type of dependence produced in different species may differ.


AMAKOVE, DRWALAELIZABETH.  1988.  Precipitation of abstinence in nordiazepam- and diazepam-dependent dogs. McNicholas LF, Martin WR, Sloan JW, Wala E.J Pharmacol Exp Ther. 1988 Apr;245(1):221-4.. J Pharmacol Exp Ther. 1988 Apr;245(1):221-4.. : Kisipan, M.L. Abstract
Dogs were made dependent on p.o. administered diazepam (24 or 36 mg/kg/day) or nordiazepam (18 mg/kg/day). Flumazenil (2, 6 or 18 mg/kg) administered p.o. once a week according to a Latin Square design precipitated abstinence in both groups of dogs. Abstinence was evaluated using a Nordiazepam Precipitated Abstinence Scale (NPAS) of various signs of abstinence and by counting seizure episodes. Flumazenil caused dose-related increases in the NPAS scores of both diazepam- and nordiazepam-dependent dogs; the slopes of the two dose-response lines were not different. Both groups of dogs also had both clonic and tonic-clonic seizures after flumazenil administration. CGS-8216 (2, 6 or 18 mg/kg) administered p.o. did not cause a dose-related elevation in NPAS scores for either group of dogs but clonic and tonic-clonic seizures were seen. Thus, flumazenil precipitates the benzodiazepine abstinence syndrome, as evidenced by tremors, tachypnea and other signs, including seizures, whereas CGS-8216 may have some selectivity in precipitating seizures without other signs of abstinence.
AMAKOVE, DRWALAELIZABETH.  1988.  The comparative binding characteristics of nicotinic ligands and their pharmacology. Sloan JW, Martin WR, Bostwick M, Hook R, Wala E. Pharmacol Biochem Behav. 1988 May;30(1):255-67.. Pharmacol Biochem Behav. 1988 May;30(1):255-67.. : Kisipan, M.L. Abstract
Five drugs [(-)- and (+)-nicotine, (-)-lobeline, (-)-anabasine and (-)-cytisine] were infused IV into the urethane-pentobarbital anesthetized rat. Changes in heart rate, blood pressure, respiratory rate, minute and tidal volume, which appeared to be largely centrally mediated, were studied. Each of these compounds produced different pharmacologic profiles. The nature of these dissimilarities is not readily explained on the basis of pharmacokinetic considerations suggesting that the drugs have different mechanisms of action. Binding data obtained with these compounds using the rat brain P2 preparation also show differences. (-)-Lobeline and (-)-anabasine, like the nicotinic antagonists mecamylamine and hexamethonium, bind predominantly to low affinity sites with KDs in the micromolar range whereas (-)-cytisine binds only to a single high affinity site with a KD in the nanomolar range. Further, the binding patterns of these drugs are different from (-)- and (+)-nicotine which bind to both high and low affinity sites but differ from each other in binding characteristics. Thus the binding data are consistent with the pharmacologic data in suggesting that the drugs have different modes of action and support the concept that the low affinity site has an important role in the central nervous system action of these compounds.
AMAKOVE, DRWALAELIZABETH.  1988.  Flumazenil oral absorption in dogs. Wala E, McNicholas LF, Sloan JW, Martin WR.Pharmacol Biochem Behav. 1988 Aug;30(4):945-8.. Pharmacol Biochem Behav. 1988 Aug;30(4):945-8.. : Kisipan, M.L. Abstract
Flumazenil is rapidly absorbed after oral or gastric fistula administration to the dog reaching peak plasma concentrations in about an hour. Plasma level decrease rapidly thereafter reaching barely detectable levels by four hours. The onset of signs of flumazenil precipitated abstinence in diazepam-dependent dogs is well correlated with the rise of flumazenil plasma levels, however, precipitated abstinence seizures occur when plasma levels have markedly decreased. Oral dosing is a more efficient way of administering flumazenil than gastric fistula dosing.

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