Long Duration Of Effect Research Articles

THE DURATION OF EFFECT OF CENTRIFUGE CONCENTRATED INTRAVITREAL TRIAMCINOLONE ACETONIDE

To estimate the duration of activity for intravitreal triamcinolone injected with a new technique using centrifuge concentration (Centrifuge concentrated IntraVitreal Triamcinolone, C-IVT). All injections were performed by a single surgeon (M.D.O.) using a 30-gauge needle. A vial of Triesence (triamcinolone; Alcon Laboratories, Fort Worth, TX) was drawn into a 1-mL syringe and the plunger cut off. The contents were spun in a centrifuge, and a second plunger was placed. Records of all patients receiving C-IVT with 0.05 mL or 0.1 mL from January 1, 2009, through December 31, 2009, were retrospectively reviewed. Eighty-four injections from 69 eyes of 57 patients were included. Sixty-nine injections from 54 eyes of 44 patients received 0.05 mL of C-IVT, whereas 15 injections from 15 eyes of 13 patients received 0.1 mL of C-IVT. Triamcinolone acetonide was still visualized in the vitreous on an average of 5.0 ± 2.4 months (median 5 months) after 0.05 mL of C-IVT and 8.3 ± 4.0 months (median 8 months) after 0.1 mL of C-IVT during follow-up visits. The longest duration recorded was 14 months for the 0.05-mL group and 18 months for the 0.l-mL group. The C-IVT results in a long duration of effect that seems to be greater than previously published techniques. It may be considered for patients requiring chronic steroid therapy, in which the benefits of long-term intravitreal steroids are believed to outweigh their risk.

Differential characteristics of incobotulinumtoxinA and its use in the management of glabellar frown lines

ObjectivesThis review examines the pharmacologic and clinical characteristics of incobotulinumtoxinA (Xeomin®/Xeomeen®/Bocouture®/XEOMIN Cosmetic™; botulinum toxin type A [150 kDa]), which is free from complexing proteins, and discusses its efficacy and safety in the treatment of glabellar frown lines. Differences between incobotulinumtoxinA and other commercially available botulinum neurotoxin type A (BoNT/A) products that have been approved by the European Medicines Agency, US Food and Drug Administration, and other regulatory agencies for this indication are also discussed.FindingsIncobotulinumtoxinA differs from other commercially available BoNT/A preparations, in that it is free from complexing proteins and contains only active neurotoxin, minimizing foreign protein load. IncobotulinumtoxinA is commonly used at a 1:1 dose ratio with onabotulinumtoxinA and displays comparable efficacy and safety; furthermore, it is associated with early onset and long duration of effect, and high levels of subject satisfaction. In terms of practical considerations, incobotulinumtoxinA does not require cold storage and demonstrates low spread, enabling precise treatment and good tolerability.ConclusionIncobotulinumtoxinA is an efficacious and well-tolerated treatment for glabellar frown lines. It differs from other BoNT/A preparations, in that it is free from complexing proteins and contains only active neurotoxin, which is relevant clinically, as this reduces the foreign protein load and minimizes the risk of neutralizing antibody production. In practical terms, incobotulinumtoxinA has a long shelf-life, remaining stable without the need for refrigeration, and due to its limited spread is a precise localized treatment.

Hepatocyte-targeted RNAi Therapeutics for the Treatment of Chronic Hepatitis B Virus Infection

RNA interference (RNAi)-based therapeutics have the potential to treat chronic hepatitis B virus (HBV) infection in a fundamentally different manner than current therapies. Using RNAi, it is possible to knock down expression of viral RNAs including the pregenomic RNA from which the replicative intermediates are derived, thus reducing viral load, and the viral proteins that result in disease and impact the immune system's ability to eliminate the virus. We previously described the use of polymer-based Dynamic PolyConjugate (DPC) for the targeted delivery of siRNAs to hepatocytes. Here, we first show in proof-of-concept studies that simple coinjection of a hepatocyte-targeted, N-acetylgalactosamine-conjugated melittin-like peptide (NAG-MLP) with a liver-tropic cholesterol-conjugated siRNA (chol-siRNA) targeting coagulation factor VII (F7) results in efficient F7 knockdown in mice and nonhuman primates without changes in clinical chemistry or induction of cytokines. Using transient and transgenic mouse models of HBV infection, we show that a single coinjection of NAG-MLP with potent chol-siRNAs targeting conserved HBV sequences resulted in multilog repression of viral RNA, proteins, and viral DNA with long duration of effect. These results suggest that coinjection of NAG-MLP and chol-siHBVs holds great promise as a new therapeutic for patients chronically infected with HBV.

Onset, longevity, and patient satisfaction with incobotulinumtoxinA for the treatment of glabellar frown lines: a single-arm, prospective clinical study.

BackgroundIncobotulinumtoxinA (Bocouture®) is free from complexing proteins and effective for treating glabellar frown lines.PurposeTo determine the efficacy, onset, and duration of action of incobotulinumtoxinA for the treatment of glabellar frown lines.Patients and methodsIn this single-arm, prospective, proof-of-concept study, 23 patients were treated with 25 U incobotulinumtoxinA, equally split between five injection sites in the glabella. Severity of glabellar frown lines was rated by an independent rater from standardized photographs using the validated Merz 5-point scale at several visits over 5 months following treatment. To assess patient satisfaction, patients completed a questionnaire before and 2 weeks after treatment.ResultsThe percentage of responders at maximum frown 2–4 days after treatment was 95.2% and 85.0% when responders were defined as patients with ≥1-point and ≥2-point improvement on the 5-point scale compared with baseline, respectively. At this time point, 84% of the maximum effect had occurred. The responder rate at maximum frown, according to both definitions, was 100% for at least the next two visits (days 8 ± 1 and 14 ± 2). At all visits, the change from baseline in the mean glabellar frown-line score at maximum frown was statistically significant, with on average an almost 1-point improvement from baseline 5 months after treatment.ConclusionIncobotulinumtoxinA is an effective and well-tolerated treatment for glabellar frown lines, with a rapid onset of action and a long duration of effect lasting for more than 5 months.

The use of lisdexamfetamine dimesylate for the treatment of ADHD

ADHD is a common neurobehavioral disorder characterized by significant impairment in attention, hyperactivity and impulsivity. Symptoms begin in childhood and can persist into adulthood. Current data suggest that abnormal functioning of the prefrontal cortex, cortical and subcortical regions of the brain have roles in ADHD. All currently approved drugs used to treat ADHD enhance dopamine and norepinephrine signals in these regions. Lisdexamfetamine dimesylate (LDX) is a long-acting amphetamine prodrug indicated for the treatment of ADHD and has been shown to be effective in children, adolescents and adults. The prodrug properties of LDX make it a desirable treatment because of its long duration of effect, and low intrasubject and intersubject pharmacokinetic variability, and attenuated response on measures of abuse liability when compared with immediate-release amphetamine. However, LDX is still classified as a controlled substance. In this article, the pharmacokinetic parameters and efficacy and safety of LDX are reviewed.

Masseter spasm after induction of general anaesthesia using propofol and remifentanil

Editor, A 54-year old female patient (height 165 cm, weight 58 kg, ASA II) was scheduled for elective glaucoma surgery. In addition to the glaucoma, the patient suffered from chronic obstructive pulmonary disease, which was treated with inhalative b2-adrenergic agonists and inhalative corticosteroids, and sleeping impairments that were under treatment with clomipramine, which had been discontinued 36 h prior to anaesthesia. The patient showed no difficulties in opening the mouth and the distance between upper and lower incision teeth was more than 4 cm, resulting in a reported Mallampati score of II. Previous medical history revealed two general anaesthesias without any complications. No premedication was prescribed.

Clinical safety and efficacy of bepotastine besilate ophthalmic solution to treat allergic conjunctivitis

The mast cell-stabilizer–antihistamine class of medications has become physicians’ first choice for treating seasonal allergic conjunctivitis owing to the rapid onset of action, long duration of effect and improved comfort. Bepotastine besilate ophthalmic solution 1.5% (Bepreve™, ISTA Pharmaceuticals, Inc., CA, USA) has recently been approved by the US FDA for the treatment of itching associated with the signs and symptoms of allergic conjunctivitis. Bepotastine besilate has multiple mechanisms of action, selectively inhibiting histamine H1 receptors, stabilizing mast cells, inhibiting eosinophil infiltration, and inhibiting production of inflammatory cytokines or chemokines. Although not approved for other indications, a clinical study has shown that bepotastine besilate reduces nonocular (principally nasal) symptoms and thus may be particularly helpful for people with rhinoconjunctivitis. As per FDA approval, bepotastine besilate is well tolerated and safe for subjects as young as 2 years of age. Bepotastine besilate ophthalmic solution provides an alternative choice of treatment for allergic conjunctivitis.

Analysis of physicians’ perspectives versus patients’ preferences: direct assessment and discrete choice experiments in the therapy of multiple myeloma

Against the background of patient involvement, understanding patients' preferences for treatments is crucial: Do physicians have the same or a different perception of the patients' preferences? As there is currently no cure for patients with multiple myeloma, primary objectives of treatment are to extend survival at the best possible quality of life. In this study, physicians' beliefs about patients' preferences regarding the treatment of multiple myeloma (MM) were explored in a direct assessment and a discrete choice experiment (DCE), and were compared to the previously explored patients' views. How much do physicians know about their patients' preferences? In a preceding study with German multiple myeloma patients, relevant attributes of an ideal multiple myeloma treatment were collected by reviewing the literature and by conducting a qualitative study with focus groups. The attributes were analyzed using both a direct measurement (16 items on a five-point Likert scale) and a DCE (eight pairs with eight characteristics). For the present study, 30 German physicians reviewed the treatment attributes from the previous study for completeness. A total of 243 physicians participated in the study (including the 30 participants in the pre-test). The direct assessment and the DCE covered four major preference dimensions that both the literature review and the focus groups revealed: Aspects of medical effectiveness (including prolonged life expectancy, effectiveness and long duration of effect), side effects, quality of life (including social, physical and emotional quality of life) and flexibility (breaks in therapy and further treatment options). In the direct measurement of patients' preferences, physicians rated physical quality of life (specified as "reduced mobility or good mobility"), rare side effects and effectiveness aspects (duration of effect, maximal prolonged life expectancy and effectiveness) as the most important attributes from the patients' perspective, followed by emotional quality of life (specified as "Not always think of the disease") and therapy-free intervals. Especially further treatment options and dosage were more important to patients than physicians believed. In this case, the physicians had quite obviously underestimated the importance of these attributes from the perspective of those affected. Physicians ranked prolonged life expectancy as relatively the most important and significantly more important than all other treatment attributes. Further treatment options were the second most important attribute and significant compared to the attributes breaks in therapy and physical quality of life, whereas the patients ordered these two attributes in reverse order. Similarly, the patients gave the opposite relative importance to the next two priorities: self-application of treatment and emotional quality of life. Asking patients or physicians about the multiple myeloma patients' treatment preferences, the combination of direct assessment and DCE proves to be a valid survey technique. Over a broad range of treatment attributes, the physicians' perceptions of preferences were very close to those of multiple myeloma patients. Both the direct assessment of importance in order to rank the patient perceptions and the DCE provide important insights into the preference structure of patients with multiple myeloma. The findings can subsequently be used as a basis for tailoring health care services for multiple myeloma patients in reference to their preferences.

Characterization of Aclidinium Bromide, a Novel Inhaled Muscarinic Antagonist, with Long Duration of Action and a Favorable Pharmacological Profile

Aclidinium bromide is a novel potent, long-acting inhaled muscarinic antagonist in development for the treatment of chronic obstructive pulmonary disease. Aclidinium showed subnanomolar affinity for the five human muscarinic receptors (M(1)-M(5)). [(3)H]Aclidinium dissociated slightly faster from M(2) and M(3) receptors than [(3)H]tiotropium but much more slowly than [(3)H]ipratropium. Its association rate for the M(3) receptor was similar to [(3)H]ipratropium and 2.6 times faster than [(3)H]tiotropium. Residence half-life of [(3)H]aclidinium at the M(2) receptor was shorter than at the M(3) receptor, demonstrating kinetic selectivity for the M(3) receptor. In isolated guinea pig trachea, aclidinium showed comparable potency to ipratropium and tiotropium, faster onset of action than tiotropium, and duration of action similar to tiotropium and significantly longer than ipratropium. Nebulized aclidinium inhibited bronchoconstriction induced by acetylcholine in guinea pigs in a concentration-dependent manner with an onset of action faster than tiotropium. Duration of action of aclidinium (t(1/2) = 29 h) was much longer than ipratropium (8 h) but shorter than tiotropium (64 h). In dogs, aclidinium induced a smaller and more transient increase in heart rate than tiotropium at comparable supratherapeutic doses. Therefore, under these conditions, aclidinium showed a greater therapeutic index than tiotropium (4.2 versus 1.6). These results indicate that aclidinium is a potent muscarinic antagonist with a fast onset of action, a long duration of effect, and a favorable cardiovascular safety profile.

Antihypertensive efficacy of telmisartan vs ramipril over the 24-h dosing period, including the critical early morning hours: a pooled analysis of the PRISMA I and II randomized trials

Cardiovascular risk is subject to circadian variation, with peak morning incidence of myocardial infarction and stroke correlating with the early morning blood pressure (BP) surge (EMBPS). Ideally, antihypertensive therapy should maintain control of BP throughout the 24-h dosing cycle. In two sister studies, Prospective, Randomized Investigation of the Safety and efficacy of Micardis vs Ramipril Using ABPM (ambulatory BP monitoring) (PRISMA) I and II, BP control was compared in patients with essential hypertension (24-h mean baseline ambulatory BP approximately 148/93 mm Hg) randomized to the angiotensin receptor blocker, telmisartan (80 mg; n=802), or the angiotensin-converting enzyme inhibitor, ramipril (5 or 10 mg; n=811), both dosed in the morning. The primary end point was the change from baseline in mean ambulatory systolic BP (SBP) and diastolic BP (DBP) during the final 6 h of the 24-h dosing cycle. The adjusted mean treatment differences in the last 6-h mean ambulatory SBP/DBP were -5.8/-4.2 mm Hg after 8 weeks and -4.1/-3.0 mm Hg after 14 weeks, in favour of telmisartan (P<0.0001 for all four comparisons). Secondary end point results, including the mean 24-h ambulatory BP monitoring, day- and night-time BP and 24-h BP load, also significantly favoured telmisartan (P<0.0001). Both treatments were well tolerated; adverse events, including cough, were less common with telmisartan. These findings suggest that telmisartan is more effective than ramipril throughout the 24-h period and during the EMBPS; this may be attributable to telmisartan's long duration of effect, which is sustained throughout the 24-h dosing period.

Cross-species comparison of in vivo PK/PD relationships for second-generation antisense oligonucleotides targeting apolipoprotein B-100

The in vivo pharmacokinetics/pharmacodynamics of 2′- O-(2-methoxyethyl) (2′-MOE) modified antisense oligonucleotides (ASOs), targeting apolipoprotein B-100 (apoB-100), were characterized in multiple species. The species-specific apoB antisense inhibitors demonstrated target apoB mRNA reduction in a drug concentration and time-dependent fashion in mice, monkeys, and humans. Consistent with the concentration-dependent decreases in liver apoB mRNA, reductions in serum apoB, and LDL-C, and total cholesterol were concurrently observed in animal models and humans. Additionally, the long duration of effect after cessation of dosing correlated well with the elimination half-life of 2′-MOE modified apoB ASOs studied in mice ( t 1/2 ≅ 20 days) and humans ( t 1/2 ≅ 30 days) following parental administrations. The plasma concentrations of ISIS 301012, observed in the terminal elimination phase of both mice and monkeys were in equilibrium with liver. The partition ratios between liver and plasma were similar, approximately 6000:1, across species, and thus provide a surrogate for tissue exposure in humans. Using an inhibitory E max model, the ASO liver EC 50s were 101 ± 32, 119 ± 15, and 300 ± 191 μg/g of ASO in high-fat-fed (HF) mice, transgenic mice containing the human apoB transgene, and monkeys, respectively. The estimated liver EC 50 in man, extrapolated from trough plasma exposure, was 81 ± 122 μg/g. Therefore, extraordinary consistency of the exposure–response relationship for the apoB antisense inhibitor was observed across species, including human. The cross-species PK/PD relationships provide confidence in the use of pharmacology animal models to predict human dosing for second-generation ASOs targeting the liver.

Insulin glargine has a long duration of effect following administration either once daily or twice daily in divided doses in healthy cats.

The pharmacological effects of glargine administered once or twice daily were compared in six healthy cats. A two-way crossover study was performed with insulin and glucose concentrations measured following subcutaneous administration of glargine once daily (0.5 U/kg) or twice daily (0.25 U/kg, repeated after 12h). Nadir glucose concentration and mean daily glucose concentration did not differ significantly following insulin administration once daily or twice daily in divided doses. Time to reach last glucose nadir differed, with longer intervals occurring following twice daily dosing. Blood glucose failed to return to baseline concentration by 24h in three of six cats in each treatment group. Insulin variables were not significantly different following once or twice daily dosing. This study in healthy cats demonstrates that glargine has a long duration of action with carry-over effects to the next day likely, regardless of dosing regimen. A study in diabetic cats is required to determine the best dosing regimen.

A Double-Blind, Randomized, Placebo-Controlled, Two-Dose Comparative Study of Botulinum Toxin Type A for Treating Glabellar Lines in Japanese Subjects

BackgroundSystematic, well-controlled clinical trials of botulinum toxin type A (BoNTA) in diverse patient populations are needed. The aim of this study was to characterize the safety and efficacy of 10-U and 20-U BoNTA doses versus placebo for treating glabellar lines in Japanese subjects.MethodsA 16-week, multicenter, double-blind, randomized, placebo-controlled trial comparing 10 or 20 U of BoNTA versus placebo in 142 Japanese subjects with glabellar lines of at least moderate severity at maximal contraction. The primary efficacy endpoint was physician-rated line severity at maximal contraction 4 weeks after treatment. Secondary efficacy endpoints included physician/subject ratings and estimates of the effect’s duration.ResultsResponse rates by physician-rated line severity at maximal contraction (week 4) were 86.4% (10 U), 88.6% (20 U), and 0% (placebo, p < 0.001). Line severity at maximal contraction in each BoNTA group (p < 0.001) improved significantly from baseline at each visit. BoNTA and placebo differed significantly on all other efficacy measures. Mean duration of effect was 9.4 weeks in the 20-U group and 7.9 weeks in the 10-U BoNTA group. No serious adverse events occurred.ConclusionDoses of BoNTA of 10 and 20 U are effective and safe for treating glabellar lines in Japanese subjects, and the 20-U dose provides greater efficacy and longer duration of effect.

Discriminative stimulus functions in rats of AM1346, a high-affinity CB1R selective anandamide analog

To characterize in vivo the high-affinity CB(1) cannabinoid receptor (CB(1)R) selective anandamide analog AM1346 [alkoxyacid amide of N-eicosa-tetraenylamine] using drug discrimination. Substitution tests involved Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and R-(+)-methanandamide (mAEA), a metabolically stable analog of anandamide (AEA), as well as the CB(1)R antagonist/inverse agonist rimonabant; D: -amphetamine and morphine were also examined to assess pharmacological specificity. Rats were initially trained to discriminate between i.p.-injected vehicle and 3 mg/kg AM1346 (group 3 mg/kg; t' = 20 min); subsequently, the rats were retrained with 5.6 mg/kg AM1346 (group 5.6 mg/kg; t' = 20 min). Dose-generalization curves of AM1346, Delta(9)-THC, and mAEA suggested the following order of potency: Delta(9)-THC > AM1346 > mAEA both for rats discriminating between 3 and 5.6 mg/kg AM1346 from vehicle. In group 3 mg/kg, challenge by 1 mg/kg rimonabant resulted in parallel shifts to the right of the dose-generalization curves for Delta(9)-THC and AM1346, suggesting surmountable antagonism. Surmountable antagonism was not demonstrated with rimonabant-mAEA combinations. A long duration of effect was indicated when 3 mg/kg AM1346 was examined after different time intervals following i.p. administration (group 3 mg/kg). The in vivo half-life was close to 5 h. Neither D: -amphetamine nor morphine generalized in either of groups 3 mg/kg and 5.6 mg/kg, suggesting pharmacological specificity. Unlike mAEA, the surmountable antagonism between rimonabant and AM1346 showed that the structural features of AEA can be modified to produce novel ligands that reduce the dissociation between the discriminative stimulus and rate decreasing effects of CB(1)R agonists derived from an AEA template.

Lisdexamfetamine dimesylate: the first long-acting prodrug stimulant treatment for attention deficit/hyperactivity disorder

Background: Lisdexamfetamine dimesylate is the first long-acting prodrug stimulant and is indicated for the treatment of attention deficit/hyperactivity disorder. Lisdexamfetamine dimesylate is a therapeutically inactive molecule. Methods: Following oral ingestion, it is converted to L-lysine and active d-amphetamine, which is responsible for the therapeutic effect. Lisdexamfetamine dimesylate was developed with the goal of providing a long duration of effect with the potential for less abuse-related liking. Results: In controlled clinical trials lisdexamfetamine dimesylate demonstrated a significant efficacy and extended duration of action as well as a safety profile consistent with other once-daily stimulants (mixed amphetamine salts extended release). In addition, abuse liability studies have shown that lisdexamfetamine dimesylate has lower abuse-related liking scores compared with equipotent doses of immediate-release d-amphetamine.

Evolution of the treatment of attention-deficit/hyperactivity disorder in children: A review

Background: Efficacious and well-tolerated medications are available for the treatment of attention-deficit/hyperactivity disorder (ADHD). Stimulants such as methylphenidate (MPH) and amphetamines are the most widely used medications approved by the US Food and Drug Administration for the treatment of ADHDin children. Objective: This article reviews the literature on the development and use of medications for the treatment of ADHD in children. Methods: A search of MEDLINE was conducted toidentify relevant studies and critical reviews on the treatment of ADHD in children.The main criteria for inclusion of a study were that it have a controlled design, enroll >100 subjects if a clinical trial and >20 subjects if a classroom study, assess symptoms with the most widely used scales and tests,and be published from 2000 to 2008.A few older pivotal studies were also included. Results: Many studies have reported the long-term efficacy and tolerability of immediate-release formulations of MPH. The disadvantages of such formulations include the need for multiple daily dosing and a potential for abuse. Various extended-release formulations of MPH have been found effective in controlled studies enrolling large numbers of children with ADHD. The efficacy and tolerability of dexmethylphenidate, the active D-isomer of MPH, in an extended-release formulation have also been reported. An extended-release formulation of mixed amphetamine salts (MMAS-XR) that is dosed once daily has been found to be efficacious and well tolerated. The non-stimulant atomoxetine has been reported to be well tolerated and efficacious, although it may not be as effective as stimulants; this formulation is, however, less likely than stimulants to be associated with abuse and diversion. A recently approved prodrug stimulant, lisdexamfetamine dimesylate (LDX), was developed to provide a long duration of effect that is consistent throughout the day, with a reduced potential for abuse. In a placebo-controlled study in children with ADHD, less intersubject variability in T max, C max, and AUC from time zero to the last quantifiable concentration was seen in the 8 subjects who received LDX (percent coefficient of variation, 15.3, 20.3, and 21.6, respectively) compared with the 9 subjects who received MAS-XR (52.8, 44.0, and 42.8).In 2 clinical trials, significantly greater improvements in teacher and parent ratings of ADHD symptoms were seen with LDX compared with placebo (P<0.001).A study of the abuse potential of LDX evaluated subjective responses to the effects of oral LDX and immediate-release d-amphetamine in adults with a history of stimulant abuse. LDX was associated with a significantly lower abuse-related liking effect than d-aamphetamine ( P = 0.039). Conclusions: Currently available treatments for ADHD in children are efficacious and well tolerated, but many of them are limited by the requirement for multiple daily dosing and abuse potential. LDX, a long-acting prodrug of d-amphetamine, has been reported to be effective and appears to overcome some of these limitations.

Armodafinil: a new treatment for excessive sleepiness

Background: Armodafinil is a wake-promoting agent developed by Cephalon that was approved in mid-2007 for the treatment of excessive sleepiness associated with narcolepsy, obstructive sleep apnea and shift work disorder. It is the R-enantiomer of the compound modafinil. Like modafinil, the mechanism of action for armodafinil is not fully characterized. Objective: To determine what data are available to support the potential use of armodafinil in clinical settings. Methods: There are limited data on armodafinil available in the public domain, particularly in regard to chemistry and pharmacokinetics/dynamics. Data were reviewed from refereed journals, scientific presentations, and published labeling. Results/conclusion: Clinical trials demonstrated efficacy and safety profiles that were similar to those of the parent compound with wake promotion sustained throughout the day. The longer duration of effect has the potential for improved patient response and compliance but this will require further study. The primary commercial challenge may be the future availability of generic modafinil.

Pharmacological Characterization of Noroxymorphone as a New Opioid for Spinal Analgesia

Noroxymorphone is one of the major metabolites of oxycodone. Although oxycodone is commonly used in the treatment of acute and chronic pain, little is known about the antinociceptive effects of noroxymorphone. We present an in vivo pharmacological characterization of noroxymorphone in rats. The antinociceptive properties of noroxymorphone were studied with thermal and mechanical models of nociception in rats. Intrathecal noroxymorphone (1 and 5 microg/10 microL) induced a significantly longer lasting antinociceptive effect compared with oxycodone (200 microg/10 microL) and morphine (1 and 5 microg/10 microL). Pretreatment with subcutaneous naloxone (1 mg/kg) 15 min before intrathecal drug administration significantly decreased the antinociceptive effect of both noroxymorphone and morphine, indicating an opioid receptor-mediated antinociceptive effect. In the hotplate, paw pressure, and tail flick tests, subcutaneous noroxymorphone was inactive in doses of 5, 10, and 25 mg/kg. Also, no effect on motor function was observed in the rotarod test with doses studied. No antihyperalgesic effect was observed in the carrageenan model for inflammation in rats with subcutaneous noroxymorphone 25 mg/kg. The results of this study indicate that noroxymorphone is a potent mu-opioid receptor agonist when administered intrathecally. The lack of systemic efficacy may indicate reduced ability of noroxymorphone to penetrate the blood-brain barrier due to its low calculated logD value (log octanol/water partition coefficient). Thus, noroxymorphone should have a negligible role in analgesia after systemic administration of oxycodone. Because of its spinal efficacy and long duration of effect, noroxymorphone is an interesting opioid for spinal analgesia with a low potential for abuse. Its safety for spinal administration should be assessed before clinical use.

A Randomized, Comparative Trial of a Potassium-Competitive Acid Blocker (AZD0865) and Esomeprazole for the Treatment of Patients With Nonerosive Reflux Disease

AZD0865 is a gastric acid-suppressing agent that has a rapid onset of action and long duration of effect. This double-blind, randomized, multicenter study investigated the efficacy and safety of AZD0865 in the treatment of patients with nonerosive reflux disease (NERD). Patients with troublesome heartburn for at least 6 months and no evidence of erosions at endoscopy were randomized to receive AZD0865 (25, 50, or 75 mg/day) or esomeprazole 20 mg/day, for 4 wk. Throughout the treatment period, patients reported the presence and intensity of heartburn and other NERD symptoms twice daily using an electronic diary. Twenty-four-hour ambulatory intraesophageal/intragastric pH monitoring was performed in a subset of patients on day 14. A total of 1,469 patients were randomized. The median time to sustained absence of heartburn (for 7 consecutive days) was approximately 12 days for all treatment groups and did not differ significantly for any of the AZD0865 doses or compared with esomeprazole. There were no significant differences among treatment groups in the cumulative incidence of sustained absence of heartburn during 4 wk treatment (i.e., 65-70%). The percentage of time for which intragastric pH was greater than 4 was significantly greater for AZD0865 75 mg/day compared with esomeprazole 20 mg (75% vs 60%, P < 0.05). AZD0865 was generally well tolerated although reversible elevations of liver transaminases occurred in some patients receiving the agent. AZD0865 did not provide clinical benefit over esomeprazole 20 mg in the management of patients with NERD.

Medical Therapy for Glaucoma: The Next 20 Years

Current medical therapy for glaucoma relies on intraocular pressure (IOP) regulation via enhancing aqueous humor outflow and/or decreasing aqueous inflow. The relationship between inflow and outflow determines IOP and may be modulated by receptors or mediators within the eye, which detect changes in IOP and trigger responses to adjust fluid balance. Inflow via aqueous humor formation (AHF) is the result of three physiologic processes: diffusion, ultrafiltration and active secretion, which can be affected by therapies using betablockers, carbonic anhydrase inhibitors and α2-adrenergic agonists. Decreased blood flow can also decrease AHF. Aqueous humor outflow occurs principally via the trabecular and the uveoscleral routes, which are targeted with cholinergics, adrenergic agonists and prostaglandin (PG) analogs. The chronic nature of the disease makes patient compliance with multiple, additive therapies problematic. As described below, the next 20 years will see the development of new treatment strategies with longer duration of effect and increased efficacy that will decrease the role of the patient in the treatment equation and reduce adverse events.