Specific serotonin reuptake inhibitor-induced decreases in lymphocyte activity require endogenous serotonin release. Inhibition of phenytoin hydroxylation in human liver microsomes by several selective serotonin re-uptake inhibitors. Rx drugs

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Neuroimmunomodulation. 2000;8(4):179-87.
Specific serotonin reuptake inhibitor-induced decreases in lymphocyte activity require endogenous serotonin release.

Pellegrino TC, Bayer BM.

Department of Pharmacology, Georgetown University Medical Center, Washington, DC 20007, USA.

OBJECTIVES: We have previously reported that acute administration of the specific serotonin reuptake inhibitor (SSRI), fluoxetine, resulted in a decrease in mitogen-induced blood lymphocyte proliferation. The present studies further examine the specificity of this response to serotonin reuptake systems and the potential role of endogenous serotonin in mediating these effects. METHODS: Male Sprague-Dawley rats were treated intraperitoneally with the SSRIs, fluoxetine (6-10 mg/kg) or sertraline (20 mg/kg), dopamine and norepinephrine reuptake inhibitors, GBR 12909 and desipramine, respectively (6 mg/kg) or the serotonin precursor, 5-hydoxytryptophan (5-HTP, 50 mg/kg) 2 h prior to sacrifice. The serotonin-depleting agents, p-chlorophenylalanine (PCPA, 2 x 200 mg/kg) or the serotonin-lesioning agent, p-chloroamphetamine (PCA, 2 x 10 mg/kg) were administered intraperitoneally 5-7 days prior to fluoxetine (10 mg/kg) administration. RESULTS: Unlike the SSRIs, which significantly suppressed lymphocyte proliferation responses, selective norepinephrine or dopamine reuptake inhibition had no effect on lymphocyte proliferation. Elevation of extracellular serotonin levels with the serotonin precursor, 5-HTP, resulted in a similar decrease in lymphocyte proliferation as that seen with SSRI administration. Conversely, decreases in endogenous serotonin following PCA or PCPA treatment prevented the fluoxetine-induced decreases in lymphocyte proliferation. CONCLUSIONS: These results suggest that decreases in mitogen-induced lymphocyte proliferation following acute fluoxetine administration were due to elevations in extracellular serotonin following reuptake inhibition. Copyright 2001 S. Karger AG, Basel

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Epilepsy Res. 2001 Apr;44(1):71-82.
Inhibition of phenytoin hydroxylation in human liver microsomes by several selective serotonin re-uptake inhibitors.

Nelson MH, Birnbaum AK, Remmel RP.

Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, 8-101 WDH, 308 Harvard Street, S.E., Minneapolis, MN 55455, USA.

Several case reports have indicated that the selective serotonin re-uptake inhibitor (SSRI) fluoxetine increases phenytoin blood levels when given concurrently. The mechanism of this drug-drug interaction has been attributed to inhibition of CYP2C9-catalyzed hydroxylation of phenytoin to its major oxidative metabolite in humans, para-hydroxyphenyl phenyl hydantoin (HPPH). With a bank of human liver microsomes (HLM), four SSRIs (fluoxetine, norfluoxetine, sertraline, and paroxetine) were tested for inhibition of HPPH formation. Initially, the K(m) and V(max) values of phenytoin hydroxylation to HPPH were determined in the individual HLM samples. The average K(m) (n=8) was 9.7+/-2.9 microM. The V(max) varied fivefold, with an average value of 113+/-53 pmol HPPH/min/nmol CYP450. All of the SSRIs inhibited HPPH formation; resulting Ki values were 31.1+/-10.1 microM (fluoxetine) (n=5), 51.1+/-9.4 microM (norfluoxetine) (n=3), 52.2+/-21.5 microM (sertraline) (n=3), and 80.0+/-7.2 microM (paroxetine) (n=3). Sulfaphenazole (10 microM), utilized as a positive control for inhibition of HPPH formation, inhibited phenytoin hydroxylation (>95%) in all HLM samples. Diclofenac hydroxylation to 4'-OH diclofenac, a specific marker for CYP2C9 activity, was determined in HLM1-HLM6 and was highly correlated with HPPH formation in HLM1-HLM6, indicating that phenytoin hydroxylation in human liver microsomes is largely due to CYP2C9. This work presents direct evidence that the effect of fluoxetine on phenytoin blood levels may be explained by inhibition of CYP2C9-catalyzed phenytoin hydroxylation. In light of typical SSRI blood levels observed in patients, this study also suggests that the risk of a SSRI-phenytoin interaction is highest with fluoxetine and norfluoxetine, and less likely with sertraline and paroxetine.

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med.showa-u.ac.jp

We have previously identified 204 partial cDNA fragments (ADRG1-204) as antidepressant related genes/expressed sequence tags. Then, we developed our original cDNA microarrays, on which the 194 clones out of ADRG1-204 were spotted. With this ADRG microarray, we found that the expression of a spot, ADRG55, which representing cysteine string protein (CSP), was significantly increased in rat brain after chronic treatment with a selective serotonin reuptake inhibitor, sertraline. In the present study, reverse transcription-polymerase chain reaction analysis confirmed the induction of CSP at mRNA levels in rat frontal cortex after chronic treatment with two different classes of antidepressants, imipramine or sertraline. Western blot analysis also revealed that CSP-immunoreactivity was increased after antidepressant treatment. In conclusion, our data suggest that CSP is one of the common functional molecules induced after chronic antidepressant treatment.

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