Effect of venlafaxine on anhedonia and amotivation in patients with major depressive disorder.

OBJECTIVE: Serotonin norepinephrine reuptake inhibitors (SNRIs) have been postulated to afford benefits in alleviating anhedonia and amotivation. This post hoc pooled analysis evaluated the effect of venlafaxine XR, an SNRI, on these symptoms in patients with major depressive disorder (MDD). METHODS: Data was pooled from five short-term randomized, placebo-controlled studies of venlafaxine XR for the treatment of MDD, comprising 1087 (venlafaxine XR, n = 585; placebo, n = 502) adult subjects. The change from baseline score in the MADRS anhedonia factor (based on items 1 [apparent sadness], 2 [reported sadness], 6 [concentration difficulties], 7 [lassitude], and 8 [inability to feel]) for anhedonia, and in motivational deficits (based on 3 items of HAM-D17: involvement in work and activities, psychomotor retardation, and energy level [ie, general somatic symptoms]) for amotivation, were measured through 8 weeks. Mixed model repeated measures (MMRMs) were used to analyze changes over time and ANCOVA to analyze the change from baseline at week 8 with LOCF employed to handle missing data. RESULTS: At the end of 8 weeks, the change from baseline was significantly greater in patients on venlafaxine XR in both anhedonia (mean, 95% CI: -2.73 [-3.63, -1.82], p < 0.0001) and amotivation scores (mean, 95% CI: -0.78 [-1.04, -0.52], p < 0.0001) than those on placebo. For both measures, the between-group separation from baseline was statistically significant starting from week 2 onwards, and it increased over time. CONCLUSION: This analysis demonstrates that venlafaxine XR is effective in improving symptoms of anhedonia and motivational deficits in patients with MDD.

CYP2D6 Phenotype Influences Pharmacokinetic Parameters of Venlafaxine: Results from a Population Pharmacokinetic Model in Older Adults with Depression.

In this study, we aimed to improve upon a published population pharmacokinetic (PK) model for venlafaxine (VEN) in the treatment of depression in older adults, then investigate whether CYP2D6 metabolizer status affected model-estimated PK parameters of VEN and its active metabolite O-desmethylvenlafaxine. The model included 325 participants from a clinical trial in which older adults with depression were treated with open-label VEN (maximum 300 mg/day) for 12 weeks and plasma levels of VEN and O-desmethylvenlafaxine were assessed at weeks 4 and 12. We fitted a nonlinear mixed-effect PK model using NONMEM to estimate PK parameters for VEN and O-desmethylvenlafaxine adjusted for CYP2D6 metabolizer status and age. At both lower doses (up to 150 mg/day) and higher doses (up to 300 mg/day), CYP2D6 metabolizers impacted PK model-estimated VEN clearance, VEN exposure, and active moiety (VEN + O-desmethylvenlafaxine) exposure. Specifically, compared with CYP2D6 normal metabolizers, (i) CYP2D6 ultra-rapid metabolizers had higher VEN clearance; (ii) CYP2D6 intermediate metabolizers had lower VEN clearance; (iii) CYP2D6 poor metabolizers had lower VEN clearance, higher VEN exposure, and higher active moiety exposure. Overall, our study showed that including a pharmacogenetic factor in a population PK model could increase model fit, and this improved model demonstrated how CYP2D6 metabolizer status affected VEN-related PK parameters, highlighting the importance of genetic factors in personalized medicine.

Moving from serotonin to serotonin-norepinephrine enhancement with increasing venlafaxine dose: clinical implications and strategies for a successful outcome in major depressive disorder.

INTRODUCTION: Mental health disorders, especially depressive and anxiety disorders, are associated with substantial health-related burden. While the second-generation antidepressants are widely accepted as first-line pharmacological treatment for major depressive disorder (MDD), patient response to such treatment is variable, with more than half failing to achieve complete remission, and residual symptoms are frequently present. AREAS COVERED: Here, the pharmacodynamics of venlafaxine XR are reviewed in relation to its role as both a selective serotonin reuptake inhibitor (SSRI) and a serotonin-norepinephrine-reuptake inhibitor (SNRI), and we look at how these pharmacodynamic properties can be harnessed to guide clinical practice, asking the question 'is it possible to develop a symptom-cluster-based approach to the treatment of MDD with comorbid anxiety utilizing venlafaxine XR?.' Additionally, three illustrative clinical cases provide practical examples of the utility of venlafaxine-XR in real-world clinical practice. The place of venlafaxine XR in managing fatigue/low energy, a frequent residual symptom in MDD, is explored using pooled data from clinical trials of venlafaxine XR. EXPERT OPINION: Venlafaxine XR should be considered as a first-line treatment for MDD with or without comorbid anxiety, and there are clear pharmacodynamic signals supporting a symptom cluster-based treatment paradigm for venlafaxine XR.

Efficacy and tolerability of desvenlafaxine in the real-world treatment of patients with major depression: a narrative review and an expert opinion paper.

INTRODUCTION: Major depressive disorder (MDD) is a common severe mental disorder, requiring a tailored and integrated treatment. Several approaches are available including different classes of antidepressants various psychotherapeutic approaches, and psychosocial interventions. The treatment plan for each patient with MDD should be differentiated on the basis of several clinical, personal, and contextual factors. AREAS COVERED: Desvenlafaxine - a serotonine-noradrenergic reuptake inhibitor (SNRI) antidepressant - has been approved in the United States in 2008 for the treatment of MDD in adults, and has been recently rediscovered by clinicians due to its good side-effect profile and its clinical effectiveness. A narrative review on efficacy, tolerability and use of desvenlafaxine in clinical practice was carried out. The keywords: 'major depression', 'depression,' 'desvenlafaxine,' 'efficacy,' 'clinical efficacy,' 'side effects', 'tolerability,' 'elderly patients', 'consultation-liaison', 'menopausal', 'young people', 'adolescent' were entered in PubMed, ISI Web of Knowledge, Scopus and Medline. No time limit was fixed, the search strategy was implemented on May 10, 2023. EXPERT OPINION: Desvenlafaxine should be listed among the optimal treatment strategies for managing people with MDD, whose main strengths are: 1) ease of dosing; 2) favorable safety and tolerability profile, 3) absence of sexual dysfunctions, weight gain and low rate of discontinuation symptoms; 4) low risk of drug-drug interactions.

Psychopharmacological properties and therapeutic profile of the antidepressant venlafaxine.

Major depression (MD) is one of the most common psychiatric disorders worldwide. Currently, the first-line treatment for MD targets the serotonin system but these drugs, notably the selective serotonin reuptake inhibitors, usually need 4 to 6 weeks before the benefit is felt and a significant proportion of patients shows an unsatisfactory response. Numerous treatments have been developed to circumvent these issues as venlafaxine, a mixed serotonin-norepinephrine reuptake inhibitor that binds and blocks both the SERT and NET transporters. Despite this pharmacological profile, it is difficult to have a valuable insight into its ability to produce more robust efficacy than single-acting agents. In this review, we provide an in-depth characterization of the pharmacological properties of venlafaxine from in vitro data to preclinical and clinical efficacy in depressed patients and animal models of depression to propose an indirect comparison with the most common antidepressants. Preclinical studies show that the antidepressant effect of venlafaxine is often associated with an enhancement of serotonergic neurotransmission at low doses. High doses of venlafaxine, which elicit a concomitant increase in 5-HT and NE tone, is associated with changes in different forms of plasticity in discrete brain areas. In particular, the hippocampus appears to play a crucial role in venlafaxine-mediated antidepressant effects notably by regulating processes such as adult hippocampal neurogenesis or the excitatory/inhibitory balance. Overall, depending on the dose used, venlafaxine shows a high efficacy on depressive-like symptoms in relevant animal models but to the same extent as common antidepressants. However, these data are counterbalanced by a lower tolerance. In conclusion, venlafaxine appears to be one of the most effective treatments for treatment of major depression. Still, direct comparative studies are warranted to provide definitive conclusions about its superiority.

Venlafaxine and O-desmethylvenlafaxine serum levels are positively associated with antidepressant response in elder depressed out-patients.

BACKGROUND: Therapeutic Drug Monitoring (TDM) represents one of the most promising tools in clinical practice to optimise antidepressant treatment. Nevertheless, little is still known regarding the relationship between clinical efficacy and serum concentration of venlafaxine (VEN). The aim of our study was to investigate the association between serum concentration of venlafaxine + O-desmethylvenlafaxine (SCVO) and antidepressant response (AR). METHODS: 52 depressed outpatients treated with VEN were recruited and followed in a naturalistic setting for three months. Hamilton Depression Rating Scale-21 was administered at baseline, at month 1 and at month 3 to assess AR. SCVO was measured at steady state. Linear regression analysis and nonlinear least-squares regression were used to estimate association between SCVO and AR. RESULTS: Our results showed an association between AR and SCVO that follows a bell-shaped quadratic function with a progressive increase of AR within the therapeutic reference range of SCVO (i.e. 100-400 ng/mL) and a subsequent decrease of AR at higher serum levels. DISCUSSION: This study strongly suggests that TDM could represent a more appropriate tool than the oral dosage to optimise the treatment with VEN. Specifically, highest efficacy might be achieved by titrating patients at SCVO levels around 400 ng/mL.

Discovery of the Selective Protein Kinase C-θ Kinase Inhibitor, CC-90005.

The PKC-θ isoform of protein kinase C is selectively expressed in T lymphocytes and plays an important role in the T cell antigen receptor (TCR)-triggered activation of mature T cells, T cell proliferation, and the subsequent release of cytokines such as interleukin-2 (IL-2). Herein, we report the synthesis and structure-activity relationship (SAR) of a novel series of PKC-θ inhibitors. Through a combination of structure-guided design and exploratory SAR, suitable replacements for the basic C4 amine of the original lead (3) were identified. Property-guided design enabled the identification of appropriately substituted C2 groups to afford potent analogs with metabolic stability and permeability to support in vivo testing. With exquisite general kinase selectivity, cellular inhibition of T cell activation as assessed by IL-2 expression, a favorable safety profile, and demonstrated in vivo efficacy in models of acute and chronic T cell activation with oral dosing, CC-90005 (57) was selected for clinical development.

Desvenlafaxine in the treatment of major depression: an updated overview.

Introduction: Major depressive disorder (MDD) remains one of the most prevalent mental health conditions. It is a chronic, relapsing condition and despite multiple treatment options, many patients fail to achieve remission of symptoms. Inadequacy of treatment has stimulated the search for agents with significant therapeutic advantages.Areas covered: This review examines literature concerning the use of desvenlafaxine in the treatment of MDD published since a previous analysis in this journal in 2014. Published papers were identified via a PubMed and Web of Science search and excluded congress presentations. Results from clinical trials in MDD, systematic reviews, and post hoc analyses in patient subgroups, are reviewed.Expert opinion: Desvenlafaxine was an effective antidepressant with favorable safety and tolerability in adults. Efficacy was demonstrated in the subgroup of peri- and post-menopausal women with MDD but not in children and adolescents. There is a relatively low potential for drug-drug interactions due to its metabolic profile. Hepatic impairment does not significantly alter dose requirements, whereas severe renal disease requires some adjustments of dose. Desvenlafaxine maybe suitable in patients with comorbid physical illnesses. Desvenlafaxine can be a first line consideration for the treatment of cases of MDD uncomplicated by medical comorbidities.

The synthetic CB1 cannabinoid receptor selective agonists: Putative medical uses and their legalization.

More than 500 molecules have been identified as components of Cannabis sativa (C. sativa), of which the most studied is Δ9-tetrahydrocannabinol (Δ9-THC). Several studies have suggested that Δ9-THC exerts diverse biological effects, ranging from fragmentation of DNA to behavioral disruptions. Currently, it is accepted that most of the pharmacological properties of Δ9-THC engage the activation of the cannabinoid receptors, named CB1 and CB2. Interestingly, multiple pieces of evidence have suggested that the cannabinoid receptors play an active role in the modulation of several diseases leading to the design of synthetic cannabinoid-like compounds. Advances in the development of synthetic CB1 cannabinoid receptor selective agonists as therapeutical approaches are, however, limited. This review focuses on available evidence searched in PubMed regarding the synthetic CB1 cannabinoid receptor selective agonists such as AM-1235, arachidonyl-2' chloroethylamide (ACEA), CP 50,556-1 (Levonantradol), CP-55,940, HU-210, JWH-007, JWH-018, JWH-200 (WIN 55,225), methanandamide, nabilone, O-1812, UR-144, WIN 55,212-2, nabiximols, and dronabinol. Indeed, it would be ambitious to describe all available evidence related to the synthetic CB1 cannabinoid receptor selective agonists. However, and despite the positive evidence on the positive results of using these compounds in experimental models of health disturbances and preclinical trials, we discuss evidence in regards some concerns due to side effects.

Comparison of venlafaxine alone versus venlafaxine plus late partial sleep deprivation therapy combination for major depressive disorder.

Treatment resistance, medication non-adherence, and side effects of pharmacotherapeutics make treatment difficult in major depressive disorder. Sleep deprivation is a fast-acting and tolerable reinforcement treatment method. In this study, we investigated the effects of late partial sleep deprivation (PSD) therapy added to venlafaxine treatment on symptoms of anxiety and depression, sleep quality and treatment process. This study was conducted in a sample of 40 patients who were admitted to our inpatient psychiatric unit with a diagnosis of major depressive disorder. While the venlafaxine (Ven) group received only venlafaxine treatment, the venlafaxine+partial sleep deprivation (Ven+PSD) group underwent late partial sleep deprivation therapy three times in the first week in addition to venlafaxine treatment. The Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Rating Scale (HAM-D), Beck Depression Inventory, Pittsburgh Sleep Quality Index, and Insomnia Severity Index (ISI) were administered to both groups at the baseline and at the end of the 1st, 4th, and 6th weeks and, additionally, Profile of Mood State (POMS) was administered to the Ven+PSD group before and after each PSD. The Ven+PSD group had lower HAM-D and HAM-A scores than the Ven group at the end of the 1st and 6th week. Both anxiety and depression subscale scores on the POMS showed a significant decrease after PSD in the Ven+PSD group. The mean venlafaxine dose (mg/d) was significantly lower in the Ven+PSD group than in the Ven group. Late partial sleep deprivation is a fast-acting and tolerable therapy in major depressive disorder.

Clustering patients by depression symptoms to predict venlafaxine ER antidepressant efficacy: Individual patient data analysis.

OBJECTIVE: To identify clusters of patients with major depressive disorder (MDD) based on the baseline 17-item Hamilton Rating Scale for Depression (HAM-D17) items and to evaluate the efficacy of venlafaxine extended release (VEN) vs placebo, and the potential effect of dose on efficacy, in each cluster. METHODS: Cluster analysis was performed to identify clusters based on standardized HAM-D17 item scores of individual patient data at baseline from 9 double-blind, placebo-controlled studies of VEN for MDD. Change from baseline in HAM-D17 total score was analyzed using a mixed-effects model for repeated measures for each cluster; response and remission rates at week 8 were analyzed using logistic regression. Discontinuation rates were also evaluated in each cluster. RESULTS: In 2599 patients, 3 patient clusters were identified, characterized as High modified Core (mCore) Symptoms/High Anxiety (cluster 1), High mCore Symptoms/Medium Anxiety (cluster 2), and Medium mCore Symptoms/Medium Anxiety (cluster 3). Significant effects of VEN vs placebo were observed on change from baseline in HAM-D17 total score at week 8 for both clusters 1 and 2 (both P < 0.001), but not for cluster 3. In cluster 3, a significant treatment effect of VEN was observed at week 8 in the lower-dose subgroup but not in the higher-dose subgroup. All-cause discontinuation rates were significantly higher in placebo than VEN in each cluster. CONCLUSIONS: Three unique clusters of patients were identified differing in baseline mCore symptoms and anxiety. Cluster membership may predict efficacy outcomes and contribute to dose effects in patients treated with VEN. CLINICAL TRIALS REGISTRATION: NCT01441440; other studies included in this analysis were conducted before the requirement to register clinical studies took effect.

Efficacy of a skin care cream with TRPV1 inhibitor 4-t-butylcyclohexanol in the topical therapy of perioral dermatitis.

BACKGROUND: Perioral dermatitis is a clinically distinctive reaction pattern of facial dermatitis, including redness, dryness, burning, pruritus and skin tightness. A gold standard treatment remains unclear. OBJECTIVES: Our study evaluates the clinical value of a skin care cream with the transient receptor potential vanilloid type 1 inhibitor 4-t-butylcyclohexanol in POD patients over 8 weeks. METHODS: This open, unblinded 8-week clinical trial included 48 patients. A skin care cream containing 4-t-butylcyclohexanol was applied over a period of 8 weeks. Standardized questionnaires were used at baseline, 4 and 8 weeks, for history documentation, objective and subjective severity scores, and quality of life assessments. Six different skin physiology parameters were assessed at all timepoints. RESULTS: The perioral dermatitis severity score decreased significantly during the treatment period. This was mirrored by significantly lower patients' subjective numerical rating score and an improved quality of life score. Transepidermal water loss, stratum corneum hydration and skin erythema improved significantly during the treatment period. CONCLUSION: This transient receptor potential vanilloid type 1 inhibitor-based skin care cream improved subjective and objective parameters of perioral dermatitis. Decreased transepidermal water loss values and increased stratum corneum hydration demonstrate a restored skin barrier function. Consequently, the topical inhibition of these receptors is a promising management option for POD.

Δ9-THC and related cannabinoids suppress substance P- induced neurokinin NK1-receptor-mediated vomiting via activation of cannabinoid CB1 receptor.

Δ9-THC suppresses cisplatin-induced vomiting through activation of cannabinoid CB1 receptors. Cisplatin-evoked emesis is predominantly due to release of serotonin and substance P (SP) in the gut and the brainstem which subsequently stimulate their corresponding 5-HT3-and neurokinin NK1-receptors to induce vomiting. Δ9-THC can inhibit vomiting caused either by the serotonin precursor 5-HTP, or the 5-HT3 receptor selective agonist, 2-methyserotonin. In the current study, we explored whether Δ9-THC and related CB1/CB2 receptor agonists (WIN55,212-2 and CP55,940) inhibit vomiting evoked by SP (50 mg/kg, i.p.) or the NK1 receptor selective agonist GR73632 (5 mg/kg, i.p.). Behavioral methods were employed to determine the antiemetic efficacy of cannabinoids in least shrews. Our results showed that administration of varying doses of Δ9-THC (i.p. or s.c.), WIN55,212-2 (i.p.), or CP55,940 (i.p.) caused significant suppression of SP-evoked vomiting in a dose-dependent manner. When tested against GR73632, Δ9-THC also dose-dependently reduced the evoked emesis. The antiemetic effect of Δ9-THC against SP-induced vomiting was prevented by low non-emetic doses of the CB1 receptor inverse-agonist/antagonist SR141716A (<10 mg/kg). We also found that the NK1 receptor antagonist netupitant can significantly suppress vomiting caused by a large emetic dose of SR141716A (20 mg/kg). In sum, Δ9-THC and related cannabinoids suppress vomiting evoked by the nonselective (SP) and selective (GR73632) neurokinin NK1 receptor agonists via stimulation of cannabinoid CB1 receptors.

High ANXA7 Potentiates Eucalyptol Toxicity in Hormone-refractory Prostate Cancer.

BACKGROUND/AIM: Our studies showed that ANXA7 is a novel tumor suppressor gene that is lost in various aggressive forms of prostate cancer. However, little is known about the role of ANXA7 in the anticancer drug treatment towards different cancers. MATERIALS AND METHODS: The expression of ANXA7 was measured in the 60 cancer cell lines of the NCI-60 ADS project and correlated with the enhanced sensitivity to over 30,000 natural and synthetic compounds. RESULTS: Eucalyptol showed a high positive correlation with ANXA7 expression and castration-resistant prostate cancer cell death occurred very effectively in response to the combination of eucalyptol and overexpressed wt-ANXA7 than either agent alone. The synergistic effects of ANXA7 and eucalyptol resulted in concordant changes in gene expression profiles particularly of Ras family members, MDM4, NF-ĸB and VEGF. CONCLUSION: Overexpression of ANXA7 enhances eucalyptol cytotoxicity in prostate cancer cell lines.

Randomized investigator-blinded comparative study of moisturizer containing 4-t-butylcyclohexanol and licochalcone A versus 0.02% triamcinolone acetonide cream in facial dermatitis.

BACKGROUND: Facial dermatitis can result from various conditions, some of which are of a chronic and relapsing nature. The use of topical corticosteroid therapy may lead to additional adverse effects. OBJECTIVE: To compare the efficacy of moisturizer containing 4-t-butylcyclohexanol, which acts as a sensitivity regulator, and licochalcone A, an anti-inflammatory agent from the licorice plant Glycyrrhiza inflata, with that of 0.02% triamcinolone acetonide (TA) for the treatment of facial dermatitis. METHODS: This was a randomized, prospective, investigator-blinded study. Eighty participants with mild to moderate facial dermatitis were randomly treated with either the test facial moisturizer or 0.02% TA twice daily for the first 2 weeks. For the subsequent 2 weeks, all patients used only the test moisturizer. Clinical assessment by investigators, bioengineering measurements, patients' subjective evaluation, and clinical photography were performed at baseline, week 2, and week 4. RESULTS: Both treatments showed a statistically significant improvement with regard to physician clinical assessment, skin hydration, transepidermal water loss, and patient-assessed visual analog scale after 2 and 4 weeks of treatment compared with baseline. The test facial moisturizer produced better skin hydration than TCS. The improvement in TEWL after 4 weeks of using the test moisturizer was comparable with 2-week treatment with 0.02% TA cream. However, subjective evaluation by patients indicated that TA more rapidly improved sensation sensitivity. CONCLUSION: The test facial moisturizer was slower than 0.02% TA in improving facial dermatitis, but showed greater benefit in erythema control and skin hydration.

Sex differences in antinociceptive response to Δ-9-tetrahydrocannabinol and CP 55,940 in the mouse formalin test.

Cannabinoids have shown promise for the treatment of intractable pain states and may represent an alternative pharmacotherapy for pain management. A growing body of clinical evidence suggests a role for sex in pain perception and in cannabinoid response. We examined cannabinoid sensitivity and tolerance in male and female mice expressing a desensitization-resistant form (S426A/S430A) of the cannabinoid type 1 receptor (CB1R). Mice were assessed for acute and inflammatory nociceptive behaviors in the formalin test following pretreatment with either vehicle or mixed CB1R/CB2R agonists, Δ-9-tetrahydrocannabinol ([INCREMENT]-THC) (1-6 mg/kg) or CP 55,940 (0.06-0.2 mg/kg). Tolerance to the effects of 6 mg/kg [INCREMENT]-THC or 0.1 mg/kg CP 55,940 was examined by the formalin test following chronic daily dosing. Female mice showed decreased sensitivity to the effects of [INCREMENT]-THC and CP 55,940 compared with male mice. The S426A/S430A mutation increased the attenuation of nociceptive behaviors for both agonists in both sexes. Female mice displayed delayed tolerance to [INCREMENT]-THC compared with male mice, whereas the S426A/S430A mutation conferred a delay in tolerance to [INCREMENT]-THC in both sexes. Male S426A/S430A mutant mice also display resistance to tolerance to CP 55,940 compared with wild-type controls. This study demonstrates sex and genotype differences in response for two different cannabinoid agonists. The results underscore the importance of including both male and female mice in preclinical studies of pain and cannabinoid pharmacology.

Antidepressant polypharmacy and the potential of pharmacokinetic interactions: Doxepin but not mirtazapine causes clinically relevant changes in venlafaxine metabolism.

BACKGROUND: To uncover pharmacokinetic interactions between venlafaxine and doxepin or mirtazapine in a naturalistic sample. METHODS: A therapeutic drug monitoring database containing plasma concentrations of venlafaxine (VEN) and its active metabolite O-desmethylvenlafaxine (ODVEN) was analyzed. We included 1067 of 1594 patients in the analysis. Three study groups were considered; a group of patients under venlafaxine without confounding medications, V0 (n = 905), a group of patients co-medicated with doxepin, VDOX (n = 25) and a second group, co-medicated with mirtazapine, VMIR, n = 137. Plasma concentrations of VEN, ODVEN and the clinically relevant active moiety, sum of venlafaxine and O-desmethylvenlafaxine (ODVEN) (AM), as well as dose-adjusted plasma concentrations (C/D) were compared. RESULTS: Median concentrations in the doxepin group showed 57.7% and 194.4% higher values for AM and VEN respectively; these differences were statistically significant (p < 0.001 for AM and p = 0.002 for VEN). Similar differences were detected for C/D concentrations of active moiety and VEN (p < 0.001 and p = 0.001) with higher values also in the doxepin group. The ratios ODVEN/VEN were lower in the doxepin group (p < 0.001). A co-medication with mirtazapine did not cause any changes in venlafaxine metabolism. CONCLUSIONS: Higher concentrations for VEN and AM imply an inhibiting effect of doxepin on the metabolism of venlafaxine, although the huge variability of concentrations has to be taken into account. It is recommended to monitor plasma concentrations in combination treatment to avoid problems in safety and efficacy. LIMITATIONS: Despite the large size of our study sample, the naturalistic nature of this data may arise some concerns of information bias potentially resulting from non-standardized data recording.

Anti-edematogenic and anti-inflammatory activity of the essential oil from Croton rhamnifolioides leaves and its major constituent 1,8-cineole (eucalyptol).

The species Croton rhamnifolioides, belonging to the Croton genus, is known in ethnomedicine as "quebra faca" and is used in the treatment of stomach pain, vomiting and fever. This study aims to evaluate the anti-edematogenic and anti-inflammatory effect of Croton rhamnifolioides leaf essential oil (OEFC) and its major constituent: 1,8-cineole (eucalyptol). The essential oil was extracted from fresh leaves through a hydrodistillation system. The chemical analysis was determined by gas chromatography-mass spectrometry (GC-MS). The acute anti-inflammatory activity was determined from the models of: ear edema by the single application of croton oil, paw edema induced by: carrageenan, dextran, histamine and arachidonic acid, while vascular permeability was determined by Evans blue extravasation and chronic anti-inflammatory activity by granuloma induction using the implantation of cotton pellets. The GC-MS results identified and quantified 11 constituents, with the major component being 1,8-cineole (41.33%). The OEFC (20mg/mL) and 1,8-cineole (8.26mg/mL) significantly reduced the edema induced by croton oil by 42.1 and 34.9%, respectively. The OEFC (25, 50, 100 and 200mg/kg) and 1,8-cineole (10.33, 20.66, 41.33 and 82.66mg/kg) statistically reduced paw edema induced by carrageenan, dextran as well as vascular permeability (protein extravasation). The OEFC (25mg/kg) and 1,8-cineole (10.33mg/kg) demonstrated efficacy in reducing edema induced by histamine and arachidonic acid and granuloma. In conclusion, the OEFC and 1,8-cineole have anti-inflammatory activity in the acute and chronic phase, suggesting therapeutic potential as a source for the development of new anti-inflammatory agents.

Immunotherapy options for painful bladder syndrome: what's the potential?

INTRODUCTION: Painful bladder syndrome/interstitial cystitis (PBS/IC) is an enigmatic disease characterized by lack of evidence-based knowledge and an ongoing scientific debate regarding its definition, pathogenesis, diagnostic and treatment algorithm. An autoimmune theory for PBS/IC etiology has suggested immunotherapy as a potential treatment choice. Areas covered: In this review, the authors report existing and future immunotherapeutic options, potentially valuable to the management of PBS/IC while evidence for the immunological aspect of PBS/IC pathogenesis are also presented. Relevant data reported in human clinical studies but also in experimental studies using animal PBS/IC models have been reviewed. Expert opinion: Promising data has emerged lately regarding use of immunotherapy drugs for PBS/IC treatment. Specifically, human monoclonal antibodies inhibiting nerve growth factor and tumor necrosis factor-a have shown high efficacy in pain control for PBS/IC. Also, many other agents modulating immunopathways linked to PBS symptom etiology and leading to positive treatment effects have been reported lately mainly in experimental animal studies. Immunotherapy could potentially improve disease-related and patient-reported outcome; nevertheless, lack of consensus regarding PBS/IC diagnostic criteria, leading to high heterogeneity of patients enrolled in PBS/IC treatment studies, and low number of well-designed randomized clinical trials are limitations which must be addressed in the future.

Evolution of anti-parkinsonian activity of monoterpenoid (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol in various in vivo models.

It has been found recently that monoterpenoid (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol (Diol) demonstrates high antiparkinsonian activity in some animal models. We carried out an extended study of the antiparkinsonian activity of Diol in a set of relevant animal models. Diol (20mg/kg) exhibited an anticataleptogenic effect in the haloperidol-induced catalepsy model and restored motor activity in animals in the reserpine-induced model of oligokinesia. The ability of Diol singly administered before MPTP injection to reduce rigidity comparable to that of activity of L-DOPA (100mg/kg) was found using the model of Parkinsonian syndrome (PS) induced by single injection of MPTP (30mg/kg) to C57BL/6 mice. In the model of PS induced by subchronic administration of MPTP (4 × 20mg/kg), Diol at a dose of 20mg/kg reduced rigidity with effectiveness comparable to that of L-DOPA, while being superior to L-DOPA in terms of its effect on motor activity. It was found using the model of PS induced by systemic administration of rotenone that subchronic daily oral administration of Diol prior to rotenone injection reduced severity of PS in rats. Assessment of the effects of chronic administration of Diol (20mg/kg) and L-DOPA to animals with 6-OHDA-induced PS showed that administration of Diol alleviated the symptoms of sensorimotor deficit in right limbs in rats. Thus, the potent antiparkinsonian activity of Diol was demonstrated in all the used rodent models experiments. Diol (20mg/kg) is as effective as the comparator agent L-DOPA administered at doses of 50-100mg/kg.