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PubMed2006

Difference in pre- and post-treatment plasma DHEA levels were significantly and positively correlated with difference in pre- and post-treatment Hamilton depression scores following successful therapy for major depression.

OBJECTIVE: Clinical studies of endogenous concentrations of dehydroepiandrosterone (DHEA) and its relation to depression are limited. This study examined whether pre- and post-treatment changes in plasma DHEA levels are correlated with pre- and post-treatment differences in Hamilton depression scores following successful antidepressant therapy for major depression with venlafaxine XR. METHOD: Thirty-four medication-free major depressive outpatients (Hamilton Rating Scale for Depression 17, HAM-D 17 score > or = 17) were treated with antidepressants. At baseline, plasma DHEA levels of all subjects were measured but only those who remitted (HAM-D 17 score < or = 7) before the end of this study had their plasma DHEA levels measured at remission-onset. Blood from subjects was drawn at 0900-1100 h. Depression severity was assessed with the HAM-D 17 scale at baseline, and on day 7, 14, 28, 56 and 84. Subjects were administered at minimum 75 mg/day venlafaxine XR until remission onset. RESULTS: Fifteen patients remitted before the end of this study. Plasma DHEA levels decreased from baseline to remission was significant (P=0.017). After controlling for age and gender, pre- and post-treatment difference in Hamilton depression scores and the pre- and post-treatment difference in DHEA concentrations were significantly correlated (P=0.044). CONCLUSION: This preliminary study provides the first clinical evidence identifying that difference in pre- and post-treatment plasma DHEA levels were significantly and positively correlated with difference in pre- and post-treatment Hamilton depression scores following successful therapy with venlafaxine XR for major depression in remitters; but non-remitters were not examined. It is not known if DHEA levels would show similar or dissimilar changes in non-remitters.

Adolescent↗
PubMed2004

Inhibitory activity of 1,8-cineol (eucalyptol) on cytokine production in cultured human lymphocytes and monocytes.

BACKGROUND: The therapeutic value of secretolytic agents in COPD and asthma is still disputed. For this reason, in a preclinical study we aimed to test the potential anti-inflammatory efficacy of 1,8-cineol (eucalyptol) in inhibiting polyclonal stimulated cytokine production by human unselected lymphocytes and LPS-stimulated monocytes. METHODS: Cytokine production was determined following 20 h of incubation cells with 1,8-cineol simultaneously with the stimuli in culture supernatants by enzyme immunoassay. RESULTS: Therapeutic concentrations of 1,8-cineol (1.5 microg/ml=10(-5)M) inhibited significantly (n=13-19, p=0.0001) cytokine production in lymphocytes of TNF-alpha > IL-1beta> IL-4> IL-5 by 92, 84, 70, and 65%, respectively. Cytokine production in monocytes of TNF-alpha > IL-1beta> IL-6> IL-8 was also significantly (n=7-16, p<0.001) inhibited by 99, 84, 76, and 65%, respectively. In the presence of 1,8-cineol (0.15 microg/ml=10(-6)M) production of TNF-alpha>IL-1beta by monocytes and of IL-1beta> TNF-alpha by lymph-ocytes was significantly inhibited by 77, 61 and by 36, 16%, respectively. 1,8-cineol (10(-6)M) had a larger impact on TNF-alpha and IL-1beta-production in monocytes compared to lymphocytes (p<0.03) and similar effects (p>0.59) at therapeutically relevant concentrations of 1,8-Cineol (10(-5)M). CONCLUSION: These results characterize 1,8-cineol as strong inhibitor of TNF-alpha and IL-1beta and suggest smaller effects on chemotactic cytokines. This is increasing evidence for the role of 1,8-cineol to control airway mucus hypersecretion by cytokine inhibition, suggesting long-term treatment to reduce exacerbations in asthma, sinusitis and COPD.

Anti-Inflammatory Agents↗
PubMed2004

Newer antidepressants in pregnancy: prospective outcome of a case series.

Antidepressant drug choice in pregnancy is a complex problem especially for new drugs. Among 590 cases exposed to drugs during pregnancy who were followed by our center, 21 cases used newer antidepressants, i.e., venlafaxine, mirtazapine, nefazodone. We present the gestational findings and fetal outcomes of these cases. Ten cases had used venlafaxine, one case had used both venlafaxine and mirtazapine, eight had used mirtazapine alone or with some other drugs and two had used nefazodone, in the first trimester. Of the 21 cases, 17 (80.9%) had healthy babies, 3 (14.3%) decided to terminate the pregnancy, and 1 (4.8%) spontaneous abortion was observed in a case exposed to mirtazapine, alprazolam, diazepam and trifluoperazine. All obstetrical findings were normal during the pregnancy of each case. No congenital abnormality and developmental problem was observed in the babies followed up for 12 months. The aim of the present study is to contribute the data to the limited knowledge available in the literature regarding human pregnancy.

Abnormalities, Drug-Induced↗
PubMed2005

The relevant effect of an intramolecular hydrogen bond on the conformational equilibrium of cis-3-methoxycyclohexanol compared to trans-3-methoxycyclohexanol and cis-1,3-dimethoxycyclohexane.

1H NMR data show that an increase in the concentration of cis-3-methoxycyclohexanol (cis-3-MCH) shifts the conformational equilibrium from the 1aa conformer, stabilized by an intramolecular hydrogen bond (IAHB), to the 1ee conformer [X(ee) = 44% (at 0.05 molL(-1)) to 59% (at 0.40 molL(-1)), in CCl4], which forms intermolecular hydrogen bonds (IEHB), as confirmed by IR data. The percentage of 1ee conformer increases with the solvent polarity, from 33% (DeltaG(ee-aa) = 1.72 kJmol(-1)) in cyclohexane (C6D12) to 97% (DeltaG(ee-aa) = -8.41 kJmol(-1)) in DMSO. For trans-3-methoxycyclohexanol (trans-3-MCH), 1ae and 1ea conformers are almost equally present in the studied solvents, 1ae increasing from 41%, in C6D12 (DeltaG(ae-ea) = 0.84 kJmol(-1)), to 49%, in DMSO (DeltaG(ae-ea) = 0.13 kJmol(-1)). A value of 18.4 kJmol(-1) for the strength of IAHB in cis-3-MCH was obtained, from the theoretical data, through the CBS-4M method.

Cyclohexanes↗
PubMed2004

Pharmacotherapy for cataplexy.

A variety of medications representing several major drug classes improve cataplexy in patients with narcolepsy. These include aminergic reuptake inhibitors such as venlafaxine and clomipramine as well as sodium oxybate. This review is intended to familiarize readers with the safety and efficacy of these medications, thus enabling clinicians to optimize their management of cataplexy.

Antidepressive Agents↗
PubMed2005

Synthesis and antiproliferative activity of A-ring aromatised and conduritol-like steroidal compounds.

A simple approach to aromatization of steroidal quinols and epoxyquinols using a catalytic amount of TMSOTf is reported. Beside acetylation of the angular OH, the acid-catalyzed (TfOH) dienone-phenol rearrangement occurred affording "para" products, or in the case of blocked position 4, the acetoxy group 1,2-migration leads to the formation of "meta" products. Using epoxyquinol derivative as a substrate, the acetoxy group elimination was observed, followed by acid-catalyzed epoxy-ring opening and subsequent double bond migration, giving as a final product Delta(9,11)A-ring aromatized compounds. Synthesis of conduritol-like compounds and structure confirmation by X-ray crystallography of the precursor of steroidal conduritol is also described. In addition, the results of extensive antiproliferative screening against a panel of 60 cancer cell lines are presented.

Catalysis↗
PubMed2006

In vitro evaluation of macrophage viability after incubation in orange oil, eucalyptol, and chloroform.

OBJECTIVE: The aim of this study was to evaluate the cytotoxicity of orange oil, eucalyptol, and chloroform in a cell culture assay by using peritoneal macrophages from Swiss mice. STUDY DESIGN: Control (Dulbecco's modified Eagle's medium [DMEM] plus 1.25% ethyl alcohol) and experimental (orange oil, eucalyptol, and chloroform) groups were studied. Solvents used were tested at 0.025% and 0.050% concentrations in DMEM plus 1.25% ethyl alcohol. RESULTS: Orange oil, eucalyptol, and chloroform were all cytotoxic in comparison to the control group (P < .001). Orange oil showed the least cytotoxicity (P < .001). No significant differences were observed regarding cell viability when comparing the eucalyptol and chloroform groups (P < .05). There were significant differences in the cytotoxicity of eucalyptol and chloroform with an increase in concentration (P < .0001). Nevertheless, this difference was not significant in the orange oil group (P < .05). CONCLUSION: Orange oil was less cytotoxic than eucalyptol and chloroform.

Analysis of Variance↗
PubMed2006

Electrical alternans and hemodynamics in the anesthetized guinea pig can discriminate the cardiac safety of antidepressants.

INTRODUCTION: The arrhythmogenic risk of fluoxetine, citalopram, and venlafaxine were evaluated through preclinical assays measuring hERG, blood pressure and electrical alternans over their respective clinical unbound concentration ranges. METHODS: Anesthetized guinea pigs were instrumented with jugular and carotid cannulae for drug infusion and blood pressure monitoring respectively; a thoracotomy was performed for placement of a monophasic action potential probe on the left ventricle and for placement of pacing wires on the left ventricular apex. Drugs were infused as a 5-min loading dose immediately followed by a 10-min maintenance dose to achieve clinically relevant plasma concentrations; blood samples were taken at the end of each maintenance dose. Ventricular pacing was performed twice at baseline and at each dose level as follows: 50 preconditioning-beats at S1=220 (or 240) ms immediately followed by 30 test-beats at S2=200 ms. This S1-S2 protocol was repeated for S2=190 to 140 ms. HERG and calcium current measurements were recorded in HEK-293 cells stably expressing hERG potassium currents and freshly isolated guinea pig cardiac myocytes using the whole-cell configuration of the patch clamp technique. RESULTS: Physiologically relevant inhibition (IC(20)) of hERG occurred at concentrations 22-fold (fluoxetine), 9-fold (citalopram), and 11-fold (venlafaxine) beyond their respective clinically effective concentration (C(eff)). At the highest achievable levels, fluoxetine (20-fold C(eff)) and citalopram (28-fold C(eff)) significantly decreased heart rate and/or blood pressure as well as increasing electrical alternans by 5 and 18 ms respectively. Venlafaxine increased blood pressure at only 1.3-fold C(eff), but did not increase electrical alternans at the highest achievable dose (3.1-fold C(eff)). DISCUSSION: These data suggest that evaluating other dose limiting side effects in relation to a drug's therapeutic range may be crucial for accurate assessment of arrhythmia liability.

Action Potentials↗
PubMed2002

Lack of correlation between NF-kappaB activation and induction of programmed cell death in PC12 pheochromocytoma cells treated with 6-hydroxydopamine or the cannabinoid receptor 1-agonist CP55,940.

NF-kappaB is a transcriptional regulator that plays a key role in immunity, inflammation and programmed cell death. We generated a PC12 cell line termed PC12kappaBluc that contains an integrated NF-kappaB-responsive reporter gene to directly measure NF-kappaB activity. The "classical" activators of NF-kappaB, phorbol 12-O-tetradecanoate-13-acetate and tumor necrosis factor alpha, strongly induced NF-kappaB activity in PC12kappaBluc cells. Activation of NF-kappaB could be attenuated by preincubating the cells with the cAMP analogue dbcAMP or via expression of the superrepressor IkappaBalphaS32A/S36A. PC12kappaBluc cells were subjected to several apoptotic paradigms, including treatment with 6-hydroxydopamine, H2O2, K2Cr2O7, MnCl2, C2-ceramide or the cannabinoid receptor-1 agonist CP55,940. A simultaneous measurement of the NF-kappaB activity revealed that only administration of 6-hydroxydopamine or CP55,940 increased NF-kappaB activity. Using pharmacological and genetic strategies to attenuate NF-kappaB transcriptional activity, we demonstrate that the elevation of NF-kappaB activity by 6-hydroxydopamine and CP55,940 is not an integral part of the apoptotic signaling cascade in PC12 cells.

Adrenergic Agents↗
PubMed1997

Methyl arachidonyl fluorophosphonate: a potent irreversible inhibitor of anandamide amidase.

Anandamide amidase (EC 3.5.1.4) is responsible for the hydrolysis of arachidonoyl ethanolamide (anandamide). Relatively selective and potent enzyme reversible inhibitors effective in the low micromolar range, such as arachidonyl trifluoromethyl ketone (Arach-CF3), have been described (Koutek et al., J Biol Chem 269: 22937-22940, 1994). In the current study, methyl arachidonyl fluorophosphonate (MAFP), an arachidonyl binding site directed phosphonylation reagent, was tested as an inhibitor of anandamide amidase and as a ligand for the CB1 cannabinoid receptor. MAFP was 800 times more potent than Arach-CF3 and phenylmethylsulfonyl fluoride (PMSF) as an amidase inhibitor in rat brain homogenates. In intact neuroblastoma cells, MAFP was also approximately 1000-fold more potent than Arach-CF3. MAFP demonstrated selectivity towards anandamide amidase for which it was approximately 3000 and 30,000-fold more potent than it was towards chymotrypsin and trypsin, respectively. MAFP displaced [3H]CP-55940 binding to the CB1 cannabinoid receptor with an IC50 of 20 nM vs 40 nM for anandamide. It bound irreversibly and prevented subsequent binding of the cannabinoid radioligand [3H]CP-55940 at that locus. These studies suggest that MAFP is a potent and specific inhibitor of anandamide amidase and, in addition, can interact with the cannabinoid receptors at the cannabinoid binding site. This is the first report of a potent and relatively selective irreversible inhibitor of arachidonoyl ethanolamide amidase.

Amidohydrolases↗
PubMed1998

High-level expression of the human CB2 cannabinoid receptor using a baculovirus system.

A human CB2 recombinant baculovirus (AcNPV-hCB2) was generated by site-specific transposition and employed to express the human CB2 cannabinoid receptor. Northern analysis of total RNA from Spodoptera frugiperda (Sf9) insect cells infected with AcNPV-hCB2 revealed novel expression of a unique 2.3 kb transcript when probed with hCB2 cDNA. This transcript corresponded to the size expected for hCB2 generated from the recombinant virus construct. Western immunoblot analysis of whole cell homogenates of recombinant baculovirus-infected Sf9 cells, using affinity-purified antibody to a human CB2 carboxy terminal domain (anti-hCB2.CV), revealed the presence of novel immunoreactive protein. In addition, when anti-hCB2.CV was employed in immunofluorescence staining, an intense signal was observed within AcNPV-hCB2-infected cells but not within uninfected cells or cells infected with a control beta-galactosidase recombinant baculovirus. The pattern of immunofluorescence at early periods post-infection was in a perinuclear arrangement with a "signet-ring" appearance, suggestive of glycosylation of the expressed recombinant protein. Transmission electron microscopy revealed regions of intranuclear recombinant virus assembly and the presence of numerous intracytoplasmic proteinaceous vesicular inclusions consistent with hyperproduction of hCB2. Scatchard-Rosenthal analysis of [3H]-(-)3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-[3-hydroxypro pyl]cyclohexan-1-ol ([3H]CP 55,940) receptor binding indicated a Kd of 2.24 nM and a Bmax equal to 5.24 pmol/mg of protein. The lack of [3H]CP 55,940 displacement with N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-met hyl-1H-pyrazole-3-carboxamidehydrochloride (SR 141716A), the CB1-selective antagonist, confirmed the identity of the receptor as CB2. These data indicate that AcNPV-hCB2 expresses high levels of the human CB2, which retains properties of the native receptor. Thus, this recombinant virus may prove suitable for hyperproduction of receptor for basic biochemical and biophysical characterization studies.

Animals↗
PubMed2000

Amniotic fluid and umbilical cord blood concentrations of antidepressants in three women.

BACKGROUND: Pregnancy and the postpartum period are a time of increased risk for women to develop mood disorders. As such, the reproductive safety data on antidepressant use during pregnancy have rapidly expanded over the last decade; however, there is relatively sparse information on maternal/fetal exchange of these medications and no data reporting their concentrations in amniotic fluid. METHODS: We report on three women treated during pregnancy with fluvoxamine, sertraline, and venlafaxine, respectively. Amniotic fluid at amniocentesis and umbilical cord blood and maternal blood at delivery were collected and analyzed for antidepressant concentrations using high performance liquid chromatography with UV detection. RESULTS: Antidepressant and metabolite concentrations were detectable in all amniotic fluid samples, though parent compound concentrations were less than maternal serum and umbilical cord blood concentrations. No adverse effects of the medication were reported. CONCLUSIONS: The presence of these antidepressants in amniotic fluid suggests that fetal exposure to these medications is continual and may occur through a variety of paths, thus accounting for increased fetal exposure. These paths include circulatory via placental passage, gastrointestinal via fetal swallowing, and respiratory secondary to fetal lung absorption.

Adult↗
PubMed2002

Comparative efficacy between venlafaxine and SSRIs: a pooled analysis of patients with depression.

BACKGROUND: Serotonergic and adrenergic enhancement may be synergistic and more effective than serotonergic enhancement alone in treating depression. The dual serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine is a dual reuptake inhibitor that may therefore offer greater efficacy than selective serotonin reuptake inhibitors (SSRIs). METHODS: Data from eight randomized, double-blind, controlled studies were pooled to compare efficacy in depressed patients receiving venlafaxine/venlafaxine extended release (XR), SSRIs, or placebo for </=8 weeks. The mean changes from baseline in the 21-item Hamilton Rating Scale for Depression (HAM-D(21)), Montgomery-Asberg Depression Rating Scale (MADRS), and Clinical Global Impressions-Global Improvement (CGI-I) and CGI-Severity of Illness (CGI-S) item scores were compared, as were response rates derived from these scales. RESULTS: Statistically significant differences in mean HAM-D(21) score decrease between venlafaxine (14.5) and SSRIs (12.6) and between the active treatments and placebo (11.3) were observed. Venlafaxine significantly decreased the mean MADRS scores more than SSRIs (17.8 vs. 15.9), and both treatments were significantly better than placebo (12.9). The same pattern of significance for CGI-I, HAM-D(21), and MADRS response rates between venlafaxine (71%, 64%, and 67%, respectively), SSRIs (64%, 57%, and 59%, respectively), and placebo (50%, 42%, and 41%, respectively) was observed. CONCLUSIONS: Venlafaxine was significantly more effective than SSRIs in improving depression, perhaps due to enhancing both serotonin and norepinephrine.

Adult↗
PubMed2003

Differential enhancement of antidepressant penetration into the brain in mice with abcb1ab (mdr1ab) P-glycoprotein gene disruption.

BACKGROUND: Mice with a genetic disruption (knockout) of the multiple drug resistance (abcb1ab) gene were used to examine the effect of the absence of the drug-transporting P-glycoprotein (P-gp) at the blood-brain barrier on the uptake of the antidepressants venlafaxine, paroxetine, mirtazapine, and doxepin and its metabolites into the brain. METHODS: One hour after subcutaneous injection of venlafaxine, paroxetine, mirtazapine, or doxepin, knockout and wildtype mice were sacrificed, and the drug concentrations in brain, spleen, kidney, liver, and plasma were measured. RESULTS: The cerebrum concentrations of doxepin, venlafaxine, and paroxetine were higher in knockout mice, demonstrating that these substances are substrates of P-gp and that abcb1ab activity at the level of the blood-brain barrier reduces the penetration of these substances into the brain. In contrast, brain distribution of mirtazapine was indistinguishable between the groups. CONCLUSIONS: The differences reported here in brain penetration of antidepressant drugs that depend on the presence of the abcb1ab gene may offer an explanation for poor or nonresponse to antidepressant treatment. Furthermore, they may be able to explain in part the discrepancies between plasma levels of an antidepressant and its clinical effects and side effects.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1999

Venlafaxine but not bupropion decreases cerebrospinal fluid 5-hydroxyindoleacetic acid in unipolar depression.

BACKGROUND: While the antidepressants venlafaxine and bupropion are known to have different neurochemical profiles in vitro, their effects on human cerebral metabolism in vivo have not been directly compared. METHODS: Cerebrospinal fluid (CSF) levels of 5-hydroxyindoleacetic acid (5-HIAA), serotonin, 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 3,4-dihydroxyphenylacetic acid (DOPAC) were examined in 14 never-hospitalized outpatients with unipolar depression and 10 age-similar healthy controls. Patients received a baseline lumbar puncture (LP), which was repeated after at least 6 weeks of randomized monotherapy with either venlafaxine or bupropion, while controls received only a baseline LP. RESULTS: Patients (n = 9) receiving venlafaxine showed a significant decrease (42%) in their CSF 5-HIAA concentrations after treatment, but no change in other CSF measures. In contrast, patients receiving bupropion (n = 8) showed no change in CSF measures compared to pretreatment values. CONCLUSIONS: While the mechanism for this differential effect of venlafaxine remains to be determined, the current study provides confirmation of the different aminergic effects of venlafaxine and bupropion.

Adult↗
PubMed1996

Thermodynamics of hydrogen bond and hydrophobic interactions in cyclodextrin complexes.

Values of K, delta G(o), delta H(o), delta S(o) and delta C(po) for the binding reaction of small organic ligands forming 1:1 complexes with either alpha- or beta-cyclodextrin were obtained by titration calorimetry from 15 degrees C to 45 degrees C. A hydrogen bond or hydrophobic interaction was introduced by adding a single functional group to the ligand. The thermodynamics of binding with and without the added group are compared to estimate the contribution of the hydrogen bond or hydrophobic interaction. A change in the environment of a functional group is required to influence the binding thermodynamics, but molecular size-dependent solute-solvent interactions have no effect. For phenolic O-H-O hydrogen bond formation, delta H(o) varies from -2 to -1.4 kcal mol(-1) from 15 degrees C to 45 degrees C, and delta C(p) is increased by 18 cal K(-1) mol(-1). The hydrophobic interaction has an opposite effect: in alpha-cyclodextrin, delta C(po) = -13.3 cal K(-1) mol(-1) per ligand -CH(2)-, identical to values found for the transfer of a -CH(2)-group from water to a nonpolar environment. At room temperature, the hydrogen bond and the -CH(2)-interaction each contribute about -600 cal mol(-1) to the stability (delta G(o)) of the complex. With increased temperature, the hydrogen bond stability decreases (i.e., hydrogen bonds "melt"), but the stability of the hydrophobic interaction remains essentially constant.

Amines↗