Glecaprevir/pibrentasvir for hepatitis C virus genotype 3 patients with cirrhosis and/or prior treatment experience: A partially randomized phase 3 clinical trial.

This study assessed the efficacy and safety of ribavirin-free coformulated glecaprevir/pibrentasvir (G/P) in patients with hepatitis C virus genotype 3 infection with prior treatment experience and/or compensated cirrhosis, a patient population with limited treatment options. SURVEYOR-II, Part 3 was a partially randomized, open-label, multicenter, phase 3 study. Treatment-experienced (prior interferon or pegylated interferon ± ribavirin or sofosbuvir plus ribavirin ± pegylated interferon therapy) patients without cirrhosis were randomized 1:1 to receive 12 or 16 weeks of G/P (300 mg/120 mg) once daily. Treatment-naive or treatment-experienced patients with compensated cirrhosis were treated with G/P for 12 or 16 weeks, respectively. The primary efficacy endpoint was the percentage of patients with sustained virologic response at posttreatment week 12 (SVR12). Safety was evaluated throughout the study. There were 131 patients enrolled and treated. Among treatment-experienced patients without cirrhosis, SVR12 was achieved by 91% (20/22; 95% confidence interval [CI], 72-97) and 95% (21/22; 95% CI, 78-99) of patients treated with G/P for 12 or 16 weeks, respectively. Among those with cirrhosis, SVR12 was achieved by 98% (39/40; 95% CI, 87-99) of treatment-naive patients treated for 12 weeks and 96% (45/47; 95% CI, 86-99) of patients with prior treatment experience treated for 16 weeks. No adverse events led to discontinuation of study drug, and no serious adverse events were related to study drug. Conclusion: Patients with hepatitis C virus genotype 3 infection with prior treatment experience and/or compensated cirrhosis achieved high SVR12 rates following 12 or 16 weeks of treatment with G/P. The regimen was well tolerated. (Hepatology 2018;67:514-523).

Unravelling cortico-hypothalamic pathways regulating unconditioned fear-induced antinociception and defensive behaviours.

The medial prefrontal cortex can influence unconditioned fear-induced defensive mechanisms organised by diencephalic neurons that are under tonic GABAergic inhibition. The posterior hypothalamus (PH) is involved with anxiety- and panic attack-like responses. To understand this cortical mediation, our study characterised anterior cingulate cortex (ACC)-PH pathways and investigated the effect of ACC local inactivation with lidocaine. We also investigated the involvement of PH ionotropic glutamate receptors in the defensive behaviours and fear-induced antinociception by microinjecting NBQX (an AMPA/kainate receptor antagonist) and LY235959 (a NMDA receptor antagonist) into the PH. ACC pretreatment with lidocaine decreased the proaversive effect and antinociception evoked by GABAA receptor blockade in the PH, which suggests that there may be descending excitatory pathways from this cortical region to the PH. Microinjections of both NBQX and LY235959 into the PH also attenuated defensive and antinociceptive responses. This suggests that the blockade of AMPA/kainate and NMDA receptors reduces the activity of glutamatergic efferent pathways. Both inputs from the ACC to the PH and glutamatergic hypothalamic short links disinhibited by intra-hypothalamic GABAA receptors blockade are potentially implicated. Microinjection of a bidirectional neurotracer in the PH showed a Cg1-PH pathway and PH neuronal reciprocal connections with the periaqueductal grey matter. Microinjections of an antegrade neurotracer into the Cg1 showed axonal fibres and glutamatergic vesicle-immunoreactive terminal boutons surrounding both mediorostral-lateroposterior thalamic nucleus and PH neuronal perikarya. These data suggest a critical role played by ACC-PH glutamatergic pathways and AMPA/kainate and NMDA receptors in the panic attack-like reactions and antinociception organised by PH neurons.

Differential frequency-dependent antidromic resonance of the Schaffer collaterals and mossy fibers.

To better understand information transfer along the hippocampal pathways and its plasticity, here we studied the antidromic responses of the dentate gyrus (DG) and CA3 to activation of the mossy fibers and Schaffer collaterals, respectively, in hippocampal slices from naïve and epileptic rats. We applied trains of 600 electrical stimuli at functionally meaningful frequencies (θ, ß/γ and γ). The responses of the DG to θ frequency trains underwent rapid potentiation that lasted about 400 stimuli, after which they progressively returned to control value. At ß/γ and γ frequencies, however, the initial potentiation was followed by a strong frequency-dependent depression within the first 50 stimuli. In kindled animals, the initial potentiation was stronger than in control preparations and the resonant phase at θ frequency lasted longer. In contrast, CA3 responses were exponentially depressed at all frequencies, but depression was significantly less intense at θ frequency in epileptic preparations. Failure of fibers to fire action potentials could account for some of the aforementioned characteristics, but waveforms of the intracellular action potentials also changed as the field responses did, i.e., half-duration and time-to-peak increased in both structures along the stimulation trains. Noteworthy, block of glutamate and GABA ionotropic receptors prevented resonance and reduced the depression of antidromic responses to ß/γ and γ stimulation recorded in the DG, but not in CA3. We show that the different behavior in the information transfer along these pathways depends on the frequency at which action potentials are generated, excitability history and anatomical features, including myelination and tortuosity. In addition, the mossy fibers are endowed with ionotropic receptors and terminal active properties conferring them their sui generis non-passive antidromic responses.

PI3K inhibition synergizes with glucocorticoids but antagonizes with methotrexate in T-cell acute lymphoblastic leukemia.

The PI3K pathway is frequently hyperactivated in primary T-cell acute lymphoblastic leukemia (T-ALL) cells. Activation of the PI3K pathway has been suggested as one mechanism of glucocorticoid resistance in T-ALL, and patients harboring mutations in the PI3K negative regulator PTEN may be at increased risk of induction failure and relapse. By gene expression microarray analysis of T-ALL cells treated with the PI3K inhibitor AS605240, we identified Myc as a prominent downstream target of the PI3K pathway. A significant association was found between the AS605240 gene expression signature and that of glucocorticoid resistance and relapse in T-ALL. AS605240 showed anti-leukemic activity and strong synergism with glucocorticoids both in vitro and in a NOD/SCID xenograft model of T-ALL. In contrast, PI3K inhibition showed antagonism with methotrexate and daunorubicin, drugs that preferentially target dividing cells. This antagonistic interaction, however, could be circumvented by the use of correct drug scheduling schemes. Our data indicate the potential benefits and difficulties for the incorporation of PI3K inhibitors in T-ALL therapy.

[Hypotensive effect of three different formulations of brimonidine tartrate in normal eyes]. / Efeito hipotensor de três formulações diferentes do tartarato de brimonidina em olhos normais.

PURPOSE: To compare the hypotensive effect in normal eyes of three formulations with different concentrations of brimonidine tartrate: 0.2%; 0.15% and 0.1%. METHODS: Prospective, randomized, double-blind study included 60 volunteers, who underwent initial ophthalmologic examination and measurement of intraocular pressure (IOP). Individuals were divided into three groups: (1) brimonidine tartrate 0.15%, (2) brimonidine tartrate 0.2% and (3) brimonidine tartrate 0.1% and randomly received one drop each of drops in each eye. The IOP was measured after 30 minutes, 1 hour and 2 hours. RESULTS: We found that all concentrations of brimonidine tartrate significantly reduced intraocular pressure during the study period, with p<0.05. When analyzing the percentage difference of the hypotensive effect of each group, we found no significant difference between the studied groups: (1) -13.50%, (2) -11.50%, (3) -11.90% after 30 minutes (p=0.650); (1) -24.30%, (2) -18.60%, (3) -18.30% after 1 hour (p=0.324); (1) -29.14%, (2) -21.20%, (3) -25.60% after 2 hours (p=0.068). CONCLUSION: There is no statistically significant difference in intraocular pressure reduction (peak period) between the three formulations of brimonidine.

Efeito hipotensor de três formulações diferentes do tartarato de brimonidina em olhos normais / Hypotensive effect of three different formulations of brimonidine tartrate in normal eyes

OBJETIVO: Comparar o efeito hipotensor a curto prazo das três formulações de colírio de tartarato de brimonidina, Alphagan®, Alphagan® P e Alphagan® Z em olhos normais. MÉTODO: Estudo prospectivo, randomizado, duplo-cego que contou com 60 voluntários, os quais foram submetidos a exame oftalmológico inicial e aferição da pressão intraocular (PIO). Os participantes foram distribuídos em três grupos: 1 tartarato de brimonidina 0,15%, 2 tartarato de brimonidina 0,2% e 3 tartarato de brimonidina 0,1%, aleatoriamente, cada um recebeu uma gota de colírio em cada olho e a pressão intraocular foi aferida após 30 minutos, 1 hora e 2 horas. RESULTADOS: Observou-se que todas as concentrações de tartarato de reduziram significativamente a pressão intraocular durante o tempo estudado, com p<0,05. Ao ser analisada a diferença percentual do efeito hipotensor de cada grupo, verificou-se que não há diferença significativa entre os colírios estudados: (1) -13,50%, (2) -11,50%, (3) -11,90% após 30 minutos (p=0,650); (1) -24,30%, (2) -18,60%, (3) -18,30% após 1 hora (p=0,324); (1) -29,14% (2) -21,20%, (3) -25,60% após 2 horas (p=0,068). CONCLUSÃO: Não há diferença estatisticamente significativa para redução da pressão intraocular (no período de pico) entre as três formulações de brimonidina.

PURPOSE: To compare the hypotensive effect in normal eyes of three formulations with different concentrations of brimonidine tartrate: 0.2%; 0.15% and 0.1%. METHODS: Prospective, randomized, double-blind study included 60 volunteers, who underwent initial ophthalmologic examination and measurement of intraocular pressure (IOP). Individuals were divided into three groups: (1) brimonidine tartrate 0.15%, (2) brimonidine tartrate 0.2% and (3) brimonidine tartrate 0.1% and randomly received one drop each of drops in each eye. The IOP was measured after 30 minutes, 1 hour and 2 hours. RESULTS: We found that all concentrations of brimonidine tartrate significantly reduced intraocular pressure during the study period, with p<0.05. When analyzing the percentage difference of the hypotensive effect of each group, we found no significant difference between the studied groups: (1) -13.50%, (2) -11.50%, (3) -11.90% after 30 minutes (p=0.650); (1) -24.30%, (2) -18.60%, (3) -18.30% after 1 hour (p=0.324); (1) -29.14%, (2) -21.20%, (3) -25.60% after 2 hours (p=0.068). CONCLUSION: There is no statistically significant difference in intraocular pressure reduction (peak period) between the three formulations of brimonidine.

Varenicline and cytisine: two nicotinic acetylcholine receptor ligands reduce ethanol intake in University of Chile bibulous rats.

RATIONALE: Neuronal nicotinic acetylcholine receptors (nAChRs) are pharmacological targets that have recently been implicated in the reinforcing effects of many drugs of abuse, including ethanol. Varenicline and cytisine are nAChR partial agonists in clinical use as smoking cessation aids. However, their efficacies to reduce alcohol consumption have not been fully studied. OBJECTIVES: This study aims to compare the effects of varenicline and cytisine on ethanol consumption by rats bred for many generations as high ethanol drinkers (UChB). RESULTS: Repeated dosing (0.5 or 1.0 mg/kg/day i.p.) of varenicline or cytisine, for three consecutive days, to male UChB rats pre-exposed to 10 % (v/v) ethanol and water 24 h/day for 4 weeks, significantly reduced alcohol intake and preference of ethanol over water during 1- and 24-h ethanol access periods. This effect was specific for ethanol intake and was not observed for 0.2 % saccharin or water consumption. Varenicline appears to be more effective than cytisine, probably due to its more favorable pharmacokinetic and pharmacodynamic properties. Long-term use of both nAChRs ligands for more than 8-10 days induced tolerance to their effects on ethanol consumption. CONCLUSIONS: This preclinical study in UChB rats demonstrated that both varenicline and cytisine reduce alcohol intake, with varenicline producing a greater and longer-lasting reduction than cytisine. However, dose adjustment will have to be considered as a possible way to counter tolerance arising after continued use.

Effectiveness of coadministration of varenicline, bupropion, and serotonin reuptake inhibitors in a smoking cessation program in the real-life setting.

INTRODUCTION: Varenicline has a significant impact on the ability to quit smoking. However, patients may have side effects similar to nicotine withdrawal symptoms. The aim of this study was to evaluate the effectiveness of varenicline in monotherapy or in combined therapy with bupropion and/or serotonin reuptake inhibitors (SRIs) in a specific cardiovascular smoking cessation service. METHODS: It is an outcome research of 427 patients that received varenicline monotherapy or combined pharmacotherapy and were followed for 52 weeks. Patients were oriented to take varenicline until week 12. During each medical visit, the patients were evaluated and in the cases of mood changes after varenicline use, SRIs were prescribed. Bupropion was combined in patients that did not achieve complete tobacco abstinence in 2 or 3 weeks after starting varenicline use or if the patient presented uncomfortable abstinent symptoms. RESULTS: The success (continuous abstinence rate in 52 weeks) in different drug regimens were: varenicline monotherapy (32.1%), varenicline + bupropion (55.0%), varenicline + SRI (50.6%), and varenicline + bupropion + SRI (57.7%). In a multivariate analysis of successful treatment predictors, compared with varenicline monotherapy, patients who used bupropion + SRI adjuvant treatment had an odds ratio (OR) of 5.05 (1.99-12.80) for a successful treatment response after 1-year follow-up, while patients who used bupropion or SRI had OR of 3.21 (1.68-6.14) and 3.58 (1.98-6.48), respectively. CONCLUSIONS: Our results suggest that adjuvant treatment to varenicline therapy may be associated with improved success in smoking cessation, especially in patients with nicotine withdrawal symptoms. These results should be tested in randomized controlled trials.

Pharmacogenetics of smoking cessation therapy.

Nicotine dependence is a major health problem, with a large amount of smoking-related premature deaths and disabilities. The dependence mechanism of nicotine is especially complex and is under strong genetic influence. Smoking cessation is associated with substantial health benefits. Evidence from animal and human studies suggests that genetic polymorphisms influencing pharmacokinetics and pharmacodynamics of nicotine may have great potential for aiding smoking treatment. There are more than 30 association studies and one genome-wide association study (GWAS) between genetic polymorphisms and smoking cessation following nicotine replacement therapy (NRT) and/or bupropion therapy. However, only a few candidate genes or regions were analyzed more than twice and even these genes require additional investigations in different therapeutic schemes. There are a growing number of new pharmacologic options that have not been pharmacogenetically assessed according to published literature. In addition, molecular genetics studies are needed to assess the functional mechanisms of some putative association results. Taken together, the preliminary findings are promising but raise the need for new studies with adequate sample sizes and adjustment for several potential confounding factors frequently neglected, such as comorbidity and sociodemographic factors. The current state of the art in the field encourages an optimist view that personalized treatment approaches may become possible. However, the current scientific evidence still does not support the use of pharmacogenetic tests in routine smoking cessation therapy.

Nitric oxide modulation of methylphenidate-induced disruption of prepulse inhibition in Swiss mice.

Drugs that facilitate dopaminergic neurotransmission induce cognitive and attentional deficits which include inability to filter sensory input measured by prepulse inhibition (PPI). Methylphenidate, an amphetamine analog is used in the treatment of attention deficit hyperactivity disorder. Given that nitric oxide (NO) modulates dopamine effect our aim is to analyze the nitric oxide synthase (NOS) and soluble guanylate cyclase (sGC) inhibitors effect on PPI disruption induced by methylphenidate. The inhibitors effects were compared to those produced by haloperidol and clozapine. Male Swiss mice received a first i.p. injection (one hour before testing), of either saline, or N(G) nitro l-arginine (10, 40 or 90 mg/kg), or 7-Nitroindazole (3, 10, 30 or 60 mg/kg), or oxadiazolo-quinoxalin (5 or 10 mg/kg), or haloperidol (1 mg/kg), or clozapine (5 mg/kg). Thirty min later mice received the second injection of either saline or methylphenidate (20 or 30 mg/kg) or amphetamine (5 or 10 mg/kg). One group of mice received intracerebroventricular 7-Nitroindazole (50 or 100 nM) followed by systemic administration of saline or methylphenidate (30 mg/kg). The results revealed a methylphenidate dose-dependent disruption of PPI comparable to amphetamine. The effect was prevented by either nitric oxide synthase or guanilate cyclase inhibitors or clozapine or haloperidol. In conclusion, methylphenidate induced a dose-dependent PPI disruption in Swiss mice modulated by dopamine and NO/sGC. The results corroborate the hypothesis of dopamine and NO interacting to modulate sensorimotor gating through central nervous system. It may be useful to understand methylphenidate and other psychostimulants effects.

Anticonvulsant and antioxidant effects of 3-alkynyl selenophene in 21-day-old rats on pilocarpine model of seizures.

This study investigated the anticonvulsant effect of 3-alkynyl selenophene (3-ASP) on pilocarpine (PC)-, pentylenetetrazole (PTZ)- and kainic acid (KA)-induced seizures and mortality in 21-day-old rats. Rats were pretreated by oral route (p.o.) with 3-ASP (10, 25 and 50mg/kg) before intraperitoneal (i.p.) administration of PC (400mg/kg), PTZ (80 mg/kg) or KA (45 mg/kg). 3-ASP increased the latency to the seizure onset on PTZ and KA models. At the dose of 50mg/kg, 3-ASP avoided the death caused by PTZ and KA. 3-ASP (50mg/kg) abolished seizures and death induced by PC in rats. To investigate the antioxidant effect of 3-ASP on rats exposed to PC, the activity of glutathione peroxidase (GPx), glutathione-S-transferase (GST), acetylcholinesterase (AChE), Na(+)K(+)ATPase, superoxide dismutase (SOD) and catalase (CAT) as well as the levels of reactive species (RS) and ascorbic acid (AA) were determined in brains of rats. 3-ASP protected against the increase in RS levels and CAT activity induced by PC in brains of rats. The decrease in the levels of AA and inhibition of Na(+)K(+)ATPase, SOD and AChE activities caused by PC were protected by 3-ASP. Subeffective doses of 3-ASP plus diazepam, 5S,10R-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) or 6,7-dinitroquinoxaline-2,3-dione (DNQX) increased the latency to the seizure onset induced by PC, suggesting the involvement of ionotropic glutamatergic and GABAergic receptors in anticonvulsant action of 3-ASP. The anticonvulsant and antioxidant effects of 3-ASP in 21-day-old rats on PC model were demonstrated.

Non-N-methyl-d-aspartate glutamate receptors in the lateral hypothalamus modulate cardiac baroreflex responses in conscious rats.

Summary 1. In the present study, we investigated the effects of inhibition of the lateral hypothalamus (LH) neurotransmission with bilateral microinjection of CoCl(2), a non-selective blocker of neurotransmission, on modulation of cardiac baroreflex responses in conscious rats as well as the involvement of LH glutamatergic neurotransmission in this modulation. 2. Reflex bradycardiac and tachycardiac responses to blood pressure increases (following i.v. infusion of phenylephrine) or decreases (following i.v. infusion of sodium nitroprusside) were investigated in conscious male Wistar rats. Responses were evaluated before and after microinjection of 1 nmol/100 nL CoCl(2), 2 nmol/100 nL 1,2,3,4-tetrahydro-6-nitro-2,3-dioxobenzoquinoxaline-7-sulphonamide (NBQX; a selective non-N-methyl-d-aspartate (NMDA) glutamate receptor antagonist) or different doses (2, 4 or 8 nmol/100 nL) of the selective NMDA glutamate receptor antagonist LY235959. 3. Microinjection of CoCl(2) into the LH had no effect on the tachycardiac baroreflex response, but did evoke a decrease in the reflex bradycardia caused by increases in blood pressure. Microinjection of NBQX into the LH had a similar effect on reflex bradycardia as CoCl(2), but had no effect on the tachycardiac response. Microinjection of increasing doses of LY235959 into the LH had no effect on the cardiac baroreflex response. 4. In conclusion, the data suggest that the LH has a tonic facilitatory influence on the parasympathetic component of the baroreflex. The results also indicate that this facilitatory influence is mediated by local LH glutamatergic neurotransmission through non-NMDA glutamatergic receptors.

NOC-9, a selective nitric oxide donor, induces flight reactions in the dorsolateral periaqueductal gray of rats by activating soluble guanylate cyclase.

Previous studies have showed that SIN-1, a nitric oxide (NO) donor, injected into the dorsolateral column of the periaqueductal gray (dlPAG) induces flight reactions. This drug, however, can also produce peroxynitrite, which may interfere in this effect. In addition, it is also unknown if this effect is mediated by local activation of soluble guanylate cyclase (sGC). The aims of this study, therefore, were (1) to investigate if NOC-9 (6-(2-Hydroxy-1-methyl-2-nitrosohydrazino)-N-methyl-1-hexanamine), a NO donor that does not produce peroxynitrite, would produce flight reactions after intra-dlPAG administration similar to those induced by SIN-1; (2) to verify if these responses could be prevented by local injection of a selective guanylate cyclase inhibitor (ODQ). Male Wistar rats (n=5-12) with cannulae aimed at the dlPAG received injections of TRIS (pH 10.0, 0.5 microl), NOC-9 (75 and 150 nmol), saline or SIN-1 (200 nmol) and were placed in an open arena for 10 min. In a subsequent experiment animals (n=7-8) were pretreated with ODQ (1 nmol/0.5 microl) before receiving NOC-9 150 nmol. NOC-9 induced a significant dose-dependent increase in flight reactions in the first minute after injection (% of animals displaying flight: vehicle=0%, NOC 75=67%, NOC 150=75%). SIN-1 had a similar effect (100% of animals showing flight) but the effects lasted longer (10 min) than those of NOC-9. The effect of NOC-9 (150 nmol) was prevented by pretreatment with ODQ (% of animals displaying flight: vehicle+NOC 150=71%, ODQ+NOC 150=37%). The results suggest that NO donors injected into the dlPAG induce defensive responses that are not mediated by secondary peroxynitrite production. Moreover, they also indicate that these defensive responses depend on activation of local sGC. The data strengthen the proposal that NO can modulate defensive reactions in the dlPAG.

The efficacy and safety of two fixed combinations: timolol-dorzolamide-brimonidine versus timolol-dorzolamide. A prospective, randomized, double-masked, multi-center, 6-month clinical trial.

We compared the efficacy and safety of a new fixed combination of timolol 0.5%/odorzolamide 20%/brimonidine 0.2% in ophthalmic solution versus a fixed combination of timolol 0.5%/dorzolamide 2% in patients with open-angle glaucoma or ocular hypertension. The fixed triple combination was significantly more efficient in mean intraocular pressure reduction from baseline throughout the six-month follow-up.

An eight-week, multicentric, randomized, interventional, open-label, phase 4, parallel comparison of the efficacy and tolerability of the fixed combination of timolol maleate 0.5%/brimonidine tartrate 0.2% versus fixed combination of timolol maleate 0.5%/dorzolamide 2% in patients with elevated intraocular pressure.

PURPOSE: To compare the efficacy and tolerability of the fixed combination of timolol maleate 0.5%/brimonidine tartrate 0.2% versus fixed combination of timolol maleate 0.5%/dorzolamide 2% in patients with elevated intraocular pressure (IOP) over 8 weeks. PATIENTS AND METHODS: This 8-week, multicentric, interventional, randomized, open-label, parallel group study was conducted at 4 centers in Brazil and 1 center in Argentina. Patients with open-angle glaucoma or ocular hypertension were randomized to receive bilaterally fixed combination of brimonidine/timolol maleate 0.5% or fixed combination of dorzolamide 2%/timolol 0.5% twice daily at 8:00 AM and 8:00 PM. A modified diurnal tension curve (8:00 AM, 10:30 AM, 02:00 PM, and 4:00 PM) followed by the water drinking test (WDT), which estimates IOP peak of diurnal tension curve, were performed in the baseline and week-8 visits. Adverse events data were recorded at each visit. RESULTS: A total of 210 patients were randomized (brimonidine/timolol, n=111; dorzolamide/timolol, n=99). Mean baseline IOP was 23.43+/-3.22 mm Hg and 23.43+/-4.06 mm Hg in the patients treated with brimonidine/timolol and dorzolamide/timolol, respectively (P=0.993). Mean diurnal IOP reduction after 8 weeks were 7.02+/-3.06 mm Hg and 6.91+/-3.67 mm Hg, respectively (P=0.811). The adjusted difference between groups (analysis of covariance) at week 8 was not statistically significant (P=0.847). Mean baseline WDT peak was 27.79+/-4.29 mm Hg in the brimonidine/timolol group and 27.68+/-5.46 mm Hg in the dorzolamide/timolol group. After 8 weeks of treatment, mean WDT peaks were 20.94+/-3.76 mm Hg (P<0.001) and 20.98+/-4.19 (P<0.001), respectively. The adjusted difference between groups (analysis of covariance) was not statistically significant (P=0.469). No statistical difference in terms of adverse events was found between groups. CONCLUSIONS: Both fixed combinations were capable of significantly reducing the mean diurnal IOP, mean diurnal peak, and mean WDT peak after 8 weeks of treatment. Also, both fixed combinations are well tolerated with few side effects.

The microinjection of AMPA receptor antagonist into the accumbens shell, but not into the accumbens core, induces anxiolysis in an animal model of anxiety.

This study investigated the effect of the AMPA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) microinjected into the core and shell sub-regions of the accumbens nucleus (Acb), on the level of fear/anxiety and emotional learning, in female rats submitted to the elevated plus-maze (EPM), an animal model of anxiety. Bilateral microinjections of DNQX (330 and 660 ng) into the Acb shell (AP, +1.08 to +2.16) induced an anxiolytic-like effect in relation to rats microinjected with vehicle, since there was an increased percentage of entries in the open arms of the maze. The 660 ng DNQX microinjection into the Acb shell also increased the percentage of entries into the open arms in relation to 660 ng DNQX microinjection into the Acb core. Prior DNQX microinjections in both core and shell sub-regions of the Acb failed to impair the emotional learning, since the animals exhibited an increase of the open arm avoidance on EPM Trial 2 in relation to EPM trial 1. DNQX microinjections into both sub-regions of the Acb did not change the number of entries into the enclosed arms, either in the EPM Trial 1 or in the EPM Trial 2, which indicates an absence of drug-induced locomotor impairment. Similarly, DNQX microinjections into both sub-regions of the Acb failed to alter the total arm entries, rearing, grooming and head-dipping frequency. The anxiolytic-like effect induced by DNQX suggests that the AMPA receptor in the Acb shell, but not in the Acb core, may underlie anxiety regulation in the EPM.

Effect of brimonidine tartrate 0.15% on scotopic pupil: controlled trial.

PURPOSE: The aim of this study was to evaluate the duration of the effect of one single dose of brimonidine tartrate 0.15% on pupil diameter, under scotopic conditions, when applied topically in 1 eye of normal subjects. METHODS: The eyes of 19 normal volunteers were randomized so that 1 eye had 1 drop of brimonidine tartrate 0.15% and the other received no medication. Pupil diameter was measured using an infrared pupillometer. The first measure was obtained before the instillation of brimonidine. After that, four measures, with 2-h intervals, were performed. RESULTS: From 19 participants, 14 were women and 5 were men, with a mean age of 25.05 years (standard deviation, +/- 6.98). Before brimonidine instillation, mean pupil diameter in the control eyes was 5.11 mm, and in the brimonidine eyes it was 5.15 mm. After 8 h, the mean pupil size was 4.01 mm in the treated eyes, and 4.56 mm in the untreated eyes. There was a tendency of miotic effect to be more important on the treated eye, as compared to the control eye in all intervals, but this did not reach statistical significance (P = 0.375). When comparing both eyes, independently of the periods, the treated eye had a smaller diameter than the untreated eye (P = 0.038). The miotic effect was observed for at least 8 h after instillation. CONCLUSIONS: Miotic response of brimonidine tartrate 0.15% lasted for at least 8 h and has a significant effect on the nontreated eye.

Intracerebroventricular administration of nitric oxide-sensitive guanylyl cyclase inhibitors induces catalepsy in mice.

RATIONALE: Catalepsy is a preclinical test that predicts extrapyramidal symptoms in humans. It models symptoms of acute extrapyramidal side effects induced at the beginning of antipsychotic treatment. Nitric oxide (NO) plays a role in a series of neurobiological functions underlying behavior. For example, inhibition of NO synthesis disrupts rodent exploratory behavior and induces catalepsy. Although several effects mediated by NO involve the activation of soluble guanylyl cyclase (sGC), the transduction mechanism of the catalepsy-inducing effect of NO has not yet been investigated. OBJECTIVES: The study was designed to test if intracerebroventricular (i.c.v.) microinjection of NO-sensitive inhibitors of sGC (NO-sGC) induces catalepsy in mice similar to that induced by NO synthase (NOS) inhibitors. Exploratory behavior was tested in the open field. In addition, the effects of a NOS inhibitor on oxidative metabolites of NO were measured in the striatum. MATERIALS AND METHODS: Drug effects were examined in the hanging-bar test after the following i.c.v. treatments: oxadiazolo-quinoxalin (ODQ, 30-300 nmol) or methylene blue (MB, 3-100 nmol), selective and nonselective sGC inhibitors, respectively, or 7-nitroindazole (7-NI, 3-90 nmol) and G-nitro-L: -arginine methyl ester (L: -NAME, 3-90 nmol), selective and nonselective neuronal NOS inhibitors. To test if the effects were related to interference with the NO system, additional groups received 7-NI (30 nmol), ODQ (100 nmol), or L-NAME (90 nmol) preceded by L: -arginine (L: -arg, 30-100 nmol, i.c.v. 30 min before). A possible interference of ODQ and 7-NI on exploratory behavior was tested in an open field. The concentration of nitrites and nitrates (NO( x )) in striatum homogenates was measured by the Griess reaction. RESULTS: Both NO-sGC and NOS inhibitors induced catalepsy in mice that lasted for at least 2 h. The range of effective doses of these drugs, however, was limited, and the dose-effect curves had an inverted U shape. The cataleptic effect induced by L: -NAME was inversely correlated with NO( x ) products in the striatum. The cataleptic effect of 7-NI and ODQ was prevented by pretreatment with L: -arginine. No drug changed exploratory behavior in the open field. CONCLUSION: This study showed that pharmacological disruption of the endogenous NO-sGC signaling in the central nervous system induces long-lasting catalepsy in mice. Moreover, the cataleptic effect of NOS inhibition correlates with the decrease in NO( x ) products formation in the striatum. The results give further support to the hypothesis that NO plays a role in motor behavior control mediated, at least in part, by cyclic guanosine monophosphate production in the striatum.

Comparing the fixed combination brimonidine-timolol versus fixed combination dorzolamide-timolol in patients with elevated intraocular pressure.

PURPOSE: To evaluate the efficacy of fixed combination brimonidine-timolol (FCBT) versus fixed combination dorzolamide-timolol (FCDT) given twice daily in patients with primary open angle glaucoma (POAG) or ocular hypertension (OH). DESIGN: Prospective, multicentre, masked-observer, crossover comparison. PARTICIPANTS: Sixteen patients with POAG and 14 with OH. METHODS: The participants of the study were washed out from their previous medication and randomized to fixed FCBT or FCDT for the first 4-week treatment period. Subjects then were washed for 4 weeks and started on the opposite medication for the second 4-week period. Intraocular pressure (IOP) was measured with a Goldmann applanation tonometer at 8:00 a.m., 12:00 noon and 4:00 p.m. at each baseline and at the end of each treatment period. Unsolicited ocular adverse events were also recorded. MAIN OUTCOME MEASURES: Comparison of the IOP lowering effect of FCBT and FCDT. RESULTS: The baseline mean diurnal IOP for all 30 subjects (30 eyes) was 22.9 +/- 1.6 mmHg. Both fixed combinations significantly reduced IOP compared with baseline (p < 0.00001). The mean diurnal IOP following 4 weeks of therapy was 15.0 +/- 2.1 mmHg for FCBT and 15.4 +/- 2.1 mmHg for FCDT (p = 0.510). The mean diurnal IOP reduction was 7.8 +/- 1.9 mmHg for FCBT and 7.4 +/- 1.8 mmHg for FCDT (p = 0.430). Overall, 14 subjects complained about ocular adverse events: two only for FCBT, seven only for FCDT and five for both drugs. Although there was no significant difference between the number of subjects that reported ocular adverse events with FCBT (n = 7) and FCDT (n = 12) (p = 0.359), FCDT caused more ocular stinging upon instillation (n = 9) than FCBT (n = 1) (p = 0.027). CONCLUSION: This study suggests that FCBT and FCDT, each given twice daily, have similar efficacy in patients with POAG or OH.