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1.
Rengelshausen J Beedgen B Tsamouranis K Mikus G Walter-Sack I Haefeli WE Linderkamp O 《European journal of clinical pharmacology》2006,62(9):773-777
Objective Pharmacokinetic parameters are important for dose adjustment of aminoglycosides, but they are highly variable in neonates. In this study the pharmacokinetics of a netilmicin loading dose was investigated on the first postnatal day in preterm neonates with very low gestational age (GA).Methods In an open prospective study, 20 neonates with GA between 22.9 and 32.0 weeks and suspected postnatal bacterial infection received an intravenous loading dose of 5 mg/kg netilmicin over 1 h during the first postnatal day. Netilmicin serum concentrations were determined by an enzyme multiplied immunoassay.Results The systemic clearance of netilmicin normalized to body weight (BW) was not significantly different in three GA subgroups (0.59± 0.02 ml/min/kg for GA <24 weeks, 0.72±0.14 ml/min/kg for GA 24–27 weeks, and 0.62±0.19 ml/min/kg for GA 27–32 weeks, P=0.123). Similar results were also obtained for serum elimination half-time and for the distribution volume normalized to BW. Multiple regression analysis showed that systemic clearance and volume of distribution (both not normalized to BW) significantly correlated with BW (P<0.0001) but not with GA. In the entire group, 20% of peak concentrations were below the target of 6 mg/l, and 63% of trough concentrations were above the target of 2 mg/l.Conclusion In neonates with very low GA, the pharmacokinetic parameters of netilmicin determined after an intravenous loading dose were not dependent on GA when normalized to BW. A number of neonates did not reach targeted peak and trough netilmicin serum concentrations, suggesting that a higher loading dose and a prolonged dosing interval might enhance the effectiveness and safety of netilmicin in preterm neonates immediately after birth. 相似文献
2.
Allegaert K Anderson BJ Naulaers G de Hoon J Verbesselt R Debeer A Devlieger H Tibboel D 《European journal of clinical pharmacology》2004,60(3):191-197
Background The aim of this study was to describe propacetamol pharmacokinetics in term and preterm neonates to suggest dosing regimens.Methods A population pharmacokinetic analysis of paracetamol (acetaminophen) time–concentration profiles in 48 neonates was undertaken using non-linear mixed-effects models. Neonates were given either single (n=30) or multiple doses (n=18) of propacetamol infusion over 15 min. Neonates had a median postnatal age of 1 day (range, 1–76 days). Median post-conceptual age (PCA) was 35 weeks (range, 27–42 weeks), and median weight was 2.4 kg (range, 0.51–4 kg).Results The population volume of distribution estimate and between-subject variability (%) for a one-compartment model with zero-order input and first-order elimination was 70.4 l (30.7%)/70 kg. Clearance increased from 2.85 l/70 kg, CV 40.7% at 27 weeks PCA to reach 7.05 l/h per 70 kg by 42 weeks PCA (standardised to a 70-kg person using allometric 1/4-power models). Between-occasion variability for volume of distribution and clearance were 17.4% and 26%, respectively.Conclusions A mean paracetamol steady-state target concentration above 10 mg/l at trough can be achieved using a loading dose of 40 mg/kg and maintenance doses of 20 mg/kg 6 h in 28-week PCA neonates, 25 mg/kg 6 h at 32 weeks, 30 mg/kg 6 h at 36 weeks and 20 mg/kg 4 h at term (propacetamol doses). Since the role of the oxidative enzyme CYP2E1 and production of the hepatotoxic metabolite N-acetyl-p-benzoquinone-imine still is unknown in premature neonates, lower doses scaled by age-related clearance and centred on a daily dose of 60 mg/kg per day in a child of 6–8 years with a clearance of 0.25 l/h per kg (12.5 l/h per 70 kg) may be more appropriate.Research of Gunnar Naulaers is supported by the Fund for Scientific Research—Flanders (Belgium), Clinical Doctoral Grant A6/5—CM. D 11.354. Warning: all doses in this paper are reported as prodrug; 1 g of propacetamol equals 0.5 g of paracetamol. 相似文献
3.
Hepatoprotective Effects of the Shark Bile Salt 5{beta}-Scymnol on Acetaminophen-Induced Liver Damage in Mice 总被引:2,自引:0,他引:2
MACRIDES THEODORE; NAYLOR LEE M.; KALAFATIS NICOLETTE; SHIHATA AMAL; WRIGHT PAUL F. A. 《Toxicological sciences》1996,33(1):31-37
The hepatoprotective effect of the shark bile salt 5ß-Scymnolhas been studied in the model of acute hepatotoxicity inducedby administration of acetaminophen (APAP, paracetamol). 5ß-Scymnolat doses of 20, 35, and 70 mg/kg intraperitoneally (ip) decreasedsignificantly the serum activity of alanine aminotransferase,sorbitol dehydrogenase, and lactate dehydrogenase (p < 0.05)caused by APAP treatment (350 mg/kg ip) alone. The highest doseof 5ß-Scymnol remained hepatoprotective when administered4 hr after the APAP overdose. N-Acetylcysteine (NAC) is protectiveagainst APAP-induced hepatotoxicity at 250 and 500 mg/kg (ip)when administered up to 3 hr after APAP overdose, as shown bya significant reduction in serum enzyme activity. Coadministrationof 5ß-Scymnol (70 mg/kg) and NAC (250 mg/kg) alsoreduced serum enzyme levels and histopathological effects; however,a similar level of hepatoprotection was conferred by 5ß-Scymnoltreatment alone. In addition, 5ß-scymnol has potenthydroxyl radical quenching activity as it markedly inhibiteddeoxyribose degradation in a ferrous/ascorbate Fenton reactionsystem. These results indicate a possible role for the use of5ß-scymnol, either alone or concomitant with NAC,in the prevention of hepatic necrosis following toxic dosesof APAP. 相似文献
4.
The purpose of this work was (1) to assess the ability of selected antipsychotic and comparison drugs to induce arrest of
movement phenomena during operant responding and (2) to evaluate the capacity of muscarinic anitcholinergics to block such
effects. The effects of haloperidol (0.02–0.12 mg/kg, IP, 45 min), raclopride (0.05–0.80 mg/kg, IP, 30 min) eticlopride (0.02–0.16
mg/kg, IP, 45 min), clozapine (1.0–8.0 mg/kg, IP, 60 min) and SCH 23390 (0.01–0.16 mg/kg, IP, 30 min) were administered to
rats for 4 weeks in a between-groups dosing design. Operant responses in 15 min and the maximum duration of the rat’s muzzle
entry into the reinforcement dipper well (the measure of arrest of movement that reflected microcatalepsy) were the quantitative
measures of behavior. The D2 antagonists dose-relatedly decreased operant responding and increased maximum muzzle duration, effects that were significantly
reversed by the anticholinergic scopolamine (0.1 mg/kg) or atropine (6.0 mg/kg). Although the atypical antipsychotic drug
clozapine and the selective D1 antagonist SCH 23390 both significantly reduced operant responding, these drugs did not produce microcatalepsy. The results
suggested that microcatalepsy expressed in the context of ongoing operant behavior may model low-dose extrapyramidal side
effects.
Received: 12 January 1998 / Final version: 27 March 1998 相似文献
5.
Modulation of behaviour on trials 1 and 2 in the elevated plus-maze test of anxiety after systemic and hippocampal administration of nicotine 总被引:4,自引:4,他引:0
Rationale: The elevated plus-maze provides a test situation in which distinctive states of anxiety are elicited on trials 1 and 2 and
the dorsal hippocampus has previously been shown to mediate the anxiogenic effects of (–)-nicotine in the social interaction
test. Objective: To determine the effects of a wide dose range of (–)-nicotine on trial 1 and 2 in the plus-maze after systemic administration
and whether the dorsal hippocampus is a site mediating the anxiogenic effect of nicotine. Methods: (–)-Nicotine (0.001, 0.005, 0.01, 0.05, 0.1, 0.5 and 1 mg/kg) was injected IP 30 min before testing for 5 min in the plus-maze.
Rats receiving dorsal hippocampal infusions received bilateral infusions of 0.5 μl of artificial CSF or (–)-nicotine (0.1,
1, 4 or 8 μg). The needle was left in place for 50 s after injection and testing took place 3 min later. Rats tested on trial
1 were naive to the plus-maze, those tested on trial 2 had received a previous 5-min undrugged exposure to the maze 48 h earlier.
Results: Low doses of (–)-nicotine (0.001, 0.005, 0.01, 0.05 and 0.1 mg/kg, IP) were without effect on either trial, but higher doses
(0.5 and 1 mg/kg, IP) had anxiogenic effects on both trials, as shown by decreases in percentage time spent and percentage
entries onto the open arms. Infusion of (–)-nicotine (0.1, 1, 4 and 8 μg) bilaterally into the dorsal hippocampus was without
effect on trial 1, but 1 μg had an anxiolytic effect on trial 2, shown by an increased percentage time spent on the open arms.
Conclusions: The results on both trials in the plus-maze after systemic administration of nicotine add to previous reports from the social
interaction test that high doses of nicotine have anxiogenic effects. However, the effects of nicotine in the dorsal hippocampus
are different in all three anxiety tests (anxiogenic in social interaction, ineffective on trial 1, anxiolytic on trial 2)
showing that nicotinic cholinergic control in this brain region may vary depending on the state and/or type of anxiety generated
by the test. The brain region(s) underlying the anxiogenic effects of IP nicotine on both trials in the plus-maze remain to
be identified.
Received: 16 August 1998 / Final version: 10 December 1998 相似文献
6.
P. J. Wellman Dennis K. Miller Christina L. Livermore Thomas A. Green Lance R. McMahon Jack R. Nation 《Psychopharmacology》1998,135(2):133-140
The intent of the present study was to determine the effects of systemic injections of the sympathomimetic agent ephedrine
(EPH) on extracellular dopamine (DA) levels within the rat nucleus accumbens (NAC) and to compare these effects with those
of EPH on locomotion and on feeding. In experiment 1, adult male rats were prepared with an indwelling 3 mm microdialysis
probe positioned within the NAC. The rats were injected (IP) with vehicle, 5, 10, or 20 mg/kg (–)-EPH with dialysates collected
every 20 min for 100 min after drug injection. Systemic injections of 5, 10 or 20 mg/kg (–)-EPH significantly enhanced extracellular
levels of NAC DA over baseline by 79%, 130%, and 400%. Systemic injection of 20 mg/kg EPH significantly reduced NAC levels
of DOPAC and HVA by 37% and 31%. The effects of EPH on brain dopamine activity were stereospecific given that an additional
group of rats injected with 20 mg/kg (+)-EPH exhibited smaller changes in NAC DA (<25%), DOPAC (<10%), and HVA levels (<20%)
than did rats injected with 20 mg/kg (–)-EPH. In experiment 2, adult male rats were injected (IP) with 0, 5, 10, or 20 mg/kg
(–)-EPH prior to placement in automated activity chambers. Total distance traveled was significantly increased by 10 and 20 mg/kg
(–)-EPH, but not by 5 mg/kg (–)-EPH. In experiment 3, adult male rats were injected (IP) with 0, 2.5, 5, or 10 mg/kg (–)-EPH
or with 0, 2.5, 5, or 10 mg/kg (+)-EPH prior to a 30-min feeding test. Although each EPH enantiomer decreased feeding, (–)-EPH
was more potent in feeding suppression than was (+)-EPH. The present results suggest that EPH may alter locomotion and feeding
via an indirect action on brain dopamine activity.
Received: 23 January 1997 / Final version: 2 August 1997 相似文献
7.
William F. Salminen Xi Yang Qiang Shi James Greenhaw Kelly Davis Akhtar A. Ali 《Food and chemical toxicology》2012
Green tea extract (GTE) has been advocated as a hepatoprotective compound and a possible therapeutic agent for acetaminophen (APAP) overdose. This study was conducted to determine if GTE can provide protection against APAP-induced hepatotoxicity. Three different exposure scenarios were tested. The first involved administering APAP (150 mg/kg, orally) to mice followed 6 h later by GTE (500 or 1000 mg/kg). The other two involved administering GTE prior to the APAP dose. GTE (500 or 1000 mg/kg, orally) was administered 3 h prior to APAP (200 mg/kg, orally) or for three consecutive days (once-daily) followed by APAP (300 mg/kg) on the fourth day. Indices of hepatotoxicity were assessed 24 h after the APAP dose. GTE potentiated APAP-induced hepatotoxicity when administered after the APAP dose. GTE caused significant glutathione depletion and this effect likely contributed to the observed potentiation. In contrast, GTE provided protection against APAP-induced hepatotoxicity when administered prior to the APAP dose. GTE dramatically decreased APAP covalent binding to protein indicating that less reactive metabolite was available to cause hepatocellular injury. These results highlight the potential for drug-dietary supplement interactions and the importance of testing multiple exposure scenarios to adequately model different types of potential interactions. 相似文献
8.
Kourosh Parivar Arne Wessén Marianne Widman Anders Nilsson 《Journal of pharmacokinetics and pharmacodynamics》1996,24(6):535-549
Disposition of intravenous anaesthetic eltanolone was studied when administered as a bolus injection (B) of 0.75 mg/kg and
constant rate intravenous infusion at 2 mg/kg/hr (I2) and 3.5 mg/kg/hr (I3.5) for 2 hr in healthy male volunteers. Venous
blood samples were collected for 12 hr and 20 hr following bolus injection and intravenous infusion, respectively. Serum eltanolone
concentrations were determined by a specific gas chromatographic mass spectrometric assay. Using a nonlinear regression analysis,
the individual data sets were best fitted by a three-compartment mamillary model with central elimination. Derived pharmacokinetic
parameters expressed as median and 95% confidence intervals indicated an initial fast distribution with a half-life of 1.80
(0.23–5.47) min (B), 1.44 (0.97–2.06) min (I2) and 1.44 (0.95–2.39) min (I3.5), an intermediate phase with a half-life of
35.4 (28.7–45.2) min (B), 39.6 (31.0–47.9) min (I2) and 35.4 (33.3–44.9) min (I3.5) and a moderately short terminal phase
with a half-life of 3.8 (2.7–5.9) hr (B), 5.0 (4.2–6.1) hr (I2) and 4.6 (4.0–4.8) hr (I3.5). The serum clearance after bolus
injection was 1.37 (1.23–1.67) L/hr/kg and after infusion was 1.36 (1.25–1.52) L/hr/kg (I2) and 1.17 (1.11–1.31) L/hr/kg (I3.5).
The pharmacokinetics of eltanolone appear to be linear over the dosage range studied. Pharmacokinetic parameters obtained
after bolus injection were very much similar to the parameters obtained after infusion with the exception of t1/2β which was longer after the infusion (significant) and the volume of central compartment which was lower after infusion (not
significant). Context sensitive times were estimated for a 30%, 50% and 80% drop in the concentration of eltanolone after
different infusion times. A 30% drop in concentration is estimated to take about 2 to 3 min. A 50% drop in concentration,
is estimated to take about 8 min when duration of infusion is 3 hr and reaches a value of about 10 min by a duration of infusion
of 10 hr. A 80% drop in concentration is estimated to take about 55 min following an infusion of 1 hr and it reaches a value
of 70–80 min following an infusion of 10 hr. 相似文献
9.
Endotoxin-induced reduction of social investigation by mice: interaction with amphetamine and anti-inflammatory drugs 总被引:4,自引:0,他引:4
Previous studies indicate that some aspects of endotoxin-induced sickness behavior in rats may be mediated by interleukin-1
stimulated events and can be attenuated by corticosteroids, cyclooxygenase inhibitors and the interleukin-1-receptor antagonist.
In the current studies, we replicate and extend these findings in adult male mice. A relatively low dose of lipopolysaccharide
(LPS; 15 μg/kg, IP) was used to reliably induce a 50–60% reduction in the social investigation of a juvenile conspecific at
2–3 h after injection. Amphetamine (2.0–4.0 mg/kg, IP, 30 min pre-LPS) exacerbated LPS-induced decreases in investigation.
Administration of methylprednisolone (10–30 mg/kg, IP), indomethacin (3–30 mg/kg, IP), and ibuprofen (1–100 mg/kg, IP) 1 h
before LPS significantly reduced LPS-induced sickness behavior at several doses. Dexamethasone (0.1–10 mg/kg, IP) partially
antagonized sickness. Representative flavonoids rohitukine (0.01–100.0 mg/kg, IP) and chrysin (0.01–10 mg/kg, IP) also antagonized
LPS-induced deficits in social investigation. These studies replicate and extend previous studies in rat to demonstrate systematic
effects of low doses of LPS, antagonism by anti-inflammatory drugs and enhancement of LPS effects by amphetamine. The latter
findings are consistent with a modulatory role for adrenergic activation on interleukin-1 release stimulated by endotoxicity.
Received: 7 August 1996 / Final version: 13 March 1997 相似文献
10.
Mohamed E. Shaker 《Basic & clinical pharmacology & toxicology》2014,114(3):263-270
Nilotinib, a second‐generation tyrosine kinase inhibitor, has been recently approved for the treatment for chronic myeloid leukaemia. The objective of this study was to explore the potential effects of clinically relevant doses of nilotinib against acetaminophen (APAP)‐induced hepatotoxicity in mice. To simulate the clinical application in human beings, nilotinib (25 and 50 mg/kg) was administered to mice 2 hr after APAP intoxication (500 mg/kg). The results indicated that nilotinib (25 mg/kg) (i) abolished APAP‐induced liver injury and necro‐inflammation, (ii) increased hepatic‐reduced glutathione (GSH) and its related enzymes synthesis, (iii) suppressed hepatic oxidative/nitrosative stress cascades, (iv) decreased neutrophil accumulation in the liver, and (v) prevented the over‐expression of B‐cell lymphoma‐2 (bcl‐2), cyclin‐D1 and stem cell factor receptor (c‐Kit) proteins in the liver. Although nilotinib (50 mg/kg) acted through the same mechanisms, there was severe depletion in hepatic GSH content by nilotinib itself at that dose level, rather than the potent stimulation observed by using a dose of 25 mg/kg. Consequently, the mortality rate after 18 hr was 100% for nilotinib (50 mg/kg) + APAP (750 mg/kg) versus 60% for APAP (750 mg/kg) and 40% for nilotinib (25 mg/kg) + APAP (750 mg/kg) in the survival analysis experiment. In conclusion, nilotinib can counteract the hepatotoxicity produced by a non‐lethal dose of APAP. However, there is a risk of aggravating the mortality for a lethal dose of APAP when nilotinib is co‐administered at doses relatively high, or near to the clinical range because of hepatic GSH depletion and c‐kit inhibition. 相似文献
11.
Reinforcing and discriminative stimulus effects of the neuroactive steroids pregnanolone and Co 8-7071 in rhesus monkeys 总被引:1,自引:0,他引:1
James K. Rowlett Gail Winger Richard B. Carter Paul L. Wood James H. Woods W. L. Woolverton 《Psychopharmacology》1999,145(2):205-212
Rationale and Objectives: The present study was designed to assess possible abuse-related effects of the endogenous neuroactive steroid pregnanolone
(3α-hydroxy-5β-pregnan-20-one) and the orally bioavailable, water-soluble neuroactive steroid pro-drug Co 8-7071 (3α,21-dihydroxy-3β-trifluoromethyl-5β-pregnan-20-one,
21-hemisuccinate). Methods: Four rhesus monkeys were prepared with chronic intravenous (IV) catheters and trained to press a lever under a ten-response
fixed-ratio (FR) schedule of methohexital injection (0.1 mg/kg per injection). Three rhesus monkeys were trained to discriminate
intragastric infusions of pentobarbital (10 mg/kg) from saline infusions under a FR5 schedule of stimulus-shock termination. Results: At least two doses of pregnanolone (0.003–0.1 mg/kg per injection) maintained injections per session above saline levels
in the four monkeys tested, whereas Co 8-7071 (0.01–1.0 mg/kg per injection) maintained injections per session above saline
levels in two of four monkeys at relatively low levels of injections per session. In rhesus monkeys trained to discriminate
pentobarbital, IV pregnanolone injections (0.1–1.7 mg/kg, 5-min presession) dose-dependently reproduced the discriminative
stimulus effects of pentobarbital in all monkeys tested. Intravenous administration of Co 8-7071 (1–10 mg/kg, 5-min presession)
resulted in a dose-dependent increase to >80% pentobarbital-appropriate responding in two of three monkeys tested. Following
intragastric infusions of Co 8-7071 (1.0–30 mg/kg), ≥80% pentobarbital-appropriate responding occurred in one out of three
monkeys at 10 mg/kg when administered 60 min before the session. When administered 120 min before the session, however, 10–30
mg/kg Co 8-7071 reproduced the discriminative stimulus effects of pentobarbital in each of the three monkeys tested. Conclusions: These data demonstrate barbiturate-like abuse-related effects that differed between two pregnane steroids. Whereas pregnanolone
functioned as a reinforcer, suggesting that this compound has abuse potential, Co 8-7071 did not, despite having pentobarbital-like
discriminative effects.
Received: 17 November 1998 / Final version: 22 January 1999 相似文献
12.
It was recently documented that the relatively selective dopamine D3 receptor antagonist, PNU-99194A, is capable of establishing discriminative stimulus control in rats and that the discriminative
cue associated with this compound is not similar to that produced by psychostimulants. The present experiment further characterized
the discriminative stimulus properties of PNU-99194A by examining several other dopaminergic agents for stimulus generalization
in 23 male Sprague-Dawley rats trained to discriminate 10 mg/kg PNU-99194A (SC, 15 min) from vehicle in a two-choice discrimination
procedure under an FR10 schedule of food reinforcement. Rats achieved a criterion of ten consecutive sessions with correct
lever choice after a median of 35.5 sessions (range 23–78). In substitution tests, the non-selective D2 receptor antagonist, halo- peridol (0.01– 0.1 mg/kg), and the mixed D2/D3 antagonists, amisulpiride (3.2–32 mg/kg) and sulpiride (32–200 mg/kg), failed to produce stimulus generalization, while the
D3-preferring antagonists, (–)-DS121 (1–10 mg/kg) and (+)-AJ76 (3.2–32 mg/kg), produced complete stimulus generalization. Direct
and indirect DA agonists, including apomorphine (0.01–0.32 mg/kg) and d-amphetamine (0.1–1 mg/kg), the D1 agonist SKF-38393 (10–100 mg/kg), the D2 selective agonist PNU-95666E (0.32–3.2 mg/kg) and the D3-preferring agonist pramipexole (0.032–1 mg/kg), all produced non-significant amounts of drug-appropriate responding and significantly
reduced response rate. It is concluded that PNU-99194A produces a distinctive subjective cue which is probably based on D3 receptor antagonism.
Received: 3 September 1997 / Final version: 21 January 1998 相似文献
13.
Milton V. Marshall K. Dee Carey Daniel D. Von Hoff John G. Kuhn 《Investigational new drugs》1995,13(1):33-36
Summary The alkylating agent Hepsulfam (Sulfamic acid 1,7-heptanediyl ester, NSC 329680) was developed as a more hydrophilic analog
of busulfan. The objective of this study was to determine partitioning of hepsulfam between blood, plasma, and cerebrospinal
fluid (CSF) in two female baboons following intravenous administration. Hepsulfam was administered at 11 mg/kg, and blood
and CSF levels were determined by gas chromatography with electron capture detection. Blood levels were fairly constant btween
animals (17–25 and 20–23 μg/ml) for six hours after administration, following peak levels of 43 and 33 μg/ml, respectively,
for the two animals. Peak plasma levels of 35 and 36 μg/ml were achieved, and initial plasma half-lives in babbons were similar
to those seen in other species, with at1/2 α of 1 h. The plasma terminal half life of 0.2 h, estimated from limited sampling times, was shorter in baboons than in mice,
dogs, or humans. Baboon CSF levels decreased from 1.7 to 0.3 μg/ml during 6h post infusion, and peak concentrations in CSF
lagged behind plasma levels. CSF/plasma ratios ranged from 0.33 to 0.62 in one animal, whereas ratios of 0.2–0.25 were maintained
in the other animal during the same period. Results from this study indicate hepsulfam will enter the CSF following intravenous
administration, and the CSF/plasma ratios are lower than those obtained following oral busulfan administration. 相似文献
14.
The psychopharmacological responses to separate and combined stimulation of dopamine D1 and D2 receptors were examined in
neonatal (postnatal day 3–4, P3–4), infant (P10–11) and weanling (P21–22) rat pups. Thirty minutes prior to testing rat pups
received a subcutaneous (SC) injection of saline, 1.0 (P3–4, P10–11) or 0.5 (P21–22) mg/kg of the D2 agonist quinpirole. Fifteen
minutes later all animals received an additional SC injection of 0, 0.01, 0.1, 1.0 or 10.0 mg/kg of the D1 agonist SKF-38393.
Pups were tested for 5 min via a time-sampling procedure in a humidity controlled incubator for 3- and 10-day-old animals
and in a divided glass aquarium for 21-day-old pups. Although administration of either agonist alone induced increases in
forward locomotion and/or sniffing behavior at all test ages, the adult-typical grooming response to SKF-38393 and increase
in vertical movements in response to quinpirole were not evident until weaning. Similarly, although combined administration
of the agonists induced synergistic responding at each test age, only weanlings exhibited an adult-typical synergistic increase
in licking. Thus, although the D1 and D2 receptor subtypes appear to be functionally present and coupled in some fashion throughout
the neonatal to weanling age period, ontogenetic differences are evident in the behavioral responses elicited by separate
and combined stimulation of these receptor subtypes. 相似文献
15.
Dennis K. Miller Lance R. McMahon Thomas A. Green Jack R. Nation P. J. Wellman 《Psychopharmacology》1998,140(1):52-56
Systemic injection of the sympathomimetic agent ephedrine (EPH) stimulates locomotion in drug-naive rats, an effect that
may be dependent on the enantiomer of EPH employed [(–)-EPH or (+)-EPH]. The present experiments examined the effects of repeated
EPH exposure on locomotion in rats to assess whether these treatments result in drug tolerance or sensitization. In experiment
1, adult male rats were injected once daily with 0, 10, 20, or 40 mg/kg (–)-EPH (IP) on each of 11 days. Locomotor activity
was assessed for 60 min after drug injection. Acute exposure to (–)-EPH treatment increased locomotion for animals receiving
20 or 40 mg/kg, and this effect was augmented after 11 days of drug administration. A vehicle-only injection was given to
all animals on day 12 to determine the influence of environmental cues on sensitization. On day 13, all rats were injected
with 10 mg/kg cocaine HCl to assess whether repeated (–)-EPH exposure produced a cross-sensitization to cocaine (10 mg/kg,
IP). Only rats treated repeatedly with 40 mg/kg (–)-EPH exhibited increases in cocaine-stimulated locomotion relative to saline-treated
rats. In experiment 2, repeated exposure to (+)-EPH, 40 mg/kg, but not 20 mg/kg, increased activity and demonstrated the development
of sensitization. Cross-sensitization to cocaine (10 mg/kg, IP) was not evident following treatment with either concentration
of (+)-EPH. There was no evidence that contextual events alone played a role in the effects observed here.
Received: 25 November 1997 / Final version: 14 March 1998 相似文献
16.
Fluoxetine (FLU) increases brain concentrations of serotonin by blocking its uptake, without appreciably affecting the dopamine
or norepinephrine systems. The present experiments provide evidence that a subcutaneous injection of FLU enhanced post-memory
processing (“consolidation”) and retrieval, but not acquisition in young adult mice. FLU (15 mg/kg) enhanced 1-week memory
retention when injected 2 min post-training. Similar enhancement was obtained with intracerebroventricular injection (20 μg
per mouse). FLU enhanced retention when administered prior to training (1–5 mg/kg). FLU (2.5 mg/kg) enhanced recall scores
when injected 1 h before the 1-week retention test, indicating an enhancing effect on memory retrieval. Neither the pre-training
nor pre-testing effects depended on improved acquisition, since FLU did not improve acquisition of T-maze foot-shock avoidance
over the dose range 0.5–35 mg/kg. The sensitive period for post-training enhancement by FLU (15 mg/kg) was less than 90 min,
as shown by the temporal gradient typical of memory-enhancing drugs. The amnesia induced by a protein synthesis inhibitor
anisomycin, or by an anticholinergic drug scopolamine, was blocked by FLU (15 mg/kg) injected post-training. Finally, FLU
(15 mg/kg) injected after one-trial passive avoidance training enhanced 1-week retention, demonstrating effectiveness in this
task as well as in the active avoidance task. 相似文献
17.
Gladys Corley 《Pharmacology, biochemistry, and behavior》2009,92(3):503-507
Acetaminophen (APAP) produces antinociception and hypothermia. Because the antinociceptive effect in rats is partially dependent on opioid and cannabinoid CB1 receptor activation, we determined if activation of these receptors also contributes to the hypothermic effect of APAP. Rats injected with APAP (100, 250, 375 or 500 mg/kg, i.p.) displayed dose-related hypothermia. For combined administration, the hypothermic effect of APAP (400 mg/kg, i.p.) was not altered by pretreatment with: naltrexone (10 mg/kg, s.c.), a non-selective opioid antagonist; naltrindole (1 mg/kg, s.c.), a delta opioid antagonist; nor-binaltorphimine (10 mg/kg, i.p.), a kappa opioid antagonist; SR 141716A (3 mg/kg, i.m.), a cannabinoid CB1 receptor antagonist; or JTC-801(1 mg/kg, i.p.), a nociceptin/orphanin FQ peptide (NOP) receptor antagonist. The demonstration that APAP produces hypothermia independent of opioid, cannabinoid CB1 or NOP receptor activation is contrary to its antinociceptive effect, which requires opioid and cannabinoid CB1 receptor activation. 相似文献
18.
Manipulations of GABA function have been found to produce highly variable effects in animal models of anxiety. In the present
series, an ethological version of the murine elevated plus-maze was used to examine in detail the behavioural profiles of
diazepam (1.5 mg/kg; positive control) and a range of GABA-related compounds: valproic acid (100–400 mg/kg), No-711 (1.25–10.0 mg/kg),
muscimol (0.5–3.0 mg/ kg), (+)bicuculline (4.0–8.0 mg/kg), picrotoxin (0.25– 2.0 mg/kg), R(+)baclofen (0.375–3.0 mg/kg) and CGP 35348 (25–200 mg/kg). On both conventional and ethological indices, results confirmed
the anxiolytic profile of diazepam under present test conditions, and revealed substantially similar effects for the GABA-T
inhibitor, valproic acid (100–400 mg/kg), and the GABAA receptor agonist, muscimol (2 mg/kg). The GABA reuptake inhibitor, No-711, produced weak anxiolytic-like effects at low doses
(1.25–2.5 mg/kg) but disrupted behaviour at the highest dose tested (10 mg/ kg). Although the GABAA receptor antagonists, (+)bicuculline and picrotoxin, produced changes indicative of anxiety enhancement, concomitant behavioural
suppression was evident at high doses (8 mg/kg and 1–2 mg/kg, respectively). Further studies suggested that the effects observed
with bicuculline may be mediated by an active metabolite, such as bicucine. In contrast to the effects of valproic acid and
direct GABAA receptor manipulations, the GABAB receptor agonist, R(+) baclofen, non-specifically disrupted behaviour at the highest dose tested (3 mg/kg) while the GABAB receptor antagonist, CGP 35348, was inactive over the dose range studied. Although present data confirm the sensitivity of
the plus-maze to agents which modify GABAA receptor function, further studies will be required in order more fully to characterize this relationship.
Received: 8 March 1996/Final version: 28 July 1996 相似文献
19.
Xiao-yan Sheng Yan Liang Xue-yuan Yang Li-e Li Xia Ye Xia Zhao Yi-min Cui 《European journal of clinical pharmacology》2020,76(3):383-391
The aim of the present study was to evaluate the safety, pharmacokinetic (PK) and pharmacodynamic (PD) properties of remimazolam besylate following single ascending dose (SAD) and continuous infusion in healthy Chinese volunteers. This was a randomized phase I study conducted in two parts. Part I was a double-blind, placebo- and midazolam-controlled, SAD study among healthy Chinese participants with a remimazolam dose of 0.025–0.4 mg/kg. Part II was an open-label, midazolam-controlled, continuous infusion study. Bispectral index (BIS) monitoring and Modified Observers Assessment of Alertness and Sedation (MOAA/S) score assessment were used to assess the PD properties. The half-life range of remimazolam was from 34.1 ± 8.1 to 59.8 ± 20.5 min in the SAD study. The sedation function was initially observed at the dose of 0.05 mg/kg remimazolam. Doses of ≥ 0.075 mg/kg exerted a peak sedation effect within 1–2 min after injection, resulting in a deeper and more rapid sedation. In the 2 h continuous infusion, remimazolam showed a deeper sedation and more rapid recovery than midazolam. For general anesthesia, an induction dosage of 0.2 mg/kg/min and a maintenance dosage of 1 mg/kg/h can achieve a satisfactory efficacy effect. Remimazolam was safe and well tolerated in healthy Chinese participants. Based on the phase I clinical study, we suggest that remimazolam besylate demonstrates greater sedation and quicker recovery from sedation than midazolam. 相似文献
20.
Rationale The effect of manipulation of the serotonin (5-HT) system on conditioned gaping (presumably reflective of nausea in rats)
was evaluated.
Objective The potential of the selective serotonin reuptake inhibitor (SSRI), fluoxetine (which produces nausea in the clinic), to produce
conditioned gaping in rats and of the 5-HT3 antagonists (ondansetron and palonosetron) and the 5-HT1A autoreceptor agonist (8-OH-DPAT) to reverse this effect were evaluated.
Materials and methods In each of four experiments, rats received three pairings of intraorally delivered 17% sucrose solution and fluoxetine (0,
2, 10 or 20 mg/kg) and 72 h later were given a drug-free test trial. In experiment 2, rats were pretreated with the 5-HT3 antagonists, ondansetron (0, 0.1 or 1.0 mg/kg) or the longer acting palonosetron (0.1 mg/kg), 30 min before each of three
sucrose–fluoxetine (20 mg/kg) pairings. In experiment 3, rats were injected with palonosetron (0.1 mg/kg) 2 h before each
of three sucrose–fluoxetine (20 mg/kg) or sucrose–lithium chloride (LiCl, 25 mg/kg) pairings. In experiment 4, rats were pretreated
with the 5-HT1A autoreceptor agonist, 8-OH-DPAT (DPAT, 0.1 mg/kg) 30 min before each of three sucrose–fluoxetine (20 mg/kg) pairings.
Results After two sucrose–fluoxetine pairings, the highest dose of fluoxetine tested (20 mg/kg) produced conditioned gaping reactions.
These conditioned gaping reactions were prevented by pretreatment with DPAT, but not with the 5-HT3 antagonists. On the other hand, palonosetron administered 2 h prior to sucrose–LiCl pairings attenuated conditioned gaping
reactions.
Conclusions These results suggest that the conditioned nausea produced by SSRIs, but not LiCl, may be resistant to treatment with 5-HT3 antagonists, but not 5-HT1A autoreceptor agonists. 相似文献