Actions of ritanserin, a 5-HT(2/1C) antagonist, in benzodiazepine-dependent rats

The effects of ritanserin on spontaneous benzodiazepine (BZ) withdrawal-induced weight loss, anorexia and hypodipsia were studied. Groups of female rats initially received i.p. injections b.i.d. (11.00 and 17.00h) of either saline or chlordiazepoxide (CDP). CDP doses increased by 2mg/kg/day from 10mg/kg to a final does of 30mg/kg. Treatment was maintained for 26 days. Over the next 6 days animals were either treated b.i.d. with vehicle, CDP, or ritanserin at one of three doses (0.16,0.63 and 2.5mg/kg). In CDP-pretreated animals subsequently treated with vehicle, significant weight loss, anorexia and hypodipsia were seen, relative to controls. In saline-pretreated animals ritanserin had no effect on body weight. However, CDP withdrawal-induced weight loss was actually exacerbated by ritanserin, in a dose-related fashion. Thus, ritanserin potentiated withdrawal-induced weight loss, by a process which did not involve functional (additive) effects of withdrawal and ritanserin treatment. Ritanserin stimulated food intake in saline-pretreated animals. Despite this effect it failed to alleviate CDP withdrawal-induced anorexia. However, in contrast to the weight loss index, no evidence was obtained for potentiation of withdrawal-induced anorexia. In saline-pretreated animals ritanserin had no effect on water intake, nor did it alleviate or potentiate CDP withdrawal-hypodipsia. Thus the effects of ritanserin on somatic BZ withdrawal signs depended upon the specific sign studied, different signs showing potentiation or no effect. However, for none of the signs studied was there any evidence that ritanserin alleviated the effect of CDP withdrawal. 5-HT(2/1C) antagonists may therefore be of limited value in the treatment of somatic aspects of the BZ withdrawal syndrome. They may even exacerbate some BZ withdrawal signs, although a full characterization of the effects of such drugs on BZ withdrawal requires that a number of other different withdrawal signs and symptoms should be studied, since it seems likely that different BZ withdrawal signs involve different underlying mechanisms.     

Evaluation of the dependence potential of the selective 5-H1A agonist ipsapirone in rats and of its effects on benzodiazepine withdrawal

Two initial studies investigated: i) the effects of withdrawal from ipsapirone [a putative non-benzodiazepine (BZ) anxiolytic] and chlordiazepoxide (CDP); and ii) effects of ipsapirone in animals withdrawn from CDP. Rats were injected b.i.d. for 21 days with saline, ipsapirone or CDP at doses up to 40 mg/kg/injection. Subsequently, controls received the treatment administered previously, other subjects received saline during withdrawal from ipsapirone or CDP. Further subjects received ipsapirone (3, 10 or 30 mg/kg b.i.d.) during CDP withdrawal. Withdrawal indices recorded were body weight and food intake. Withdrawal signs were absent after ipsapirone treatment but present after CDP treatment, when food intake and bodyweight measures fell and then recovered. At the high dose of 30 mg/kg (b.i.d.) ipsapirone potentiated CDP withdrawal signs. Potentiation of withdrawal wasnot seen in animals treated with ipsapirone at lower doses (3 and 10 mg/kg, b.i.d.). In a subsequent study we found that ipsapirone conditioned a taste aversion, a possible index of drug-induced malaise, at doses as low as 7.5 mg/kg. Therefore a possible explanation for the potentiation of BZ withdrawal in subjects treated with high doses of ipsapirone was that drug-induced malaise reduced food intake and body weight, rather than ipsapirone causing true potentiation of BZ withdrawal. However, in a further study we showed that the ipsapirone treatment regime which potentiated BZ withdrawal didnot significantly reduce food intake or body weight, suggesting that high doses of ipsapirone potentiate BZ withdrawal by a mechanism that does not simply involve malaise. The most plausible account of the observed potentiation of withdrawal by ipsapirone involves actions of the ipsapirone metabolite (1-(2-pyrimidinyl)-piperazine) on alpha₂-adrenoceptors, which are known to be implicated in BZ withdrawal. However, the precise mechanism involved remains unclear. Collectively, the studies reported show that ipsapirone does not induce the type of withdrawal signs seen with BZs. However, there was no evidence that ipsapirone attenuated BZ withdrawal. It is therefore likely that patients withdrawn from BZs will experience withdrawal if treated with ipsapirone, and that if treated with high doses withdrawal may be exacerbated.An abstract report of some of the data reported here has been published previously (Goudie A.J., Leathley M., McNally J. (1989a))     

Modulation of monomethylhydrazine-induced seizures by ivermectin.

Exposure to monomethylhydrazine (MMH), a common rocket propellant, can cause dose-related central nervous system (CNS) disturbances ranging from tremors to tonic-clonic convulsions to death. MMH inhibits gamma-aminobutyric acid (GABA) synthesis in the CNS. Diazepam (BZ) acts at the GABA receptor site, and it is also here that ivermectin (AVM) is pharmacologically active. Mice were injected with 30 mg/kg MMH. Groups of 12 mice each were then given varying doses of AVM (5, 10 and 15 mg/kg), or AVM + BZ combinations (5 mg/kg AVM with 5 mg/kg BZ, 10 mg/kg AVM with 5 mg/kg BZ). Time to first convulsion and time to death were recorded over the next 7 h and all groups were monitored over the next 7 days. Times to convulsion were not altered with AVM alone, but death was significantly prevented with AVM dosages. A treatment of 10 mg/kg AVM with 5 mg/kg BZ resulted in no seizures or deaths.     

Dioxin treatment of rats results in increased in vitro induction of sister chromatid exchanges by alpha-naphthoflavone: an animal model for human exposure to halogenated aromatics

Recent reports have shown that alpha-naphthoflavone (alpha-NF) in vivo enhances the sister chromatid exchange (SCE) frequency in lymphocytes from human populations exposed to cigarette smoke or polychlorinated biphenyls and dibenzofurans. In this study, female Sprague-Dawley rats (9-11 weeks old) were administered a single oral dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and killed 6 days after treatment. Blood cultures were established with or without alpha-NF. The baseline and alpha-NF-induced SCE frequencies were assessed in lymphocytes after a 72-hr culture period. No effect on the SCE baseline frequency (cultures without alpha-NF) was detected in rats exposed to 0-30 micrograms TCDD/kg. However, the SCE frequencies from cultures incubated in the presence of alpha-NF were significantly higher in lymphocytes from rats treated with TCDD. Moreover, delta SCE values (SCE alpha-NF minus SCE baseline) were significantly higher in lymphocytes from rats treated with TCDD than in controls. A dose-dependent increase in delta SCE values was observed between 0 and 3 micrograms TCDD/kg, followed by a plateau at higher doses. This induction pattern closely resembled the induction of the liver microsomal aryl hydrocarbon hydroxylase activity by TCDD. In contrast to TCDD, phenobarbital treatment of rats (75 mg/kg/day) had no effect on alpha-NF-induced SCE frequencies in lymphocytes. Liver microsomes from TCDD-treated rats metabolized alpha-NF at a rate much faster than that of control microsomes. These studies indicate that TCDD-exposed rats provide a useful model to investigate the mechanism of enhanced in vitro induction of SCE frequency in lymphocytes from humans exposed to toxic halogenated aromatics or cigarette smoke.     

Is maintenance antiparkinsonian treatment necessary?

The authors designed a three-phase prospective trial in which only those patients who developed an acute, neuroleptic-induced extrapyramidal side effect (EPSE) received benztropine (BZ) at 2 mg i.m. and then 1 mg p.o. b.i.d. for 2 days after their symptoms were rated for severity and type (Preparatory Phase 1). They were then randomly assigned under double-blind conditions to continue BZ or be switched to placebo for 8 days (Experimental Phase 2). Finally in Phase 3 (Followup), all patients continued on placebo in a single-blind design until Day 30. If the patient re-experienced an acute EPSE that was of sufficient severity to require immediate BZ administration, he or she was rated, treated, and then dropped from the study. EPSE scores and dropout rates did not differ in Phase 2 between the placebo- and BZ-treated groups. Implications for the continuation, cessation, or intermittent use of antiparkinsonian (AP) drugs are discussed.     

Effects of the 5-HT3 antagonist ondansetron on benzodiazepine-induced operant behavioural dependence in rats

This study was designed to assess whether rats made tolerant to the suppressant action on Fixed Ratio operant responding of the benzodiazepine (BZ) chlordiazepoxide (CDP) would show behavioural disruption on drug withdrawal—so-called operant behavioural dependence. In addition, the study examined the effects of the 5-HT₃ antagonist ondansetron on such operant behavioural dependence. During 42 consecutive days of CDP treatment, at deses escalated from 10 to 30 mg/kg/day, marked tolerance developed to the rate-suppressant action of CDP. On subsequent days, during spontaneous withdrawal, response rates declined significantly by around 30% in animals treated with saline, although some recovery of responding was seen over successive days of withdrawal. Similar reductions in responding followed by recovery were seen in rats treated with the 5-HT₃ antagonist ondansetron (0.01–0.1 mg/kg, b.i.d.). These findings demonstrate for the first time that it is possible to use operant procedures to detect spontaneous BZ withdrawal. They also suggest, in agreement with recent studies from this laboratory (Leathley and Goudie 1992), that 5-HT₃ antagonists may have relatively limited utility in treating some signs of BZ dependence.     

Effects of the 5HT(1A) agonist anxiolytic gepirone on benzodiazepine withdrawal signs in rats

The effects of gepirone at 3, 9 and 27mg/kg (b.i.d.) on benzodiazepine (BZ) withdrawal signs were studied in rats pretreated with chlordiazepoxide for 21 days at doses up to 40mg/kg b.i.d. The BZ withdrawal indices studied were weight loss and anorexia. At 9 and 27, but not 3mg/kg (b.i.d.) gepirone potentiated the weight loss and anorexia seen during BZ withdrawal. These effects could not be attributed simply to high dose drug-induced "malaise" inhibiting food intake, since in drug-naive animals gepirone stimulated food intake and increased bodyweight. These data show clearly that gepirone potentiates BZ withdrawal signs. Similar findings have been reported recently in studies with ipsapirone (Goudie and Leathley, 1991). Such effects could be mediated by the a(2)-adrenoceptor antagonist actions of 1-(2-pyrimidinyl)piperazine (1-PP), an active metabolite of both gepirone and ipsapirone. Such findings may explain why prior BZ experience impairs the clinical response to buspirone-type anxiolytics acting at the 5-HT(1A) receptor.     

Effects of the 5-HT3 antagonist ICS 205-930 on benzodiazepine withdrawal signs in rats

Effects of the 5-HT3 antagonist ICS 205-930 on chlordiazepoxide (CDP) withdrawal were assessed in rats treated for 21 days with doses of CDP up to 40mg/kg/day (b.i.d.). Withdrawal signs recorded were body weight and 24h food intake, which both fell during withdrawal and then recovered. ICS 205-930 (0.001-1.0mg/kg) was administered b.i.d. during withdrawal. At no dose over the wide range tested did ICS 205-930 reduce withdrawal signs. These data contrast with published findings with the 5-HT3 antagonist ondanestron, some of which indicated that ondansetron completely alleviated the "anxiogenic" suppression of exploratory behaviour observed during benzodiazepine (BZ) withdrawal. Possible reasons for these differing findings are discussed. Collectively, these findings suggest that 5-HT3 antagonists may have limited utility in the clinical treatment of BZ withdrawal.     

枸橼酸咖啡因与氨茶碱治疗早产儿呼吸暂停的疗效比较

目的：观察枸橼酸咖啡因治疗早产儿呼吸暂停的疗效。方法：选择妊娠26～32周出生、出生后24 h或更长一段时间呼吸暂停发作1次或1次以上的早产儿66例,按床位先后顺序分为2组,枸橼酸咖啡因组（观察组）33例,采用负荷量20 mg／kg（相当于咖啡因碱基10 mg／kg）静脉滴注（30 min）,间隔24 h后给予5 mg／（ kg· d）[相当于咖啡因碱基2.5 mg／（ kg· d）]静脉滴注或口服;氨茶碱组（对照组）33例,采用首剂5.0 mg／kg静脉滴注,间隔8～12 h后给予1次2.0 mg／kg、2次／d,治疗5 d。结果：观察组治疗方案在降低呼吸暂停发病率方面与对照组的差异无统计学意义（P＞0.05）。结论：静脉注射枸橼酸咖啡因20 mg／kg（相当于咖啡因碱基10 mg／kg）,后续5 d静脉注射或口服枸橼酸咖啡因5 mg／（ kg· d）[相当于咖啡因碱基2.5 mg／（ kg· d）],对治疗妊娠26～32周的早产儿呼吸暂停的疗效与氨茶碱相当。     

Preventive and therapeutic effects of sugar cane extract on cyclophosphamide-induced immunosuppression in chickens

Effects of oral administration of sugar cane extract (SCE) on immunosuppression in chickens treated with cyclophosphamide (CPA) were evaluated. Three-week-old inbred chickens were inoculated into the crop with SCE (500 mg/kg/day) for three consecutive days before or after injection of CPA 12 or 20 mg/chicken. At the last day of SCE or CPA treatment, all chickens were immunized intravenously with sheep red blood cells (SRBC) and Brucella abortus (BA). Chickens administered SCE showed a significant increase in body weight, gain in body weight/day, relative weight of the bursa of Fabricius and antibody responses to SRBC and BA than untreated control chickens. Chickens injected with CPA alone showed significantly decreased body weight, gain in body weight/day, relative weight of the bursa and antibody responses to SRBC and BA, showing immunosuppression in the bursa-dependent immune system. All chickens administered SCE before or after the treatment with CPA showed significantly higher values in body weight, gain in body weight/day, relative bursal weight and antibody responses to both antigens, when compared to chickens treated with CPA alone. In histological examination, chickens administered SCE showed a typical bursa with well constituted follicles, although chickens treated with CPA alone showed a severely atrophied bursa with rudimentary follicles and enormous proliferation of interfollicular connective tissue. Chickens treated with SCE and CPA showed a well-reconstituted bursa with almost normal structure. These results suggest that SCE has functionally and morphologically reconstituting effects on the bursa-dependent immune system in immunosuppressed chickens induced by injection of CPA.     

Tolerance,cross-tolerance and dependence measured by operant responding in rats treated with triazolam via osmotic pumps

Previous research has found that drugs with affinity for (benzodiazepine) sites differ in their abilities to produce tolerance and dependence. The present study therefore investigated the effects of ligands of (BZ) sites in rats that had been rendered tolerant to a benzodiazepine. Two experiments were carried out in separate groups of rats. Behavioral changes induced by chronic infusion of triazolam (3 mg/kg/day, SC, for 14 days) via osmotic pumps were studied in animals trained on a fixed ratio 10 schedule of food presentation. Control animals were implanted with pumps containing the vehicle. Test drugs were administered IP using cumulative dosing. In one experiment triazolam decreased response rates on days 1, 2 and 3 after implantation of the pumps and tolerance developed to this depressant effect. In the other experiment, vehicle and triazolam treated rats differed in their responding during chronic infusion but differences were not statistically significant on any particular day. Flumazenil (3.0–30 mg/kg) greatly decreased rates of responding on day 11 in triazolam treated rats. This effect may represent a precipitated withdrawal syndrome. However, no withdrawal effects on operant performance were observed upon pump removal. Chronic infusion of triazolam did not affect the sensitivity of rats to alpidem on day 11 (10–100 mg/kg) whereas it abolished the stimulant effect of bretazenil (0.1–1.0 mg/kg). Chronic triazolam treatment produced tolerance to the depressant effects of triazolam (1.0–3.0 mg/kg), lorazepam (0.3–3.0 mg/kg) and zopiclone (10 mg/kg) but no tolerance to those of CL 218,872 (3.0–30 mg/kg) and zolpidem (0.3–3.0 mg/kg) when tested 3–14 days after pump removal. Differences between compounds highlighted with this model are in agreement with previous observations that these agents possess different pharmacological profiles and different potentials to induce tolerance and dependence.     

Increased sensitivity to benzodiazepine antagonists in rats following chronic treatment with a low dose of diazepam

The effects of benzodiazepine (BZ) antagonists on operant behavior were examined in rats chronically administered a low dose of diazepam (DZ). The low maintenance dose of DZ (5 mg/kg twice daily) was selected as more closely associated with its anxiolytic effects than the higher treatment doses previously used to study BZ dependence. Food-restricted rats were trained to press a lever for food reinforcement under a FR20 schedule of reinforcement prior to the start of DZ administration. Acute administration of DZ caused a dose-dependent reduction of response rates, with 5 mg/kg causing a 50% decrease. Rats treated chronically with DZ became tolerant to its rate-suppressant effects as shown by a 5-fold increase in the dose of DZ required to reduce FR20 response rates by 50%. The BZ antagonist flumazenil (formerly Ro 15-1788; 10–56 mg/kg) suppressed rates of responding in rats treated chronically with DZ. The suppression of operant responding was obtained when flumazenil was given up to 3 h, but not 18 h, after the last treatment with DZ. In contrast, only the highest dose of flumazenil (56 mg/kg) caused reductions of operant responding when given to rats treated with saline. The BZ antagonist CGS 8216 (3.3–33 mg/kg IP), given 10 min prior to the session, was similarly more potent and effective at suppressing operant responding in rats treated chronically with DZ than saline. This procedure may provide a model for the clinical problem of physical dependence to chronically-administered low, anxiolytic doses of BZ tranquilizers.     

Discriminative stimulus properties of the benzodiazepine receptor inverse agonist methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM)

The purpose of this study was to determine whether rats could be trained to discriminate the stimulus properties of the benzodiazepine (BZ) receptor inverse agonist DMCM from saline in a conditioned taste aversion paradigm. On a drug trial, water-deprived rats were injected with DMCM (0.55–0.6 mg/kg IP), allowed access to a 0.25% saccharin solution for 30 min, and then injected with LiCl. On non-drug trials, saline injections bracketed the drinking period. Conditioned controls were treated similarly with DMCM and saline on drug and non-drug trials, but received injections of saline instead of LiCl. At the completion of training, DMCM produced a 69% reduction of saccharin consumption on drug trials, compared with 23% for conditioned controls. The stimulus properties of DMCM were then measured by its ability to reduce the preference for saccharin over water in a two-bottle choice test. DMCM reduced saccharin preference in rats that received discrimination training from 68% to 19%, but did not alter saccharin preference in conditioned controls. Other compounds with varying activity at BZ receptors were evaluated for their ability to substitute for the discriminative stimulus effects of DMCM. Two BZ receptor inverse agonists, -CCE (10–18 mg/kg) and FG 7142 (3.2–18 mg/kg), substituted completely for DMCM. Partial substitution for DMCM was shown by the BZ receptor antagonist CGS 8216 (3.2–10 mg/kg) and the non-BZ convulsant pentylenetetrazol (10–20 mg/kg). The BZ receptor agonists chlordiazepoxide (0.32–5.0 mg/kg), diazepam (0.32–10 mg/kg), and alprazolam (0.1–3.2 mg/kg) and the BZ receptor antagonist flumazenil (1.0–32 mg/kg) failed to substitute for the DMCM stimulus. Pretreatment with flumazenil (1.0 mg/kg) blocked the stimulus effects of the training dose of DMCM and produced a shift to the right of the DMCM generalization curve. The pattern of compounds that substituted for the DMCM stimulus and the blockade of that stimulus by flumazenil indicate that the stimulus properties of DMCM are associated with its effects as a BZ receptor inverse agonist.     

Pharmacokinetic and clinical evaluation of aztreonam in neonates and premature infants

In order to study serum concentration and urinary concentration (urinary recovery rate) of aztreonam (AZT), AZT was administered via intravenous bolus injection at dose levels of 10 mg/kg, 20 mg/kg and 50 mg/kg to 7 cases of 4 to 26 days old mature or premature infants nearing cure-stage of various bacterial infections upon the treatment with AZT. Clinical evaluation was made in 19 cases with therapy with AZT alone and 13 cases with combination therapy with AZT + ampicillin (ABPC), with a total of 32 cases. The former group included 10 males and 9 females of 0 to 43 days of age and the latter group included 7 males and 6 females of 6 to 41 days of age. All the cases treated with AZT alone including 5 cases for prophylaxis were evaluable. In the 13 combination therapy cases, however, the effect of AZT was evaluable only in 3 cases excluding the cases in which ABPC-susceptible bacteria were the culprits. 1. Changes in serum concentrations and urinary recovery of AZT. Pharmacokinetics of AZT in serum was examined in 5 matured infants at dose levels of 10 mg/kg in 2 cases and 20 mg/kg in 3 cases. Highest levels were observed with the first sampling at 30 minutes after administration in all the cases with values of 29.1 micrograms/ml with 10 mg/kg dose, and 37.8 micrograms/ml and 55.5 micrograms/ml with 20 mg/kg dose in in cases with ages between 4 and 7 days and 1 case with age above 8 days, respectively. Half-life (T 1/2) values were 3.42, 3.05 and 1.58 hours, respectively for the above three groups of patients. As is described here, the T 1/2 value in the infant with age above 8 days was considerably shorter than the T 1/2 values in infants of younger day-ages. Urinary recovery rates of administered AZT were between 10.4 and 52.6%, showing a large individual diversity. In addition to the above cases, one premature infant was administered with AZT (the dose level: 50 mg/kg) and examined for pharmacokinetic parameters at day-ages of 11 days and 19 days. Serum levels of AZT examined were the highest at 30 minutes after dosage (the first sampling) and were 106.8 micrograms/ml at 11 days of age, and 90.4 micrograms/ml at 19 days of age. Serum levels decreased to 16.2 and 9.6 micrograms/ml, respectively, in 8 hours after dosage, at ages of 11 and 19 days. T 1/2 values were 2.62 and 2.35 hours, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)     

Chlordiazepoxide-induced spatial learning deficits: dose-dependent differences following prenatal malnutrition

The sensitivity of prenatally protein-malnourished rats to the amnestic properties of the benzodiazepine (BZ) receptor agonist, chlordiazepoxide (CDP), was studied in the male offspring of rats provided with a protein-deficient diet (6% casein) for 5 weeks prior to mating and throughout pregnancy. Rats were tested during acquisition of the submerged platform version of the Morris water maze task using three systemic doses of CDP (3.2, 5.6, and 7.5 mg/kg i.p.) at two ages (day 30 and day 90). At 30 days, prenatally malnourished rats showed less sensitivity to the amnestic effect of the 5.6-mg/kg dose when compared with well-nourished controls by displaying shorter swim paths during acquisition and a more selective search of the target quadrant upon removal of the platform (probe trial). At 90 days, prenatally malnourished rats again showed less sensitivity to CDP at a dose of 5.6 mg/kg, but more sensitivity to the 3.2-mg/kg dose (indicated on the probe trial). No obvious relationship was identified between the nutritional group differences in behavioral sensitivity to CDP at 90 days and their BZ receptor density in the hippocampus or medial septum. It can be concluded that prenatal malnutrition alters the amnestic response to CDP in a dose-dependent and developmentally specific manner, thus providing further support for functional changes within the GABAergic system subsequent to malnutrition.     

Effects of glucocorticoids on 5-HT1A presynaptic function in the mouse

8-OH-DPAT, a selective 5-HT_1A agonist, produced a hypothermic response in mice at a dosage of 0.5 mg/kg. Administration of corticosterone-21-acetate (0.5, 5 and 50 mg/kg, daily for 3 and 10 days) produced a dose-dependent attenuation of this hypothermic response in mice. When all controls and corticosterone treated mice were retested, 14 days after initial testing, they did not differ in the hypothermic responses induced by 8-OH-DPAT. Mice treated with aldosterone (50 mg/kg), dexamethasone (50 mg/kg) and the specific type 2 corticosteroid receptor agonist, 11b,17b-dihydroxy-21-methyl-17a-pregna-1,4,6-trien-20-yn-3-one (RU26988, 30 mg/kg) for 10 days, did not differ from vehicle treated controls in the hypothermic response to 8-OH-DPAT. Mice administered corticosterone-21-acetate (30 mg/kg, daily) for 10 days displayed a motor behavioural syndrome, which was not seen in controls, when injected with 5-hydroxytryptophan (5-HTP, 100 mg/kg) 15 min after the injection of carbidopa (25 mg/kg). This was significantly decreased by pretreatment with the 5-HT_1A receptor antagonist 1-(2-methoxyphenyl)-4-(4-phthalimidobutyl)-piperazine (NAN-190 5 mg/kg, 30 min prior to administration of carbidopa). Taken together, this evidence is compatible with a specific corticosterone induced facilitation of 5-HT release due to attenuation of inhibitory 5-HT_1A autoreceptor function.     

Changes in noradrenaline plasma levels and behavioural responses induced by benzodiazepine agonists with the benzodiazepine antagonist Ro 15-1788

Noradrenaline (NA) plasma levels were examined in 18 healthy volunteers on 2 consecutive days after a single treatment with either lormetazepam (0.06 mg/kg) (LMZ group), flunitrazepam (0.03 mg/kg) (FNZ group) or placebo (PLA group) in combination with the benzodiazepine (BZ) antagonist Ro 15-1788 (0.1 mg/kg). Behavioural responses (mood changes, anxiety) were also investigated in parallel. Both BZ decreased NA plasma levels to 50% of the basal values 10 min after the injection; administration of Ro 15-1788 15 min later reinstated NA plasma levels to basal values. A second administration of Ro 15-1788 (0.1 mg/kg) 24 h after BZ or PLA treatment increased NA plasma levels, estimated 10 min after the injection in both the LMZ- and the FNZ groups, but not in the PLA group. Behavioural responses measured under the same treatment also indicated minor anxiety responses followed by mood impairment. These data suggest that a stressful situation may be precipitated by the antagonist Ro 15-1788 24 h after a single BZ treatment, which resembles a withdrawal response, and increases NA plasma levels.     

Clinical and pharmacokinetic evaluation of ceftazidime in neonates and young infants

Seventeen newborn and young infants including 6 premature infants were treated with ceftazidime (CAZ) and the clinical efficacy and side effects were evaluated. Ages of the patients ranged from zero to 55 days, and their body weights ranged from 1.35 to 3.87 kg. Doses of CAZ ranged 10-50 mg/kg every 6 to 12 hours for 3 to 14 days. Twelve infants with infections including meningitis, sepsis, pneumonia and urinary tract infections, were considered to have responded to the CAZ treatment. Among them, results were excellent in 2, good in 9 and fair in 1 patient. The drug was well tolerated, but 1 had diarrhea and 3 patients had eosinophilia among the 17 patients. The pharmacokinetics of CAZ was studied in 22 patients including 11 premature infants. Their ages ranged from 1 to 60 days, and body weights ranged from 0.85 to 3.96 kg. Serum concentrations in 7 patients ranged from 24.2-38.5 micrograms/ml at 30 minutes after single doses of 10 mg/kg intravenous bolus injections and 4.36-12.4 micrograms/ml at 6 hours. Mean elimination half-lives of the drug were 3.20 hours in 2 patients under 7 days of age and 2.31 hours in 5 patients from 7 days of age or older. In 8 patients, serum concentrations ranged 32.6-57.9 micrograms/ml at 30 minutes and 8.10-20.7 micrograms/ml at 6 hours after single doses of 20 mg/kg. Elimination half-lives were 3.53 hours in 4 patients under 7 days of age and 2.79 hours in 4 patients from 7 days of age or older.(ABSTRACT TRUNCATED AT 250 WORDS)     

A model of 'antipredator' defense in Swiss-Webster mice: effects of benzodiazepine receptor ligands with different intrinsic activities

A mouse defense test battery (MDTB) has been designed to assess defensive reactions of Swiss-Webster mice to situations associated with nonpainful threat. When compared to mice approached by a leather glove, animals confronted with an anesthetized or a conscious rat displayed potentiated flight responses and defensive threat/attack reactions, while risk assessment performances were generally similar in all three conditions. Furthermore, escape attempt responses following removal of the stimulus were higher in the conscious rat condition compared to the two other groups. Taken together, these results suggest that flight reactions and defensive threat/attack responses are specific to the rat, and thus indicate that the MDTB may relate to 'antipredator' defense. In mice confronted with an anaesthetized rat, administration of the benzodiazepine (BZ) receptor full agonist chlordiazepoxide (5-25mg/kg, i.p., 30min) and the BZ partial agonist Ro 19-8022 (0.5-2mg/kg, i.p., 30min) altered one of two risk assessment measures and inhibited defensive attack behaviors, but failed to counter the post-predator increase in escape attempts. In addition, Ro 19-8022 also strongly reduced flight responses. The overall behavioral profile suggests a fear/anxiety-reducing action of both drugs. By contrast, administration of the BZ inverse agonist Ro 19-4603 (0.025-0.1mg/kg, i.p., 30min) reliably released these defensive responses. Interestingly, the BZ antagonist flumazenil (5-20mg/kg, i.p., 30min) manifested differential intrinsic activity depending upon the level of threat. Thus, in a weakly threatening situation, the drug potentiated flight reactions, indicating an inverse agonist-like action, decreased defensive biting in a highly threatening situation, indicating an agonist activity. These findings demonstrated that BZ ligands differently modulated 'antipredator' defense in Swiss-Webster mice, depending upon their intrinsic (positive or negative) efficacy, but also depending upon the defense strategy required by the threat.     

五味子提取物对百草枯中毒模型小鼠肺纤维化的保护作用

摘要： 目的 探讨五味子提取物对百草枯（PQ）中毒模型小鼠肺纤维化的保护作用, 并探讨其机制。方法 108 只小鼠按随机数字表法分为正常对照组, 模型组, 五味子提取物低剂量组 （200 mg/kg）、 中剂量组 （400 mg/kg）、 高剂量组 （800 mg/kg） 及维生素 C 组 （100 mg/kg）, 每组 18 只。除正常对照组以外的小鼠行一次性 PQ 溶液 （100 mg/kg） 灌胃造模, 造模成功后每 24 h 给予相应剂量药物 1 次, 分别在建模后第 7、 14、 21 天处死小鼠, 每个时间点 6 只。解剖肺脏, HE 染色观察小鼠肺组织炎症程度并进行炎症评分; Masson 染色观察肺组织纤维化程度;RT-PCR 和酶联免疫吸附试验（ELISA）分别检测各组肺组织中转化生长因子（TGF） -β1、 白细胞介素（IL） -6、 IL-17 mRNA 及蛋白表达水平。结果 （1）造模后第 7 天和第 14 天, 模型组小鼠肺组织出现大量炎性细胞浸润、 肺泡间隔充血, 炎症评分较正常对照组升高（P < 0.05）, 而五味子提取物中、 高剂量组小鼠肺组织炎症评分较模型组和维生素 C 组降低（P < 0.05）。（2）造模后第 14 天和第 21 天, 五味子中、 高剂量组小鼠肺组织纤维化程度较模型组降低（P < 0.05）。（3）随着造模时间的延长, 模型组 TGF-β1 mRNA 及蛋白表达水平升高, IL-6 表达降低, IL-17 则先升高后降低。五味子提取物中、 高剂量组与模型组比较, 造模后第 7 天和第 14 天, IL-6 表达降低, 造模后第 14 天和第 21 天, TGF-β1 表达降低, 而 3 个时间点 IL-17 表达均降低 （P < 0.05）。结论 五味子提取物可通过抑制 TGF-β1、 IL-6 和 IL-17 的表达来减轻 PQ 中毒造成的炎症反应和肺纤维化。