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Herein we reportthe synthesis of new bifunctional sigma-1 (σ1)-selectiveligands with antioxidant activity. To achievethis goal, we combined the structure of lipoic acid, a universal antioxidant,with an appropriate sigma aminic moiety. Ligands 14and 26displayed high affinity and selectivity for σ1receptors (Kiσ1= 1.8 and 5.5 nM; Kiσ2/σ1= 354 and 414, respectively). Compound 26exhibited in vivo antiopioid effects on kappa opioid (KOP)receptor-mediated analgesia. In rat liver and brain mitochondria (RLM,RBM), this compound significantly reduced the swelling and the oxidationof thiol groups induced by calcium ions. Our results demonstrate thatthe tested compound has protective effects against oxidative stress. [ABSTRACT FROM AUTHOR]

cis - N -Substituted N -normetazocine enantiomers possess peculiar pharmacological profiles. Indeed, dextro enantiomers bind with high affinity σ 1 receptor while opposite enantiomers bind opioid receptors. In spite of their stereochemistry, cis - N -2-phenylethyl N -normetazocine (phenazocine) enantiomers showed mixed opioid/σ 1 receptor profiles and a significant in vivo analgesia. To the best of our knowledge, there is no information available regarding the evaluation of σ 1 pharmacological profile in the antinociceptive effects of (+) - and (−) - phenazocine. Therefore, the present study was designed to ascertain this component by in vitro and in vivo studies. In particular, we tested the σ 1 affinity of both enantiomers by a predictive binding assay in absence or presence of phenytoin (DPH). Our results showed that DPH (1 mM) did not increase the σ 1 receptor affinity of (+) - and (−) - phenazocine (K i = 3.8 ± 0.4 nM, K i = 85 ± 2.0 nM, respectively) suggesting a σ 1 antagonist profile of both enantiomers. This σ 1 antagonistic component of two phenazocine enantiomers was corroborated by in vivo studies in which the selective σ 1 receptor agonist PRE - 084, was able to unmask their σ 1 antagonistic component associated with the opioid activity. The σ 1 antagonistic component of (+)- and (−) - phenazocine may justify their analgesic activity and it suggests that they may constitute useful lead compounds to develop new ligands with this dual activity. [ABSTRACT FROM AUTHOR]

Abstract: A high performance liquid chromatography (HPLC) method was developed to detected simultaneously l-dihydroxyphenylalanine (l-DOPA), dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in rat striatum dilaysates following oral administration of l-DOPA or its prodrugs. The chromatographic system uses a reversed-phase C18 column with electrochemical detection at +0.30V. Mobile phase consisted of 0.05M citric acid, sodium EDTA 50μM, sodium octylsulphonate 0.4nM at pH of 2.9 and 8% methanol (v/v) at a flow rate of 1ml/min. The calibration curves were linear over the concentration range of 10nm to 100μM and the lower limits of detections were 125fmol for l-DOPA, 50fmol for DOPAC, 250fmol for DA and 150fmol for HVA at signal noise to ratio of 3. The repeatability (or intra-day precision), expressed by the relative standard deviation, were better than 4%. The construction of microdialysis probes has been described. The in vitro relative recoveries of each microdialysis probe were evaluated and the results show that they are similar and reproducible for all the analytes with CVs from 1 to 4%. The HPLC–EC method was applied to detect the extracellular levels of l-DOPA, DA, DOPAC and HVA in the striatum dialysates of freely moving rats after oral administration of six new potential l-DOPA prodrugs. [Copyright &y& Elsevier]

The 2-arylpropionic acid derivatives or ‘profens’ are an important group of non-steroidal anti-inflammatory drugs that have been used for the symptomatic treatment of various forms of arthritis. These compounds are chiral and the majority of them are still marketed as racemate although it is known that the (S)- form is the principal effective in the cyclooxygenase inhibition. However, recent findings suggest that certain pharmacological effect of 2-arylpropionic acids cannot be attributed exclusively to the (S)-(+) enantiomer. To obtain further insights into the pharmacological effect of profens, the present study investigated the influence of racemic and pure enantiomers of flurbiprofen on the production of nitric oxide and glycosaminoglycans, key molecules involved in cartilage destruction. The culture of human articular cartilage stimulated by interleukin-1β (IL-1β), which plays an important role in the degradation of cartilage, has been established, as a profit experimental model, for reproducing the mechanisms involved in the pathophysiology of arthritic diseases. Our results show that mainly (S)-(+)-flurbiprofen decreases, at therapeutically concentrations, the IL-1β induced cartilage destruction. [Copyright &y& Elsevier]

Anthranilic acid (ANA) and 3-hydroxyanthranilic acid (3-HANA) have attracted considerable attention as two of the l-tryptophan kynurenine pathway metabolites in the central nervous system. In this study, a highly sensitive and accurate method for the quantification of ANA and 3-HANA has been developed using reversed-phase high performance liquid chromatography (HPLC) with fluorimetric detection. The HPLC assay was carried out using a C18 column (5 μm, 250×4.6 mm i.d.). The mobile phase consisted of a mixture of 25 mM sodium/acetic acid buffer (pH 5.5) and methanol (90:10 v/v). Fluorimetric detection at λex=316 nm and λem=420 nm was used. The assay was applied to the measurement of ANA and 3-HANA acid in rat brain dialysate following administration of l-tryptophan or l-kynurenine. 3-HANA and ANA levels were progressively increased during 90 min following administration of l-tryptophan, then decreased progressively to basal levels. 3-HANA levels were significantly higher than ANA levels after l-kynurenine administration. These findings suggest that the assay developed should provide an improved means for investigation of neurobiology of kynurenine pathway. [Copyright &y& Elsevier]

To determine practicing physicians' strategies for diagnosing and managing uncomplicated urinary tract infection, we surveyed physicians in general internal medicine, family practice, obstetrics and gynecology, and emergency medicine in four states. Responses differed significantly by respondents' specialty. For example, nitrofurantoin was the antibiotic of first choice for 46% of obstetricians, while over 80% in the other specialties chose trimethoprim-sulfamethoxazole. Most surveyed said they do not usually order urine culture, but the percentage who do varied by specialty. Most use a colony count of 10(5) colony-forming units or more for diagnosis although evidence favors a lower threshold, and 70% continue antibiotic therapy even if the culture result is negative. This survey found considerable variation by specialty and also among individual physicians regarding diagnosis and treatment of urinary tract infection and also suggests that some of the new information from the literature has not been translated to clinical practice. [ABSTRACT FROM AUTHOR]

Objective: To assess the prevalence of idle peripheral intravenous (IV) catheters (those without any therapeutic use) on regular-care medical wards.Design: Observation, interviews, and chart review.Setting: A university-affiliated VA medical center.Patients: All 959 inpatients on 4 regular-care medical wards during a 6-week period, including 484 IV catheter episodes and 2983 patient-days of IV catheter use.Main Outcome Measure: Idle IV catheter use.Results: Thirty-five percent of all IV catheter episodes (95% CI, 32% to 38%) had 2 or more consecutive idle days. In only 6 of these (1%) could a specific reason for the catheter be determined. Seventeen percent of all patients on regular-care medical wards (CI, 15% to 19%) had an idle IV catheter for 2 or more consecutive days. Twenty percent of all patient-days of IV catheter use were idle (CI, 19% to 21%).Conclusions: Our data suggest that IV are frequently used unnecessarily. Future efforts to reduce IV catheter complication rates should focus on reducing unnecessary use as well as on improving techniques to reduce infection rates when use is appropriate. [ABSTRACT FROM AUTHOR]