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1.
Branched chain amino acids decrease tardive dyskinesia symptoms 总被引:1,自引:0,他引:1
M. A. Richardson Margaret L. Bevans Josephine B. Weber Janet J. Gonzalez Cheryl J. Flynn Leora Amira Laura L. Read Raymond F. Suckow Timothy J. Maher 《Psychopharmacology》1999,143(4):358-364
Rationale: Prior studies had suggested (a) that a lessened ability to clear ingested forms of the large neutral amino acid (LNAA),
phenylalanine (Phe), was associated with having tardive dyskinesia (TD), and (b) that greater availability of a group of LNAA,
the branched chain amino acids (BCAA), concomitant with the lower availability of Phe to the brain are associated with a decrease
in TD symptoms. The present study was then conducted to test whether increasing the daily intake of the BCAA would decrease
the symptoms of TD. Methods: A 2-week trial of a BCAA medical food administered three times a day was conducted in nine men with long neuroleptic treatment
histories. Frequency counts of TD movements were collected by videotape throughout the trial and these tapes were analyzed
in blind random sequence for both patient and time for TD symptom level changes subsequent to completion of the trial. Plasma
levels of the LNAA were also collected throughout the trial. Results: A statistically significant decrease in the level of TD symptoms was observed for the sample. The symptom changes were also
clinically significant in that six of the nine subjects had symptom decreases of at least 58%, with all subjects having a
decrease of at least 38%. BCAA administration increased plasma BCAA concentrations and BCAA/LNAA ratios and decreased plasma
Phe concentrations and the Phe/LNAA ratio. Analyses indicated a strong significant correlation between the percent increase
in the plasma BCAA values at the first administration and the percent improvement in TD over the trial in eight of the nine
subjects. Conclusions: The BCAA show promise as a treatment for TD. The decrease in TD symptoms seen in the trial may have been modulated by the
BCAA treatment-induced increased availability of the BCAA and decreased availability of Phe to the brain.
Received: 13 August 1998/Final version: 14 December 1998 相似文献
2.
The effect of comedication with fluvoxamine on the plasma concentrations of the enantiomers of citalopram and its metabolites
in dextromethorphan/mephenytoin phenotyped patients pretreated with citalopram (CIT) was studied: seven female patients (45.1 ± 13.9
years) suffering from a major depressive episode [ICD-10: F
32.2 (n = 3 patients), F
33.2 (n = 2), F
32.10 (n = 1) or F
32.11 (n = 1)] , who were non-responders to a 3-week treatment with 40 mg/day CIT (From day-21 to day 0) (day 0: MADRS score ≥12),
were comedicated for another 3 weeks with fluvoxamine (50 mg/day from day 1–7, 100 mg/day from day 14–21). All patients were
extensive metabolizers of mephenytoin (CYP2C19) and dextromethorphan (CYP2D6), except one patient, who had a genetic deficiency
of CYP2D6. There was a significant increase of the plasma concentrations of S- and R-citalopram from day 0 (27 ± 14 μg/l and 55 ± 23 μg/l, respectively) to day 21 (83 ± 38 μg/l and 98 ± 44 μg/l, respectively),
after addition of fluvoxamine (P < 0.02, for each comparison), and the mean ratio S/R-citalopram increased from 0.48 to 0.84. S-Citalopram inhibits more potently 5-HT uptake than R-citalopram: therefore, fluvoxamine increases the pharmacologically more active S-citalopram with some stereoselectivity. According to a previous in vitro study, this pharmacokinetic interaction occurs on
the level of CYP2C19, but also of CYP2D6 and CYP3A4 which, in contrast to CYP1A2, contribute to the N-demethylation of citalopram and which are stereoselectively inhibited by fluvoxamine. All but one patient showed clinical
improvement by a decrease of the MADRS score by at least 50% and a final score ≤13 (mean ± SD: day 0:30.6 ± 9.2; day 21:11.0
± 6.5). Some patients showed minor symptoms, such as nausea and tremor, but the combined treatment was generally well tolerated.
Received: 29 May 1996 /Final version: 2 September 1996 相似文献
3.
Methcathinone (“CAT”) is a CNS stimulant that is a very significant drug of abuse in the former Soviet Union. It has also
appeared on the clandestine market in the United States and has been recently classified as a Schedule I substance. In the
present study, S(−)-methcathinone [S(−)-CAT, 0.50 mg/kg, IP] was employed as the training drug in a two-lever drug discrimination task in rats. Once established,
the S(−)-CAT stimulus was shown to have a rapid onset to action (within 5 min) and a duration of effect of approximately 60–90 min.
In tests of stimulus generalization (substitution), the S(−)-CAT (ED50 = 0.11 mg/kg) stimulus generalized to S(+)-methamphetamine (ED50 = 0.17 mg/kg), S(−)-cathinone (ED50 = 0.19 mg/kg), S(+)-amphetamine (ED50 = 0.23 mg/kg), aminorex (ED50 = 0.27 mg/kg), (±)-CAT (ED50 = 0.25 mg/kg), (±)-cathinone (ED50 = 0.41 mg/kg), R(+)-CAT (ED50 = 0.43 mg/kg), cis-4-methylaminorex (ED50 = 0.49 mg/kg), methylphenidate (ED50 = 0.83 mg/kg), and cocaine (ED50 = 1.47 mg/kg). S(−)-CAT-stimulus generalization did not occur to fenfluramine, a structurally related nonstimulant anorectic. Lastly, haloperidol
(AD50 = 0.18 mg/kg), a dopamine receptor antagonist, potently antagonized the S(−)-CAT stimulus. It is concluded that S(−)-methcathinone is a very potent CNS stimulant, which appears to produce its stimulus effect, at least in part, via a dopaminergic
mechanism.
Received: 4 August 1997/Final version: 27 March 1998 相似文献
4.
Within a 4-h period after parturition, the ewe learns the odor of her lamb that will later allow recognition of her offspring
from an alien lamb. This study investigated the involvement of the cholinergic system in this olfactory learning. At parturition
and 2 h later, ewes received IM injections of saline (C group, n = 21), scopolamine methylbromide (METSCOP group, 100 μg/kg, n = 14) a peripherally acting muscarinic antagonist, a low dose of scopolamine hydrobromide (SCOP32 group, 32 μg/kg, n = 15) or a higher dose of scopolamine hydrobromide (SCOP100 group, 100 μg/kg, n = 18). Maternal behavior was observed at parturition and selective behavior was tested after 4 h of mother-young contact.
No differences in maternal behavior at parturition were found between groups. By contrast, the proportion of ewes showing
selectivity was significantly lower in the SCOP100 group (7/18) than in the METSCOP group (12/14, P = 0.01), SCOP32 group (12/15, P = 0.03), or C group (17/21, P = 0.01). In addition, saline-treated ewes, after having established their selective bond, received 100 μg/kg scopolamine and
were again tested for selectivity 20 min later. Only one out of the 17 tested ewes failed to recognize their lambs after this
treatment. These results indicate that intact central muscarinic transmission of the brain is required for the learning of
individual lamb odor at parturition but not for the recall of this information.
Received: 1 July 1996/Final version: 12 September 1996 相似文献
5.
Phenacetin O-deethylation by human liver microsomes in vitro: inhibition by chemical probes,SSRI antidepressants,nefazodone and venlafaxine 总被引:2,自引:0,他引:2
L. L. von Moltke David J. Greenblatt Su Xiang Duan Jürgen Schmider Leena Kudchadker Steven M. Fogelman Jerold S. Harmatz Richard I. Shader 《Psychopharmacology》1996,128(4):398-407
Biotransformation of phenacetin via O-deethylation to acetaminophen, an index reaction reflecting activity of Cytochrome P450-1A2, was studied in microsomal preparations
from a series of human livers. Acetaminophen formation was consistent with a double Michaelis-Menten system, with low-Km (mean Km1 = 68 μM) and high-Km (mean Km2 = 7691 μM) components. The low-Km enzyme accounted for an average of 96% of estimated intrinsic clearance, and was predicted to contribute more than 50% of
net reaction velocity at phenacetin concentrations less than 2000 μM. Among index inhibitor probes, α-naphthoflavone was a
highly potent inhibitor of the low-Km enzyme (Ki1 = 0.013 μM); furafylline also was a moderately active inhibitor (Ki1 = 4.4 μM), but its inhibiting potency was increased by preincubation with microsomes. Ketoconazole was a relatively weak
inhibitor (Ki1 = 32 μM); quinidine and cimetidine showed minimal inhibiting activity. Among six selective serotonin reuptake inhibitor (SSRI)
antidepressants, fluvoxamine was a potent inhibitor of 1A2 (mean Ki1 = 0.24 μM). The other SSRIs were more than tenfold less potent. Mean Ki1 values were: fluoxetine, 4.4 μM; norfluoxetine, 15.9 μM; sertraline, 8.8 μM; desmethylsertraline, 9.5μM; paroxetine, 5.5 μM.
The antidepressant nefazodone and four of its metabolites (meta-chloro-phenylpiperazine, two hydroxylated derivatives, and a triazoledione) were very weak inhibitors of P450-1A2. Venlafaxine
and its O- and N-desmethyl metabolites showed minimal inhibitory activity.
Received: 18 March 1996/Final version: 10 July 1996 相似文献
6.
Harold J. G. M. van Megen Herman G. M. Westenberg Johan A. den Boer Bernard Slaap Fenny van Es-Radhakishun Atul C. Pande 《Psychopharmacology》1997,129(3):243-248
The effects of the cholecystokinin-B (CCK-B) receptor antagonist CI-988 on symptoms elicited by the cholecystokinin tetrapeptide
(CCK4) were studied in DSM-IIIR patients with panic disorder. The study employed a double-blind, two-period incomplete block design.
Patients (n = 14) received two different dosages of CI-988 (50 mg or 100 mg) or placebo 2 h prior to an IV bolus injection of CCK4 (20 μg) on two separate occasions. The primary efficacy parameter was the total intensity score on the Panic Symptoms Scale
(PSS). Secondary parameters were the number of panic symptoms, time to and occurrence of the first panic symptoms, duration
of symptoms, intensity of apprehension and the percentage of patients who did not have a panic attack. The PSS failed to show
a statistically significant treatment effect on any of these outcome measures. The average panic rate was 50%, 14.3% and 37.5%
after placebo, 50 and 100 mg CI-988, respectively. The differences in panic rate were not statistically significant. The results
of this study suggest that CI-988 in doses up to 100 mg is not effective in reducing symptoms of panic anxiety induced by
CCK4.
Received: 13 May 1996/Final version: 27 September 1996 相似文献
7.
Kazuo Mihara K. Otani Akihito Suzuki Norio Yasui Hajime Nakano Xianmin Meng Tadashi Ohkubo Takako Nagasaki Sunao Kaneko Shigeki Tsuchida Kazunobu Sugawara Frank J. Gonzalez 《Psychopharmacology》1997,133(1):95-98
The relationship between the cytochrome P450 (CYP) 2D6 genotype and the steady-state plasma concentrations (Css) of trazodone
and its active metabolite m-chlorophenylpiperazine (mCPP) was studied in 54 depressed Japanese patients receiving trazodone 150 mg at bedtime. By use
of allele-specific PCR analysis, the wild type allele, three mutated alleles causing absent enzyme activity (CYP2D6A, CYP2D6B
and CYP2D6D) and one mutated allele causing decreased enzyme activity (CYPZD6 Ch) were identified. The means (ranges) of the
Css of trazodone, corrected to the median body weight in 17 cases with no mutated allele, 27 cases with one mutated allele
and 10 cases with two mutated alleles, were 556 (281–1115), 643 (302–1362) and 671 (234–1418) ng/ml, respectively, while the
values of mCPP were 60 (35–121), 65 (33–99) and 58 (38–112) ng/ml, respectively. Neither the Css of trazodone (F = 0.80, P = 0.45) nor that of mCPP (F = 0.49, P = 0.61) significantly differed among the three groups. The present study thus suggests that the CYP2D6 genotype cannot predict
the Css of these compounds.
Received: 24 January 1997/Final version: 26 March 1997 相似文献
8.
L. L. von Moltke David J. Greenblatt Su Xiang Duan Jürgen Schmider C. Eugene Wright Jerold S. Harmatz Richard I. Shader L. L. Von Moltke 《Psychopharmacology》1997,132(4):402-407
Biotransformation of the selective serotonin reuptake inhibitor antidepressant, fluoxetine, to its principal metabolite,
norfluoxetine, was evaluated in human liver microsomes and in microsomes from transfected cell lines expressing pure human
cytochromes. In human liver microsomes, formation of norfluoxetine from R,S-fluoxetine was consistent with Michaelis-Menten kinetics (mean Km = 33 μM), with evidence of substrate inhibition at high substrate concentrations in a number of cases. The reaction was minimally
inhibited by coincubation with chemical probes inhibitory for P450-2D6 (quinidine), -1A2 (furafylline, α-naphthoflavone),
and -2E1 (diethyldithiocarbamate). Substantial inhibition was produced by coincubation with sulfaphenazole (Ki = 2.8 μM), an inhibitory probe for P450-2C9, and by ketoconazole (Ki = 2.5 μM) and fluvoxamine (Ki = 5.2 μM). However, ketoconazole, relatively specific for P450-3A isoforms only at low concentrations, reduced norfluoxetine
formation by only 20% at 1 μM, and triacetyloleandomycin (≥ 5 μM) reduced the velocity by only 20–25%. Microsomes from cDNA-transfected
human lymphoblastoid cells containing human P450-2C9 produced substantial quantities of norfluoxetine when incubated with
100 μM fluoxetine. Smaller amounts of product were produced by P450-2C19 and -2D6, but no product was produced by P450-1A2,
-2E1, or 3A4. Cytochrome P450-2C9 appears to be the principal human cytochrome mediating fluoxetine N-demethylation. P450-2C19 and -3A may make a further small contribution, but P450-2D6 is unlikely to make an important contribution.
Received: 23 December 1996 / Final version: 4 March 1997 相似文献
9.
Corinne Maudhuit Elisabeth Prévot Laure Dangoumau Patrick Martin Michel Hamon J. Adrien 《Psychopharmacology》1997,130(3):269-275
Chronic treatment with antidepressants renders serotonergic neuronal firing less sensitive to the inhibitory effect of serotonin
(5-HT) reuptake blockers in the rat, and this has been considered as a major correlate of the therapeutic action of these
drugs. We investigated whether the same mechanisms could be evidenced in an experimental model of depression, the learned
helplessness paradigm. Rats rendered helpless by a single session of inescapable electrical footshocks exhibit, for several
days, depression-like behavioural deficits which can be reversed by sub-chronic, but not acute, treatment with antidepressants.
Recording of serotonergic neurons in the dorsal raphe nucleus revealed that, under baseline conditions, the spontaneous firing
was similar in helpless rats and in non-helpless controls. However, neurons in the former group exhibited an enhanced sensitivity
to the inhibitory action of the 5-HT reuptake blocker, citalopram (ED50 = 0.18 ± 0.02 mg/kg IV in helpless rats versus 0.27 ± 0.03 mg/kg IV in controls, P < 0.05). Treatment with zimeldine during 3 consecutive days induced in both helpless and control rats, a decrease in the
inhibitory response of serotonergic neurons to the citalopram challenge, which resulted in a normalization of the neuronal
reactivity in the helpless group (ED50 = 0.31 ± 0.03 mg/kg IV). Since this adaptive phenomenon parallels the behavioural improvement induced by the repeated administration
of zimeldine and other antidepressants in helpless rats, it might be considered as a crucial event in the mechanism of therapeutic
action of these drugs.
Received: 14 August 1996 / Final version: 4 November 1996 相似文献
10.
A comparison of bd and tid dose regimens of quetiapine (Seroquel) in the treatment of schizophrenia 总被引:2,自引:0,他引:2
Quetiapine (Seroquel, ICI 204,636) is an atypical antipsychotic that is effective in the treatment of both positive and negative
symptoms of schizophrenia, and has a low propensity to cause extrapyramidal symptoms. The compound has a relatively short
plasma elimination half-life (approximately 7 h). However, since dopamine D2 receptor occupancies correlate poorly with plasma concentrations of antipsychotics, plasma elimination half-life may not
predict either duration of clinical effect or dosing frequency. Accordingly, the efficacy and tolerability of three dosing
regimens (450 mg/day given in two or three divided doses daily, and 50 mg/day given twice daily) were compared in a 6-week,
double-blind, randomized, multicentre, parallel-group study. The study recruited hospitalized men and women aged 18–65 years
meeting DSM-IIIR criteria for acute exacerbation of chronic or subchronic schizophrenia. Six hundred and eighteen patients
were randomly assigned to treatment with quetiapine 150 mg tid (n = 209), 225 mg bd (n = 200), or a comparator dose of 25 mg bd (n = 209). At day 42, the last day of randomized treatment and the primary timepoint for efficacy, quetiapine 450 mg/day was
more effective than 50 mg/day: 225 mg bd was consistently superior to 25 mg bd in all measures of efficacy (total BPRS, P = 0.006; CGI severity, CGI improvement and SANS, P < 0.03), and 150 mg tid was statistically significantly superior to 25 mg bd with respect to BPRS total score (P = 0.05). The 225 mg bd and 150 mg tid groups were not significantly different from each other with respect to any efficacy
measure. Quetiapine was generally well tolerated. Extrapyramidal symptom (EPS) adverse events were generally rare, and occurred
with similar frequencies in the two 450 mg/day groups. Quetiapine was not associated with sustained increases in plasma prolactin
at any dose. These data support the atypical profile developed from preclinical studies and show that quetiapine is an effective,
well tolerated antipsychotic that can be given twice daily.
Received: 16 May 1997/Final version: 13 October 1997 相似文献
11.
I. Kantola A. Terént T. Honkanen V. Järveläinen K. Ekman M. Kataja 《European journal of clinical pharmacology》1996,50(3):155-159
Objective: To compare the safety, efficacy, tolerability and duration of the antihypertensive effect of an ACE-inhibitor spirapril
3 mg or 6 mg in elderly (≥ 60 y) hypertensive patients in a multicentre, observational, double-blind randomised study.
Methods:
After a four-week placebo period, 39 patients were randomised to six weeks of treatment with spirapril 3 mg and 47 patients
with spirapril 6 mg.
Results:
In the sitting position the mean (SD) decrease in systolic blood pressure (SBP) was 12(15) mmHg (95% confidence interval 7
to 17 mmHg) and in dia- stolic blood pressure (DBP) 10(7) mmHg (8 to 12 mmHg) in the 3-mg group and 10(13) mmHg (6 to 14 mmHg)
and 9(7) mmHg (7 to 11 mmHg), respectively, in the 6-mg group (P < 0.001 compared to placebo period in both groups). Spirapril 3mg and 6 mg produced DBP ≤ 90 mmHg or a fall ≥ 10 mmHg in 53%
and 51% of the patients, respectively. DBP was ≤ 90 mmHg in 36% and SBP ≤ 160 mmHg in 67% of the patients taking 3 mg and
in 26% and 63% of the patients taking 6 mg spirapril. The most commonly reported adverse effects were cough (13–17%), dizziness,
headache and insomnia. A trend to a more frequent adverse effects was observed in patients receiving spirapril 6 mg. Spirapril
was both cholesterol- and glucose-neutral.
Conclusion:
According to our study, spirapril 3mg seems to be a suitable starting dose for the treatment of hypertension in the elderly
patients.
Received: 8 August 1995/Accepted in revised form: 7 November 1995 相似文献
12.
A. J. Hiltunen O. Beck P. Hjemdahl P. Liljeberg U. Almström K. Brodin J. von Wachenfeldt S. Borg 《Psychopharmacology》1999,143(4):385-393
Rationale: One of the major problems in methadone maintenance treatment is to find optimal individual doses for the patients. Objective: The present study investigated whether the use of rating scales together with enantioselective analysis of l-methadone might facilitate dose adjustments in a clinical situation. Methods: Rating scales were used to evaluate subjective and objective signs of well-being in relation to plasma methadone concentrations
in two groups of patients receiving methadone maintenance treatment. The first group (n = 25) was well-adjusted according to clinical observations and were satisfied with their methadone doses (86.2 ± 4.3 mg).
The second group (n = 25) was in need of the methadone dose adjustment; they complained of low dosing, despite a dose level of 69.2 ± 4.0 mg/day.
Results: Results indicated a significant correlation between dose and methadone concentration among dissatisfied patients only. The
trough levels of d,l-methadone and l-methadone, as well as their elimination rates, were similar in the two groups of patients. There was a variable predominance
of l- over d-methadone in plasma (ratio ≈1.2; range 0.7–3.6). Illicit use of drugs by the patients was related to the methadone dose and
to satisfaction with the dose received. Increased illicit drug use among dissatisfied patients was successfully eliminated
by raising the methadone dose. Subjective and objective ratings of the satisfied patients were quite stable throughout the
evaluation period, whereas the ratings of the dissatisfied patients were unstable. These patients seemed to be more sensitive
to low trough levels of methadone than the satisfied patients. Associations between the subjective and objective ratings and
plasma methadone, along with background characteristics, were characterized by multiple regression analyses. The plasma concentrations
of l-methadone were one of the most important explanatory variables in these analyses. Associations between well-being and methadone
concentrations in plasma were stronger for l-methadone than for d,l-methadone. Conclusions: Selective measurements of the active isomer and the use of rating scales should be of clinical value when monitoring methadone
maintenance treatment patients.
Received: 17 June 1998/Final version: 10 December 1998 相似文献
13.
Effect of fluvoxamine on platelet 5-HT2A receptors as studied by [3H]lysergic acid diethylamide ([3H]LSD) binding in healthy volunteers 总被引:1,自引:0,他引:1
Alterations in platelet 5-HT2A receptor characteristics have been reported in major depression as well as in other psychiatric diseases, and some effort
has been made to utilize platelet 5-HT2A receptor status as a biological correlate to antidepressant drug response. In order to investigate whether treatment with
a selective serotonin reuptake inhibitor affects platelet 5-HT2A receptors, we have studied platelet [3H]lysergic acid diethylamide ([3H]LSD) binding in healthy subjects treated with fluvoxamine in increasing dosage once weekly for 4 weeks. After 1 week of
fluvoxamine treatment (25 mg/day), both Bmax and Kd were significantly lower than before the start of the treatment (19.9 versus 25.5 fmol/mg protein, P = 0.005 for Bmax; 0.45 versus 0.93 nM, P = 0.006 for Kd). Bmax returned to baseline during week 2, whereas Kd was lower than the baseline value throughout the treatment period. After discontinuation of fluvoxamine treatment, there
was a significant increase in Kd (0.50 nM before discontinuation vs. 1.14 nM after discontinuation; P = 0.001), but not in Bmax. The study demonstrates that fluvoxamine affects platelet 5-HT2A receptor status irrespective of underlying psychiatric disease, and that this effect is evident already after 1 week at a
subtherapeutic fluvoxamine dose.
Received: 11 October 1996/Final version: 12 March 1997 相似文献
14.
D. O. Stichtenoth D. Tsikas F.-M. Gutzki J. C. Frölich 《European journal of clinical pharmacology》1996,51(3-4):231-234
Objective:
In the present randomized, four-way crossover study we determined the effects of two oral doses each of ketoprofen and ibuprofen
on platelet aggregation and prostanoid formation in man.
Methods:
Twelve healthy female volunteers received for 2 consecutive days, followed by a 5-day drug-free interval, one of the following:
ketoprofen 3 × 25 mg per day, or ketoprofen 3 × 50 mg per day, or ibuprofen 3 × 200 mg per day, or ibuprofen 3 × 400 mg per
day. The response criteria, determined before and on the 2nd day of each treatment period, were: maximal platelet aggregation
in response to 1.0 mmol ⋅ l–1 arachidonic acid measured by the method of Born and Cross, thromboxane B2 (TXB2) concentration in platelet-rich plasma after aggregation measured by radioimmunoassay, and PGE-M, the index metabolite of
total body prostaglandin E2 (PGE2) production, assessed by gas chromatography/tandem mass spectrometry using 18O2-PGE-M as internal standard.
Results:
Platelet aggregation was significantly reduced by ketoprofen 3 × 25 mg per day (−57%) and ketoprofen 3 × 50 mg per day (−85%)
as compared to control, whereas ibuprofen 3 × 200 mg per day (−3%) and ibuprofen 3 × 400 mg per day (−22%) had no significant
effects. TXB2 synthesis was significantly decreased by ketoprofen 3 × 25 mg per day (−72%), ketoprofen 3 × 50 mg per day (−97%) and ibuprofen
3 × 400 mg per day (−48%) as compared to control; ibuprofen 3 × 200 mg per day did not reduce TXB2 formation significantly (−23%). All four treatments reduced 24-h urinary excretion of PGE-M significantly in the range of−39%
(ketoprofen 3 × 25 mg per day) to −53% (ibuprofen 3 × 400 mg per day) without significant differences between treatments.
Conclusion:
Our data show that both ketoprofen dosages were more effective in inhibition of platelet aggregation and platelet thromboxane
synthesis than ibuprofen in low or high dosage. Total body synthesis of the E-prostaglandins was inhibited by all drug schedules
without significant differences between treatments.
Received: 26 January 1996;/Accepted in revised form: 11 June 1996 相似文献
15.
Ehrenreich H Rinn T Kunert HJ Moeller MR Poser W Schilling L Gigerenzer G Hoehe MR 《Psychopharmacology》1999,142(3):295-301
Rationale and objective: The present study tested the hypothesis that chronic interference by cannabis with endogenous cannabinoid systems during
peripubertal development causes specific and persistent brain alterations in humans. As an index of cannabinoid action, visual
scanning, along with other attentional functions, was chosen. Visual scanning undergoes a major maturation process around
age 12–15 years and, in addition, the visual system is known to react specifically and sensitively to cannabinoids. Methods: From 250 individuals consuming cannabis regularly, 99 healthy pure cannabis users were selected. They were free of any other
past or present drug abuse, or history of neuropsychiatric disease. After an interview, physical examination, analysis of
routine laboratory parameters, plasma/urine analyses for drugs, and MMPI testing, users and respective controls were subjected
to a computer-assisted attention test battery comprising visual scanning, alertness, divided attention, flexibility, and working
memory. Results: Of the potential predictors of test performance within the user group, including present age, age of onset of cannabis use,
degree of acute intoxication (THC+THCOH plasma levels), and cumulative toxicity (estimated total life dose), an early age
of onset turned out to be the only predictor, predicting impaired reaction times exclusively in visual scanning. Early-onset
users (onset before age 16; n = 48) showed a significant impairment in reaction times in this function, whereas late-onset users (onset after age 16; n = 51) did not differ from controls (n = 49). Conclusions: These data suggest that beginning cannabis use during early adolescence may lead to enduring effects on specific attentional
functions in adulthood. Apparently, vulnerable periods during brain development exist that are subject to persistent alterations
by interfering exogenous cannabinoids.
Received: 15 June 1998/Final version: 30 September 1998 相似文献
16.
Michael Deuschle Sebastian Härtter Christoph Hiemke Harald Standhardt Isabella Heuser 《Psychopharmacology》1997,131(1):19-22
Little information exists on the concentrations of antidepressants and their metabolites in CSF. We measured plasma and CSF
levels of trans-doxepin (trans-DOX) and DOX metabolites in 12 depressed patients treated with DOX (250 mg/day) for 6 days. Spinal taps and blood samples
were taken on day 7, 10 h after drug administration. Trans-DOX, cis-desmethyldoxepin (cis-DM-DOX), trans-desmethyldoxepin (trans-DM-DOX) and di-desmethyldoxepin (DDM-DOX) were analyzed in CSF and plasma samples by HPLC with column-switching. Although
DOX was given as a mixture of 85% trans-DOX and 15% of the pharmacologically more active cis-DOX, we found similar amounts of cis-DM-DOX and trans-DM-DOX in plasma (59.8 ± 45.1 versus 72.0 ± 60.0 ng/ml; NS), suggesting that isomerization of DOX had taken place. Trans-DOX and DOX metabolites could be detected in CSF of most patients. Relatively low CSF concentrations of the active metabolite
cis-DM-DOX were measured. Clinical efficacy, as assessed by HAMD scores, was not significantly related to plasma or CSF concentrations
of trans-DOX or its metabolites. Trans-DOX and DOX metabolites were distributed differently between plasma and CSF. It is concluded that isomerization of DOX is
not only relevant for neuronal uptake inhibition, but also for the transport of the metabolites.
Received: 13 May 1996/Final version: 16 December 1996 相似文献
17.
R. D. Hurt K. P. Offord I. T. Croghan G. A. Croghan L. C. Gomez-Dahl T. D. Wolter L. C. Dale T. P. Moyer 《Psychopharmacology》1998,140(1):98-104
Nicotine nasal spray and nicotine gum have been found to be effective in relieving nicotine withdrawal symptoms. In this
randomized single-blind study, 91 cigarette smokers were randomly assigned to a single 1 mg dose of active nicotine nasal
spray (n = 29), active 4 mg nicotine gum (n = 31), saline placebo nasal spray (n = 16) or placebo gum (n = 15). Following overnight abstinence, subjects repeatedly completed visual analog scales for assessing nicotine withdrawal
symptoms over 30 min preceding (time -30 min to time 0) and 120 min following a single dose of study medication. This sequence
was performed 3 times during the day. Nicotine withdrawal symptoms were assessed on a 41-point visual analog scale (1 = no
withdrawal, 41 = extreme withdrawal). At the initial session only, blood samples for serum nicotine levels were taken at baseline,
then at 5, 10, 30 and 120 min following study drug administration. The mean (± SD) age of the subjects was 38.6 (±10.1) years,
48% were females, smoking rate was 24.5 (±7.8) cigarettes per day, and years of smoking was 19.9 (±10.0). A single 1 mg dose
of nicotine nasal spray provided more immediate relief for craving for a cigarette compared to a single 4 mg dose of nicotine
gum. Serum venous nicotine levels for the active nicotine nasal spray and nicotine gum were comparable at 5 and 10 min while
the levels were higher for nicotine gum at 30 and 120 min. Changes in withdrawal symptoms were not found to be related to
serum venous nicotine levels. Our findings provide a rationale for the as needed use of nicotine nasal spray to control withdrawal
symptoms, possibly in combination with other medications with longer acting effects.
Received: 18 February 1998/Final version: 1 May 1998 相似文献
18.
H. J. G. M. van Megen Herman G. M. Westenberg Johan A. den Boer Bernard Slaap Antoinette Scheepmakers 《Psychopharmacology》1997,129(4):357-364
Data from animal studies suggest a functional relationship between the cholecystokinin-ergic (CCK) and the serotonergic (5-HT)
system. There is increasing evidence that the cholecystokinin-4 (CCK4) challenge test could be a valid experimental model for panic attacks in man. The aim of the present study is twofold; 1)
to validate this model further and 2) to shed more light on the putative CCK\5-HT interaction. To this end, we studied the
effect of the selective serotonin reuptake inhibitor (SSRI) fluvoxamine on CCK4-induced panic attacks. Twenty-six panic disorder (PD) patients received, before and after a double blind 8-week treatment
period with fluvoxamine (n = 17) or placebo (n = 9), a single blind bolus injection with 50 μg CCK4. Treatment with fluvoxamine (150 mg daily) significantly decreased the sensitivity of PD patients for CCK4 while placebo was without effect. Of the patients who responded to treatment, 83% no longer experienced a panic attack when
rechallenged with CCK4, whereas in the non-responders group this was only 28%. In the fluvoxamine group the treatment response evaluated by the
Hamilton Anxiety Scale (HAS) showed a statistically significant treatment effect. The results of this study strengthen the
validity of the CCK4 test as an experimental human model for panic attacks and yield evidence supporting the hypothesis that both CCK and serotonin
are implicated in the regulation of anxiety.
Received: 15 April 1996/Final version: 27 September 1996 相似文献
19.
M. C. Mauri R. Rudelli S. Bravin S. Gianetti E. Giuliani A. Guerrini R. Orlandi G. Invernizzi 《Psychopharmacology》1998,137(4):341-344
A possible relationship between haematological adverse reactions and clozapine (CLZ) metabolism rate was studied. Sixteen
chronic schizophrenic outpatients (mean age 34.62 years ± 7.56 SD) were treated with CLZ, 75–600 mg/daily for 9 weeks. CLZ
and norclozapine (NCLZ) plasma levels were determined weekly, contemporarily with blood cell counts. CLZ plasma levels ranged
from 25 to 1270 ng/ml (mean 266.27 ng/ml ± 197.44 SD), while NCLZ plasma levels ranged from 25 to 1280 ng/ml (mean 169.0 ng/ml
± 127.94 SD). NCLZ/CLZ ratio ranged from 0.13 to 1.72 (mean 0.72 ± 0.28 SD). Leukocyte count ranged from 5.2 to 18.8 109/l (mean 9.37 109/l ± 2.94 SD) and neutrophil count ranged from 1.8 to 13.4 109/l (mean 5.73 ± 2.57 SD). No correlation was found between CLZ dosage and NCLZ plasma levels. Both CLZ and NCLZ plasma levels
correlated positively with neutrophil count (CLZ: P = 0.001, r = 0.26; NCLZ: P = 0.01, r = 0.20). The correlation between NCLZ/CLZ plasma level ratio and neutrophil count was significantly negative (P = 0.002, r
= 0.25). These preliminary data suggest that the NCLZ/CLZ ratio, as an index of CLZ metabolism, might be a possible risk factor
associated with CLZ treatment.
Received: 15 May 1997/Final version: 3 October 1997 相似文献
20.
Endogenous opioid peptides have been implicated in the reinforcement of smoking and opioid antagonists have been examined
to determine their role in smoking behavior. To date, the relationship between smoking behavior and chronic opiate antagonist
administration during ad libitum smoking has not been investigated. The purpose of this study was to examine the relationships
between naltrexone, an opiate antagonist administered orally, and smoking behavior and mood states during ad libitum smoking.
A repeated measures experimental design was used. Normal adult male and female volunteers, admitted to the Clinical Research
Center, were randomly assigned to naltrexone-treated (n = 22) or placebo-control (n = 21) groups in a double-blind manner. Day 1 was considered acclimation to the unit and day 2 was baseline, or pre-drug administration.
On days 3, 4, and 5, subjects received 50 mg naltrexone or a placebo at 0700 and 1600 hours. Plasma nicotine and expired air
carbon monoxide levels were measured daily at 1900 hours. Number of cigarettes smoked, mood states, withdrawal symptomatology
and self-reported satisfaction with smoking were also quantified daily. Results indicated that plasma nicotine levels (P = 0.005), number of cigarettes smoked daily (P = 0.003) and self-reported satisfaction with smoking (P = 0.043) were significantly lower among those treated with naltrexone, compared to the placebo-control group. Expired air
carbon monoxide levels did not differ between the two groups. In addition, mood states and withdrawal symptoms did not differ
between groups. These findings suggest that endogenous opioid peptides influence specific smoking behavior variables.
Received: 7 November 1997/ Final version: 7 April 1998 相似文献