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PubMedDate not supplied

Immediate switching of antidepressant therapy: results from a clinical trial of duloxetine.

BACKGROUND: Approximately half of all treated depressed patients fail to show adequate response to their initially prescribed antidepressant medication. Switching to another medication represents one possible next-step approach for nonresponsive or partially responsive patients. However, specific techniques for switching between antidepressants have not been well studied. We examined the efficacy and tolerability associated with a switch from a selective serotonin reuptake inhibitor (SSRI) or venlafaxine to duloxetine. METHODS: All patients met criteria for major depressive disorder as defined in DSM-IV. Patients (N = 88) exhibiting suboptimal response or poor tolerability to their current antidepressant medication (citalopram or=10% of patients in both treatment groups were nausea, headache, dry mouth, insomnia, and diarrhea. Patients switched to duloxetine reported significantly lower rates of nausea and fatigue compared with patients initiating duloxetine. CONCLUSIONS: In this study, the efficacy of duloxetine in switched patients was comparable to that observed in patients initiating duloxetine therapy. Immediate switching from an SSRI or venlafaxine to duloxetine (60 mg QD) was well tolerated.

Adult↗
PubMed1976

Structural relationships of sugars to taste.

Chemical modification of sugars and their simple analogues indicates that these types of compound are almost always sweet, bitter, or bitter/sweet; hence, the two basic tastes may be intimately associated features of the same molecule. Stepwise modification at each chiral center around the sugar ring allows the sapid functions in these molecules to be mapped and leads to the inescapable conclusion that sugar molecules may be "polarized" on taste bud receptors, so that one end of the molecule elicits sweetness and the other bitterness. However, more extensive chemical modification evidently causes the molecule to realign itself in entirely different ways on the receptor. In most oligosaccharides only one sugar residue is likely to bind to the taste receptor, and this is probably a nonreducing end group, because the anomeric center of glucopyranose types of structure does not appear to affect sweetness. Sweetness depresses bitterness and bitterness depresses sweetness. Hence, it is not possible to make structural comparisons between analogues without correcting for these effects. However, some semiquantitative studies have established the value of current hydrogen bond theories of sweetness and the ideal oxygen-oxygen interorbital spacings for sweetness criteria in sugar molecules.

Acetates↗
PubMed1996

Etrank: a ranking procedure for handling missing data in clinical trials: application to venlafaxine extended-release depression clinical trial.

ETRANK is a statistical software which uses nonparametric (randomization) technique to analyze incomplete repeated measures data, where the pattern of withdrawal is treatment related. This stand alone program is written in C, presently runs in MS-DOS, and a Windows version is in development. The program has been developed based on methods developed by Entsuah (1990). These methods were presented at Statistics and Statistical Graphics Section of the 1991 SAS Users Group International Conference (SUGI-16). They were also presented to the Biometric Division of US Food and Drug Administration (FDA). ETRANK is now being used by CNS group of Wyeth-Ayerst Research as part of their NDA submission. This paper discusses ETRANK, and compares it with SAS PROC MIXED, and GEE. These methods are applied to Wyeth-Ayerst antidepressant Effexor-ER (extended release) data.

Antidepressive Agents, Second-Generation↗
PubMedDate not supplied

Substance use disorder comorbidity in major depressive disorder: a confirmatory analysis of the STAR*D cohort.

The demographics and clinical features were compared between those with (29.4%) and without concurrent substance use disorder (SUD) in 2541 outpatients with major depression (MDD) enrolled in the Sequenced Treatment Alternatives to Relieve Depression study. Compared to those without SUD, MDD patients with concurrent SUD were more likely to be younger, male, divorced or never married, and at greater current suicide risk, and have an earlier age of onset of depression, greater depressive symptomatology, more previous suicide attempts, more frequent concurrent anxiety disorders, and greater functional impairment (p = 0.048 to <0.0001). They were also less likely to be Hispanic and endorse general medical comorbidities (p = 0.006 and 0.002, respectively).

Adolescent↗
PubMed2001

Biotransformation of 1,8-cineole by human liver microsomes.

The biotransformation of 1,8-cineole has been investigated by using human liver microsomes. A single oxidized metabolite, 2-exo-hydroxy-1,8-cineole, was isolated. Its formation was investigated under various conditions by changing incubation time, P450 level in liver microsomes, and substrate concentration.

Biotransformation↗
PubMedDate not supplied

In vitro transcutaneous delivery of ketoprofen and essential polyunsaturated fatty acids from a fish oil vehicle incorporating 1,8-cineole.

Transcutaneous administration of nonsteroidal anti-inflammatory drugs and essential fatty acids from fish oil, principally eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may simultaneously lead to increased cyclooxygenase inhibition and the production of less potent inflammatory mediators within joints. The objective of our study was to determine the permeation of ketoprofen, EPA, and DHA (from fish oil) across pig ear skin in vitro in the presence of the enhancer 1,8-cineole. Formulations containing 2.5% ketoprofen in fish oil with varying concentrations of 1,8-cineole were prepared and applied to full-thickness pig ear skin mounted in all glass Franz-type diffusion cells. Simultaneous permeation of ketoprofen and EPA and DHA from these formulations was determined by reverse phase HPLC over a 48-hr period (n = 6). We found that fish oil alone enhanced the permeation of ketoprofen across pig ear by a factor of 1.72 relative to a water vehicle. There was a dose-dependent increase in the rate of permeation of ketoprofen relative to the concentration of 1,8-cineole. The highest Q24 and Q48 was obtained with a 20% 1,8-cineole formulation with values of 355.78 +/- 50.73 microg cm(-2) and 963.29 +/- 136.69 microg cm(-2), respectively. Surprisingly, no clear effect upon the permeation of EPA and DHA by 1,8-cineole was observed, with the highest Q24 and Q48 values seen in a formulation containing no 1,8-cineole. This may have been due to differential solvation effects prior to or during the permeation process or modulation of the skin during the permeation process.

Administration, Cutaneous↗
PubMed2004

The effects of the DRD2 polymorphism on smoking cessation and negative affect: evidence for a pharmacogenetic effect on mood.

This study evaluated the relationship between smoking cessation treatment outcome and the DRD2 polymorphism. Participants were 134 smokers who took part in a larger clinical trial evaluating the effects of an antidepressant medication (venlafaxine or placebo) plus standard care (brief counseling and nicotine replacement therapy). Venlafaxine is an antidepressant that inhibits the reuptake of serotonin and norepinephrine. A1 smokers were expected to quit significantly less often on placebo, although the abstinence rates between A1s and A2s on active drug were not expected to differ (i.e., an interaction between genotype and drug was hypothesized). In addition, antidepressant therapy was expected to have a similar genotype x treatment interaction on negative affect reduction. The results showed that smokers carrying the DRD2 A1 allele (A1/A1/A2) quit significantly less often than the homozygous A2s (OR=1.54, 95% CI=1.01-2.36). No interaction with treatment was observed. A significant pharmacogenetic effect of the drug on negative mood while quitting also was noted. Smokers absent the A1 allele (A2/A2) responded to the drug with a substantial reduction in negative affect, whereas those with the A1 allele showed no significant reduction in negative mood, F(1, 130)=5.95, p=.01. These results are contrary to expectations and suggest that although A1s may have more difficulty quitting, adding venlafaxine does not improve abstinence or mood. However, the results for the A2s provide evidence for a genotype-specific response to a pharmacological intervention, which could have implications for the development of future treatments.

Adult↗
PubMed2000

DNA phosphodiester bond hydrolysis mediated by Cu(II) and Zn(II) complexes of 1,3,5,-triamino-cyclohexane derivatives.

The hydrolytic activity of the 1,3,5-triaminocyclohexane derivatives TACH, TACI and TMCA complexed to Zn(II) and Cu(II) towards a model phosphoric ester and plasmid DNA has been evaluated by means of spectroscopic and gel-electrophoresis techniques. At conditions close to physiological, a prominent cleavage effect mediated by the nature of the ligand and metal ion was generally observed. TACI complexes are the most active in relaxing supercoiled DNA, the effect being explained by the affinity of the hydroxylated ligand for the nucleic acid. As indicated by the dependence of cleavage efficiency upon pH, Zn(II)-complexes act by a purely hydrolytic mechanism. In the case of Cu(II)-complexes, although hydrolysis should be prominent, involvement of an oxidative pathway cannot be completely ruled out.

Cations↗
PubMed2006

Interference by venlafaxine ingestion in the detection of tramadol by liquid chromatography linked to tandem mass spectrometry for the screening of illicit drugs in human urine.

Confirmation of the presence of illicit drugs in human fluids by liquid chromatography linked to atmospheric pressure ionisation tandem mass spectrometry (LC/MS/MS) is becoming increasingly popular. A rapid LC/MS/MS method is described using reversed phase gradient elution chromatography on a 50 x 3 mm base deactivated C8 column with identification of drugs based on their Multiple Reaction monitoring (MRM) transitions, retention time, and co-elution of stable isotopic analogues where available. The method is used for drug confirmation following initial screening by immunoassay, and identification of drugs such as tramadol, for which no immunoassay is available. False positive results for tramadol were observed in cases where subjects were being treated with the commonly prescribed antidepressant drug venlafaxine. This was a result of the presence of the metabolite O-desmethylvenlafaxine, which has a similar transition to tramadol. This study highlights the need to consider drug metabolites, as well as parent drugs in interferences in LC/MS/MS methods.

Antidepressive Agents, Second-Generation↗
PubMed2006

Topiramate use in alprazolam addiction.

Alprazolam is successful in reducing anxiety but has a high addictive/misuse potential. Topiramate is a novel anticonvulsant which has been used as a mood stabilizer. Other anticonvulsants, such as carbamazepine and valproate, have been used in alcohol and benzodiazepine withdrawal. Topiramate has recently been used in alcohol, cocaine and opiates withdrawal. There has been also one report of topiramate use in midazolam withdrawal. In our case of a patient with recurrent major depressive disorder, subthreshold anxiety disorder and addiction to alprazolam, topiramate appears to be efficient and safe in alprazolam withdrawal.

Adult↗
PubMed2004

Cost-effectiveness of psychological and pharmacological interventions for generalized anxiety disorder and panic disorder.

OBJECTIVE: To assess from a health sector perspective the incremental cost-effectiveness of interventions for generalized anxiety disorder (cognitive behavioural therapy [CBT] and serotonin and noradrenaline reuptake inhibitors [SNRIs]) and panic disorder (CBT, selective serotonin reuptake inhibitors [SSRIs] and tricyclic antidepressants [TCAs]). METHOD: The health benefit is measured as a reduction in disability-adjusted life years (DALYs), based on effect size calculations from meta-analyses of randomised controlled trials. An assessment on second stage filter criteria ("equity", "strength of evidence", "feasibility" and "acceptability to stakeholders") is also undertaken to incorporate additional factors that impact on resource allocation decisions. Costs and benefits are calculated for a period of one year for the eligible population (prevalent cases of generalized anxiety disorder/panic disorder identified in the National Survey of Mental Health and Wellbeing, extrapolated to the Australian population in the year 2000 for those aged 18 years and older). Simulation modelling techniques are used to present 95% uncertainty intervals (UI) around the incremental cost-effectiveness ratios (ICERs). RESULTS: Compared to current practice, CBT by a psychologist on a public salary is the most cost-effective intervention for both generalized anxiety disorder (A$6900/DALY saved; 95% UI A$4000 to A$12 000) and panic disorder (A$6800/DALY saved; 95% UI A$2900 to A$15 000). Cognitive behavioural therapy results in a greater total health benefit than the drug interventions for both anxiety disorders, although equity and feasibility concerns for CBT interventions are also greater. CONCLUSIONS: Cognitive behavioural therapy is the most effective and cost-effective intervention for generalized anxiety disorder and panic disorder. However, its implementation would require policy change to enable more widespread access to a sufficient number of trained therapists for the treatment of anxiety disorders.

Antidepressive Agents, Tricyclic↗
PubMed2000

Venlafaxine treatment of cocaine abusers with depressive disorders.

OBJECTIVE: There appears to be a link between depression and cocaine that is both complex and elusive. The purpose of this study was to examine the effect of venlafaxine, a broad spectrum antidepressant, in the treatment of 13 patients who were diagnosed with cocaine dependence and comorbid major depressive disorder (MDD). METHOD: The majority of the patients in the study were part of a larger double-blind trial using desipramine. This subgroup consisted of people who had failed to respond to desipramine or could not tolerate its side effects. Thirteen patients were enrolled, 10 men and 3 women. Of the patients, 11 completed the 12-week study. All of the patients had a Hamilton Depression (HAM-D) score greater than 14 at baseline, and each had used at least $20 worth of cocaine per week in the 4 weeks prior to entering the study. In addition, all of the patients received weekly relapse prevention therapy throughout the study. The median dose of venlafaxine was 150 mg/day. RESULTS: The 11 patients who completed the study had significant reductions in mood symptoms by the end of the study. The average total HAM-D score at baseline was 18.0 +/- 3.2; at Week 2, it was 1.9 +/- 0.94; and at the end of the study, it was 1.4 +/- 1.8. The majority of patients reported reductions of cocaine use short of abstinence. All subjects reported a greater than 75% reduction in cocaine use compared to baseline. There were no serious side effects. CONCLUSIONS: The results of this small study indicate that venlafaxine may be a safe, well-tolerated, rapidly acting, and effective treatment for patients with a dual diagnosis of depression and cocaine dependence.

Adult↗
PubMed2000

A depressed myocardium.

BACKGROUND: Venlafaxine is a potent neuronal serotonin and noradrenaline re-uptake inhibitor, and to a lesser extent an inhibitor of dopamine reuptake. Paroxetine is a potent selective inhibitor of serotonin reuptake. CASE REPORT: A 27-year-old man ingested 1987.5 mg of venlafaxine and 360 mg of paroxetine. He subsequently developed systolic and diastolic hypertension, transient electrocardiographic abnormalities, and an area of persistent myocardial damage. He recovered from his overdose with his blood pressure and electrocardiogram returning to normal. The area of myocardial damage was documented on echocardiogram as an area of marked hypokinesia at the basal anterior septum. Despite the absence of confirming blood levels or the absolute exclusion of cocaine, this case indicates that venlafaxine and paroxetine have the potential for serious cardiotoxicity when taken in overdose.

Adult↗
PubMed2003

Massive venlafaxine overdose resulted in a false positive Abbott AxSYM urine immunoassay for phencyclidine.

CASE REPORT: A 13-yr-old girl overdosed on 48 x 150 mg venlafaxine (Effexor XR). She was taking venlafaxine regularly for depression. Her only other medications included topical Benzamycin and pyridoxine 50 mg daily for acne. The Abbott AxSYM assay was positive only for phencyclidine, but GC/MS did not confirm the presence of phencyclidine. Toxilab identified only one substance, confirmed by GC/MS as venlafaxine. A serum sample obtained 3 h after her ingestion revealed a venlafaxine concentration of 24460 ng/mL and an O-desmethylvenlafaxine concentration of 3930 ng/mL, confirming the massive acute overdose (therapeutic range of venlafaxine and O-desmethylvenlafaxine together is 250-750 ng/mL). Urine spiked with 4.2 mg/mL ofvenlafaxine and 0.7 mg/mL of O-desmethylvenlafaxine was interpreted as positive with the Abbott AxSYM fluorescent polarized immunoassay for phencyclidine (readout of 28 ng/mL). CONCLUSION: Venlafaxine may cause a false positive Abbott AxSYM phencyclidine assay when present in very high concentrations. Physicians should be aware of this potential reaction when interpreting urine drug immunoassays.

Adolescent↗
PubMed2004

Comparative toxicity of citalopram and the newer antidepressants after overdose.

OBJECTIVE: To compare the toxicity of citalopram, venlafaxine, mirtazapine, and nefazadone after overdose. METHODS: Two-year retrospective review of consecutive patients admitted to the toxicology unit of Edinburgh Royal Infirmary. Outcome measure included physiological variables, ECG recordings, peak creatine kinase, development of arrhythmias, seizure, tremor or agitation, and the need for admission to a critical care facility. RESULTS: A total of 225 patients were studied. Venlafaxine was associated with a significantly higher pulse rate (p < 0.0001) and tremor (p = 0.007) than other antidepressants. Citalopram was associated with a significantly longer QT interval on ECG recording (p < 0.0001) but mean QTc durations were not significantly different between all drugs studied. No arrhythmias were recorded. Only venlafaxine and citalopram caused seizures and were associated with the need for admission to Intensive Care, but there was no significant difference between them. CONCLUSIONS: Mirtazapine and nefazadone appear safe in overdose and were associated with minimal features of neurological or cardiovascular toxicity. Citalopram is more likely to cause QT prolongation but other features of cardiovascular toxicity were uncommon. Both citalopram and venlafaxine are proconvulsants. Venlafaxine also causes more frequent features of the serotonin syndrome.

Administration, Oral↗
PubMed1998

Na+-dependent Ca2+ extrusion governs response recovery in frog olfactory receptor cells.

To study the mechanism by which Ca2+, which enters during the odor response, is extruded during response recovery, recordings were made from isolated frog olfactory receptor cells using the suction pipette technique, while superfusing the olfactory cilia with solutions of modified ionic composition. When external Na+ was substituted with another cation, the response to odor was greatly prolonged. This prolongation of the response was similar irrespective of whether Na+ was replaced with Li+, which permeates the cyclic nucleotide-gated conductance, or choline, which does not. The prolonged current was greatly reduced by exposure to 300 microM niflumic acid, a blocker of the calcium-activated chloride channel, indicating that it is carried by this conductance, and abolished if Ca2+ was omitted from the external solution, demonstrating that Ca2+ influx is required for its generation. When the cilia were exposed to Na+-free solution after odor stimulation, the recovery of the response to a second stimulus from the adaptation induced by the first was greatly reduced. We conclude that a Na+-dependent Ca2+ extrusion mechanism is present in frog olfactory cilia and that it serves as the main mechanism that returns cytoplasmic Ca2+ concentration to basal levels after stimulation and mediates the normally rapid recovery of the odor response and the restoration of sensitivity after adaptation.

Adaptation, Physiological↗
PubMed2003

Cross-adaptation between olfactory responses induced by two subgroups of odorant molecules.

It has long been believed that vertebrate olfactory signal transduction is mediated by independent multiple pathways (using cAMP and InsP3 as second messengers). However, the dual presence of parallel pathways in the olfactory receptor cell is still controversial, mainly because of the lack of information regarding the single-cell response induced by odorants that have been shown to produce InsP3 exclusively (but not cAMP) in the olfactory cilia. In this study, we recorded activities of transduction channels of single olfactory receptor cells to InsP3-producing odorants. When the membrane potential was held at -54 mV, application of InsP3-producing odorants to the ciliary region caused an inward current. The reversal potential was 0 +/- 7 mV (mean +/- SD, n = 10). Actually, InsP3-producing odorants generated responses in a smaller fraction of cells (lilial, 3.4%; lyral, 1.7%) than the cAMP-producing odorant (cineole, 26%). But, fundamental properties of responses were surprisingly homologous; namely, spatial distribution of the sensitivity, waveforms, I-V relation, and reversal potential, dose dependence, time integration of stimulus period, adaptation, and recovery. By applying both types of odorants alternatively to the same cell, furthermore, we observed cells to exhibit symmetrical cross-adaptation. It seems likely that even with odorants with different modalities adaptation occurs completely depending on the amount of current flow. The data will also provide evidence showing that olfactory response generation and adaptation are regulated by a uniform mechanism for a wide variety of odorants.

Adaptation, Physiological↗
PubMed2006

Odorant inhibition of the olfactory cyclic nucleotide-gated channel with a native molecular assembly.

Human olfaction comprises the opposing actions of excitation and inhibition triggered by odorant molecules. In olfactory receptor neurons, odorant molecules not only trigger a G-protein-coupled signaling cascade but also generate various mechanisms to fine tune the odorant-induced current, including a low-selective odorant inhibition of the olfactory signal. This wide-range olfactory inhibition has been suggested to be at the level of ion channels, but definitive evidence is not available. Here, we report that the cyclic nucleotide-gated (CNG) cation channel, which is a key element that converts odorant stimuli into electrical signals, is inhibited by structurally unrelated odorants, consistent with the expression of wide-range olfactory inhibition. Interestingly, the inhibitory effect was small in the homo-oligomeric CNG channel composed only of the principal channel subunit, CNGA2, but became larger in channels consisting of multiple types of subunits. However, even in the channel containing all native subunits, the potency of the suppression on the cloned CNG channel appeared to be smaller than that previously shown in native olfactory neurons. Nonetheless, our results further showed that odorant suppressions are small in native neurons if the subsequent molecular steps mediated by Ca(2+) are removed. Thus, the present work also suggests that CNG channels switch on and off the olfactory signaling pathway, and that the on and off signals may both be amplified by the subsequent olfactory signaling steps.

Animals↗