Three-month,randomized, parallel-group comparison of brimonidine–timolol versus dorzolamide–timolol fixed-combination therapy

ABSTRACT

Objective: Fixed combinations of 0.2% brimonidine–0.5% timolol and 2% dorzolamide–0.5% timolol are used to lower intraocular pressure (IOP). The objective of this study was to evaluate the IOP-lowering efficacy and ocular tolerability of brimonidine–timolol compared with dorzolamide–timolol when used as monotherapy or as adjunctive therapy to a prostaglandin analog (PGA) in patients with glaucoma or ocular hypertension.

Study design and methods: Pooled data analysis of two randomized, investigator-masked, 3-month, parallel-group studies with identical protocols (ten sites). In all, 180 patients with open-angle glaucoma or ocular hypertension who were in need of lower IOP received topical brimonidine–timolol BID or dorzolamide–timolol BID as monotherapy (n?=?101) or as adjunctive therapy to a PGA (latanoprost, bimatoprost, or travoprost) (n?=?79).

Clinical trial registration: The studies are registered with the identifiers NCT00822081 and NCT00822055 at http://www.clinicaltrials.gov.

Main outcome measures: IOP was measured at 10 a.m. (peak effect) at baseline and at months 1 and 3. Tolerability/comfort was evaluated using a patient questionnaire.

Results: There were no statistically significant between-group differences in patient demographics. Most patients were Caucasian, and the mean age was 68 years. There were also no statistically significant differences between treatment groups in baseline IOP. At month 3, the mean (SD) reduction from baseline IOP for patients on fixed-combination monotherapy was 7.7 (4.2) mmHg (32.3%) with brimonidine–timolol versus 6.7 (5.0) mmHg (26.1%) with dorzolamide–timolol (p?=?0.040). The mean reduction from PGA-treated baseline IOP for patients on fixed-combination adjunctive therapy was 6.9 (4.8) mmHg (29.3%) with brimonidine–timolol versus 5.2 (3.7) mmHg (23.5%) with dorzolamide–timolol (p?=?0.213). Patients on brimonidine–timolol reported less burning (p?<?0.001), stinging (p?<?0.001), and unusual taste (p?<?0.001) than patients on dorzolamide–timolol.

Conclusions: Fixed-combination brimonidine–timolol provided the same or greater IOP lowering compared with fixed-combination dorzolamide–timolol. Both fixed-combination medications were safe and well-tolerated. Brimonidine–timolol received higher ratings of ocular comfort than dorzolamide–timolol. The duration of the studies was 3 months, and additional studies will be needed to compare the efficacy and tolerability of brimonidine–timolol and dorzolamide–timolol during long-term treatment.     

Trends in opioid analgesics consumption,Israel, 2000–2008

Objective  

To describe trends in opioid consumption in Israel (morphine, methadone, oxycodone, pethidine, fentanyl, buprenorphine, codeine, and dextropropoxyphene) over the 9 years, 2000–2008, and to explore explanations for changes in consumption, in amounts and the pattern.     

A multi-technique approach using LC–NMR,LC–MS,semi-preparative HPLC,HR–NMR and HR–MS for the isolation and characterization of low-level unknown impurities in GW876008, a novel corticotropin-release factor 1 antagonist

A multi-technique approach was applied in order to fully characterize four low-level unknown impurities of GW876008, a novel CRF₁ receptor antagonist. Liquid chromatography (LC)–NMR spectroscopy was used in combination with LC–MS to obtain detailed information regarding the structure of the two major impurities present in batches of GW876008 and observed in the first synthetic scale-up for preclinical use. Two additional impurities were unexpectedly found at greater levels in a large scale synthesis for clinical use and their structure was elucidated by means of high resolution (HR)–MS and HR–NMR, after a small scale preparative HPLC purification step. This structural information was useful in terms of shedding light on the typical impurity profile of this new chemical entity with the aim to support the early development package for Phase I clinical studies.     

Imported malaria in Slovenia, 2001–2011

Background  

A retrospective analysis was conducted to determine the epidemiological and clinical characteristics of imported malaria in Slovenia.     

Carisoprodol abuse in Texas, 1998–2003

Introduction

Texas poison centers identified carisoprodol as a skeletal muscle relaxant that is subject to abuse, and this investigation explores the abuse reported by Texas poison centers.

Methods

This study used data from six Texas poison centers to describe the epidemiology of carisoprodol abuse and drug identification (ID) calls from 1998 to 2003.

Results

Drug ID and abuse calls were 217% higher in 2003 than in 1998. Although eastern and central Texas contains 43% of the state’s population, this region reported 77% of all drug ID calls and 64% of abuse calls. Male patients accounted for 51% of abuse calls and 37% of other human exposure calls. Patients from 13 to 19 years of age accounted for 17% of abuse calls and 9% of other human exposure calls. Among those human exposure calls with a known medical outcome, a higher percentage of abuse calls involved minor effects while a greater proportion of other human exposure calls involved outcomes that ranged from moderate effects to death.

Conclusions

Carisoprodol abuse is increasing in Texas and is substantially more common in the eastern part of the state. Carisoprodol abuse is much more likely, than other types of adverse carisoprodol exposures, to involve males and adolescents; and it less likely to involve adverse medical outcomes.     

Vitamin D deficiency,myositis–myalgia,and reversible statin intolerance

Abstract

Objective:

In 150 hypercholesterolemic patients, unable to tolerate ≥1 statin because of myositis-myalgia, selected by low (<32?ng/ml) serum 25 (OH) vitamin D, we prospectively assessed whether vitamin D supplementation with resolution of vitamin D deficiency would result in statin tolerance, free of myositis–myalgia.     

Analysis of bioactive compounds using LC–ESI–MS/MS,cytotoxic, antimicrobial effects,and enzyme activities from Cyclotrichium origanifolium

Cyclotrichium origanifolium is a medicinal plant belonging to the Lamiaceae family. In this study, phenolic content analysis, antimicrobial effects, and cytotoxic effects of extracts of C. origanifolium were investigated. In the extracts, phenolic compound analysis by the liquid chromatography–electrospray ionization–tandem mass spectrometry method, antimicrobial effect by the minimum inhibition concentration method, and cytotoxic effect on human dermal fibroblasts (HDF), glioblastoma cell (U87), ovarian adenocarcinoma cell (Skov-3), and human colorectal adenocarcinoma cell (CaCo-2) cancer cell lines were investigated. Cytotoxicity analyses were performed by the MTT method. In addition, the GST and AChE enzyme activities of the extracts were also measured. Around 18 compounds were detected in both the methanol and ethanol extract. It was found that the best antimicrobial effect on Gram-negative Pseudomonas aeruginosa was on methanol extract, while the ethanol extract was on Candida albicans fungus (respectively, 2.50 mg/ml, 5.0 μg/ml). A 500 μg/ml of methanol extract has been shown to have cytotoxic activity high effect on HDF cells. GST and AChE activity were found to decrease in a concentration-dependent manner.     

Edoxaban drug–drug interactions with ketoconazole,erythromycin, and cyclosporine

AimsEdoxaban, a novel factor Xa inhibitor, is a substrate of cytochrome P450 3 A4 (CYP3A4) and the efflux transporter P‐glycoprotein (P‐gp). Three edoxaban drug–drug interaction studies examined the effects of P‐gp inhibitors with varying degrees of CYP3A4 inhibition.MethodsIn each study, healthy subjects received a single oral dose of 60 mg edoxaban with or without an oral dual P‐gp/CYP3A4 inhibitor as follows: ketoconazole 400 mg once daily for 7 days, edoxaban on day 4; erythromycin 500 mg four times daily for 8 days, edoxaban on day 7; or single dose of cyclosporine 500 mg with edoxaban. Serial plasma samples were obtained for pharmacokinetics and pharmacodynamics. Safety was assessed throughout the study.ResultsCoadministration of ketoconazole, erythromycin, or cyclosporine increased edoxaban total exposure by 87%, 85%, and 73%, respectively, and the peak concentration by 89%, 68%, and 74%, respectively, compared with edoxaban alone. The half‐life did not change appreciably. Exposure of M4, the major active edoxaban metabolite, was consistent when edoxaban was administered alone or with ketoconazole and erythromycin. With cyclosporine, M4 total exposure increased by 6.9‐fold and peak exposure by 8.7‐fold, suggesting an additional interaction. Pharmacodynamic effects were reflective of increased edoxaban exposure. No clinically significant adverse events were observed.ConclusionsAdministration of dual inhibitors of P‐gp and CYP3A4 increased edoxaban exposure by less than two‐fold. This effect appears to be primarily due to inhibition of P‐gp. The impact of CYP3A4 inhibition appears to be less pronounced, and its contribution to total clearance appears limited in healthy subjects.     

Novel phenolic glycosides,adenophorasides A–E,from Adenophora roots

Five novel phenolic glycosides, adenophorasides A (1), B (2), C (3), D (4), and E (5), were isolated from commercial Adenophora roots, together with vanilloloside (6), 3,4-dimethoxybenzyl alcohol 7-O-β-d-glucopyranoside (7), and lobetyolin (8). The structures of the new compounds (1–5) were characterized as 4-hydroxy-3-methoxyphenylacetonitrile 4-O-β-d-glucopyranoside (1), 4-hydroxy-3-methoxyphenylacetonitrile 4-O-β-d-glucopyranosyl-(1→6)-β-d-glucopyranoside (2), 4-hydroxy-3-methoxyphenylacetonitrile 4-O-α-l-rhamnopyranosyl-(1→6)-β-d-glucopyranoside (3), 4-hydroxyphenylacetonitrile 4-O-β-d-glucopyranosyl-(1→6)-β-d-glucopyranoside (4), and 4-hydroxy-3-methoxybenzyl alcohol 4-O-β-d-glucopyranosyl-(1→6)-β-d-glucopyranoside (5), respectively, by means of spectroscopic and chemical analyses.     

General overview of lipid–polymer hybrid nanoparticles,dendrimers, micelles,liposomes, spongosomes and cubosomes

Introduction: In recent years, the wider use of nanotechnology has attracted greater attention from scientists in multi-disciplinary fields. Nanotechnological research has come a long way in the past decade, with major advances being made, both in terms of diagnostic and therapeutic potential of nanoparticles.

Areas covered: Some of the prominently discussed nanoparticles in this day and age are polymeric micelles, liposomes, lipid–polymer hybrid nanoparticles, dendrimers, spongosomes and cubosomes. This review attempts to focus on the conventional advantages and exemplary features that these particles possess, thus making them some of the most ideal vehicles for drug delivery.

Expert opinion: Particulate systems, which have been extensively studied in this article, have been employed to enhance the pharmacokinetic and pharmacodynamic characteristics of various hydrophobic and hydrophilic drug moieties, thus attempting to prolong the blood circulation times and increase their efficacy over unmodified drug molecules. These modification techniques have enabled these drug molecules to be delivered to the pharmacological sites of action at an optimised controlled rate, thus trying to minimise the potential for any toxicity resulting from the non-specific distribution of drug to various organs.     

The zebrafish embryo model in toxicology and teratology,September 2–3, 2010, Karlsruhe,Germany

The use of fish embryos is gaining popularity for research in the area of toxicology and teratology. Particularly embryos of the zebrafish offer an array of different applications ranging from regulatory testing to mechanistic research. For this reason a consortium of two research centres and a company with the support of the COST Action EuFishBiomed has organised the Workshop “The zebrafish embryo model in toxicology and teratology”, in Karlsruhe, Germany, 2nd–3rd September 2010. The workshop aimed at bringing together experts from different areas of toxicology using the (zebra)fish embryo and stimulating networking between scientists and representatives from regulatory bodies, research institutions and industry. Recent findings, presented in various platform presentations in the area of regulatory toxicity, high throughput screening, toxicogenomics, as well as environmental and human risk assessment are highlighted in this meeting report. Furthermore, the constraints and possibilities of the model as discussed at the workshop are described. A follow up-meeting was appreciated by the about 120 participants and is planned for 2012.