A randomized, double-blind, placebo-controlled, duloxetine-referenced, fixed-dose study comparing the efficacy and safety of Lu AA21004 in elderly patients with major depressive disorder

The efficacy and tolerability of Lu AA21004 at 5 mg/day, a novel multimodal antidepressant, were assessed in elderly patients with recurrent major depressive disorder. Patients were randomly assigned (1:1:1) to Lu AA21004 5 mg/day, duloxetine 60 mg/day (reference) or to placebo in an 8-week double-blind study. The primary efficacy measure was the 24-item Hamilton Depression Scale (HAM-D(24)) total score (analysis of covariance, last observation carried forward). Patients (mean age 70.6 years) had a mean baseline HAM-D(24) score of 29.0. Lu AA21004 showed significantly (P = 0.0011) greater improvement on the primary efficacy endpoint compared with placebo at week 8 (3.3 points). Duloxetine also showed superiority to placebo at week 8, thereby validating the study. HAM-D(24) response (53.2 vs. 35.2%) and HAM-D(17) remission (29.2 vs. 19.3%) rates at endpoint were higher for Lu AA21004 than for placebo. Lu AA21004 showed superiority to placebo in cognition tests of speed of processing, verbal learning and memory. The withdrawal rate due to adverse events was 5.8% (Lu AA21004), 9.9% (duloxetine) and 2.8% (placebo). Whereas nausea was the only adverse event with a significantly higher incidence on treatment with Lu AA21004 (21.8%) compared with placebo (8.3%), the incidence of nausea, constipation, dry mouth, hyperhidrosis and somnolence was higher for duloxetine. In conclusion, Lu AA21004 was efficacious and well tolerated in the treatment of elderly patients with recurrent major depressive disorder.     

Lu AA21004, a multimodal psychotropic agent, in the prevention of relapse in adult patients with generalized anxiety disorder

The purpose of this study was to investigate the long-term maintenance of the efficacy of Lu AA21004 5 or 10 mg/day in the prevention of relapse in patients with generalized anxiety disorder (GAD). Patients (n = 687) with a primary diagnosis of GAD (DSM-IV criteria) and a baseline Hamilton Anxiety (HAM-A) total score of at least 20 underwent a 20-week, open-label Lu AA21004 treatment. In all, 459 patients responded and were randomized to 24-56 weeks of a double-blind treatment with Lu AA21004 (n = 229) or placebo (n = 230). The predefined primary efficacy endpoint was time to relapse (HAM-A total score ≥ 15) using a Cox model; the key secondary efficacy endpoint under multiplicity control was time to relapse for patients responding to treatment for at least 12 weeks. The primary analysis showed a statistically significant effect of Lu AA21004 relative to the placebo on the time to relapse of GAD, with a hazard ratio of 2.71 (P < 0.001). There was a statistically significant effect of Lu AA21004 in the stable responders (hazard ratio = 3.06, P < 0.001). Lu AA21004 was well tolerated, with withdrawal rates due to adverse events of 9% (open-label) and 3% (placebo) and 4% (Lu AA21004) in the double-blind period. In this study, Lu AA21004 5 or 10 mg/day was efficacious in preventing relapse and was well tolerated in the maintenance treatment of GAD.     

The clinical pharmacokinetics of Lu AA21004 and its major metabolite in healthy young volunteers

Lu AA21004 is a novel multimodal antidepressant that is currently in phase 3 development. The objective of this report was to detail the clinical pharmacokinetics of Lu AA21004 and its major but inactive metabolite Lu AA34443 (3‐methyl‐4‐(2‐piperazine‐1‐yl‐phenylsulfanyl)‐benzoic acid) in healthy men and women aged between 18 and 53 years. Data from two single‐dose and one multiple‐dose study were combined; the total number of volunteers was 97 (64 men, 33 women). Blood and urine samples were collected after p.o. and i.v. administrations to determine the content of Lu AA21004 and Lu AA34443 performed with a validated method. Standard pharmacokinetic parameters were estimated with non‐compartmental analysis. The absolute bioavailability was 75%. After oral administration, Lu AA21004 showed an extended absorption phase, a medium clearance and a large volume of distribution resulting in late t_max values and a mean elimination half‐life of 57 hr. The exposure of Lu AA21004 showed a linear relationship with dose in the dose ranges studied (up to 75‐mg single dosing and 60‐mg multiple dosing). After weight correction, no differences in exposure for Lu AA21004 and Lu AA34443 were observed between men and women. The renal clearance of Lu AA21004 was negligible. The major metabolite Lu AA34443 had a half‐life similar to that of Lu AA21004 but a lower accumulation ratio at steady‐state, indicating formation‐rate‐limited elimination. In conclusion, Lu AA21004 showed an extended absorption phase, a medium clearance and a large volume of distribution.     

Vortioxetine (Lu AA21004) in generalized anxiety disorder: Results of an 8-week,multinational, randomized,double-blind,placebo-controlled clinical trial

Vortioxetine is a multimodal antidepressant, with anxiolytic properties observed in preclinical studies. The goal of the current study was to evaluate the efficacy and tolerability of vortioxetine 5 mg vs placebo in adults with generalized anxiety disorder (GAD). Adults with a primary diagnosis of GAD (HAM-A total score ≥20 and MADRS score ≤16) received vortioxetine 5 mg or placebo for 8 weeks. The primary efficacy endpoint was reduction in HAM-A total scores from baseline after 8 weeks of treatment compared with placebo. Key secondary measurements were HAD anxiety subscore, CGI-I, SDS total score, HAM-A response rates, HAM-A total score for subjects whose baseline HAM-A total score was ≥25, and SF-36 social functioning subscore. HAM-A remission rates were also measured. Adverse events (AEs) were assessed throughout the study. In total, 301 subjects (mean age, 45.2 years; 31% male) were randomized (1:1) to receive vortioxetine 5 mg (n=150) or placebo (n=151). After 8 weeks of treatment, there was a statistically significant difference in reduction from baseline in HAM-A total score for the vortioxetine group (?14.30) compared with placebo recipients (?10.49) (P<0.001). Statistically significant differences were observed for all key secondary outcomes favoring vortioxetine treatment (vs placebo), using a mixed model for repeated measurements (MMRM) analysis. Active treatment resulted in a significantly higher rate of remission. Vortioxetine was well tolerated. The most common treatment-related AEs were nausea, headache, dizziness, and dry mouth. In sum, vortioxetine was safe and effective in treating adults with GAD in this multinational population.     

Effects on cognitive functioning after olanzapine–ziprasidone crossover in recent-onset schizophrenia

IntroductionTo enhance functional outcome in schizophrenia improvement of cognitive symptoms is crucial.Experimental proceduresUsing a comprehensive test battery, this follow-up examines cognitive effects in patients with recent-onset schizophrenia after a change of medication following insufficient clinical response and intolerance.ResultsAfter eight weeks cognitive outcomes had not improved in the patients having switched from olanzapine to ziprasidone (n = 11; mean dose 136 mg) nor in those having switched from ziprasidone to olanzapine (n = 10; mean 16 mg), while the symptoms of patients maintaining olanzapine (n = 18; mean 10.9 mg) or ziprasidone (n = 18; mean 88.9 mg) treatment had not improved further.DiscussionThe findings suggest that also in early-stage schizophrenia the antipsychotics tested affect cognitive symptoms similarly.     

Inhibitory actions of mGlu4 receptor ligands on cocaine-, but not nicotine-, induced sensitizing and conditioning locomotor responses in rats

BackgroundMale Wistar rats were used to verify the hypothesis that metabotropic glutamate 4 (mGlu₄) receptor ligands may modulate the locomotor effects evoked by cocaine or nicotine.MethodsThe preferential mGlu₄ receptor orthosteric agonist (2S)-2-amino-4-[hydroxy[hydroxy(4-hydroxy-3-methoxy-5-nitrophenyl)methyl]phosphoryl]butanoic acid (LSP1-2111) and the mGlu₄ receptor positive allosteric modulator (+)-cis-N¹-(3,4-dichlorophenyl)cyclohexane-1,2-dicarboxamide (Lu AF21934) were used in the study. Rats were given repeated pairings of a test environment with cocaine (10 mg/kg), nicotine (0.4 mg/kg) or the respective vehicles for 5 days. On day 10, animals were challenged with cocaine (10 mg/kg, cocaine sensitization), nicotine (0.4 mg/kg, nicotine sensitization) or vehicle (conditioned hyperlocomotion) in experimental cages.ResultsGiven on day 10, LSP1-2111 (3 mg/kg) as well as Lu AF21934 (2.5–5 mg/kg) decreased the expression of cocaine sensitization. In another set of experiments, LSP1-2111 (3 mg/kg) and Lu AF21934 (5 mg/kg) administered on day 10 attenuated the conditioned hyperlocomotion in rats treated repeatedly with cocaine. Neither LSP1-2111 (1–3 mg/kg) nor Lu AF21934 (2.5–5 mg/kg) changed the expression of nicotine sensitization and conditioned hyperlocomotion in rats treated repeatedly with nicotine. None of the mGlu₄ receptor agonist/modulator altered the basal locomotor activity or acute hyperactivity to cocaine or nicotine.ConclusionsThe present data indicate that pharmacological stimulation of mGlu₄ receptors reduces the cocaine-induced expression of sensitization as well as conditioned hyperactivity. In contrast, mGlu₄ receptor activation seems to be devoid of any effect on the locomotor effects of nicotine.     

A comparison of two fixed doses of aripiprazole with placebo in acutely relapsed,hospitalized patients with bipolar disorder I (manic or mixed) in subpopulations (CN138-007)

This study evaluated the efficacy and safety of two fixed doses of aripiprazole (15 mg/day, n = 131 and 30 mg/day, n = 136) compared with placebo (n = 134) in acutely manic or mixed bipolar I hospitalized patients. The mean change from baseline to Week 3 in the YMRS Total Scores was − 10.01 (95% CI: − 11.92, − 8.09) for aripiprazole 15 mg/day, − 10.80 (95% CI: − 12.71, − 8.90) for aripiprazole 30 mg/day, and − 10.12 (95% CI: − 12.01, − 8.24) for placebo. The most frequent adverse events (≥ 10% and greater than placebo) for either of the aripiprazole treatment groups were headache, nausea, dyspepsia, insomnia, agitation, constipation, akathisia, anxiety, lightheadedness, vomiting, diarrhea, asthenia and extremity pain. Aripiprazole 15 or 30 mg/day was not significantly more effective than placebo in the treatment of bipolar I disorder acute mania at endpoint (Week 3). A high placebo response rate may have accounted for the lack of separation between treatment groups.     

Duloxetine-bupropion combination for treatment-resistant atypical depression: A double-blind,randomized, placebo-controlled trial

The efficacy, safety, and tolerability of combined bupropion versus placebo using duloxetine as active reference drug, in patients with a DSM-IV diagnosis of major depression with atypical features and a history of treatment resistance, were evaluated in this preliminary six-week study. Patients (n=46) had a baseline Hamilton Depression Scale (HAM-D) ≥14 and were randomly assigned to 150/300 mg/day bupropion vs. placebo, which was added to 60 to 120 mg/day duloxetine depending on baseline depression severity. Atypical features of depression were assessed using the additional eight-item module of the Structured Interview Guide for the HAM-D with the Atypical Depression Supplement. By week 6, only five (21.7%) patients receiving duloxetine+placebo vs. six (26.1%) patients on the bupropion combination achieved response. No significant difference in final HAM-D scores between the two groups was observed between those patients achieving response. The presence of a higher number of atypical features significantly predicted non-response, with the relevant binary logistic regression model correctly classifying 17 out 22 (77.3%) of non-responders [Exp(B)=0.294; p=0.016] vs. 17 out 23 (73.9%) [Exp(B)=0.353; p=0.028] non-responder cases in the “+placebo” and “+bupropion” groups, respectively. In those patients receiving bupropion, treatment-emergent adverse events leading to withdrawal were more common among those receiving lower doses of the combination drug, and no life-threating dangers were noted. Additional studies, including an adequate course of duloxetine trial, are nonetheless aimed to allow a firm conclusion about the usefulness of the combination of duloxetine and bupropion for treatment-resistant cases of major depression with atypical features.     

A phase II/III trial of bitopertin monotherapy compared with placebo in patients with an acute exacerbation of schizophrenia – Results from the CandleLyte study

Bitopertin is a glycine reuptake inhibitor postulated to improve N-methyl-d-aspartate receptor hypofunction by increasing synaptic glycine concentrations. This randomised, double-blind, placebo- and active-controlled phase II/III trial evaluated the efficacy and safety of bitopertin monotherapy over 4 weeks in patients with acute exacerbation of schizophrenia. Of 301 patients randomised, 299 received placebo (n=80), bitopertin 10 mg (n=80) or 30 mg (n=77), or olanzapine 15 mg (n=62). The primary endpoint, change from baseline in mean Positive and Negative Syndrome Scale (PANSS) total score, showed non-statistically significant improvements with bitopertin 30 mg and olanzapine vs. placebo: bitopertin 10 mg (–11.7; standard error [SE], 1.89; p=0.945), bitopertin 30 mg (–15.3; SE, 1.87; p=0.211), olanzapine (–14.9; SE, 2.13; p=0.295) and placebo (–11.9; SE, 1.90). The PANSS positive subscale score, a secondary endpoint, also showed improvement with bitopertin 30 mg (p=0.030) whereas a trend was observed with olanzapine (p=0.072) vs. placebo. Although not statistically significant, bitopertin 30 mg and olanzapine reduced overall illness severity (Clinical Global Impression–Severity Scale; p=0.098 and p=0.126, respectively). More patients receiving bitopertin 30 mg (51.3%) or olanzapine (52.5%) than placebo (32.9%) were ready for hospital discharge at Week 4 (bitopertin, p=0.014; olanzapine, p=0.024). In summary, this study failed due to lack of statistical separation of either bitopertin or olanzapine (active control) from placebo on the primary endpoint. Of interest, improved positive symptoms and readiness for hospital discharge were associated with both bitopertin and olanzapine treatment. Bitopertin was safe and well tolerated in this study.     

Neurobehavioral and genotoxic parameters of duloxetine in mice using the inhibitory avoidance task and comet assay as experimental models

Duloxetine is a potent inhibitor of serotonin and noradrenaline reuptake, with weak effects on dopamine reuptake, used in the treatment of major depression. It has been recognized that some antidepressants can affect memory in humans, but there is not study that report the duloxetine effect on memory using the inhibitory avoidance. The aim of this work was to investigate the effect of duloxetine on short- and long-term memory (STM and LTM) in the inhibitory avoidance task in mice. Duloxetine (10 and 20 mg/kg; i.p.) administered before or after the inhibitory avoidance training was not able to produce effects on STM e LTM (p > 0.05). The group that received MK-801 (0.0625 mg/kg), an NMDA receptor antagonist, showed an impairment in STM and LTM (p < 0.01). These effects were not reversed by duloxetine administration (p = 0.114 and p = 0.06, respectively). Duloxetine effect on memory 5 days after i.p. administration was also investigated. After this treatment both duloxetine doses used were unable to affect STM or LTM in the inhibitory avoidance task (p = 0.371 and p = 0.807, respectively). DNA damages were evaluated in brain tissues and blood by the comet assay, after subacute treatment (10 or 20 mg/kg by 5 days). Duloxetine did not induce genotoxic effects. However, when the cells were treated ex vivo hydrogen peroxide, a pro-oxidant effect on brain tissue from treated animals was observed with significantly higher DNA damage in comparison to untreated animals, suggesting increased susceptibility to injuries by reactive oxygen species in brain after treatment with duloxetine. Duloxetine did not produce any effect on memory after acute and subacute administration, suggesting that this antidepressant does not affect either memory acquisition or consolidation.     

Endothelial and neural factors functionally involved in the modulation of noradrenergic vasoconstriction in healthy pig internal mammary artery

The role of endothelial and neural factors as modulators of neurogenic- and noradrenaline-induced vasoconstriction was examined in healthy pig internal mammary artery (IMA). Tetrodotoxin-, guanethidine-sensitive electrical field stimulation (EFS)-, and noradrenaline-elicited contractions were significantly diminished by prazosin (n = 8, P < 0.001) and less so by rauwolscine, indicating functional α₁- and α₂-adrenoceptor-mediated noradrenergic innervation of the IMA. Endothelium removal reduced neurogenic (n = 8, P < 0.01) but augmented noradrenaline responses (n = 8, P < 0.01), suggesting the release of two endothelium-dependent factors with opposite effects. In the presence of endothelium, neurogenic and exogenous noradrenaline vasoconstrictions were enhanced by l-NOArg (n = 7, P < 0.05 and P < 0.01 respectively) and ODQ (n = 7, both P < 0.05); in denuded arteries, nNOS inhibition with N^ω-propyl-l-arginine increased neurogenic contraction (n = 7, P < 0.05). Western blotting indicated the presence of neural and endothelial origin NO (n = 6, P < 0.001). Tetraethylammonium (n = 9, P < 0.001), iberiotoxin (n = 7, P < 0.001) and 4-aminopyridine (n = 8, P < 0.01) enhanced vasoconstrictions revealing a modulatory role of big conductance Ca²⁺-activated K⁺ (BK_Ca) and voltage-dependent K⁺ (K_v) channels in noradrenergic responses. Bosentan pretreatment (n = 8, P < 0.05) suggested endothelin-1 as the inferred contractile neurogenic endothelial-dependent factor. Indomethacin-induced inhibition involved a muscular prostanoid (n = 9, P < 0.05), functionally and immunologically localized, and derived from cyclooxygenase (COX)-1 and COX-2, as revealed by Western blots (n = 5, P = 0.1267). Thus, noradrenergic IMA contractions are controlled by contractile prostanoid activation and endothelin-1 release, and offset by BK_Ca and K_v channels and neural and endothelial NO. These results help clarify the mechanisms of vasospasm in IMA, as the preferred vessel for coronary bypass.     

The cardiovascular safety profile of escitalopram

The cardiovascular effects of escitalopram were examined in a large group of participants in double-blind, randomized, placebo-controlled studies. Escitalopram (n=3298) was administered at doses between 5 and 20 mg/day. Patients were treated in acute (8–12 weeks) and long-term (24 weeks) studies. Assessment of cardiovascular safety included heart rate, blood pressure (BP), treatment-emergent adverse events (TEAEs) and electrocardiograms (ECGs). In the short-term, there was a small, but statistically significant 2 beats per minute decrease in heart rate with escitalopram compared with placebo. The difference compared to placebo in systolic or diastolic BP was not clinically or statistically significant. Valid ECG assessments at both baseline and last assessment were available for 2407 escitalopram patients and 1952 placebo patients. Escitalopram–placebo differences in mean changes in ECG values were not clinically meaningful. The mean difference to placebo in the corrected QT [Fridericia's (QTcF)] interval was 3.5 ms (all escitalopram doses); 1.3 ms (escitalopram 10 mg) and 1.7 ms (escitalopram 20 mg) (p=0.2836 for 10 versus 20 mg). One out of 2407 escitalopram patients had a QTcF interval >500 ms and a change from baseline >60 ms. The incidence and types of cardiac-associated adverse events were similar between patients treated for 8–12 weeks with placebo (2.2%) or escitalopram (1.9%) and for 24 weeks with placebo (2.7%) or escitalopram (2.3%). Analyses of data from long-term studies and studies of the elderly showed similar results. In conclusion, these data demonstrate that escitalopram, like other SSRIs, has a statistically significant effect on heart rate and no clinically meaningful effect on ECG values, BP, with a placebo-level incidence of cardiac-associated adverse events.     

Identification of the cytochrome P450 and other enzymes involved in the in vitro oxidative metabolism of a novel antidepressant, Lu AA21004

1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine (Lu AA21004) is a novel antidepressant that is currently in late-stage clinical development for major depressive disorder. In the present study, the metabolism of Lu AA21004 was investigated using human liver microsomes (HLM), human liver S9 fraction, and recombinant enzymes. Lu AA21004 was found in vitro to be oxidized to a 4-hydroxy-phenyl metabolite, a sulfoxide, an N-hydroxylated piperazine, and a benzylic alcohol, which was further oxidized to the corresponding benzoic acid [3-methyl-4-(2-piperazin-1-yl-phenysulfanyl)-benzoic acid (Lu AA34443)]. The formation of the 4-hydroxy-phenyl metabolite was catalyzed by CYP2D6 with some contribution from CYP2C9, whereas the formation of the sulfoxide was mediated by CYP3A4/5 and CYP2A6. CYP2C9 and CYP2C19 were the primary enzymes responsible for formation of the N-hydroxylated metabolite. The benzylic alcohol was formed by CYP2D6 only. The oxidation of the benzylic alcohol to the corresponding benzoic acid of Lu AA21004 was catalyzed by alcohol dehydrogenase and aldehyde dehydrogenase, with some contribution from aldehyde oxidase. CYP2D6 was also capable of catalyzing the formation of the benzoic acid of Lu AA21004; however, its overall contribution to this pathway was negligible. Enzyme kinetic parameters revealed that the rate-limiting step in the formation of the benzoic acid from Lu AA21004 is the formation of the corresponding alcohol. Thus, the intrinsic clearance (V(max)/K(m)) in HLM for metabolism of Lu AA21004 to the benzylic alcohol was 1.13 × 10(-6) l · min(-1) · mg(-1), whereas the subsequent metabolism of the benzylic alcohol to the benzoic acid of Lu AA21004 is characterized by an intrinsic clearance (V(max)/K(m)) in S9 fraction of 922 × 10(-6) l · min(-1) · mg(-1).     

A randomized,double-blind,placebo-controlled trial to assess prevention of mood episodes with risperidone long-acting injectable in patients with bipolar I disorder

The efficacy and safety of risperidone long-acting injectable (LAI) for preventing recurrence of mood episodes in patients with bipolar I disorder was evaluated in a randomized, placebo-controlled study. After a 12-week open-label period with risperidone LAI (n=560), patients who did not experience a recurrence entered an 18-month randomized, double-blind period with risperidone LAI (n=132) or placebo (n=135); a third treatment arm (n=131) was randomized to oral olanzapine (10 mg/day) for reference and exploratory comparisons. The primary efficacy endpoint was time to recurrence of any mood episode for risperidone LAI versus placebo in the double-blind period (Kaplan–Meier analysis). Additional efficacy endpoints included Young Mania Rating Scale, Montgomery–Asberg Depression Rating Scale and Clinical Global Impression. During the double-blind period, dosing was fixed at patients' final open-label dose (25 mg, 66% of patients; 37.5 mg, 31%; 50 mg, 4%). The primary outcome demonstrated a median time to mood episode recurrence of 198 day in the placebo arm, whereas the median was not reached in the risperidone LAI arm (p=0.057). Time to recurrence of any mood episode was significantly longer with risperidone LAI versus placebo (log-rank test stratified by region only, p=0.031); the difference was significant for time to recurrence of elevated mood episodes (p=0.005) but not depressive episodes (p=0.655). Significant improvement of manic symptoms and global condition versus placebo were observed for risperidone LAI, with no evidence of worsening of depression. In conclusion, risperidone LAI significantly delayed time to recurrence of elevated mood episodes, with a safety profile consistent with previous studies.     

Correlates of extramedical use of OxyContin versus other analgesic opioids among the US general population

BackgroundThere has been substantial public and media attention regarding extramedical use of OxyContin^®, but few studies focus on the characteristics of extramedical OxyContin^® users and whether they differ from extramedical other opioid users.MethodsWe used data from 8218 respondents who were past-year extramedical opioid analgesic users in the 2005 and 2006 National Survey of Drug Use and Health (NSDUH). We investigated differences in socio-demographic and psychiatric characteristics associated with past-year extramedical OxyContin^® use (n = 1144) versus extramedical other opioid analgesics use (n = 7074). Data on opioid sources was compared among past-month users. We also compared extramedical opioid users (n = 8218) versus other drug users (n = 16,214), and individuals with an analgesic disorder who had past-year extramedical OxyContin^® use (n = 339) versus those with other opioid use (n = 820).ResultsPast-year opioid users were more likely than users of other illegal drugs to be more educated and have a past-year major depressive episode. Past-year OxyContin^® users were more likely than other opioid users to be 18–25 years old (aOR = 1.9[1.1,3.2]), and have mental health and deviant behavior problems. Those with past-year analgesic disorder who used OxyContin^® were more likely to be younger, sell illegal drugs (aOR = 2.5[1.5,4.2]), and use illegal drugs than those who used other opioids. Past-month OxyContin^® users were more likely than past-month other opioid users to buy analgesics from drug dealers/other strangers and obtain opioid analgesics from multiple sources.ConclusionOur findings point out differences between OxyContin^® and other opioid users that might help prevention specialists and assist efforts to curb opioid analgesics diversion.     

Normothermic and hypothermic models for studying the deleterious effects of hypoxia-reoxygenation on EDHF-mediated relaxation in isolated porcine coronary arteries

IntroductionThe vasomotor response of the coronary artery is altered by hypoxia–reoxygenation (H–R) induced damage. The aim of our study was to compare and evaluate normothermic and hypothermic models which are suitable for future drug studies of vasoprotective action against H–R injury.MethodsPorcine coronary arterial rings were isolated and placed in Krebs–Henseleit (K–H) solution. Rings were exposed to normoxic conditions (control group) and two different H–R conditions: the first induced by a 95% N₂–5% CO₂ gas mixture (40- and 60-min hypoxia) in a normothermic protocol, and the second induced by hypothermic (4 °C) hypoxia–reoxygenation in an air-tight beaker filled with K–H solution (24- and 48-hours hypoxia). Reoxygenation was applied by introducing K–H solution aerated with a 95% O₂–5% CO₂ mixture under normothermic (37 °C) conditions. To test the EDHF-mediated relaxation by substance P, rings were first incubated in L-NNA, nitric oxide synthase inhibitor, and indomethacin, cyclooxygenase inhibitor, and then pre-contracted with thromboxane analogue U-46619. Analysis of the maximum relaxation of the arterial rings was performed by one-way ANOVA, followed by Bonferroni's post-test.ResultsDistal segments of the coronary artery responded faster to contraction induced by U-46619 and were relaxed by substance P to a greater extent than proximal segments. Maximal relaxations of arterial rings induced by a 10 nM solution of substance P were significantly reduced (p < 0.001) from the values for normoxic rings (81.0 ± 1.0%, n = 30) after 40-min H–R (50.5 ± 5.3%, n = 30), 60-min H–R (32.1 ± 3.5%, n = 30), 24-hours hypothermic H–R (56.0 ± 2.3%, n = 30) and after 48-hours hypothermic H–R (38.5 ± 5.1%, n = 30).ConclusionsThe model employing 40-min normothermic H–R is as effective as 24-hours hypothermic H–R, and 60-min normothermic H–R as 48-hours hypothermic H–R for studying the deleterious effects of H–R on EDHF-mediated relaxation.     

Drug interaction between oral contraceptives and St. John's Wort: appropriateness of advice received from community pharmacists and health food store clerks.

ObjectiveTo estimate the extent to which community pharmacists and health food store clerks provide appropriate advice regarding a drug interaction between oral contraceptives and St. John's wort (SJW).DesignCross-sectional study.SettingThree community pharmacy chains and three health food store chains in four highly populated counties in California.ParticipantsCommunity pharmacists (n = 99) and health food store clerks (n = 184).InterventionInvestigators, posing as consumers, telephoned pharmacists and health food store clerks and asked the following question: "Is there a problem with taking SJW with birth control pills?"Main outcome measuresRespondents were classified based on their ability to correctly identify the drug interaction (yes or no) and on the overall appropriateness (i.e., the absence of incorrect advice) of their advice. Comparisons were made between men and women respondents and between pharmacists and health food store clerks.ResultsCommunity pharmacists were more likely than health food store clerks to correctly identify the drug interaction (50.5% versus 10.9%; χ²(1df) = 54.32,P < 0.001). Overall, 31.8% of respondents provided inappropriate advice that implied the absence of a drug interaction (26.3% of 99 pharmacists and 34.8% of 184 health food store clerks; χ²(1df) = 2.15,P = 0.14). Appropriateness of advice varied significantly among the three pharmacy chains (P < 0.001) and the three health food store chains (P < 0.05). Responses did not differ by gender of respondents (P = 0.18).ConclusionLack of awareness of the potentially serious drug interaction between SJW and oral contraceptives by those who sell these products places the public at risk. Training and education, more comprehensive product labeling, and policies to refer consumers to drug information centers are needed.     

Nicotine dependence and self-esteem in adolescents with mental disorders

Recent studies in adolescents have found a weak association between lower self-esteem and smoking. However, this association has not been investigated in a psychiatric setting.In 223 inpatient adolescents [140 girls (16.5 years) and 83 boys (16.4 years)], self-esteem was measured with Coopersmith's self-esteem inventory (SEI), and smoking dependence with the Fagerström Test for Nicotine Dependence (FTND). DSM-IV categories included major depression (n = 35), anxiety disorders (n = 35), psychotic disorders (n = 31), eating disorders (n = 9), and conduct disorders (n = 113). There were 101 smokers and 122 nonsmokers.Self-esteem scores were lower in smokers than in nonsmokers (p = 0.039). Self-esteem scores were very significantly lower in smokers showing moderate or high nicotine dependence (i.e., FTND score ≥ 4) when compared with nonsmokers (p = 0.002). Smoking with moderate or high nicotine dependence was associated with lower self-esteem in both girls and boys, whereas smoking with no or low nicotine dependence was associated with lower self-esteem only in girls. Smoking was associated with lower self-esteem in all diagnostic categories, except in eating disorders.Interventions targeted on self-esteem might be used to prevent smoking in adolescents with mental disorders.     

Deposition of ethyl glucuronide in WHP rat hair after chronic ethanol intake

BackgroundThis study investigated the relationship between ethanol intake in rats and the resulting level of ethyl glucuronide (EtG) in rat hair.MethodsRats (n = 50) consumed a 10% ethanol solution for 4 weeks, then EtG was extracted from samples of their hair using a novel extraction procedure involving freezing and thawing. The EtG concentration was measured using gas chromatography and mass spectrometry. The animals voluntarily drank ethanol, with daily consumption in most rats exceeding 5 g/kg b.w. The silylated EtG was stable for at least 28 h. The limit of detection was 0.03 ng/mg, and the limit of quantification was 0.1 ng/mg.ResultsHair samples from rats that consumed ethanol had EtG levels ranging from 0.17–20.72 ng/mg in female rats and 0.15–13.72 ng/mg in males. There was a correlation between the amount of alcohol consumed and the EtG levels in hair from female (p < 0.01), but not male, rats.ConclusionThe method presented allows detection and quantification of EtG in rat hair. We also observed differences in EtG deposition in male and female rats.