Lack of tolerance and physical dependence upon repeated treatment with the novel hypnotic zolpidem.

Zolpidem is a new, short-acting hypnotic of imidazopyridine structure which binds selectively to a subpopulation of receptors involved in the action of benzodiazepines [omega 1 (BZ1) sites of the gamma-aminobutyric acidA receptors]. The present study investigated whether tolerance and physical dependence develop after repeated treatment with zolpidem as is observed with benzodiazepines. Mice were given zolpidem or the benzodiazepine midazolam (2 x 30 mg/kg, p.o.) for 10 consecutive days. Tolerance to central depressant effects (evaluated by recording spontaneous locomotor activity) and to anticonvulsant effects (measured against pentylenetetrazole-, electroshock- and isoniazid-induced convulsions) was assessed 42 hr after the last administration. A decrease in the latency to isoniazid-induced convulsions was taken as an index of physical dependence and was evaluated 3, 6, 14, 24, 42 and 67 hr after the end of chronic drug treatment. Repeated treatment with midazolam produced tolerance to its sedative and anticonvulsant activities as indicated by shifts of the dose-response curves by a factor of 3 to 5. Fourteen hr after discontinuation of treatment, spontaneous withdrawal was observed and lasted 3 days. When flumazenil was given 3 or 6 hr after the final midazolam injection, precipitated withdrawal was observed. In contrast, after repeated treatment with zolpidem, there was no change in its ability to produce sedative and anticonvulsant effects. Moreover, neither spontaneous nor flumazenil-induced precipitated withdrawal was observed in zolpidem-treated mice.     

Pharmacologic characterization of acute chlordiazepoxide dependence in the rat

A single intoxicating dose of chlordiazepoxide HCl (p.o.) in the rat can induce quantifiable manifestations of physical dependence. Dependence was revealed by antagonist precipitation (Ro 15-1788, CGS-8216) as well as spontaneous emergence of neurobehavioral signs of withdrawal observed by multiple raters blind to treatments. Ro 15-1788 was 45% more effective than CGS-8216 in both reversing chlordiazepoxide intoxication and expressing withdrawal signs. The severity of Ro 15-1788-precipitated withdrawal varied with chlordiazepoxide dose, Ro 15-1788 dose and the agonist-antagonist dose interval. Maximal precipitated dependence was evoked 3 days after chlordiazepoxide HCl (450 mg/kg) by Ro 15-1788 (25 mg/kg i.p.). The precipitated syndrome consisted of tail erection, reduced motor activity, high step, curled claw, arched back, muscle hypertonus and piloerection. Ro 15-1788-precipitated dependence emerged between 28 and 52 hr, peaked at 76 hr and disappeared by 124 hr. Spontaneous withdrawal had emerged from 100 to 124 hr and then faded gradually. The neurobehavioral expression of central nervous system depression and its reversal were necessary but not sufficient conditions for the induction and expression of acute chlordiazepoxide dependence. These results suggest caution in reviving acute benzodiazepine-overdosed patients to avoid iatrogenic withdrawal analogous to naloxone for opiates.     

Midazolam and discriminative motor control: chronic administration, withdrawal and modulation by the antagonist Ro 15-1788

To evaluate the effects of chronic midazolam (8-chloro-6-(2-fluorophenyl)-1-methyl-4H- imidazo[1,5-a][1,4]benzodiazepine) administration on discriminative motor control, rats were trained to hold a force transducer operated with a paw so that it remained between upper and lower limits of a force band for a continuous 1.5-sec period to deliver each food pellet. Acute doses of midazolam (0.75-3.0 mg/kg s.c.) impaired indices of motor performance as well as session work rate, a measure of sedation. Separate groups received chronic midazolam injections either pressession (Before Group) or postsession (After Group), or presession vehicle (Vehicle Group). The After and Vehicle Groups indicated that neither chronic postsession midazolam, its withdrawal, nor time alone, changed motor performance. The Before Group was affected, and although complete tolerance to work-rate decrements developed rapidly to chronic dosing (3.0 mg/kg), tolerance to motor impairment was incomplete even after 4 months. Presession drug probes with midazolam to the After Group revealed that, although tolerance to work-rate decrement had developed, no tolerance had developed with respect to the capacity for midazolam to impair motor performance. During the chronic phase of midazolam injection to the Before Group, sessions that omitted midazolam, or antagonized it with Ro 15-1788, led to improved motor performance (a drug-purge effect). Precipitated withdrawal was not produced by Ro 15-1788, although simple drug withdrawal did disrupt Before Group motor performance after 4 months of chronic dosing. Ensuing sessions showed a marked improvement in motor performance which returned to the original, prechronic, base-line level.     

In vitro,pharmacokinetic, and pharmacodynamic interactions of ketoconazole and midazolam in the rat

Interactions of midazolam and ketoconazole were studied in vivo and in vitro in rats. Ketoconazole (total dose of 15 mg/kg intraperitoneally) reduced clearance of intravenous midazolam (5 mg/kg) from 79 to 55 ml/min/kg (p < 0.05) and clearance of intragastric midazolam (15 mg/kg) from 1051 to 237 ml/min/kg (p < 0.05), increasing absolute bioavailability from 0.11 to 0.36 (p < 0.05). Presystemic extraction occurred mainly across the liver as opposed to the gastrointestinal tract mucosa. Midazolam increased electroencephalographic (EEG) amplitude in the beta-frequency range. Ketoconazole shifted the concentration-EEG effect relationship rightward (increase in EC(50)), probably because ketoconazole is a neutral benzodiazepine receptor ligand. Ketoconazole competitively inhibited midazolam hydroxylation by rat liver and intestinal microsomes in vitro, with nanomolar K(i) values. At a total serum ketoconazole of 2 microg/ml (3.76 microM) in vivo, the predicted reduction in clearance of intragastric midazolam by ketoconazole (to 6% of control) was slightly greater than the observed reduction in vivo (to 15% of control). However, unbound serum ketoconazole greatly underpredicted the observed clearance reduction. Although the in vitro and in vivo characteristics of midazolam in rats incompletely parallel those in humans, the experimental model can be used to assess aspects of drug interactions having potential clinical importance.     

Mianserin attenuates naloxone-precipitated withdrawal signs in rats acutely or chronically dependent upon morphine

The effects of the atypical antidepressant and serotonin antagonist mianserin on the expression of opiate withdrawal was examined using an acute and a chronic model of morphine dependence. In the first experiment, rats, trained to perform a food-reinforced, autoshaped lever touch response, were injected with naloxone (5 mg/kg) 4 hr after treatment with a single moderate dose of morphine (15 mg/kg). Mianserin (0.25, 1.0 and 2.5 mg/kg) attenuated the naloxone-induced suppression of autoshaped responding. Colonic temperatures were also monitored. Morphine treatment resulted in significant hyperthermia, while precipitation of withdrawal by naloxone produced hypothermia. Mianserin also attenuated the naloxone-induced hypothermia. In the second experiment, rats were implanted s.c. with a single 75-mg morphine or placebo pellet. Withdrawal was precipitated with naloxone (5 mg/kg) 24, 48 and 120 hr post implantation. Mianserin (2.5 mg/kg) blocked or attenuated signs of withdrawal precipitated by naloxone. Naloxone-precipitated weight loss was also attenuated 48 and 120 hr post implantation. At 120 hr post implantation, rats were decapitated 1 hr after the administration of naloxone and trunk blood was collected. Mianserin did not block the naloxone-induced rise in plasma corticosterone levels. Thus, several signs of withdrawal (e.g., behavioral effects, weight loss and hypothermia) seem to involve serotonergic mediation and can be blocked by mianserin, while others (e.g., rise in plasma corticosterone), which may be unaffected by mianserin, may be a reflection of a compensatory response to withdrawal stress, rather than a mediator of maladaptive consequences of withdrawal that are not mediated by serotonin.     

Hepatic vs. gastrointestinal presystemic extraction of oral midazolam and flurazepam

An experimental model was developed to elucidate the site of presystemic extraction of drugs with incomplete bioavailability due to high extraction after p.o. dosage. Domestic pigs received single i.v. or p.o. doses of midazolam (1 mg/kg) or flurazepam (2 mg/kg), two benzodiazepine derivatives with high presystemic extraction after p.o. dosage. Multiple blood samples were simultaneously drawn from the portal vein and from a systemic vein during 8 hr after dosage. After i.v. administration, both drugs had high systemic serum clearance, averaging 24 ml/min/kg. Area under the serum concentration curve (AUC) for systemic vs. portal sites was nearly identical for midazolam (769 vs. 737 ng/ml x hr); for flurazepam, systemic AUC exceeded portal AUC (1035 vs. 778 ng/ml x hr, P less than .01). After p.o. dosage, the systemic/portal AUC ratio averaged 0.15 for midazolam and 0.11 for flurazepam; for both drugs, portal AUC after p.o. dosage did not differ significantly from systemic AUC after i.v. administration. Thus, the extensive presystemic extraction of orally administered midazolam and flurazepam are mainly attributable to hepatic biotransformation rather than metabolism either within the gastrointestinal tract or during absorption into the portal circulation.     

Acute opioid physical dependence in postaddict humans: naloxone dose effects after brief morphine exposure

Antagonist-precipitated withdrawal after acute opioid administration (acute physical dependence) is an interesting phenomenon in that the opioid abstinence syndrome is generally thought to develop only after prolonged exposure to opioid agonists. The purpose of this study was to examine further this phenomenon in humans by characterizing the antagonist dose-response function. The effects of i.m. naloxone (0, 0.1, 0.3, 1, 3, 10 and 30 mg/70 kg) were assessed 6 hr after single i.m. injections of morphine (18 or 30 mg/70 kg) in six subjects with a history of chronic opiate use. Naloxone reversed residual morphine effects, including miosis and respiratory depression. The degree of reversal was dose-related to 10 mg/70 kg of naloxone with no further increases at the highest naloxone dose. Simultaneously, observer ratings of withdrawal signs and subjective reports of withdrawal symptoms were increased in an orderly dose-related manner to 30 mg/70 kg of naloxone. Reversal of residual morphine effects and onset of precipitated withdrawal were evident by 5-min postnaloxone; peak effects occurred within 15 min. This study confirmed the occurrence of antagonist-precipitated withdrawal after brief opioid exposure in humans, demonstrated the rapid onset of withdrawal effects and characterized the naloxone dose-response function.     

Effect of dosing frequency on the development of physical dependence and tolerance to pentobarbital

Many studies have suggested the importance of the rate of drug elimination in the development of pharmacodynamic tolerance and physical dependence to sedative-hypnotic drugs. Our previous study demonstrated that the role of individual variation in elimination kinetics played an important part in producing pharmacodynamic tolerance and physical dependence when the drug was given at a fixed dose-frequency schedule. The present study investigated the effect of various dose-frequency schedules on the production of tolerance and physical dependence. Controlling the frequency of administration was thought to be the most rational clinical approach in avoiding the production of tolerance and physical dependence with repeated sedative-hypnotic medication. Groups of animals were treated with Na pentobarbital according to the "maximally tolerable" dosing schedule described previously, except that with different dose-frequency schedules, i.e., twice a day, once every day, once every 1.5 days and once every other day for 70 consecutive doses and then withdrawn abruptly. The relationship between the number of Na pentobarbital doses under each dose-frequency schedule and the pharmacokinetic and pharmacodynamic tolerance production, plus the intensity of withdrawal, were studied. The withdrawal intensity was further correlated to the time lag between each drug administration by estimating the maximal time allowed between doses that does not produce any spontaneous withdrawal convulsions and overt withdrawal signs. It was concluded that the time required for repeated Na pentobarbital administration that does not produce withdrawal convulsion and overt withdrawal signs was 4.9 and 5.7 times the average pentobarbital half-life, respectively.     

Tolerance, cross-tolerance and withdrawal in rats made dependent on diazepam.

Rats were trained to discriminate pentylenetetrazole (PTZ; 20 mg/kg) from midazolam (MDZ; 1 mg/kg) and from saline using a three-lever food-reinforced choice task. Using a cumulative dosing procedure, PTZ substituted for PTZ, and MDZ, chlordiazepoxide and diazepam (DZP) substituted for MDZ, in a dose-dependent manner. The animals were then treated with chronic DZP (20 mg/kg/8 hr for 7 days); 24 hr after the last dose of this regimen, the dose-effect curve of DZP was redetermined. The ED50 for the discrimination of DZP increased 4.8-fold after chronic DZP. In a second group of subjects trained on this discrimination and treated with DZP (20 mg/kg/8 hr for 7 days), the ED50 for the discrimination of MDZ was increased 2.2-fold. After 14 days of recovery, the MDZ dose-effect curve shifted back to the left and was not significantly different from the ED50 value obtained before chronic DZP treatment. When the benzodiazepine antagonist flumazenil was tested in a cumulative manner (1.0-32.0 mg/kg), the animals selected the saline lever. Analogous to the previous chronic dosing regimen, DZP (20 mg/kg/8 hr/7 days) was then administered, and a combination of three tests were then given at 1, 2, 4, 7, 10 and 14 days after the last DZP treatment. On each of these days, a saline test was given first; it was followed by a DZP (2.5 mg/kg) test; which was then followed by a flumazenil (32.0 mg/kg) test. On the 1st day of testing, tolerance was seen to DZP and precipitated withdrawal (PTZ lever selection) was seen with flumazenil.(ABSTRACT TRUNCATED AT 250 WORDS)     

Behavioral dependence upon phencyclidine and ketamine in the rat

The present studies examined whether dependence could be induced by continuous i.v. infusion of phencyclidine (PCP) in rats as demonstrated by disruptions of operant behavior during withdrawal. Rats were trained to lever press for their daily food rations under fixed-ratio 30 schedules of reinforcement during four, daily, 0.5-hr sessions. In the first study, withdrawal from 10 days of PCP infusion at a rate of 0.5 mg/kg/hr resulted in markedly reduced response rates which typically occurred within 6 to 12 hr and recovered within 24 to 48 hr, providing evidence of dependence in the four rats tested. The PCP withdrawal effect was replicated systematically in seven additional rats which had been given individually maximally tolerated PCP infusion regimens. Additionally, when PCP was readministered during withdrawal, the downward trend in response rates was halted and rates increased rapidly to control levels, providing evidence of reversal of PCP withdrawal effects. When ketamine, another arylcyclohexylamine dissociative anesthetic, was administered during PCP withdrawal at a dose of 2.5 mg/kg/hr, it also was able to reverse PCP withdrawal effects, demonstrating cross-dependence from PCP to ketamine. Response rates were also reduced markedly relative to control levels during withdrawal from continuous i.v. ketamine infusion in three rats tested, providing evidence that dependence upon this drug could also be induced. Withdrawal of PCP and ketamine administration can disrupt operant behavior, providing further evidence for the ability of these drugs to produce dependence.     

Changes in urination/defecation,auditory startle response,and startle-induced ultrasonic vocalizations in rats undergoing morphine withdrawal: similarities and differences between acute and chronic dependence

In drug-free subjects, a single dose of morphine followed by an opioid antagonist a few hours later results in signs of a withdrawal syndrome, suggesting a state of physical dependence. Increased urination/defecation, altered startle, and ultrasonic vocalizations (USV) are some signs of the withdrawal syndrome in rats chronically dependent on morphine. We investigated whether naltrexone stimulates urination/defecation and alters startle and USV in male rats that were pretreated with only a single dose of morphine and compared these indices to the ones of chronic dependence. Separate groups of rats were pretreated with either a single dose (10 mg/kg) or with a continuous s.c. infusion of morphine via an osmotic pump. Naltrexone (0.01-1.0 mg/kg) was administered 2 to 6 h after the single dose of morphine and on days 7 to 11 of the infusion. Immediately after the naltrexone injection subjects were placed in sound-attenuating boxes to record startle and USV and to collect urine/feces. Subjects chronically exposed to morphine also were tested during spontaneous withdrawal 3 to 24 h after pump removal. Naltrexone increased urination/defecation in subjects pretreated with morphine either chronically or acutely; it increased startle and USV in acutely dependent rats but decreased them in chronically dependent rats. In the latter group, changes in the four variables during spontaneous withdrawal were qualitatively similar to those during precipitated withdrawal but smaller in magnitude. Differences in withdrawal signs between acute and chronic dependence suggest that the neural substrates that mediate those particular components of the withdrawal syndrome are affected differently in the two states of dependence.     

Acute opioid physical dependence in humans: effect of varying the morphine-naloxone interval. I

Acute opioid physical dependence refers to the withdrawal symptoms precipitated by an opioid antagonist administered after a single dose or short-term infusion of an opioid agonist. This phenomenon is particularly interesting given that the abstinence syndrome has generally been thought to develop only after chronic exposure to opioid agonists. The purpose of this study was to determine the minimum time after agonist administration when antagonist-precipitated withdrawal could be observed. Naloxone (10 mg/70 kg) was administered i.m. either 0, 15, 45 or 90 min after single i.m. injections of morphine (18 mg/70 kg) in five nondependent male opiate users. Physiological and subjective report measures revealed no effect of morphine or naloxone at the 0 and 15 min morphine-naloxone interval conditions; however, before the naloxone challenge 45 and 90 min post-morphine, agonist effects (e.g., miosis, respiratory depression and good drug effect subjective ratings) were clearly evident. Naloxone reversed these effects to premorphine levels and simultaneously precipitated subjective symptoms and observer rated signs of opiate withdrawal. Thus, this study showed that antagonist-precipitated withdrawal in humans was first observed 45 min after agonist administration. Further, the onset of naloxone-precipitated withdrawal effects closely paralleled the onset of morphine agonist effects. The results of this study suggest that adaptational changes underlying the development of physical dependence begin within minutes after acute exposure to an opiate.     

Continuous intravenous infusion of phencyclidine in unrestrained rats results in the rapid induction of tolerance and physical dependence

The continuous infusion of 45 mg/kg/24 hr of phencyclidine (PCP) into the jugular vein of unrestrained rats induced tolerance to PCP-induced impairment of forced motor activity and physical dependence in 3.5 and 7 days, respectively. In drug-naive rats, an i.v. 2-mg/kg PCP test dose abolished rotarod performance for more than 20 min which returned to pretreatment values at 40 min. Eight hours after the termination of 3.5 days of infusion, rotarod performance of PCP-infused rats was significantly less impaired by the PCP test dose at 20 min than that of saline-infused controls. After infusion of PCP for 7 days, the duration of performance abolition produced by the PCP test dose (given 8 hr after the termination of infusion) was shortened further with performance significantly better than that of saline-infused controls at both 10 and 20 min. The results showed a greater than 2-fold tolerance development to this PCP effect and suggest the observed tolerance to be mainly functional in nature. Abrupt withdrawal of PCP after infusion for 7 days resulted in an abstinence syndrome with the following signs: piloerection, increased susceptibility to audiogenic seizures, transient weight loss and reductions in exploratory activity and rotarod performance. The first withdrawal signs were noted 4 hr after the termination of infusion. At 24 hr of abstinence, most of the withdrawal signs had subsided. The reduced rotarod performance, associated with withdrawal, could be reversed by a single i.v. dose of 2 mg/kg of PCP. The reversibility of this sign supports the interpretation of impaired rotarod performance after withdrawal as being an abstinence sign and adds to the experimental evidence that physical dependence on PCP is inducible within 7 days in rats.     

d-Methadone blocks morphine tolerance and N-methyl-D-aspartate-induced hyperalgesia

Previous in vitro and in vivo studies have determined that the d isomer of methadone has N-methyl-D-aspartate (NMDA) receptor antagonist activity. The present studies examined the ability of d-methadone to attenuate the development of morphine tolerance in mice and rats and to modify NMDA-induced hyperalgesia in rats. A decrease in the percentage of mice analgesic (tail-flick response) after 5 days of once-daily morphine (7 mg/kg s.c.) was completely blocked by coadministration of d-methadone given s.c. at 10 mg/kg. Morphine given s.c. to mice on an escalating three times per day dosing schedule resulted in a nearly 3-fold increase in the tail-flick ED50 dose of morphine which was prevented by s.c. coadministered d-methadone at 15 mg/kg. In rats, intrathecal (i.t.) morphine produced a 38-fold increase in the ED50, which was completely prevented by the coadministration of i.t. d-methadone at 160 micrograms/rat. A decrease in thermal paw withdrawal latency induced by the i.t. administration of 1.64 micrograms/rat NMDA was completely blocked by pretreatment with 160 micrograms/rat d-methadone. Thus, systemically coadministered d-methadone prevents systemically induced morphine tolerance in mice, i.t. d-methadone attenuates tolerance produced by i.t. morphine in rats, and i.t. d-methadone, at the same dose which modulates morphine tolerance, blocks NMDA-induced hyperalgesia. These results support the conclusion that d-methadone affects the development of morphine tolerance and NMDA-induced hyperalgesia by virtue of its NMDA receptor antagonist activity.     

Characterization of a pentylenetetrazol-like interoceptive stimulus produced by ethanol withdrawal

Rats were trained with food reinforcement to discriminate the anxiogenic drug pentylenetetrazol (PTZ, 20 mg/kg) from saline in a two-lever-choice task. In Experiment 1, ethanol, 8.25% w/v was given by gavage (7/day) for 4 days, with doses titrated to maintain moderate intoxication. After termination of ethanol, the rats exhibited mild overt signs of withdrawal and, in discrimination tests with saline as the test substance, they selected the PTZ lever, an effect reversed by ethanol, 2 g/kg, and by diazepam, 5 mg/kg. In Experiment 2, rats drank a nutritionally complete liquid diet containing ethanol, 4.5% w/v, for 1 week. They became tolerant to the intoxicating effect of ethanol, and blood ethanol concentration mounted with continued dosing. On termination of chronic ethanol, rats selected the PTZ lever before the onset of overt physical signs of withdrawal, and both measures returned to base line within 3 days. In Experiment 3 the percentage of rats selecting the PTZ lever after termination of ethanol depended upon the dose (up to 12.5 g/kg) and duration (up to a ceiling effect by 3 days) of ethanol administered chronically. These results indicate that a PTZ-like stimulus produced interoceptively can be demonstrated in the rat as an objective measure of ethanol withdrawal. This paradigm may provide insight into the symptom of anxiety associated with ethanol withdrawal.     

Alternative dosing regimens of liposomal amphotericin B (AmBisome) effective in treating murine systemic candidiasis

OBJECTIVES: This study was done to determine whether high dose AmBisome (4-20 mg/kg), given intermittently, could reduce the frequency of dosing needed to treat murine systemic candidiasis when compared with conventional daily treatment. METHODS: Mice were immunosuppressed with cyclophosphamide every 3 days, beginning day -3 before challenge with log(10) 5.0 cfu Candida albicans. Treatment was begun 48-72 h post-challenge with daily or intermittent dose regimens of AmBisome, followed by determination of kidney cfu for up to 1 month post-treatment. RESULTS: A single AmBisome dose of 4 mg/kg was as effective as four daily, 1 mg/kg treatments. A total of 8 mg/kg, given as 4 mg/kg on days 2 and 4, or as 5 mg/kg on day 2 followed by 1 mg/kg on days 3, 4, and 5, also produced comparable efficacy. While 20 mg/kg given day 2, 4 and 6 post-challenge as a 1 week loading dose, followed by one 10 mg/kg treatment on day 13, decreased the fungal burden by up to 5 logs compared with controls (log(10) 2.3 cfu/g and log(10) 7.5 cfu/g, respectively), 20 mg/kg given Monday, Wednesday and Friday for 5 weeks, reduced the fungal burden to undetectable levels (i.e. log(10) 1.0 cfu). CONCLUSIONS: Significant reduction or clearance of kidney cfu, following intermittent, high dose AmBisome treatment, indicated that non-daily dosing regimens could be successfully used instead of conventional daily dosing to treat established C. albicans infection in immunosuppressed mice.     

Withdrawal from diazepam substitutes for the discriminative stimulus properties of pentylenetetrazol

Rats were trained to discriminate pentylenetetrazol (PTZ, an anxiogenic drug), 20.0 mg/kg, from saline using a food-maintained two-lever-choice task. When treated chronically with diazepam (DZP) and tested with the benzodiazepine-receptor antagonist Ro 15-1788, withdrawal from DZP produced a PTZ-like stimulus in these subjects that was related directly to the dose of DZP given every 8 hr for 6 days. In contrast, only the highest dose of DZP (80 mg/kg/8 hr) given chronically produced even minimal physical signs of precipitated abstinence after Ro 15-1788. In a separate experiment, Ro 15-1788 produced a PTZ-like stimulus when given at 2-day intervals during chronic administration of DZP. In this experiment, rats were maintained on DZP, 40.0 mg/kg/6 hr for 14 days. These subjects were tested with Ro 15-1788, 40.0 mg/kg, every 2 days during days 6 through 14 of chronic DZP, and Ro 15-1788 substituted for PTZ on 4 of these 5 tests. Because these experiments involved periods of nontraining on the discrimination task, a final experiment was performed to test the stability of stimulus control in rats trained to detect PTZ. DZP was administered for up to 20 days, withdrawal was precipitated by Ro 15-1788 and after an additional 16 to 40 days of nontraining, stimulus control was tested. There was no significant decline in stimulus control over this period. These results suggest that PTZ discrimination provides a sensitive, stable assay for the detection of withdrawal from benzodiazepine dependence.     

不同时段剂量腹腔注射百草枯致小鼠肺损伤及肺纤维化效果评价

目的 观察不同时段、剂量腹腔注射百草枯(PQ)对于小鼠肺损伤及肺纤维化诱导效果的区别,以期建立更为合适、操作简便且结果稳定的肺损伤和/或肺纤维化动物模型.方法 8～10周龄雄性C57BL/6J小鼠,分别采取腹腔注射单次给药(40 mg/kg、50 mg/kg、60 mg/kg),连续给药(10 mg/kg、12.5 mg/kg、15 mg/kg),以及间断给药(20 mg/kg、22.5 mg/kg、25 mg/kg)的方法,同组随机(随机数字法)匹配生理盐水对照组.分别于末次给药后1周、2周处死小鼠.监测小鼠一般情况,体质量状况及病死率.收获日检测肺功能指标;肺泡支气管灌洗液(BALF)细胞计数及分类;羟脯氨酸浓度;以及组织病理学分析.结果 单次或间断腹腔注射不同剂量PQ,均可诱导部分小鼠发生急性肺损伤,早期观察时间点的炎症表现随剂量增高而加重;晚期观察点少量存活小鼠可发生肺间质纤维化.病理切片见损伤部位主要集中在背后段、外周及胸膜下.但以上两组给药方式早期均有较高病死率,故晚期肺纤维化致病率较低.小剂量PQ连续给药法在各时间点诱导C57BL/6J小鼠的肺部病变缺乏显著意义.结论 单次大剂量或间断中等剂量腹腔注射作为PQ全身性给药的方法之一,可以成功诱导出早期小鼠急性肺损伤,但研究终点肺纤维化的致病率较低.PQ小剂量连续给药法致C57BL/6J鼠系肺损伤及肺纤维化的效果不明显.     

Evaluation of anticonvulsants in barbiturate withdrawal

Four prototypic anticonvulsants were tested for their effectiveness against barbiturate withdrawal in cats. The effects were evaluated on a total of over 20 motor, autonomic and behavioral withdrawal signs. The animals were made physically dependent by 5 weeks of twice daily "maximally tolerable" sodium pentobarbital dosing intragastrically. Anticonvulsants were administered by intravenous infusion 25 hours after the final dose of chronic pentobarbital treatment when all withdrawal signs had become severe and grand mal type withdrawal convulsions were observed. Phenobarbital blocked withdrawal signs quite effectively at doses that caused no significant acute central nervous system depression. Trimethadione also reversed most withdrawal signs, but some signs persisted even at doses causing overt acute toxicity. Dimethadione was less effective than the parent compound, trimethadione, in reversing withdrawal but caused greater acute toxicity. Phenytoin was in effective for most withdrawal signs and some signs were made worse. The clonic phase of withdrawal convulsions was accentuated and the overall condition of the animals worsened. During withdrawal, the animals were less sensitive (tolerant) to phenobarbital but were more sensitive to acute toxicity from the other drugs tested.     

Oxytrex Minimizes Physical Dependence While Providing Effective Analgesia: A Randomized Controlled Trial in Low Back Pain

Physical dependence or withdrawal is an expected effect of prolonged opioid therapy. Oxytrex (oxycodone + ultralow-dose naltrexone) is an investigational drug shown here to minimize physical dependence while providing strong analgesia with twice-daily dosing. In this 719-patient, double-blind, placebo- and active-controlled Phase III clinical trial in chronic low back pain, patients were randomized to receive placebo, oxycodone qid, or oxytrex qid or bid. Each oxytrex tablet contains 1 microg naltrexone; oxytrex bid and qid treatments provide 2 and 4 microg naltrexone/day, respectively. Following a washout, patients with pain >or=5 on a 0-10 scale were dose-escalated weekly from 10 up to 80 mg/day until reaching adequate pain relief (相似文献