Hot Water Extract of Curcuma longa L. Improves Serum Inflammatory Markers and General Health in Subjects with Overweight or Prehypertension/Mild Hypertension: A Randomized, Double-Blind, Placebo-Controlled Trial.

To investigate the effect of a hot water extract of C. longa L. (WEC) containing anti-inflammatory agents, bisacurone, and turmeronol on chronic inflammation, a randomized double-blind placebo-controlled study was conducted in middle-aged and elderly subjects aged 50-69 years with overweight or prehypertension/mild hypertension. The subjects consumed 900 mg WEC tablets, containing 400 µg bisacurone, 80 µg turmeronol A and 20 µg turmeronol B (WEC group: n = 45), or placebo tablets without WEC (placebo group: n = 45) daily for 12 weeks. Serum inflammatory and metabolic markers were measured. The subjects also completed the MOS 36-item short-form health survey (SF-36) and the Profile of Mood States scale (POMS). In the WEC group, the serum levels of C-reactive protein, tumor necrosis factor-α, interleukin-6, and soluble vascular cell adhesion molecule-1 decreased significantly. Compared with the placebo group, the WEC group had significantly lower serum levels of glucose, hemoglobin A1c, and triglycerides, as well as higher serum levels of high-density lipoprotein cholesterol. The WEC group also showed significant improvement of SF-36 scores (for general health, vitality, mental health, and mental summary component) and POMS scores for positive mood states (vigor-activity and friendliness). In conclusion, WEC may ameliorate chronic low-grade inflammation, thus contributing to the improvement of associated metabolic disorders and general health.

Targeting the SHIP1 Pathway Fails to Show Treatment Benefit in Interstitial Cystitis/Bladder Pain Syndrome: Lessons Learned from Evaluating Potentially Effective Therapies in This Enigmatic Syndrome.

PURPOSE: In this 12-week, randomized, double-blind, placebo controlled, multicenter, 3-arm, parallel group, phase 3 trial we assessed the effects of a novel SHIP1 activator on bladder pain and urinary symptoms in patients with interstitial cystitis/bladder pain syndrome. MATERIALS AND METHODS: Subjects with interstitial cystitis/bladder pain syndrome and a mean pain score of 5 or greater on an 11-point scale despite treatment were randomized to 100 or 200 mg of an oral SHIP1 activator or placebo once daily for 12 weeks. Maximum pain scores and urinary frequency were recorded in an e-diary. The ICSI (O'Leary-Sant Interstitial Cystitis Symptom Index) and BPIC-SS (Bladder Pain Interstitial Cystitis Symptom Score) questionnaires were administered. Safety was monitored through 12 weeks of treatment. RESULTS: A total of 298 female subjects with moderate to severe symptoms of interstitial cystitis/bladder pain syndrome were treated with 100 or 200 mg SHIP1 activator orally once daily for 12 weeks. Treatment demonstrated no difference in maximum daily bladder pain compared to placebo. There was no treatment benefit over that of placebo in the secondary end points of urinary voiding frequency, the BPIC-SS, the ICSI and a global response assessment. Exploratory analysis in 87 male subjects yielded a similar result, that is no difference from placebo. Treatment was generally well tolerated at both doses. CONCLUSIONS: SHIP1 activation is a safe but ineffective therapeutic approach to interstitial cystitis/bladder pain syndrome. Although this was a negative trial, the important lessons learned from this study in respect to inflammatory phenotype differentiation, including the potential importance of cystoscopy based classification, will improve current treatment in patients with interstitial cystitis/bladder pain syndrome and allow for better future trial design in those with this difficult urological chronic pain syndrome.

Do you feel it now? Route of administration and Δ9-tetrahydrocannabinol-like discriminative stimulus effects of synthetic cannabinoids in mice.

A recent push to provide more translationally relevant preclinical models for examination of pharmacological mechanisms underlying inhaled substances of abuse has resulted in the development of equipment and methods that allows exposure of freely moving rodents to aerosolized psychoactive drugs. In the present study, synthetic cannabinoids (CP55,940, AB-CHMINACA, and AMB-FUBINACA) were administered intraperitoneally (i.p.) or aerosolized via a modified electronic cigarette device. Subsequently, the compounds were evaluated in adult male and female C57/Bl6 mice trained to discriminate i.p. 5.6 mg/kg Δ9-tetrahydrocannabinol (THC) for food reinforcement. When administered i.p., THC and AB-CHMINACA were equally potent at producing THC-like effects in both sexes, but CP55,940 and AMB-FUBINACA were more potent in males. Upon aerosol exposure, all compounds continued to produce THC-like effects in both sexes, with AMB-FUBINACA remaining the most potent. In contrast, aerosolized CP55,940 showed substantial decreases in potency in both sexes. Aerosolized nicotine did not substitute for THC in either sex. In females, aerosolized cumyl-4CN-BINACA produced concentration-dependent increases in responding on the THC-associated nosepoke. In addition, the effects of an active concentration of AMB-FUBINACA were reversed by rimonabant, suggesting CB1 receptor mediation. These results show that synthetic cannabinoids produce THC-like effects when injected i.p. or after aerosolization. This study adds to a growing literature suggesting that evaluation of abuse liability of substances via aerosol exposure is feasible and may provide a translationally relevant method that allows for investigation of factors important to the abuse of drugs which humans typically smoke or vape.

Volatile Components of the Essential Oil of Artemisia montana and Their Sedative Effects.

The sedative effects of volatile components in the essential oil of Artemisia montana ("Yomogi") were investigated and measured using gas chromatography-mass spectrometry (GC-MS). Major components identified included 1,8-cineol, camphor, borneol, α-piperitone, and caryophyllene oxide. Among them, 1,8-cineol exhibited the highest flavor dilution (FD) value in an aroma extract dilution analysis (AEDA), followed by borneol, o-cymene, ß-thujone, and bornyl acetate. The sedative effects of yomogi oil aroma were evaluated by sensory testing, analysis of salivary α-amylase activity, and measurement of relative fluctuation of oxygenated hemoglobin concentration in the brain using near-infrared spectroscopy (NIRS). All results indicated the stress-reducing effects of the essential oil following nasal exposure, and according to the NIRS analysis, 1,8-cineol is likely responsible for the sedative effects of yomogi oil.

Combinations of 1,8-cineol and oseltamivir for the treatment of influenza virus A (H3N2) infection in mice.

It is need for development of new means against influenza virus due to the lack of efficacy of available therapeutic strategies. In previous research, 1,8-cineol exert its inhibition of nuclear factor (NF)-κB, the main regulator of cytokine and chemokine production in influenza, and anti-inflammatory activity. These fact supports and helps establish the hypothesis that 1,8-cineol may have synergism with an antiviral on influenza virus infection. The combined effect of 1,8-cineol with oseltamivir in a mouse type A influenza virus (Victoria/3/75,H3N2) model were examined. We initially tested combinations of 1,8-cineol (30, 60, and 120 mg/kg/day) and oseltamivir (0.1, 0.2, and 0.4 mg/kg/day). In addition, the 0.4 mg/kg/day of oseltamivir combined with 120 mg/kg of 1,8-cineol was selected for further combination studies. Oseltamivir was 30%, 40%, and 60% protective at 0.1, 0.2, and 0.4 mg/kg/d. Combinations of 1,8-cineol (30, 60, and 120 mg/kg/d) and oseltamivir (0.1, 0.2, and 0.4 mg/kg/d) increased the number of survivors and mean survival time (MST) following combination treatment was greater than monotherapy alone. Three dimensional analysis of drug interactions using the MacSynergy method showed a strong synergistic effect of these drug combinations. Survival, MST, lung parameters (lung index, viral titers, and pathology), and cytokines (IL-10, TNF-α, IL-1ß, and IFN-γ) expression in lung demonstrated the high effectiveness of the combination. Combined treatment was associated with longer MST and more reduced cytokine levels than oseltamivir alone. These data demonstrate that combinations of 1,8-cineol and oseltamivir have synergistic effect against influenza A virus (H3N2) infection.

Eucalyptol attenuates cigarette smoke-induced acute lung inflammation and oxidative stress in the mouse.

Short-term cigarette smoke (CS) exposure does not cause emphysema; however, some pathogenesis hallmarks are maintained, such as oxidative stress and inflammation. This study aimed to test the efficacy of eucalyptol against short-term CS exposure in mice. C57BL/6 mice were exposed to 12 cigarettes per day for 5 days (CS group). The control group was exposed to sham smoking. Three groups of mice exposed to CS were treated to different concentrations of eucalyptol (1, 3, 10 mg/mL) via inhalation (15 min/daily) for 5 days (CS + 1 mg, CS+3 mg and CS+10 mg groups). CS group and control one were sham treated by using vehicle. The anti-inflammatory and antioxidant effects of eucalyptol were assessed 24 h after the last CS exposure by determining cell counts, measuring cytokine production and performing western blotting, biochemical and histological analyses. Eucalyptol at 3 mg/mL and 10 mg/mL concentrations reduced total leukocyte numbers compared to the CS group (p < 0.001), while macrophage numbers were reduced at all concentrations (p < 0.001). Myeloperoxidase, used as neutrophil marker, was reduced at 3 mg/mL (p < 0.01) and 10 mg/mL (p < 0.05) concentrations. Eucalyptol reduced cytokine levels (IL-1ß, IL-6 and KC) at 3 mg/mL and 10 mg/mL concentrations (p < 0.01) compared to the CS group. The exception was TNF-α, with a reduction only at 10 mg/mL of eucalyptol compared to the CS group (p < 0.001). Additionally, eucalyptol decreased the NF-kappa B p65 subunit at 3 mg/mL and 10 mg/mL compared to the CS group (p < 0.01). Regarding oxidative stress, eucalyptol reduced reactive oxygen species, superoxide dismutase, catalase and malondialdehyde, mainly at 3 mg/mL and 10 mg/mL concentrations compared to the CS group (at least p < 0.05), parallel to reduced glutathione levels at the same concentrations (p < 0.001). Furthermore, treatment with eucalyptol attenuated CS-induced histopathological alterations. Collectively, these results indicate that eucalyptol acts through a mechanism involving decreased oxidative stress, inflammation and the NF-kappa B p65 subunit against CS-induced acute lung inflammation. Thus, eucalyptol may be a potential agent in the treatment of pulmonary inflammation caused by CS in humans.

A new measurement protocol to differentiate sources of halitosis.

OBJECTIVE: Three sources of halitosis exist, potentially in any combination: mouth, nasal cavity or alveolar breath. There has been no universally accepted protocol which differentiates and quantifies each odour source separately. In this study a new gas measurement protocol is described and tested to determine whether each odour source can be separately detected without contamination. MATERIALS AND METHODS: Ninety healthy volunteers were divided into three groups. Hydrogen sulphide (H2S), volatile organic compounds (VOCs) and hydrogen (H2) were artificially generated in the mouth, nose and pulmonary alveoli, respectively. VOC, ammonia (NH3), sulphur dioxide (SO2), H2S and H2 gas readings from mouth, nose and alveolar air were measured and compared. Measurements were taken before and during gas generation. RESULTS: Contamination of nasal air (2.8%) and alveolar air (5.0%) by oral H2S; alveolar air (2.06%) and oral air (4%) by nasal organic gas; nasal air (18.43%) and oral air (9.42%) by alveolar H2 was calculated. CONCLUSION: The results demonstrated that artificially generated oral H2S nasal VOC and alveolar H2 can be individually quantified. This gas measurement protocol can be used diagnostically or to gauge response to therapy in any medical or dental setting.

A Phase II Study of the Efficacy and Safety of the Novel Oral SHIP1 Activator AQX-1125 in Subjects with Moderate to Severe Interstitial Cystitis/Bladder Pain Syndrome.

PURPOSE: In this 6-week, randomized, double-blind, placebo controlled, multicenter trial we assessed the effect of the novel SHIP1 (SH2-containing inositol-5'-phosphatase 1) activator AQX-1125 on bladder pain and urinary symptoms in patients with interstitial cystitis/bladder pain syndrome. MATERIALS AND METHODS: Women with interstitial cystitis/bladder pain syndrome and a mean pain score of 5 or greater on an 11-point scale despite treatment were randomized to AQX-1125 or placebo orally once daily for 6 weeks. Average and maximum pain scores (daily) and urinary frequency (before visits) were recorded by e-diary and at clinic visits. The O'Leary-Sant ICSI (Interstitial Cystitis Symptom Index) and ICPI (Interstitial Cystitis Problem Index), BPIC-SS (Bladder Pain Interstitial Cystitis Symptom Score) and SF-12v2® questionnaires were administered. Safety was monitored through 6 weeks of treatment and 4 weeks of followup. RESULTS: A total of 37 patients received oral AQX-1125 and 32 received placebo. At 6 weeks average daily pain on an e-diary decreased by 2.4 points for AQX-1125 vs 1.4 for placebo (p = 0.061), while average pain at clinic decreased by 2.6 vs 1.1 (p = 0.008), maximum daily pain on e-diary diary decreased by 2.6 vs 1.4 (p = 0.030) and maximum pain at clinic decreased by 2.8 vs 1.1 (p = 0.028). AQX-1125 reduced ICSI by 3.8 points vs 1.4 for placebo (p = 0.005), ICPI by 3.6 points vs 1.6 (p = 0.014) and BPIC-SS by 8.8 points vs 4.0 (p = 0.011). Urinary frequency decreased on AQX-1125 by 3.6 voids per 24 hours vs 0.8 for placebo (p = 0.040). Adverse event rates were similar for AQX-1125 and placebo (51.4% and 78.1%, respectively). No serious adverse events were reported. CONCLUSIONS: Women with moderate to severe interstitial cystitis/bladder pain syndrome who were treated with the oral SHIP1 activator AQX-1125 reported significantly reduced bladder pain and improved urinary symptoms at 6 weeks. AQX-1125 was well tolerated. AQX-1125 may be a potential new treatment for interstitial cystitis/bladder pain syndrome. It warrants further investigation.

Dose-dependent teratogenicity of the synthetic cannabinoid CP-55,940 in mice.

Potent synthetic cannabinoids (SCBs) are illegally distributed drugs of abuse that are frequently consumed in spite of their adverse consequences. This study was designed to determine if the toxicity observed in adults also extends to the prenatal period by examining the developmental toxicity/teratogenicity of one of these SCBs, CP-55,940, in a mammalian model. First, immunohistochemistry was employed for cannabinoid receptor 1 (CB1) localization within gestational day (GD) 8 mouse embryos; this receptor was identified in the cranial neural plate, suggesting that the endogenous cannabinoid system may be involved in normal development. Based on this information and on previous avian teratogenicity studies, the current investigation focused on cannabinoid exposure during neurulation. The treatment paradigm involved acute i.p. administration of vehicle, 0.0625, 0.125, 0.25, 0.5, 1.0, or 2.0mg/kg CP-55,940 to time-mated C57Bl/6J mice on their 8th day of pregnancy (n>10 litters per treatment group). On GD 17, litters were harvested and examined for numbers of live, dead, or resorbed fetuses, as well as for fetal weight, length, and gross morphological abnormalities. No effect on litter size, fetal weight, or crown rump length was seen at any of the CP-55,940 dosages tested. Major malformations involving the craniofacies and/or eyes were noted in all drug-treated groups. Selected fetuses with craniofacial malformations were histologically sectioned and stained, allowing investigation of brain anomalies. Observed craniofacial, ocular, and brain abnormalities in drug-treated fetuses included lateral and median facial clefts, cleft palate, microphthalmia, iridial coloboma, anophthalmia, exencephaly, holoprosencephaly, and cortical dysplasia. With the most commonly observed defects involving the eyes, the incidence and severity of readily identifiable ocular malformations were utilized as a basis for dose-response analyses. Ocular malformation ratings revealed dose-dependent CP-55,940 teratogenicity within the full range of dosages tested. While examination of additional critical periods and in depth mechanistic studies is warranted, the results of this investigation clearly show the dose-dependent teratogenicity of this SCB.

Gastroprotective Mechanisms of the Monoterpene 1,8-Cineole (Eucalyptol).

Recently, our research group identified and reported 1,8-cineole (CIN), a monoterpene that naturally occur in many aromatic plants, as one of the major constituent of the essential oil from leaves of Hyptis martiusii (EOHM), as well as characterized the gastroprotective action of this oil. The aim of this study was to investigate the mechanisms of action involved in the antiulcer and healing activity of CIN, in order to confirm its correlation with the gastroprotective effect of EOHM. Wistar rats were exposed to different protocols (acute ulceration, gastrointestinal motility and antisecretory activity). In addition, were determinated the involvement of nitric oxide and sulphydryl groups; the levels of gastric mucus, lipid peroxidation, sulphydryl groups and myeloperoxidase activity. The healing ability was evaluated by acetic acid-induced chronic ulcer and histological and immunohistochemical analysis (PCNA, Ki-67 and BrdU). The treatment with CIN inhibited ethanol-, ethanol/HCl- and indomethacin-induced gastric lesions. The highest doses of CIN inhibited gastric emptying, but did not affect intestinal transit. CIN (100 mg/kg) reduced the volume of basal but not stimulated acid secretion. CIN increased levels of mucus (89.3%), prevented depletion of -SH groups (62.6%) and reduced the level of lipid peroxidation (55.3%) and myeloperoxidase activity (59.4%) in the gastric mucosa. In chronic ulcer model, CIN reduced in 43.1% the gastric area lesion, promoted significant regeneration and restoration of the levels of mucus in glandular cells as confirmed by histological analysis; and promoted increase in cell proliferation as evidenced by reactivity for PCNA, Ki-67 and BrdU. This findings demonstrate the role of 1,8-cineole as an important ulcer healing agent and indicate the involvement of antioxidant and cytoprotective mechanisms in the gastroprotective effect of compound. This study also provides evidence that 1,8-cineole is related to the gastroprotective effect of the essential oil of Hyptis martiusii.

Pooled Analysis of Six Pharmacologic and Nonpharmacologic Interventions for Vasomotor Symptoms.

OBJECTIVE: To describe the effects of six interventions for menopausal vasomotor symptoms relative to control in a pooled analysis, facilitating translation of the results for clinicians and symptomatic women. The Menopause Strategies: Finding Lasting Answers for Symptoms and Health network tested these interventions in three randomized clinical trials. METHODS: An analysis of pooled individual-level data from three randomized clinical trials is presented. Participants were 899 perimenopausal and postmenopausal women with at least 14 bothersome vasomotor symptoms per week. Interventions included 10-20 mg escitalopram per day, nonaerobic yoga, aerobic exercise, 1.8 g per day omega-3 fatty acid supplementation, 0.5 mg low-dose oral 17-beta-estradiol (E2) per day, and 75 mg low-dose venlafaxine XR per day. The main outcome measures were changes from baseline in mean daily vasomotor symptom frequency and bother during 8-12 weeks of treatment. Linear regression models estimated differences in outcomes between each intervention and corresponding control group adjusted for baseline characteristics. Models included trial-specific intercepts, effects of the baseline outcome measure, and time. RESULTS: The 8-week reduction in vasomotor symptom frequency from baseline relative to placebo was similar for escitalopram at -1.4 per day (95% confidence interval [CI] -2.7 to -0.2), low-dose E2 at -2.4 (95% CI -3.4 to -1.3), and venlafaxine at -1.8 (95% CI -2.8 to -0.8); vasomotor symptom bother reduction was minimal and did not vary across these three pharmacologic interventions (mean -0.2 to -0.3 relative to placebo). No effects on vasomotor symptom frequency or bother were seen with aerobic exercise, yoga, or omega-3 supplements. CONCLUSION: These analyses suggest that escitalopram, low-dose E2, and venlafaxine provide comparable, modest reductions in vasomotor symptom frequency and bother among women with moderate hot flushes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00894543 (MsFLASH 01), NCT01178892 (MsFLASH 02), and NCT01418209 (MsFLASH 03).

1,8-Cineole Ameliorates Steatosis of Pten Liver Specific KO Mice via Akt Inactivation.

Hepatocyte-specific Phosphatase and tensin homolog (Pten)-knockout (KO) mice exhibit hepatic lesions analogous to non-alcoholic steatohepatitis (NASH). 1,8-cineole is a monoterpene oxide and it has several biological effects including hepatoprotective effects. In this study we revealed that 1,8-cineole ameliorates NASH of Pten KO mice. Pten KO mice were assigned to a control group without any medication or to a 1,8-cineole group injected with 50 mg/kg i.p. twice per week for eight weeks. At eight weeks, livers from each group were processed to measure triglyceride (TG) content, gene expression analysis, western blot analysis, and histological examination including Oil red O staining. 1,8-cineole ameliorated hepatic steatosis in Pten KO mice, revealed by TG content and Oil red O staining. Moreover, 1,8-cineole downregulated collagen 1a1 expression and improved liver fibrosis. Thus, 1,8-cineole has potential as a candidate to treat NASH by inactivating the Akt/PI3-kinase pathway.

Effects of estradiol and venlafaxine on insomnia symptoms and sleep quality in women with hot flashes.

STUDY OBJECTIVES: Determine effects of low-dose estradiol and low-dose venlafaxine on self-reported sleep measures in menopausal women with hot flashes. DESIGN: 3-arm double-blind randomized trial. Participants assigned in a 2:2:3 ratio to 17ß estradiol 0.5 mg/day (n = 97), venlafaxine XR 75 mg/day (n = 96), or placebo (n = 146) for 8 weeks. SETTING: Academic research centers. PARTICIPANTS: 339 community-dwelling perimenopausal and postmenopausal women with ≥2 bothersome hot flashes per day. MEASUREMENTS AND RESULTS: Insomnia symptoms (Insomnia Severity Index [ISI]) and sleep quality (Pittsburgh Sleep Quality Index [PSQI]) at baseline, week 4 and 8; 325 women (96%) provided ISI data and 312 women (92%) provided PSQI data at baseline and follow-up. At baseline, mean (SD) hot flash frequency was 8.1/day (5.3), mean ISI was 11.1 (6.0), and mean PSQI was 7.5 (3.4). Mean (95% CI) change from baseline in ISI at week 8 was -4.1 points (-5.3 to -3.0) with estradiol, -5.0 points (-6.1 to -3.9) with venlafaxine, and -3.0 points (-3.8 to -2.3) with placebo (P overall treatment effect vs. placebo 0.09 for estradiol and 0.007 for venlafaxine). Mean (95% CI) change from baseline in PSQI at week 8 was -2.2 points (-2.8 to -1.6) with estradiol, -2.3 points (-2.9 to -1.6) with venlafaxine, and -1.2 points (-1.7 to -0.8) with placebo (P overall treatment effect vs. placebo 0.04 for estradiol and 0.06 for venlafaxine). CONCLUSIONS: Among perimenopausal and postmenopausal women with hot flashes, both low dose oral estradiol and low-dose venlafaxine compared with placebo modestly reduced insomnia symptoms and improved subjective sleep quality. CLINICAL TRIAL REGISTRATION: NCT01418209 at www.clinicaltrials.gov.

Adherence to antidepressant combinations and monotherapy for major depressive disorder: a CO-MED report of measurement-based care.

BACKGROUND: Non-adherence to antidepressant treatment is not routinely measured in practical clinical trials. It has not been related to outcomes in a large sample of adults with chronic and/or recurrent major depressive disorder (MDD) or any sample treated with antidepressant combinations. METHODS: Adult outpatients with chronic and/or recurrent MDD were randomized to 12 weeks of treatment with bupropion-SR plus escitalopram, venlafaxine-XR plus mirtazapine, or escitalopram plus placebo. We compared non-adherence (the frequency with which daily medications were not taken) and specifically the frequency of temporarily stopping and/or skipping medication, or reducing or increasing the dose across treatments in 567 participants using a self-report questionnaire collected at each visit. We tested the association between non-adherence, and both treatment type and outcomes. RESULTS: A non-adherence rate under 10% was reported by 77.9%, 70.9%, and 71.6% of participants during weeks 1-4, 5-12, and 1-12, respectively. Antidepressant combinations were associated with a higher non-adherence rate than monotherapy during weeks 1-4 and 1-12. During weeks 1-4, 24.1% stopped/skipped doses and 6.1% reduced the dose. During weeks 5-12, 34.7% stopped/skipped doses and 9.4% reduced the dose. Across 12 weeks, 43.2% stopped/skipped doses, and 12.9% reduced the dose. Stopping/skipping doses during all time frames and dose decreases during weeks 1-12 occurred most frequently with combination treatments. Non-adherence was unrelated to symptom remission, response, or symptom change. CONCLUSIONS: With closely monitored treatment, non-adherence is low and unrelated to depressive symptom outcome. Nonadherence is highest with antidepressant combinations. Specific non-adherent events are most often sporadic.

The comparison of brand-name and generic formulations of venlafaxine: a therapeutic drug monitoring analysis.

OBJECTIVE: Venlafaxine (VEN) is a widely used antidepressant drug, which is available in both brand-name and generic formulations. Bioequivalence studies indicate some pharmacokinetic variability. However, naturalistic therapeutic drug monitoring studies of different generic formulations are lacking. METHODS: In 2010, inpatients of the Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, were treated with either slow-release brand-name VEN (Trevilor) or slow-release generic VEN (Venlafaxin Hexal) depending on the respective inpatient ward. Routine therapeutic drug monitoring analyses of both groups were compared after matching samples regarding dose of VEN, gender, age, smoking habits, and evaluation of co-medication. RESULTS: Both groups did not differ in mean values of VEN, O-desmethyl-VEN (ODV), VEN + ODV serum concentrations, and ODV/VEN ratio. No difference in dose-corrected serum concentrations between generic and brand-name VEN was revealed for males, females, smokers, or nonsmokers. In both groups, Spearman Rho correlation between VEN dose and VEN + ODV serum concentration was moderate but significant (P < 0.001; generic: r = 0.554; brand name: r = 0.668). Within the generic subgroup, females had a significantly higher dose-corrected serum concentration of VEN (U test, P < 0.05), whereas within brand name, no gender influence was detected. Spearman Rho correlation of age and dose-corrected ODV (P < 0.05) and VEN + ODV (P < 0.05) was significant only in the generic group. In the brand-name sample, smokers had significantly lower dose-corrected serum concentrations of ODV (U test, P < 0.01) and VEN + ODV (P < 0.01). In the generic group, smoking habit was without any influence. DISCUSSION: No differences in serum concentrations in dependence of either VEN formulations suggest a safe and efficient treatment of patients using the evaluated generic VEN. However, differences within one formulation regarding gender, age, and smoking status suggest variability of serum concentrations and thus could endanger safety and efficacy of drug use.

Essential oil of common sage (Salvia officinalis L.) from Jordan: assessment of safety in mammalian cells and its antifungal and anti-inflammatory potential.

Salvia officinalis L. (Lamiaceae) is a Mediterranean species, naturalized in many countries. In Jordan, it is used in traditional medicine as antiseptic, antiscabies, antisyphilitic, and anti-inflammatory, being frequently used against skin diseases. This study aimed the assessment of the antifungal and anti-inflammatory potential of its essential oils, and their cytotoxicity on macrophages and keratinocytes. The oils were investigated by gas chromatography and gas chromatography-mass spectrometry and the antifungal activity was evaluated against yeasts, dermatophyte and Aspergillus strains. Assessment of cell viability was made by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and the in vitro anti-inflammatory potential was evaluated by measuring nitric oxide production using lipopolysaccharide-stimulated mouse macrophages. The main compounds of S. officinalis oils were 1,8-cineole (39.5-50.3%) and camphor (8.8-25.0%). The oils revealed antifungal activity against dermatophyte strains and significantly inhibited NO production stimulated by LPS in macrophages, without affecting cell viability, in concentrations up to 0.64 µL/mL. This is the first report addressing the in vitro anti-inflammatory potential of S. officinalis oil. These findings demonstrated that bioactive concentrations of S. officinalis oils do not affect mammalian macrophages and keratinocytes viability making them suitable to be incorporated in skin care formulations for cosmetic and pharmaceutical purposes.

Antitumor effect of 1, 8-cineole against colon cancer.

Several essential oils possess pharmacological effects. Among the various constituents of essential oils, 1, 8-cineole has been shown to possess pharmacological effects such as anti-bacterial and anti-inflammatory effects. The effect of 1, 8-cineole on human colorectal cancer cells, however, has not reported previously. In this study, we have investigated the anti-proliferative effect of 1, 8-cineole on human colon cancer cell lines HCT116 and RKO by WST-8 and BrdU assays. The cytotoxicity of 1, 8-cineole was investigated by LDH activity and TUNEL staining. The mechanism of apoptosis by 1, 8-cineole was determined by western blot analyses. In in vivo study, RKO cells were injected into the SCID mice and the effect of 1, 8-cineole was investigated. Specific induction of apoptosis, not necrosis, was observed in human colon cancer cell lines HCT116 and RKO by 1, 8-cineole. The treatment with 1, 8-cineole was associated with inactivation of survivin and Akt and activation of p38. These molecules induced cleaved PARP and caspase-3, finally causing apoptosis. In xenotransplanted SCID mice, the 1, 8-cineole group showed significantly inhibited tumor progression compared to the control group. These results indicated 1, 8-cineole suppressed human colorectal cancer proliferation by inducing apoptosis. Based on these studies 1, 8-cineole would be an effective strategy to treat colorectal cancer.

Increase in work productivity of depressed individuals with improvement in depressive symptom severity.

OBJECTIVE: The authors sought to identify baseline clinical and sociodemographic characteristics associated with work productivity in depressed outpatients and to assess the effect of treatment on work productivity. METHOD: Employed depressed outpatients 18-75 years old who completed the Work Productivity and Activity Impairment scale (N=1,928) were treated with citalopram (20-40 mg/day) in the Sequenced Treatment Alternatives to Relieve Depression study. For patients who did not remit after an initial adequate antidepressant trial (level 1), either a switch to sertraline, sustained-release bupropion, or extended-release venlafaxine or an augmentation with sustained-release bupropion or buspirone was provided (level 2). Participants' clinical and demographic characteristics and treatment outcomes were analyzed for associations with baseline work productivity and change in productivity over time. RESULTS: Education, baseline depression severity, and melancholic, atypical, and recurrent depression subtypes were all independently associated with lower benefit to work productivity domains. During level 1 treatment, work productivity in several domains improved with reductions in depressive symptom severity. However, these findings did not hold true for level 2 outcomes; there was no significant association between treatment response and reduction in work impairment. Results were largely confirmed when multiple imputations were employed to address missing data. During this additional analysis, an association was also observed between greater impairment in work productivity and higher levels of anxious depression. CONCLUSIONS: Patients with clinically significant reductions in symptom severity during initial treatment were more likely than nonresponders to experience significant improvements in work productivity. In contrast, patients who achieved symptom remission in second-step treatment continued to have impairment at work. Patients who have demonstrated some degree of treatment resistance are more prone to persistent impairment in occupational productivity, implying a need for additional, possibly novel, treatments.

Serotonin-norepinephrine reuptake inhibitor therapy in late-life depression is associated with increased marker of bone resorption.

UNLABELLED: Antidepressants are associated with bone loss and fractures in older adults. We treated depressed older adults with an antidepressant and examined its effects on bone turnover by comparing blood samples before and after treatment. Bone resorption increased after antidepressant treatment, which may increase fracture risk. INTRODUCTION: Antidepressants have been associated with increased bone loss and fractures in older adults in observational studies, but the mechanism is unclear. We examined the effects of a serotonin-norepinephrine reuptake inhibitor, venlafaxine, on biomarkers of bone turnover in a prospective treatment study of late-life depression. METHODS: Seventy-six individuals aged 60 years and older with current major depressive disorder received a 12-week course of venlafaxine XR 150-300 mg daily. We measured serum C-terminal cross-linking telopeptide of type I collagen (ß-CTX) and N-terminal propeptide of type I procollagen (P1NP), measures of bone resorption and formation, respectively, before and after treatment. We then analyzed the change in ß-CTX and P1NP within each participant. Venlafaxine levels were measured at the end of the study. We assessed depression severity at baseline and remission status after treatment. RESULTS: After 12 weeks of venlafaxine, ß-CTX increased significantly, whereas P1NP did not significantly change. The increase in ß-CTX was significant only in participants whose depression did not remit (increase by 10 % in non-remitters vs. 4 % in remitters). Change in ß-CTX was not correlated with serum levels of venlafaxine or norvenlafaxine. CONCLUSION: Our findings suggest that the primary effect of serotonergic antidepressants is to increase bone resorption. However, such an increase in bone resorption seemed to depend on whether or not participants' depression remitted. Our results are in agreement with prior observational studies reporting increased bone loss in older adults taking serotonergic antidepressants. These negative effects on bone homeostasis could potentially contribute to increased fracture risk in older adults.