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1.
Jo A. Talledo Ashley N. Sutherland Owens Tijmen Schortinghuis Neal R. Swerdlow 《Psychopharmacology》2009,204(1):165-175
Background Dopamine agonists disrupt prepulse inhibition (PPI) of startle in male rodents. In humans, this is observed only in some studies.
We reported that PPI was disrupted by d-amphetamine in men, but only among those with high basal PPI levels. Here, amphetamine effects on PPI were tested in normal
women and female rats.
Materials and methods Acoustic startle and PPI were tested in normal women after placebo or 20 mg amphetamine, in a double-blind, crossover design,
and in female rats after vehicle or 4.5 mg/kg amphetamine. Rats were from Sprague–Dawley (SD) and Long Evans (LE) strains
that differ significantly in gene expression in PPI-regulatory circuitry, including levels of nucleus accumbens (NAC) catechol-O-methyl transferase (COMT) mRNA.
Results Amphetamine was bioactive in humans based on quantitative autonomic and self-rating measures, but did not significantly change
startle magnitude or PPI across all subjects. Amphetamine’s effects on PPI in women correlated significantly (p < 0.0008) with placebo PPI levels (reducing PPI only in women whose basal PPI levels exceeded the sample median) and with
measures of novelty and sensation seeking. Amphetamine decreased PPI in SD rats that have relatively low NAC COMT gene expression
and increased PPI in LE rats that have relatively high NAC COMT gene expression.
Conclusion The dopaminergic regulation of PPI in humans is related to basal levels of sensorimotor gating and to specific personality
traits in normal men and women. In rats, the effects of amphetamine on PPI differ significantly in strains with low vs. high
NAC COMT expression. 相似文献
2.
Swerdlow NR Stephany N Shoemaker JM Ross L Wasserman LC Talledo J Auerbach PP 《Psychopharmacology》2002,164(1):82-92
Abstract
Background. We recently reported that prepulse inhibition (PPI) in humans was increased by the dopamine (DA) agonist/N-methyl-D-aspartate (NMDA) antagonist amantadine (200 mg), but was not significantly altered by the DA agonist bromocriptine (1.25–2.5 mg).
PPI-enhancing effects of DA agonists occur in rats under specific stimulus conditions, including short prepulse intervals
(<30 ms). We characterized the effects of amantadine and bromocriptine on PPI across species, assessing: (1) dose–response
effects on PPI in rats over 10- to 120-ms prepulse intervals; (2) drug effects on PPI in humans, using this same range of
prepulse intervals; and (3) drug effects on measures related to PPI, including PPI of perceived stimulus intensity (PPIPSI),
and startle habituation.
Methods. Drug effects on PPI were assessed in male Sprague Dawley rats (n=90) and humans (n=49); startle habituation and PPIPSI were also studied in humans.
Results. Amantadine and bromocriptine exhibited dose- and stimulus-dependent effects on PPI in rats, increasing PPI with short (10–20 ms)
prepulse intervals, and decreasing PPI with long (60–120 ms) prepulse intervals. In humans, amantadine increased PPI with
both short (20 ms) and long (120 ms) prepulse intervals. Bromocriptine had no significant effect on PPI in humans, but tended
to increase PPI at short (20 ms) intervals. Amantadine eliminated PPIPSI.
Conclusions. Amantadine modifies prepulse effects on startle in rats and humans, and disrupts prepulse effects on perceived stimulus intensity
in humans; bromocriptine has clear effects on PPI in rats, but not in humans. The divergent effects of amantadine on sensorimotor
and sensory effects of prepulses may reflect a divergence of brain circuitry regulating these processes.
Electronic Publication 相似文献
3.
Martin Weber John P. Durbin Robert R. Luedtke Neal R. Swerdlow 《Pharmacology, biochemistry, and behavior》2009,93(2):141-147
Prepulse inhibition of startle (PPI) is an operational measure of sensorimotor gating that is impaired in schizophrenia. Treatment with mixed dopamine D2/D3 antagonists diminishes schizophrenia symptoms, and opposes dopamine agonist-induced PPI deficits in rats. There are reasons to believe that functional D3 receptor antagonists might offer more favorable therapeutic profiles compared to current antipsychotics. However, D3-related drug discovery is hampered by the absence of assays sensitive to D3-mediated (antipsychotic) properties in vivo. Here, we characterized two putative D3-active compounds - WC10 and WC44 - in a PPI-based screening assay, comparing the sensitivity of test compounds to oppose PPI deficits induced by the mixed D1/D2-like agonist apomorphine vs. the preferential D3 agonist pramipexole in rats. WC10, WC44 (0, 1, 3, 10 mg/kg, each), and the preferential D2 antagonist L741,626 (0, 1 mg/kg) were studied, in combination with apomorphine (0, 0.5 mg/kg), or pramipexole (0, 1 mg/kg). L741,626 prevented apomorphine-, but not pramipexole-induced PPI deficits. WC10, but not WC44, prevented apomorphine-induced PPI deficits; both compounds opposed pramipexole-induced PPI deficits, suggesting functional D3 and D1/D2 antagonist profiles for WC10, and functional D3 receptor antagonism for WC44. This assay may be valuable for detecting predominantly D3 vs. D2 receptor-linked mechanisms of action in vivo. 相似文献
4.
Qu Y Swerdlow NR Weber M Stouffer D Parsons LH 《Pharmacology, biochemistry, and behavior》2008,90(4):686-690
Startle is inhibited when the startling stimulus is preceded 30–300 ms by a weak prepulse. Prepulse inhibition (PPI), an operational measure of sensorimotor gating, is deficient in schizophrenia patients, and reduced in rats and humans by dopamine agonists. The neural basis for the PPI-disruptive effects of dopamine agonists in rats is studied to understand neural circuitry regulating PPI and its deficits in schizophrenia. Existing data suggest that ventral pallidal (VP) GABAergic transmission regulates PPI and its disruption by dopamine agonists. We measured changes in VP GABA efflux and PPI in rats in response to the D2/D3 agonist, quinelorane. Wistar rats were administered quinelorane (vehicle, 0.003 or 0.01 mg/kg). In some rats, VP dialysate was analyzed for GABA content. In others, PPI was assessed using 120 dB(A) startle pulses and prepulses 10 dB over a 70 dB(A) background. Quinelorane reduced GABA efflux, with significant effects for 0.01 but not 0.003 mg/kg, persisting for at least 100 min. Quinelorane reduced PPI for 50 min, an effect significant for both the 0.003 (p < 0.05) and 0.01 mg/kg doses (p < 0.015). Differences in time course and dose sensitivity of quinelorane effects on VP GABA efflux and PPI are discussed. 相似文献
5.
Koffarnus MN Greedy B Husbands SM Grundt P Newman AH Woods JH 《Psychopharmacology》2009,203(2):317-327
Rationale Previous research has found the stimulus effects of dopamine D2- and D3-preferring agonists difficult to distinguish in drug
discrimination studies. Antagonism studies suggest that the stimulus effects of both types of agonists may be mediated primarily
through D2 receptors.
Objectives The current study was designed to further assess the receptors mediating the stimulus effects of these agonists and to attempt
to train rats to discriminate directly between D2- and D3-preferring dopamine agonists.
Materials and methods Four groups of eight rats were trained to discriminate either 0.1 mg/kg of the D3-preferring agonist pramipexole from saline,
1.0 mg/kg of the D2-preferring agonist sumanirole from saline, 0.1 mg/kg pramipexole from either saline or 1.0 mg/kg sumanirole,
or 1.0 mg/kg sumanirole from either saline or 0.1 mg/kg pramipexole.
Results Three of eight rats in the 0.1 mg/kg pramipexole vs. 1.0 mg/kg sumanirole or saline failed to meet the training criteria,
and the discrimination in this group was tenuous. The D2-preferring antagonist L-741,626 at 1.0 mg/kg was more effective at
shifting to the right the pramipexole dose-response curve in pramipexole-trained rats, while 32 mg/kg of the selective D3
antagonist PG01037 had little effect. Quinpirole and 7-OH-DPAT fully or partially substituted for both pramipexole and sumanirole
in each group tested, while cocaine did not substitute in any group.
Conclusions Antagonist data along with the pattern of training and substitution data suggested that D2 receptor activation is primarily
responsible for the stimulus effects of both sumanirole and pramipexole with D3 receptor activation playing little or no role. 相似文献
6.
《Pharmacology, biochemistry, and behavior》2009,91(4):686-690
Startle is inhibited when the startling stimulus is preceded 30–300 ms by a weak prepulse. Prepulse inhibition (PPI), an operational measure of sensorimotor gating, is deficient in schizophrenia patients, and reduced in rats and humans by dopamine agonists. The neural basis for the PPI-disruptive effects of dopamine agonists in rats is studied to understand neural circuitry regulating PPI and its deficits in schizophrenia. Existing data suggest that ventral pallidal (VP) GABAergic transmission regulates PPI and its disruption by dopamine agonists. We measured changes in VP GABA efflux and PPI in rats in response to the D2/D3 agonist, quinelorane. Wistar rats were administered quinelorane (vehicle, 0.003 or 0.01 mg/kg). In some rats, VP dialysate was analyzed for GABA content. In others, PPI was assessed using 120 dB(A) startle pulses and prepulses 10 dB over a 70 dB(A) background. Quinelorane reduced GABA efflux, with significant effects for 0.01 but not 0.003 mg/kg, persisting for at least 100 min. Quinelorane reduced PPI for 50 min, an effect significant for both the 0.003 (p < 0.05) and 0.01 mg/kg doses (p < 0.015). Differences in time course and dose sensitivity of quinelorane effects on VP GABA efflux and PPI are discussed. 相似文献
7.
Background
Prepulse inhibition of acoustic startle (PPI) is deficient in several heritable brain disorders. In rats, the dopamine agonist, apomorphine (APO), reduces PPI and expression of the early gene, c-fos, within the nucleus accumbens (NAC) core. Both of these effects are greater in Sprague–Dawley (SD) vs. Long Evans (LE) rats, and this PPI strain pattern is inherited. Here, we examined phosphorylation of cyclic-AMP response element-binding protein (CREB), a putative intermediary step between dopamine receptor stimulation and Fos expression, in SD and LE rats. 相似文献8.
Wei-li Chang Michelle R. Breier Niveditha Thangaraj Martin Weber 《Pharmacology, biochemistry, and behavior》2010,95(4):473-478
The preferential dopamine D3 receptor agonist pramipexole (PRA) disrupts prepulse inhibition (PPI) of acoustic startle, an operational measure of sensorimotor gating, in rats. Drug effects on PPI are sensitive to numerous experimental variables; proceeding with in-depth analyses of drug effects without a clear understanding of these variables is inefficient. The present studies characterized the impact on PRA-induced PPI deficits by a range of experimental parameters. As shown previously, PRA reduced both PPI and startle magnitude beginning 5-15 min post-injection; PRA effects on PPI were statistically significant through 35 min post-injection, while those on startle magnitude were still significant 65 min post-injection. PRA-induced PPI deficits were evident under conditions that matched startle magnitude in vehicle and PRA conditions and were independent of PRA-induced changes in prepulse-elicited motor activity. Additionally, PRA-induced PPI deficits did not differ significantly between uni- vs. cross-modal stimuli or between male vs. female rats, with no robust effect of estrous phase in females. These findings demonstrate that PRA effects on PPI are observed across several different experimental conditions and are dissociable from changes in startle magnitude or prepulse-elicited responses. Recommendations are made regarding “optimal” experimental conditions for studying the neurobiology of PRA-induced changes in PPI in rats. 相似文献
9.
Prepulse inhibition (PPI) of acoustic startle and locomotor activity are both widely studied in the preclinical development of dopaminergic agents, including those acting at D3 dopamine receptors. In mice, the dopamine D3 receptor-preferential agonist pramipexole (PPX) alters locomotor activity in a biphasic manner at doses that have no effect on PPI. The present study examined the time-course of PPX effects on locomotion and PPI in rats. In adult male Sprague-Dawley rats, PPX (0, 0.1, 0.3, 1.0 mg/kg) was injected prior to measurement of locomotor activity for 90 min in photobeam chambers. Based on disparate early vs. late effects of PPX on locomotion, the effects of PPX (0 vs. 0.3 mg/kg) on PPI were tested 20 and 80 min after injection. All doses of PPX decreased locomotor activity for 30 min compared to vehicle, and the higher doses stimulated hyperlocomotion later in the session; the late hyperlocomotion, but not the early hypolocomotion, was blocked by the D2-selective antagonist, L741626 (1.0 mg/kg sc). In contrast to its locomotor effects, PPX caused a similar reduction in PPI at 20 and 80 min after administration. These findings suggest both a temporal and pharmacological dissociation between PPX effects on locomotor activity and PPI; these two behavioral measures contribute non-redundant information to the investigation of D3-related behavioral pharmacology. 相似文献
10.
Introduction
This study aims to evaluate the pharmacokinetic, behavioral, and motor effects of a liposomal preparation of hydromorphone hydrochloride (LE-hydro) in rhesus monkeys. We administered either 2 mg/kg of LE-hydro (n = 8) subcutaneous (s.c.) or 0.1 mg/kg of standard pharmaceutical hydromorphone HCl (hydro) preparation either intravenous (i.v.; n = 4) or s.c. (n = 5). 相似文献11.
Robert Wesolowski David Peereboom Patricia Weiss Paul Elson George Thomas Budd 《Investigational new drugs》2010,28(4):502-508
Purpose: This was a phase I study evaluating the dose limiting toxicity (DLT) and the maximum tolerated dose (MTD) of weekly docetaxel,
doxorubicin and daily oral cyclophosphamide with G-CSF support (ConTAC regimen). Patients and Methods: Cohorts of 3–6 patients with advanced breast or other solid malignancies were entered at subsequently higher dose levels
until dose-limiting toxicities (DLT) were noted in 2 or more patients per dose level during the first 6 weeks of therapy.
This study escalated dosages of docetaxel and doxorubicin simultaneously, while the dose of oral cyclophosphamide was fixed
at 60 mg/m2 daily. Results: Sixteen patients were enrolled. Grade 3–4 adverse events during the first 6 weeks of treatment were neutropenia (n = 1 at dose level #1 and n = 3 at dose level #4), anemia (n = 2 at dose levels 1 and 4), and nausea/vomiting (n = 1 at dose level #4). After 6 weeks of therapy, grade 3–4 toxicities included anemia (n = 3), neutropenia (n = 7), Hand-Foot syndrome (n = 2) and grade 3 cystitis and pneumonia (n = 1 at dose level #4). Five patients with advanced breast cancer and 1 patient with metastatic lung cancer responded to the
chemotherapy. Conclusions: Grade 4 neutropenia was the DLT. The MTD, was established at dose level #3 (doxorubicin at 25 mg/m2 and docetaxel at 25 mg/m2 weekly with oral cyclophosphamide dose of 60 mg/m2 daily). Myelosuppression at that dose level was moderate with G-CSF given concurrently. 相似文献
12.
M. Weber M. Breier D. Ko N. Thangaraj D. E. Marzan N. R. Swerdlow 《Psychopharmacology》2009,203(4):723-735
Rationale Prepulse inhibition (PPI) is an operational measure of sensorimotor gating that is deficient in schizophrenia patients. In
rats, PPI deficits induced by dopamine (DA) agonists are reversed by antipsychotics. Inhibition of the striatum-rich phosphodiesterase
(PDE)10A may represent a novel antipsychotic mechanism. Previous studies were controversial, showing antipsychotic-like profiles
in measures of PPI for the preferential PDE10A inhibitor papaverine (PAP) but not the novel PDE10A inhibitor TP-10.
Objective The aim of the study was to evaluate the antipsychotic profile of PAP in rats using PPI.
Materials and methods PPI deficits were induced in rats by apomorphine (APO; 0.1, 0.5 mg/kg) or d-amphetamine (AMPH; 4 mg/kg). PAP (3, 10, 30 mg/kg) or haloperidol (HAL; 0.1 mg/kg) was tested against these agonists in Sprague–Dawley
(SD) or Wistar (WI) rats. Prepulse intervals ranged from 10 to 120 ms. Further tests evaluated the effects of PAP on spontaneous
locomotion, AMPH (1 mg/kg)-induced hyperlocomotion, and core body temperature (T°).
Results HAL reversed APO-induced PPI deficits but PAP failed to reverse APO- and AMPH-induced PPI deficits at all doses, strains,
pretreatment times, and prepulse intervals. PAP (30 mg/kg) significantly reduced AMPH hyperlocomotion in SD rats, and a similar
pattern was detected in WI rats. This PAP dose also strongly reduced spontaneous locomotion and T° in SD rats.
Conclusion Our study does not support an antipsychotic-like profile of PAP in dopaminergic PPI models. 相似文献
13.
Goryachkina K Burbello A Boldueva S Babak S Bergman U Bertilsson L 《European journal of clinical pharmacology》2008,64(12):1163-1173
14.
Franklin M. Chu Joel Picus Paula M. Fracasso Robert Dreicer Zhihui Lang Brenda Foster 《Investigational new drugs》2011,29(4):674-679
Purpose We evaluated the safety and efficacy of intetumumab in combination with docetaxel in patients with castrate-resistant metastatic
prostate cancer. Patients and methods In this phase 1, open-label, multicenter, nonrandomized study, 75 mg/m2 docetaxel was administered on Day 1 of each of nine 21-day treatment cycles and intetumumab 5 or 10 mg/kg was administered
on Days 1, 8, and 15 of Cycles 2 and 3 and on Day 1 of all subsequent cycles. The primary endpoint was the incidence of dose-limiting
toxicities (DLTs) during Cycles 2 and 3. Secondary endpoints included serum prostate-specific antigen (PSA) response and objective
response based on Response Evaluation Criteria in Solid Tumors (RECIST). Results Ten patients were treated (5 mg/kg n = 3, 10 mg/kg n = 7). No DLTs occurred. Most treatment-emergent adverse events (TEAEs) occurred in the 10-mg/kg intetumumab group. Common
TEAEs were neutropenia (10 mg/kg n = 6) and nausea (5 mg/kg n = 1, 10 mg/kg n = 5). Four 10-mg/kg-treated patients reported serious TEAEs; of these, only febrile neutropenia was considered probably intetumumab-related.
In the 10-mg/kg group, four patients had a serum PSA response (two of whom responded within 3 months of treatment), one patient
demonstrated partial tumor response for 11 weeks, and none had progressive disease at Cycle 9. No PSA or tumor response was
observed in the 5-mg/kg group. Conclusions Intetumumab was generally safe and well tolerated in combination with docetaxel, with a higher incidence of TEAEs in the
10 mg/kg dose cohort. The efficacy of 10 mg/kg intetumumab in combination with docetaxel appears to warrant further study. 相似文献
15.
Schneider HJ Husser O Rihm M Fredersdorf S Birner C Dhein S Muders F Jeron A Goegelein H Riegger GA Luchner A 《Naunyn-Schmiedeberg's archives of pharmacology》2009,379(3):225-232
Congestive heart failure (CHF) is often associated with atrial fibrillation. The safety of many antiarrhythmic drugs in CHF
is limited by proarrhythmic effects. We aimed to assess the safety of a novel atrial-selective K+-channel blocker AVE0118 in CHF compared to a selective (dofetilide) and a non-selective IKr blocker (terfenadine). For the
induction of CHF, rabbits (n = 12) underwent rapid right ventricular pacing (330–380 bpm for 30 days). AVE0118 (1 mg/kg) dofetilide (0.02 mg/kg) and terfenadine
(2 mg/kg) were administered in baseline (BL) and CHF. A six-lead ECG was continuously recorded digitally for 30 min after
each drug administration. At BL, dofetilide and terfenadine significantly prolonged QTc interval (218 ± 30 ms vs 155 ± 8 ms,
p = 0.001 and 178 ± 23 ms vs. 153 ± 12 ms, p = 0.01, respectively) while QTc intervals were constant after administration of AVE0118 (p = n.s.). In CHF, dofetilide and terfenadine caused torsades de pointes and symptomatic bradycardia, respectively, and prolonged
QTc interval (178 ± 30 ms vs. 153 ± 14 ms, p = 0.02 and 157 ± 7 ms vs. 147 ± 10 ms, p = 0.02, respectively) even at reduced dosages, whereas no QTc-prolongation or arrhythmia was observed after full-dose administration
of AVE0118. In conclusion, atrial-selective K+-channel blockade by AVE0118 appears safe in experimental CHF.
H.-J. Schneider and O. Husser contributed equally. 相似文献
16.
《European neuropsychopharmacology》2010,20(6):421-425
Dopamine agonists reduce prepulse inhibition (PPI) of startle in rats. While it is used to predict antipsychotic efficacy, the specific receptor subtypes mediating this effect of dopamine agonists remain unclear. We characterized the effects of sumanirole, a highly selective D2 agonist, on PPI in rats. Sumanirole decreased PPI at 60–120 ms prepulse intervals, and increased PPI at 10–20 ms intervals. PPI deficits were antagonized by low doses of the preferential D2 antagonist L741626, supporting a D2 mechanism of action. Sumanirole is a valuable tool for parsing the role of dopamine receptor subtypes in the regulation of PPI. 相似文献
17.
Hendset M Hermann M Lunde H Refsum H Molden E 《European journal of clinical pharmacology》2007,63(12):1147-1151
Objective Aripiprazole is an atypical antipsychotic drug which is metabolized by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6).
The aim of the present study was to investigate the impact of the CYP2D6 genotype on serum concentrations of aripiprazole (ARI) and to determine the sum of ARI and the active metabolite dehydroaripiprazole
(DARI) in psychiatric patients.
Methods Data on steady-state serum concentrations and the CYP2D6 genotypes of patients treated with ARI were extracted from a routine therapeutic drug monitoring database. The 62 patients
included in the analysis were stratified into the following subgroups according to CYP2D6 genotype: *1/*1 (homozygous extensive metabolizers, EMs; n = 37), *1/*3–6 (heterozygous extensive metabolizers, HEMs; n = 17) and *3–6/*3–6 (poor metabolizers, PMs; n = 8). Dose-adjusted serum concentrations (C/D ratios) of ARI and ARI + DARI were compared between the subgroups.
Results The median serum concentration of ARI was 1.7-fold higher in PMs than in EMs (45.5 vs. 26.3 nM/mg, p < 0.01). The observed serum concentration of the active sum of ARI + DARI was 1.5-fold higher in PMs than in EMs (53.9 vs.
37.0 nM/mg, p < 0.05). Numerical differences in serum concentrations between HEMs and EMs were less pronounced, but statistically significant
for both ARI (p < 0.05) and ARI + DARI (p < 0.05).
Conclusion The present study demonstrates that serum concentrations of both ARI and the active sum of ARI + DARI in psychiatric patients
were significantly affected by CYP2D6 genotype. The observed differences in median C/D ratios indicate that PMs typically need 30–40% lower doses to achieve a
similar steady-state serum concentration as EMs. 相似文献
18.
Donald A. Richards David Loesch Svetislava J. Vukelja Hillary Wu William J. Hyman Jeffery Nieves Yunfei Wang Simin Hu Oluwatoyin O. Shonukan Datchen F. Tai 《Investigational new drugs》2011,29(5):963-970
Purpose: Pemetrexed and pegylated liposomal doxorubicin (PLD) are clinically active as single agents and preclinically synergistic.
This phase I, open-label trial evaluated the maximum tolerated dose (MTD) and safety of pemetrexed followed by PLD in patients
with breast or gynecologic cancers. Patients: Using 3 + 3 dose escalation, cohorts of 3–9 patients received escalating doses of pemetrexed 400–500 mg/m2 on days 1 and 15 and PLD 30–45 mg/m2 on day 1 of a 28-day cycle. All patients received folic acid and vitamin B12 until 21 days after last pemetrexed dose. Patients continued until dose-limiting toxicity (DLT) or progression (PD). Results: From 11/05 to 2/08, 29 patients entered treatment; median age: 60.6 years (range, 47.5–80.1); ECOG PS 0/1: 27.6%/72.4%;
primary disease site: ovarian (55.2%), breast (34.5%), peritoneum (10.3%); prior therapies: chemotherapy (100.0%), surgery
(72.4%), hormones/biologics (35%), and radiation (20.7%). Pemetrexed/PLD dose levels: L1 = 400/30 (n = 4), L2 = 400/35 (n = 6), L3 = 500/35 (n = 9), L4 = 500/40 (n = 7), and L5 = 500/45 (n = 3). Treatment-related grade 3-4 toxicities: hematologic—neutropenia (86.2%), leukopenia (58.6%), thrombocytopenia (48.3%),
anemia (41.4%); nonhematologic—mucosal inflammation (24.1%), febrile neutropenia (24.1%), hand-foot syndrome (13.8%), hypokalaemia
(10.3%). Reasons for discontinuation: PD (48.3%), toxicity (27.6%), patient request (13.8%), and investigator request (10.3%).
Efficacy: 5 ovarian patients (20.8%) achieved partial response; median time to progression (TTP) was 6.1 months (range, 1.2–12.5).
Conclusion: Pemetrexed plus PLD was reasonably tolerated in this heavily–pretreated population. MTD: pemetrexed 500 mg/m2 and PLD 40 mg/m2 may be carried forward to phase II studies in specific patient populations. TTP in platinum-refractory ovarian patients was
greater than expected. 相似文献
19.
The effects of dopamine agonists on prepulse inhibition in healthy men depend on baseline PPI values
Rationale and objectives Dopamine (DA) agonists reliably disrupt prepulse inhibition (PPI) of the startle reflex in animals but less so in humans despite
cross-species similarities in the neural regulation of PPI. This study examines whether individual variation in baseline PPI
may account for the inconsistencies in DA agonist-induced PPI disruption in humans.
Methods Baseline PPI measures were obtained from 32 healthy adult men. Subjects were subsequently tested in three sessions after ingestion
of placebo or active drug in a balanced double-blind design. Seventeen subjects were given 0.05 and 0.1 mg of pergolide (a
direct DA agonist) and 15 subjects were given 100 and 200 mg of amantadine (an indirect DA agonist). In each treatment group,
subjects were assigned to “high” and “low” PPI subgroups based on the median split of their baseline PPI.
Results Amantadine and pergolide disrupted PPI in high- but not in low-PPI subjects. In contrast, low-PPI subjects showed a trend
towards PPI facilitation especially with pergolide.
Conclusions Our results suggest that baseline PPI is an important determinant of the effect of DA agonists on PPI. 相似文献
20.
M. Vevelstad S. Pettersen C. Tallaksen O. Brørs 《European journal of clinical pharmacology》2009,65(8):795-801
Purpose Codeine/paracetamol (C/P) and levomepromazine (L) are frequently co-administered for the treatment of acute back pain, but
the efficacy/effectiveness of this combination drug therapy has not been evaluated. The demethylation of codeine to morphine
is catalyzed by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6), of which levomepromazine (methotrimeprazine) is a known
inhibitor. The aim of this study was to investigate whether low-dose levomepromazine inhibits the formation of morphine from
codeine in a patient population of homozygous extensive (EM) and heterozygous extensive (HEM) metabolizers of CYP2D6.
Methods Our patient cohort consisted of 29 patients hospitalized for acute back pain who were randomized to a 24-h treatment with
either C/P (60 mg codeine + 1000 mg paracetamol) four times daily or to L+C/P (levomepromazine 5 + 5 + 5 + 10 mg + C/P) four
times daily. After zero-urine sampling (baseline), the treatment was started and urine collected for 24 h. Blood samples were
later genotyped for the CYP2D6*3, *4, and *6 polymorphisms by the PCR (LightCycler system) and for the *5 polymorphism using
long PCR, to identify EM and HEM and to eliminate CYP2D6 poor metabolizers. Urine samples were analyzed using the CEDIA immunoassay
and gas chromatography–mass spectrometry after enzymatic hydrolysis of glucuronide conjugates. O-demethylation ratios of codeine
were calculated as hydrolyzed (total) concentrations of morphine/morphine + codeine.
Results Twenty-two of the patients fulfilled the inclusion criteria, of whom ten were EM (five C/P and five L+C/P) and twelve were
HEM (six C/P and six L+C/P) for functional CYP2D6 alleles. In the EM group, the median O-demethylation ratio was significantly
higher (P = 0.016, Mann–Whitney test) after the C/P treatment (0.092, range 0.041–0.096) than after the L+C/P treatment (0.031, range
0.009–0.042). However, there was no significant difference between these two treatments in either the HEM group [n = 12; 0.024 (range 0.011–0.042) vs. 0.026 (range 0.009–0.041), respectively; P = 1.00] or in the combined EM/HEM group [11 C/P + 11 L+C/P; 0.041 (range 0.011–0.096) vs. 0.030 (range 0.009–0.042), respectively;
P = 0.122].
Conclusions Our study revealed significant inhibition in the O-demethylation of codeine to morphine in homozygous EM of CYP2D6 treated
with low-dose levomepromazine and codeine/paracetamol, compared to treatment with codeine/paracetamol only. No significant
difference could be detected in HEM or in the mixed and heterogenous group of EM/HEM. In patients prescribed this drug combination,
the amount of morphine generated by the O-demethylation of codeine may be insufficient for effective pain relief. The therapeutic
effect of codeine in the treatment of acute back pain should be assessed with and without levomepromazine. 相似文献