Superiority of escitalopram to paroxetine in the treatment of depression

Post-hoc pooled analysis of data from two 6-month randomised controlled trials in patients with major depressive disorder (MDD) revealed superior efficacy and tolerability of escitalopram when compared with paroxetine. Escitalopram (n = 394) produced a significantly (p < 0.01) greater mean treatment difference of 2.0 points in primary endpoints, judged using the Montgomery–Åsberg Depression Rating Scale (MADRS) total score, compared with paroxetine (n = 383). Significant differences were also observed in Clinical Global Impression (CGI) — severity (escitalopram, 2.1; paroxetine, 2.4; p < 0.01) and CGI — improvement (escitalopram, 1.8; paroxetine, 2.0: p < 0.01). In the sub-group of severely depressed patients (baseline MADRS ≥ 30), escitalopram showed further improved efficacy compared with paroxetine in all scores. This analysis supports previous observations of superior efficacy and tolerability of long-term escitalopram treatment (10 to 20 mg/day) compared with paroxetine (20 to 40 mg/day). Escitalopram is a good therapeutic option for the long-term treatment of MDD, particularly in severely depressed patients.     

Involvement of NMDA receptors and l-arginine-nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effects of escitalopram in the forced swimming test

Escitalopram is a serotonin reuptake inhibitor used in the treatment of depression and anxiety disorders. This study investigated the effect of escitalopram in forced swimming test (FST) and in the tail suspension test (TST) in mice, and tested the hypothesis that the inhibition of NMDA receptors and NO-cGMP synthesis is implicated in its mechanism of action in the FST. Escitalopram administered by i.p. route reduced the immobility time both in the FST (0.3–10 mg/kg) and in the TST (0.1–10 mg/kg). Administration of escitalopram by p.o route (0.3–10 mg/kg) also reduced the immobility time in the FST. The antidepressant-like effect of escitalopram (3 mg/kg, p.o.) in the FST was prevented by the pretreatment of mice with NMDA (0.1 pmol/site, i.c.v.), l-arginine (750 mg/kg, i.p., a substrate for nitric oxide synthase) or sildenafil (5 mg/kg, i.p., a phosphodiesterase 5 inhibitor). The administration of 7-nitroindazole (50 mg/kg, i.p., a neuronal nitric oxide synthase inhibitor), methylene blue (20 mg/kg, i.p., an inhibitor of both nitric oxide synthase and soluble guanylate cyclase) or ODQ (30 pmol/site i.c.v., a soluble guanylate cyclase inhibitor) in combination with a subeffective dose of escitalopram (0.1 mg/kg, p.o.) reduced the immobility time in the FST as compared with either drug alone. None of the drugs produced significant effects on the locomotor activity in the open-field test. Altogether, our data suggest that the antidepressant-like effect of escitalopram is dependent on inhibition of either NMDA receptors or NO-cGMP synthesis. The results contribute to the understanding of the mechanisms underlying the antidepressant-like effect of escitalopram and reinforce the role of NMDA receptors and l-arginine-NO-GMP pathway in the mechanism of action of antidepressant agents.     

Effects of escitalopram on stress-related relapses in women with multiple sclerosis: An open-label,randomized, controlled,one-year follow-up study

A growing body of evidence supports the association between Stressful Life Events (SLEs) and increased risk for relapse in Multiple Sclerosis (MS). In this open-label, randomized, controlled, one-year prospective study we investigated the effects of escitalopram on stress-related relapses in 48 women with relapsing–remitting MS. Patients were randomly assigned either to receive escitalopram 10 mg/day (e-group, N = 24) or to continue with treatment as usual, as a control group (c-group, N = 24). SLEs were documented weekly in self-report diaries and were classified afterwards as short- or long-term depending on their psychological impact as this was subjectively felt by the patient. The cumulative risk for relapse was 2.9 times higher for controls than for escitalopram-treated patients (95% CI = 1.7–5.1, p < 0.001) and it was influenced only by long-term SLEs. In the e-group only 3 or more long-term SLEs were associated with a significant increase of the risk of a relapse during the following 4 weeks, and this risk was 4 times lower compared to the c-group. Our study shows preliminary evidence that escitalopram may constitute an effective and well-tolerated treatment option for the prevention of stress-related relapses in women with MS.     

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.     

Effect of lurasidone on neurocognitive performance in patients with schizophrenia: A short-term placebo- and active-controlled study followed by a 6-month double-blind extension

This double-blind study evaluated change in cognitive performance and functional capacity in lurasidone and quetiapine XR-treated schizophrenia patients over a 6-week, placebo-controlled study, followed by a 6-month, double-blind extension. Cognitive performance and functional capacity were assessed with the CogState computerized cognitive battery and the UPSA-B. Analyses were conducted for all subjects, as well as the subsample whose test scores met prespecified validity criteria. No statistically significant differences were found for change in the composite neurocognitive score for lurasidone (80 mg/day and 160 mg/day) groups, quetiapine XR and placebo in the full sample at week 6. For the evaluable sample (N=267), lurasidone 160 mg was superior to both placebo and quetiapine on the neurocognitive composite, while lurasidone 80 mg, quetiapine XR, and placebo did not differ. UPSA-B scores were superior to placebo at 6 weeks for all treatments. In the double-blind extension study, analysis of the full sample showed significantly better cognitive performance in the lurasidone (40–160 mg) group compared to the quetiapine XR (200–800 mg) group at both 3 and 6 months. Cognitive and UPSA-B total scores were significantly correlated at baseline and for change over time. This is the first study to date where the investigational treatment was superior to placebo on both cognitive assessments and a functional coprimary measure at 6 weeks, as well as demonstrated superiority to an active comparator on cognitive assessments at 6 weeks and at 6 months of extension study treatment. These findings require replication, but are not due to practice effects, because of the placebo and active controls.     

The effect of 6-week treatment with escitalopram on CCK-4 challenge: A placebo-controlled study in CCK-4-sensitive healthy volunteers

Cholecystokinin-tetrapeptide (CCK-4)-induced panic attacks are reportedly attenuated by effective treatment with antipanic antidepressants in patients with panic disorder, but in healthy volunteers such effects are not well studied. The aim of this study was to assess the effect of 6-week treatment with an SSRI escitalopram on CCK-4-induced symptoms in healthy volunteers, who previously responded with a panic attack to CCK-4 challenge. A total of 18 healthy subjects (10 males and eight females, mean age 22.5±5.8) received a 6-week treatment with escitalopram (10 mg/day) and placebo followed by CCK-4 challenge (50 μg) in a double-blind crossover design. The panic rate was 67% after treatment with escitalopram and 56% after treatment with placebo (p=0.7). Thus, the results showed a significant reduction in CCK-4-induced panic rates without significant differences between escitalopram and placebo conditions. There were no significant effects of either treatment on any other variable of anxiety or cardiovascular indices. Secondary analysis showed no effect of gender or 5-HTTLPR polymorphism on response to CCK-4 challenge. This study demonstrated that in contrast to the findings in patients with panic disorder, in CCK-4-sensitive healthy volunteers the treatment with an antipanic SSRI did not cause a reduction of CCK-4-induced panic attacks beyond the effect of placebo. The mechanisms behind this discrepancy and the reasons of the decrease in sensitivity to CCK-4 challenge on repeated administration remain to be clarified in future studies.     

The immune responses in juvenile rockfish,Sebastes schlegelii for the stress by the exposure to the dietary lead (II)

The aim of this study was to evaluate the lead toxic effects on the stress parameters and immune responses of Sebastes schlegelii. Juvenile rockfish, S. schlegelii (mean length 14.2 ± 1.9 cm, and mean weight 57.3 ± 5.2 g) were exposed for 4 weeks with the different levels of dietary lead (Pb²⁺) at 0, 30, 60, 120 and 240 mg/L. The plasma cortisol and heat shock protein 70 was evaluated as stress indicators. The plasma cortisol of S. schlegelii was significantly increased in response to the dietary lead exposure over 60 mg/kg at 2 weeks. After 4 weeks, the significant increase in the plasma cortisol was observed at 30 and 60 mg/kg, but the level was decreased over 120 mg/kg. The heat shock protein 70 of S. schlegelii was also notably elevated over 60 mg/kg for 4 weeks. In the immune response, the immunoglobulin M of S. schlegelii was considerably increased over 120 mg/kg for 4 weeks. A significant increase was observed in lysozyme activity. The plasma lysozyme activity of S. schlegelii was elevated over 120 mg/kg after 2 weeks and 60 mg/kg after 4 weeks, and kidney lysozyme activity was also increased at 240 mg/kg after 2 weeks and over 120 mg/kg after 4 weeks. The results indicate that dietary Pb exposure can cause a significant stress and immune stimulation of S. schlegelii.     

A randomized,double-blind clinical study to determine the effect of ANKASCIN 568 plus on blood glucose regulation

Diabetes is the fourth major cause of death in Taiwan. High blood glucose can lead to macrovascular diseases, small vessel diseases (retinopathy, kidney disease), and neuropathy. This study aimed to investigate whether Monascus-fermented products (ANKASCIN 568 plus) can regulate blood glucose and blood lipids. This study enrolled 39 patients with a fasting blood glucose level between 100 mg/dL and 180 mg/dL, and a glycated hemoglobin (HbA1c) level of <9%. All patients were randomly divided into placebo (n = 20) and experimental (n = 19) groups. Each patient received two placebo capsules (maltodextrin) or ANKASCIN 568 plus capsules daily for 12 weeks. The patients were screened during follow-up 4 weeks after the administration of sample or placebo had been discontinued. Blood and urine samples were collected at the initial, 6^th week, 12^th week, and 16^th week. The anthropometric indicators of blood pressure, fasting plasma glucose level, postprandial plasma glucose level, insulin level, insulin resistance, blood lipid changes, and liver, kidney, and thyroid function indices were measured. After 6 weeks, changes in fasting blood glucose, low-density lipoprotein cholesterol (LDL-C), and total cholesterol (TC) levels showed that ANKASCIN 568 plus had a more favorable effect than the placebo. Compared to baseline, a statistically significant decrease of 8.5%, 10.3%, and 7.5% was observed in fasting blood glucose, LDL-C and, TC levels, respectively (p < 0.05 for all pairs). Therefore, ANKASCIN 568 plus produced by Monascus purpureus NTU 568 fermentation may be a potentially useful agent for the regulation of blood glucose and blood lipids and for treatment of coronary artery diseases.     

Development of the 2nd generation neurokinin-1 receptor antagonist LY686017 for social anxiety disorder

The neurokinin-1 (NK-1) antagonist LY686017 showed activity in preclinical anxiety models. The clinical development of LY686017 included a PET study and a proof-of-concept in social anxiety disorder (SAD). [¹¹C]GR205171 was used healthy volunteers receiving 1–100 mg/d LY686017 for 28 days to determine brain receptor occupancy (RO). The mean NK-1 RO increased ranged from 25% with 1 mg to 93% with 100 mg. Subsequently, a 12-week randomized clinical trial tested LY686017 vs. paroxetine, or placebo in SAD. Pharmacokinetic (PK)/RO modeling based on the PET results predicted that once daily dosing of > 30 mg LY686017 led to sustained trough RO of over 80%. 189 outpatients¹ suffering from SAD were randomly assigned to 12-weeks treatment with 50 mg/d LY686017 (N = 77), placebo (N = 74), or 20 mg/d paroxetine (N = 38). There was no significant difference between LY686017 and placebo as measured with the Liebowitz Social Anxiety scale (LSAS). The active comparator paroxetine showed positive trends on primary and secondary measures. The plasma concentrations were above the level expected to produce maximal brain NK-1 RO based on the PK/RO relationship obtained in the human PET investigation. Thus, further evaluation of LY686017 for the treatment of SAD does not seem warranted.     

Serotonin transporter promoter region polymorphisms do not influence treatment response to escitalopram in patients with major depression

Several studies and meta-analyses have implicated a polymorphism in the promoter region of the serotonin transporter (5-HTT) gene, 5-HTTLPR in treatment outcomes of selective serotonin re-uptake inhibitors in patients with major depression. In this study we investigated the impact of 5-HTTLPR and a functional SNP rs25531 on the treatment outcomes to escitalopram in depressive patients. The study sample consisted of 135 outpatients with major depressive disorder (mean age 31.1 ± 11.6 years, 68% females) treated with escitalopram 10–20 mg/day for 12 weeks. There were no significant associations between 5-HTT promoter region polymorphisms and response rate or mean change of depressive symptoms during escitalopram treatment. However we showed that patients carrying S allele of 5-HTTLPR may have increased risk for some side effects, including headache, induced by escitalopram medication.     

A placebo-controlled study of three agomelatine dose regimens (10 mg, 25 mg, 25–50 mg) in patients with major depressive disorder

A randomised placebo-controlled “dose relation study” was conducted in 549 patients who met the criteria for major depressive disorder, to evaluate the efficacy and safety of three doses regimens of agomelatine during 6 weeks: low fixed dosage (10 mg/day, n=133), fixed dosage (25 mg/day, n=138) and a flexible dosage with up-titration in case of insufficient improvement at week 2 (25–50 mg/day, n=137). At last post-baseline assessment, there were significant and incremental placebo-agomelatine differences on mean HAM-D₁₇ total scores in favour of each agomelatine dose regimen (2.46±0.76 points, p=0.001 at 10 mg; 4.71+0.75 points, p<0.0001 at 25 mg and 4.92±0.76 points, p<0.0001 at 25–50 mg) with statistically significant differences between 25 mg and 25–50 mg dose regimens compared to the 10 mg dose. The response rate according to HAM-D₁₇ was significantly higher in patients taking agomelatine than those taking placebo (difference of 16.1% at 10 mg p=0.005; 25.9% and 27.4% respectively at 25 mg and 25–50 mg, p<0.0001). The benefit of agomelatine was demonstrated in the subgroup of severely depressed patients in the 25 mg and 25–50 mg/day regimens. Consistent clinical response according to CGI variables and better social functioning were found in patients receiving agomelatine. All dose regimens of agomelatine were well tolerated and no unexpected adverse event was reported. This study provides evidence of a dose effect for agomelatine between 10 mg and the therapeutic dose regimen of agomelatine 25–50 mg: the efficacy of the higher dose regimens being more efficacious than the lowest (10 mg) daily dose. The data support a definitive statement regarding the utility of 25 mg as the threshold dose for initiating agomelatine in depressed patients.     

Toxic effects and depuration after the dietary lead(II) exposure on the bioaccumulation and hematological parameters in starry flounder (Platichthys stellatus)

Platichthys stellatus (mean length 20 ± 2 cm, mean weight 160.15 ± 15 g) were exposed to the different levels of dietary lead(II) at the concentrations of 0, 30, 60, 120, 240 mg/kg for 4 weeks. Depuration was conducted for 2 weeks after exposure. The lead exposure over 60 mg Pb/kg induced the significant bioaccumulation in tissues of P. stellatus (5–30 μg/g tissue), except for brain and muscle where the exposure to 240 mg Pb/kg caused the bioaccumulation (2–4 μg/g tissue). The hematological parameters such as red blood cell (RBC) counts, hematocrit (Ht) value and hemoglobin (Hb) concentration were substantially decreased over 60 mg Pb/kg, and lasted even after the depuration period. For plasma components, calcium and magnesium levels in plasma were generally decreased over 60 mg Pb/kg, and glucose level was also mainly increased over 60 mg Pb/kg. Total protein was significantly decreased over 120 mg Pb/kg after 4 weeks exposure. Glucose and total protein showed the restoration after the depuration period in groups of fish exposed previously to over 60 and 120 mg Pb/kg, respectively. However, other parameters that changed during the exposure over 60 mg Pb/kg did not recovered. For enzymatic components in plasma, glutamic oxalate transminase (GOT), glutamic pyruvate transminase (GPT) and alkaline phosphatase (ALP) were significantly increased over 120 mg Pb/kg, and there was only restoration observed after the depuration for ALP over 120 mg Pb/kg.     

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.     

Regulatory efficacy of fermented plant extract on the intestinal microflora and lipid profile in mildly hypercholesterolemic individuals

In recent years, the use of fermented plant products to protect against various metabolic syndromes has been increasing enormously. The objective of this study was to check the regulatory efficacy of fermented plant extract (FPE) on intestinal microflora, lipid profile, and antioxidant status in mildly hypercholesterolemic volunteers. Forty-four mildly hypercholesterolemic individuals (cholesterol 180–220 mg/dL) were recruited and assigned to two groups: experimental or placebo. Volunteers were requested to drink either 60 mL of FPE or placebo for 8 weeks. Anthropometric measurements were done in the initial, 4^th, 8^th, and 10^th weeks. The anthropometric parameters such as body weight, body fat, and body mass index were markedly lowered (p < 0.05) on FPE intervention participants. Moreover, the total antioxidant capacity and total phenolics in plasma were considerably increased along with a reduction (p < 0.05) in total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-c) after FPE supplementation. Participants who drank FPE showed a pronounced increase (p < 0.05) in the number of beneficial bacteria such as Bifidobacterium spp. and Lactobacillus spp., whereas the number of harmful bacteria such as Escherichia coli and Clostridium perfringens (p < 0.05) were concomitantly reduced. Furthermore, the lag time of LDL oxidation was substantially ameliorated in FPE-administered group, thus indicating its antioxidative and cardioprotective properties. Treatment with FPE substantially improved the intestinal microflora and thereby positively regulated various physiological functions by lowering the anthropometric parameters, TC, and LDL-c, and remarkably elevated the antioxidant capacity and lag time of LDL oxidation. Therefore, we recommended FPE beverage for combating hypercholesterolemia.     

Alcohol use during a trial of N-acetylcysteine for adolescent marijuana cessation

AimsCurrent adolescent alcohol treatments have modest effects and high relapse rates. Evaluation of novel pharmacotherapy treatment is warranted. N-acetylcysteine (NAC), an over-the-counter antioxidant supplement with glutamatergic properties, is a promising treatment for marijuana cessation in adolescents; however, its effects on adolescent drinking have not been examined. To that end, this secondary analysis evaluated: (1) the effect of NAC vs. placebo on alcohol use over an eight-week adolescent marijuana cessation trial and (2) the role of marijuana cessation and reduction on subsequent alcohol use.MethodsMarijuana-dependent adolescents (ages 15–21; N = 116) interested in treatment were randomized to NAC 1200 mg or matched placebo twice daily for eight weeks. Participants were not required to be alcohol users or interested in alcohol cessation to qualify.ResultsThere were no demographic or baseline alcohol use differences between participants randomized to NAC vs. placebo (ps > 0.05). Of the 89 participants returning for ≥ one visit following randomization, 77 reported ≥ one alcoholic drink in the 30 days prior to study entry and averaged 1.3 (SD = 1.4) binge drinking days per week. During treatment, less marijuana use (measured via urine cannabinoid levels) was associated with less alcohol use in the NAC-treated group but not in the placebo-treated group (p = 0.016).ConclusionsThere was no evidence of compensatory alcohol use during marijuana treatment. In fact, in the NAC group, lower levels of marijuana use were associated with less alcohol use, suggesting NAC effects may generalize to other substances and could be useful in decreasing adolescent alcohol use. NAC trials specifically focused on alcohol-using adolescents are warranted.     

Formulation and clinical evaluation of the standardized Litchi chinensis extract for skin hyperpigmentation and aging treatments

IntroductionThe standardized litchi extract had been revealed on phytochemical actives, in vitro and cellular activities against aging and darkening of skin. However, a formulation containing the extract has never been developed as per clinical evaluated.Materials and methodsThe litchi serum was developed, safety and efficacy were clinically evaluated in human volunteers. The stable and none irritated 0.05 and 0.1% litchi serums were randomized-single blind placebo control clinical applied on the inner forearm of 29 volunteers for a consecutive 112 days and monitored by Mexameter® MX18, Cutometer® MPA 580 and Visioscan® VC 98.ResultsSkin lightening efficacy of the 0.1% and 0.05% litchi serum was significantly (P < 0.001 and P < 0.05) higher than the placebo. Skin elasticity and wrinkle reduction was significantly (P < 0.05 and P < 0.005) achieved by the 0.1% litchi serum. The efficacy of litchi serums was confirmed by a split-face, randomized, single-blind controlled that the 0.1% litchi serum was significantly (P < 0.05) better than the 0.05% one of all examined parameters.ConclusionSafety and efficacy of litchi extract are clinically confirmed for hyperpigmentation and aging of skin treatments.     

Combination therapy with lercanidipine and enalapril reduced central blood pressure augmentation in hypertensive patients with metabolic syndrome

Arterial stiffness and blood pressure (BP) augmentation are independent predictors of cardiovascular events. In a randomized, open, parallel group study we compared the effect on these parameters of combination therapy with an ACE-inhibitor plus calcium channel blocker or thiazide diuretic in 76 hypertensive patients with metabolic syndrome uncontrolled by ACE-inhibitor monotherapy.After 4 weeks run-in with enalapril (ENA, 20 mg), patients were randomized to a combination therapy with lercanidipine (LER, 10–20 mg) or hydrochlorothiazide (HCT, 12.5–25 mg) for 24 weeks. Aortic stiffness (carotid to femoral pulse wave velocity, PWV), central BP values and augmentation (augmentation index, AIx) were measured by applanation tonometry.The two groups showed similar office and central BP after run-in. Office (ENA/LER: from 149.1 ± 4.9/94.5 ± 1.5 to 131.7 ± 8.1/82.2 ± 5.3; ENA/HCT: from 150.3 ± 4.7/94.7 ± 2.1 to 133.1 ± 7.1/82.8 ± 5.3 mm Hg) and central BP (ENA/LER 127.4 ± 17.1/85.2 ± 12.1 to 120.5 ± 13.5/80.0 ± 9.5 mm Hg; ENA/HCT 121.6 ± 13.4/79.3 ± 9.5 mm Hg) were similarly reduced after 24 weeks. PWV was comparable after run-in and not differently reduced by the two treatments (ENA/LER from 8.6 ± 1.5 to 8.1 ± 1.3 m/s, p < 0.05; ENA/HCT from 8.5 ± 1.2 to 8.2 ± 1.0 m/s, p < 0.05). Finally, both combinations reduced AIx, but its reduction was significantly greater (p < 0.05) in ENA/LER (from 26.8 ± 10.9 to 20.6 ± 9.1%) than in ENA/HCT arm (from 28.2 ± 9.0 to 24.7 ± 8.7%).In conclusion, the combination with LER caused a similar PWV reduction as compared to HCT, but a greater reduction in AIx in hypertensive patients with metabolic syndrome not controlled by ENA alone. These results indicate a positive effect of the combination of ENA/LER on central BP augmentation, suggesting a potential additive role for cardiovascular protection.     

Evaluation of the sensitivity of a new fully implantable telemetry device and the importance of simultaneously measuring cardiac output and left ventricular pressure

IntroductionThe absence of drug-induced changes in heart rate (HR), aortic pressure (AOP) and ECG, the minimum endpoints suggested in ICH S7A, does not necessarily indicate the absence of cardiovascular (CV) pharmacodynamic activity. This potential pitfall can be avoided by prospectively incorporating “follow-up” endpoints in initial evaluations made possible by the advent of new telemetry implants capable of also measuring changes in cardiac output (CO) and left ventricular pressure (LVP). The purpose of this study was (1) to evaluate the sensitivity of a new, fully implantable telemetry device, and (2) to highlight the importance of the device to simultaneously measure cardiac output and left ventricular pressure in order to adequately evaluate the full potential for a drug to impact global cardiovascular function.Methods4 dogs were instrumented with Konigsberg Instruments, Inc. (KI) TU7/T27H series fully implantable telemetry device and recovered for > 8 weeks. Sotalol (8 mg/kg), milrinone (0.2 mg/kg), hydralazine (0.2 mg/kg) and control were administered 1 week apart. Data were collected for 1 h pre- and 24 h post-treatment and time-averaged to fully characterize the a priori pharmacodynamic effects of interest for each drug. This included PR and QTci (sotalol); HR, AOP and LVP (milrinone); HR, AOP, CO and systemic vascular resistance (SVR) (hydralazine).ResultsExpected changes in CV parameters were observed following all drugs with the following detection sensitivities: PR and QTci of 4 ms and 3 ms, respectively (sotalol); AOP and LVP dP/dt +_max of 5 mm Hg and 232 mm Hg/s, respectively (milrinone); HR, CO and SVR of 11 bpm, 0.302 l/min and 5 mm Hg 1 min/l, respectively (hydralazine).DiscussionKI TU7/T27H implant detects drug-induced CV changes with statistical significance using a standard, four-subject design. The ability of the TU7/T27H to also measure CO and LVP allowed for full characterization of the CV impact of hydralazine and milrinone, which could have been misinterpreted/missed altogether if these drugs were novel and the endpoints evaluated were prospectively limited to the minimum suggested in ICH S7A.     

Ceftaroline activity tested against uncommonly isolated Gram-positive pathogens: report from the SENTRY Antimicrobial Surveillance Program (2008–2011)

Ceftaroline was tested against 1859 clinically significant Gram-positive organisms from uncommonly isolated species. The organisms (31 species/groups) were collected from 133 medical centres worldwide over a 4-year period (2008–2011). Coagulase-negative staphylococci were generally susceptible to ceftaroline, with MIC₅₀ values (minimum inhibitory concentration required to inhibit 50% of the isolates) of 0.06–0.5 mg/L. Ceftaroline was active against Micrococcus spp. [minimum inhibitory concentration required to inhibit 90% of the isolates (MIC₉₀) = 0.06 mg/L], but showed more limited potency versus some Corynebacterium spp. and Listeria monocytogenes isolates. Ceftaroline was active against all β-haemolytic streptococci and viridans group streptococcal species/groups listed, with MIC₅₀ and MIC₉₀ values ranging from ≤0.015 mg/L to 0.03 mg/L and from ≤0.015 mg/L to 0.5 mg/L, respectively. Based on these in vitro findings, ceftaroline may have a potential role in the treatment of infections caused by these rarer species as guided by reference MIC test results.     

Combination of peramivir and rimantadine demonstrate synergistic antiviral effects in sub-lethal influenza A (H3N2) virus mouse model

Efficacy of combination of the intramuscularly administered neuraminidase (NA) inhibitor, peramivir, and the orally administered M2 ion channel blocker, rimantadine was evaluated in mouse influenza A/Victoria/3/75 (H3N2) model. Mice were challenged with a sub-lethal virus dose (0–40% mortality in placebo group) and changes in body weights were analyzed by three-dimensional effect analysis to assess mode of drug interactions.Compounds were administered in a 5-day treatment course starting 1 h before viral inoculation. The peramivir and rimantadine doses ranged from 0.3–3 mg/kg/d and 5–30 mg/kg/d, respectively. The maximum mean weight loss of 5.19 g was observed in the vehicle-infected group on day 10. In the 1 and 3 mg/kg/d peramivir monotherapy groups, the weight losses were 4.3 and 3.55 g, respectively. In the rimantadine monotherapy group, the weight losses were 3.43, 2.1, and 1.64 g for the 5, 10, and 30 mg/kg/d groups, respectively. Combination of 1 mg/kg/d peramivir with 5 and 10 mg/kg/d rimantadine produced weight losses of 1.69 and 0.69 (p < 0.05 vs. vehicle and individual agent), respectively, whereas the combination of 3.0 mg/kg/d peramivir with 10 and 30 mg/kg/d rimantadine did not show any weight loss (p < 0.05 vs. vehicle and individual agent). The three-dimensional analysis of the weight loss for the majority of the drug combinations of peramivir and rimantadine tested demonstrated synergistic antiviral effects.