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PubMed1999

Analogues and homologues of N-palmitoylethanolamide, a putative endogenous CB(2) cannabinoid, as potential ligands for the cannabinoid receptors.

The presence of CB(2) receptors was reported in the rat basophilic cell line RBL-2H3 and N-palmitoylethanolamide was proposed as an endogenous, potent agonist of this receptor. We synthesized a series of 10 N-palmitoylethanolamide homologues and analogues, varying by the elongation of the fatty acid chain from caproyl to stearoyl and by the nature of the amide substituent, respectively, and evaluated the affinity of these compounds to cannabinoid receptors in the rat spleen, RBL-2H3 cells and CHO-CB(1) and CHO-CB(2) receptor-transfected cells. In rat spleen slices, CB(2) receptors were the predominant form of the cannabinoid receptors. No binding of [(3)H]SR141716A was observed. [(3)H]CP-55,940 binding was displaced by WIN 55,212-2 and anandamide. No displacement of [(3)H]CP-55,940 or [(3)H]WIN 55,212-2 by palmitoylethanolamide derivatives was observed in rat spleen slices. In RBL-2H3 cells, no binding of [(3)H]CP-55,940 or [(3)H]WIN 55,212-2 could be observed and conversely, no inhibitory activity of N-palmitoylethanolamide derivatives and analogues was measurable. These compounds do not recognize the human CB(1) and CB(2) receptors expressed in CHO cells. In conclusion, N-palmitoylethanolamide was, in our preparations, a weak ligand while its synthesized homologues or analogues were essentially inactive. Therefore, it seems unlikely that N-palmitoylethanolamide is an endogenous agonist of the CB(2) receptors but it may be a compound with potential therapeutic applications since it may act via other mechanisms than cannabinoid CB(1)-CB(2) receptor interactions.

Animals↗
PubMed2001

Metabolites of dietary 1,8-cineole in the male koala (Phascolarctos cinereus).

The in vivo metabolic fate of 1,8-cineole was investigated in six male koalas. Koalas were fed ad lib a diet of Eucalyptus cephalocarpa leaf with a 1,8-cineole concentration of 2.53+/-0.70% dry mass of leaf, corresponding to a 1,8-cineole intake of 2.4+/-1.1 mmol/kg (3.1+/-1.3 g). Urine and faeces were collected for 24 h and metabolites identified by GC-MS and LC-MS. Metabolites were quantified before and after hydrolysis with beta-glucuronidase to give free and total levels, respectively. Fractional recovery of ingested 1,8-cineole was 1.3+/-0.4 and 1.4+/-0.4 (mean+/-S.D.) for free and total measurements, respectively. Seven metabolites were identified and quantified: 9- and 7-hydroxycineole, 9- and 7-cineolic acid, 7-hydroxy-9-cineolic acid, 9-hydroxy-7-cineolic acid and 7,9-dicineolic acid. The hydroxycineolic acids dominated the metabolite profile (85%). 7,9-Dicineolic acid, a novel metabolite of 1,8-cineole, accounted for almost 10% of the recovered dose making it the second most abundant metabolite after 7-hydroxy-9-cineolic acid (77%). Together, the less oxidised metabolites, the hydroxycineoles and cineolic acid, accounted for only 5% of the cineole consumed. Significant conjugation only occurred with four minor, less oxidised, alcohol and carboxylic acid metabolites. We have shown that the koala detoxifies and eliminates 1,8-cineole primarily by extensive oxidation without utilising conjugation pathways.

Animals↗
PubMed2003

Cannabinoid CB1 receptor activation does not prevent the toxicity of glutamate towards embryonic chick telencephalon primary cultures.

Cannabinoids, as a result of their ability to activate cannabinoid CB1 receptors, have been shown to possess neuroprotective properties in vivo. In vitro studies into neuroprotective effects mediated by CB1 receptors have in general used primary neuronal cultures derived from embryonic rodents. In the present study, we have investigated whether embryonic chick telencephalon primary cultures in serum-free medium are a useful alternative for such in vitro studies. The CB agonist CP 55940 reduced the cAMP response to 5 microM forskolin by 40 and 50% at concentrations of 3 nM and 30 nM, respectively. This reduction was blocked by the CB1 receptor antagonist AM251, indicating the presence of functional CB1 receptors in the cultures. Incubation of the cultures with glutamate (100 microM or 1 mM) for 1 h followed by medium change and incubation for 24 h produced a release of the cytoplasmic enzyme lactate dehydrogenase into the medium. This release was prevented by MK-801 confirming the central role of NMDA receptors in the glutamate toxicity. However, 3-30 nM CP 55940 did not produce any neuroprotection in this model regardless as to whether dibutyryl cyclic AMP was added to the culture medium. The endocannabinoid anandamide was also without effect when added either per se or together with the related N-acyl ethanolamines palmitoylethanolamide, oleoylethanolamide and stearoylethanolamide (at relative concentrations matching those seen in rat brain after excitotoxic insult). It is concluded that embryonic chick neurons in primary serum-free culture are not a useful model for the study of neuroprotective effects mediated by CB1 receptors in vitro.

Animals↗
PubMed2002

Application of solid-phase microextraction to the quantitative analysis of 1,8-cineole in blood and expired air in a Eucalyptus herbivore, the brushtail possum (Trichosurus vulpecula).

We have developed two solid-phase microextraction (SPME) methods, coupled with gas chromatography, for quantitatively analysing the major Eucalyptus leaf terpene, 1,8-cineole, in both expired air and blood from the common brushtail possum (Trichosurus vulpecula). In-line SPME sampling (5 min at 20 degrees C room temperature) of excurrent air from an expiratory chamber containing a possum dosed orally with 1,8-cineole (50 mg/kg) allowed real-time semi-quantitative measurements reflecting 1,8-cineole blood concentrations. Headspace SPME using 50 microl whole blood collected from possums dosed orally with 1,8-cineole (30 mg/kg) resulted in excellent sensitivity (quantitation limit 1 ng/ml) and reproducibility. Blood concentrations ranged between 1 and 1380 ng/ml. Calibration curves were prepared for two concentration ranges (0.05-10 and 10-400 ng/50 microl) for the analysis of blood concentrations. Both calibration curves were linear (r(2)=0.999 and 0.994, respectively) and the equations for the two concentration ranges were consistent.

Air↗
PubMed2006

Can venlafaxine in breast milk attenuate the norepinephrine and serotonin reuptake neonatal withdrawal syndrome.

A newborn infant whose mother had used venlafaxine, a selective inhibitor of both norepinephrine and serotonin reuptake, throughout pregnancy exhibited signs consistent with the norepinephrine and serotonin reuptake withdrawal syndrome. Is it possible that mother's milk can help mitigate the effects of norepinephrine and serotonin reuptake withdrawal? Pharmacokinetic analysis and review of the only published case with active treatment of a baby with venlafaxine suggest that breastfeeding may mitigate the neonatal withdrawal syndrome.

Breast Feeding↗
PubMedDate not supplied

Cannabinoid receptors on goldfish retinal bipolar cells: electron-microscope immunocytochemistry and whole-cell recordings.

Cannabinoid CB1 receptors are distributed throughout the CNS and interact with GABA, glutamate, and dopamine systems. Cannabinoids have effects on the visual system, some of which may have a retinal component, particularly the enhancement of photosensitivity. We used immunocytochemistry and whole-cell recording to study cannabinoids in the goldfish retina. Immunoblots of an antiserum against amino acids (1-14) of the rat CB1 receptor produced a single band in goldfish retina at about 70 kDa. Light microscope immunocytochemistry of CB1 receptor immunoreactivity (CB1R-IR) revealed intense staining of Müller cells and weaker staining of ON bipolar cells (verified with double labeling with PKC-IR) and the outer and inner plexiform layers. Ultrastructural analysis revealed that CB1R-IR was localized intracellularly as well as on the plasma membrane of photoreceptor terminals, bipolar cell terminals and, rarely, amacrine cell boutons. Membrane-associated CB1R-IR was restricted to cone pedicles at sites removed from the synaptic ribbon. Regarding bipolar cells, membrane-associated CB1R-IR was found at 93% of the synaptic terminals in sublamina b (ON-type) and only at 33% of the synaptic terminals in sublamina a (OFF-type). Whole-cell recordings from large ON-type Mb bipolar cells showed that the delayed rectifier (I(K(V))) was rapidly and reversibly inhibited by 1 microM of the cannabinoid agonists CP 54490 and (+)-WIN 55212-2, effects blocked completely by the antagonist SR 141716A (1 microM). Inhibition of I(K(V)) in the Mb bipolar cells by cannabinoids should result in a more tonic ON response to increments of light. As such, cannabinoids may play a role in modulating the temporal aspects of signaling in the retina.

Animals↗
PubMed2004

The isoepoxydon dehydrogenase gene of patulin biosynthesis in cultures and secondary metabolites as candidate PCR inhibitors.

The European Union (EU) has introduced statutory limits for patulin in fruit products. Species definitions need to be unambiguous for this capability, especially to determine 'weak spots' in food, drink and feed production. Fungi were analysed for the isoepoxydon dehydrogenase (IDH) gene of the patulin metabolic pathway to indicate potential patulin production. In several cases inhibition of PCR product formation was indicated. Dilution as a means of overcoming PCR inhibition and to determine optimal concentrations was assessed and the ramifications for nucleic acid analysis in general are highlighted. The inhibitors may be secondary metabolites. However, inhibition was not involved obviously for Penicillium brevicompactum. The gene was detected frequently from Aspergillus section Clavati and Penicillium subgenus Penicillium species. Some strains within certain species were negative for the gene. Detection of the gene product in Byssochlamys is reported.

Culture Media↗
PubMed2003

Treatment considerations for anxiety in the elderly.

Anxiety is common in the elderly and can present as a primary anxiety disorder or as a symptom of another disorder. Generalized anxiety disorder, in particular, is a common syndrome in late life. Anxiety symptoms are also common features of late-life depression and dementia. Treatment of anxiety in elderly persons has typically involved the use of benzodiazepines, which are often effective but problematic because they are associated with increased risk of cognitive impairment, falls, and fractures. Based on their safety and efficacy, antidepressants, particularly serotonergic medications, are considered first-line treatment for most anxiety disorders as well as anxiety symptoms of major depressive disorder. Psychotherapy, particularly cognitive-behavioral therapy, may be effective in these disorders as well; research is underway to adapt this therapy to the needs of elderly persons. Anxiety symptoms in dementia are poorly understood but may respond to atypical antipsychotics, serotonergic antidepressants, or mood stabilizers. Overall, the research in late-life anxiety has not caught up to the literature in late-life depression and, for the most part, treatment recommendations must be extrapolated from studies in young adults.

Aged↗
PubMed2006

Beyond remission: rationale and design of the Prevention of Recurrent Episodes of Depression with Venlafaxine for Two Years (PREVENT) Study.

Recurrent major depressive disorder (MDD) is a common and disabling illness, but few studies have addressed long-term antidepressant treatment of recurrent MDD (ie, beyond 1 year of maintenance therapy) or compared the efficacy and safety of different antidepressant classes in this population. This article describes the rationale and design of a unique multi-phase trial in patients with recurrent MDD. The Prevention of Recurrent Episodes of Depression with Venlafaxine for Two Years (PREVENT) study is a large double-blind, randomized, multi-center trial designed to assess the long-term efficacy of venlafaxine extended release (ER) in the prevention of depressive recurrence. Approximately 1,100 adult outpatients with MDD and a history of >or=3 lifetime episodes (with at least two occurring in the past 5 years) were randomized to 10 weeks of acute-phase treatment with either venlafaxine ER 75-300 mg/day or fluoxetine 20-60 mg/day, followed by 6 months of continuation-phase treatment for patients experiencing a satisfactory therapeutic response or remission during the acute phase. Responders and remitters to continuation phase treatment were then entered into a 2-year maintenance phase study, in which those receiving venlafaxine ER were re-randomized to either venlafaxine ER or placebo at the start of two 12-month maintenance periods. Those taking fluoxetine during the acute and continuation phases continued to receive double-blind treatment with fluoxetine. This study will address several unanswered questions about the long-term treatment of recurrent MDD, such as whether extended maintenance treatment (ie, up to 2 years) lessens the risk for developing future depressive episodes; whether fluoxetine and venlafaxine ER are effective for both short- and long-term treatment of MDD; whether rates of tachyphylaxis differ between antidepressant classes; and whether the likelihood of depressive recurrence differs according to the time point when treatment is discontinued.

Antidepressive Agents↗
PubMed2003

Venlafaxine treatment of obsessive-compulsive disorder: case reports.

About one-third of patients affected by obsessive-compulsive disorder fail to respond to serotonergic drugs and different strategies have been proposed for these resistant cases. This article reports experiences with venlafaxine in patients with obsessive-compulsive disorder who did not respond or did not tolerate serotonergic drugs.

Adult↗
PubMed2005

SNRIs: their pharmacology, clinical efficacy, and tolerability in comparison with other classes of antidepressants.

The class of serotonin and norepinephrine reuptake inhibitors (SNRIs) now comprises three medications: venlafaxine, milnacipran, and duloxetine. These drugs block the reuptake of both serotonin (5-HT) and norepinephrine with differing selectivity. Whereas milnacipran blocks 5-HT and norepinephrine reuptake with equal affinity, duloxetine has a 10-fold selectivity for 5-HT and venlafaxine a 30-fold selectivity for 5-HT. All three SNRIs are efficacious in treating a variety of anxiety disorders. There is no evidence for major differences between SNRIs and SSRIs in their efficacy in treating anxiety disorders. In contrast to SSRIs, which are generally ineffective in treating chronic pain, all three SNRIs seem to be helpful in relieving chronic pain associated with and independent of depression. Tolerability of an SNRI at therapeutic doses varies within the class. Although no direct comparative data are available, venlafaxine seems to be the least well-tolerated, combining serotonergic adverse effects (nausea, sexual dysfunction, withdrawal problems) with a dose-dependent cardiovascular phenomenon, principally hypertension. Duloxetine and milnacipran appear better tolerated and essentially devoid of cardiovascular toxicity.

Antidepressive Agents↗
PubMed2006

Defining response and remission in anxiety disorders: toward an integrated approach.

Response and remission rates are commonly used to evaluate the efficacy of treatments for anxiety disorders and other psychiatric illnesses. Response is generally regarded as a clinically meaningful improvement in symptoms, while remission, the goal of treatment, is generally thought of as the absence or near absence of symptoms following illness, accompanied by a return to premorbid levels of functioning. Response and remission are often defined using psychiatric rating scales, based on score cutoffs or the magnitude of score changes from baseline. While no universally accepted criteria exist, a commonly used threshold for response is a >50% improvement in the total score, while for remission, various cutoff points have been used. Comparison of cutoffs or change scores for disease-specific scales with Clinical Global Impressions ratings is a useful way of evaluating response and remission criteria across disorders. To illustrate the use of disease-specific and global measures, this article summarizes data from randomized, placebo-controlled studies of adult patients with generalized anxiety disorder, social anxiety disorder, or panic disorder treated with the serotonin norepinephrine reuptake inhibitor venlafaxine extended release, for which acute-phase data are available (a total of 13 trials).

Anti-Anxiety Agents↗
PubMed2001

Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials: a replication analysis of the Food and Drug Administration Database.

The assumption that depressed patients who are assigned to placebo in antidepressant clinical trials are exposed to substantial morbidity and mortality has not been based on research data. Because of worldwide concern about placebo use and the implications of our earlier findings of no increased suicide risk in placebo-treated patients, we conducted a replication study in a new patient sample. We assessed suicide risk and symptom reduction among placebo-treated patients participating in antidepressant clinical trials for two recently approved antidepressants, venlafaxine ER and citalopram, which were unavailable during our previous study. Among 23,201 participant patients, 32 committed suicide and 172 attempted suicide. Rates of suicide and attempted suicide did not differ significantly among the placebo- and drug-treated groups. Based on patient exposure years, annual rates of suicide and attempted suicide were 0.5 and 6.7% with placebo, 0.9% with active comparator (rates for attempted suicide are unavailable), and 0.6 and 6.3% with investigational antidepressants. Symptom reduction was 47.9% with investigational drugs (n = 1172), 47.5% with active comparators (n = 161), and 35.5% with placebo (n = 606). These data may inform discussions about the use of placebo in antidepressant clinical trials.

Adult↗
PubMed2002

Venlafaxine compared with fluoxetine in outpatients with depression and concomitant anxiety.

The aim of this double-blind study was to compare the efficacy and safety of venlafaxine vs. fluoxetine in the treatment of patients with depression and anxiety. A total of 146 moderately depressed patients with associated anxiety were randomized to receive 75 mg/d venlafaxine or 20 mg/d fluoxetine for 12 wk. Dose increases were permitted after 2 wk of treatment, to 150 mg/d venlafaxine and 40 mg/d fluoxetine, to optimize response. At the final visit, a statistically significantly greater efficacy of venlafaxine over fluoxetine was observed on depressive symptoms and concomitant anxiety, and 75.0 and 50.7% of patients administered venlafaxine and fluoxetine, respectively, showed an overall response. A sustained response (for at least 2 wk), present at the end of the study was achieved in 57.8 and 43.3% of patients in the venlafaxine and fluoxetine groups, respectively, and at the final visit, 59.4 and 40.3% of patients, respectively, were in remission (virtually asymptomatic). Dose increases were required by a greater percentage of patients in the fluoxetine group (52.9%), than in the venlafaxine group (37.1%), and in those patients whose dose was increased, a higher efficacy was again observed with venlafaxine. Venlafaxine and fluoxetine were well tolerated, with the most frequently experienced adverse events being nausea and headache. Fewer patients in the venlafaxine group than in the fluoxetine group reported at least one adverse event (55.7 and 67.1% patients, respectively). Venlafaxine therefore proved to be significantly more effective than fluoxetine in improving depressive symptoms and concomitant anxiety.

Adolescent↗