Presynaptic effects of moxonidine in isolated buffer perfused rat hearts: role of imidazoline-1 receptors and alpha2-adrenoceptors

Numerous studies support the concept that centrally acting antihypertensive drugs, such as imidazolines, mediate sympathoinhibition not only via activation of central nervous alpha2-adrenoceptors (alpha2-AR) but also via imidazoline-1 receptors (I1-R). An additional presynaptic involvement in sympathetic neurotransmission of imidazolines, via I1-R independent of alpha2-AR, is still controversial and remains to be clarified in the heart. Concentration response curves on endogenous norepinephrine (NE) overflow evoked by stimulation of epicardial postganglionic sympathetic nerves in isolated buffer-perfused rat hearts were performed for brimonidine, moxonidine, rauwolscine, 2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane (AGN192403), and efaroxan. To unmask an I1-R-mediated effect of moxonidine, hearts were pre-exposed in additional experiments with brimonidine or rauwolscine with or without AGN192403 or efaroxan, respectively. Moxonidine reduced stimulated NE overflow (log EC50: -6.15 +/- 0.14). AGN192403, a selective ligand at I1-R, had no influence on the dose-response curve of moxonidine (log EC50: -6.01 +/- 0.25). After pre-exposure to brimonidine [ stimulation 1 (S1) + stimulation 2 (S2); 10(-5) M], the inhibitory action of moxonidine was potentiated compared with control (32.0 +/- 2.8 versus 73.13 +/- 3.0%) and completely abolished with AGN192403 or efaroxan. This effect was also totally inhibited by pre-exposure with indomethacin (10(-7) M) and tricyclodecan-9-yl-xanthogenate (D-609), an inhibitor of phosphatidylcholine-selective phospholipase C (PC-PLC; 10(-7) M). Conversely, moxonidine was without modulating efficacy under alpha2-AR-blockade by rauwolscine. In summary, we demonstrate that moxonidine reduces NE release independently of I1-R, demonstrating the prominent effect of alpha2-AR in cardiac tissue under basal conditions. We also demonstrate that I1-R are involved in NE release under conditions of alpha2-AR-stimulation involving both a pathway of prostaglandins and PC-PLC.     

Validity of the Leg-O-Meter, an instrument to measure leg circumference

The objective of this study was to validate the Leg-O-Meter measure against the clinical assessment of edema made by physicians using data from a 1-year follow-up study of unselected patients with chronic venous disease of the leg (CVDL). The Leg-O-Meter consists of a tape measure fixed to a stand attached to a small board on which the patient is in standing position. Its reliability has been shown to be above 97%. Data from the Venous Insufficiency Epidemiologic and Economic Study (VEINES) were used: 1,521 patients from France, Belgium, Italy, and Quebec (Canada) who spontaneously consulted a physician between 1994 and 1995 with a complaint resulting from venous problems of the legs were included. Baseline variables included leg circumference measurements using the Leg-O-Meter; physicians were also asked to diagnose edema and report it as present or absent on each leg. Clinical edema and leg circumferences were assessed again 3 to 6 months after the baseline visit and 12 months after baseline. The tape measure of the Leg-O-Meter was fixed at 13 cm from the floor. The first and last assessments were used to evaluate the variation in edema during the follow-up period. Clinical variation in edema status was assessed as follows: improved, if edema was diagnosed at baseline but not at the final visit; unchanged, if edema was diagnosed at both visits; and worsened, if there was no diagnosis of edema at baseline but a diagnosis of edema was made at the final visit. Variation in measured edema was classified as improved if there was a decrease in leg circumference of more than 1 cm between baseline and final evaluation; unchanged, if the difference in leg circumference was between plus or minus 1 cm between the 2 assessments; and worsened, if there was an increase in leg circumference greater than 1 cm between the 2 assessments. Data-driven cut-off points were also used: 1.3 cm and 1.5 cm. Sensitivity and specificity of the Leg-O-Meter using physician diagnosis as "gold standard" were calculated. In addition, receiver operating characteristics (ROC) curves were calculated by using the 3 different leg circumference cut-off points in order to determine the accuracy of the Leg-O-Meter to detect changes in edema. The overall accuracy of the Leg-O-Meter was 0.84 (standard error (se) = 0.06). Accuracy was greater when 1.5 cm was used as a cut-point. The Leg-O-Meter is an objective, reliable, and standardized instrument to assess patients over time. A change of 1.5 cm between 2 measurements gives a valid estimate of improvement or worsening of edema, when compared to physicians' diagnosis. The Leg-O-Meter is also sensitive to any changes in leg circumferences, which is an advantage over the clinical evaluation of edema.     

The measurement of sense of competence in caregivers of patients with dementia

BACKGROUND: In the context of a cohort study on the socio-economic consequences of dementia in Belgium, we evaluated the validity, reliability and feasibility of the French version of the Dutch Sense of Competence questionnaire (SCQ), and of its short version (the SSCQ), in caregivers of demented patients The questionnaire was based on Zarit's burden interview and on a theoretical family-crisis model. METHODS: Construct validity was evaluated by factor analysis and by comparison of the results with those of the original SCQ study. Reliability was evaluated by Cronbach's alpha and by item-total correlations. Feasibility was assessed by a standardized index of missing values. RESULTS: The three domains found in the original SCQ were identified by factor analysis: consequences of involvement in care for the personal life of the caregiver, satisfaction with one's own performance as a caregiver and satisfaction with the elderly person as a recipient of care. The mean scores were similar to those in the original study, except for the consequences for personal life. Cronbach's alpha for both the SCQ and the SSCQ exceeded the 0.70 criterion. Two of the 27 items did not meet the item-total correlation criterion; the SSCQ items all met the criterion. The standardised index of missing values was deemed acceptable. CONCLUSIONS: The French versions of the SCQ and the SSCQ are valid and reliable. Like the Dutch version, the French version of the SCQ can be a useful outcome measure for the evaluation of intervention studies and the SSCQ is suitable for the daily practice.     

Benzene metabolites antagonize etoposide-stabilized cleavable complexes of DNA topoisomerase IIalpha

Chronic exposure to benzene is associated with hematotoxicity and acute myelogenous leukemia. Inhibition of topoisomerase IIalpha (topo II) has been implicated in the development of benzene-induced cytogenetic aberrations. The purpose of this study was to determine the mechanism of topo II inhibition by benzene metabolites. In a DNA cleavage/relaxation assay, topo II was inhibited by p-benzoquinone and hydroquinone at 10 microM and 10 mM, respectively. On peroxidase activation, inhibition was seen with 4,4'-biphenol, hydroquinone, and catechol at 10 microM, 10 microM, and 30 microM, respectively. But, in no case was cleavable complex stabilization observed and the metabolites appeared to act at an earlier step of the enzyme cycle. In support of this conclusion, several metabolites antagonized etoposide-stabilized cleavable complex formation and inhibited topo II-DNA binding. It is therefore unlikely that benzene-induced acute myelogenous leukemia stems from events invoked for leukemogenic topo II cleavable complex-stabilizing antitumor agents. (Blood. 2001;98:830-833)     

Galantamine demonstrates efficacy and safety in elderly patients with Alzheimer disease

Alzheimer disease (AD) treatment guidelines state that cholinergic agents are not cost-effective in patients with more severe disease. Because many physicians may deem an older patient unlikely to respond to treatment, older AD patients may remain untreated. Galantamine (Reminyl), a novel cholinergic agent, is effective in mild to moderate AD. This post hoc analysis of pooled phase III galantamine clinical trials was designed to assess whether older (> or =80 years) and younger (< or =79 years) AD patients experience similar benefits with galantamine based on changes in the ADAS-cog and CIBIC-plus. Mean ADAS-cog scores for older patients treated with galantamine 24 mg/day significantly improved versus baseline and versus placebo at month 3. Cognitive improvement was maintained versus placebo at month 6; the ADAS-cog score for placebo patients dropped below baseline at month 6. Change in CIBIC-plus for galantamine was significantly different from placebo at months 5 to 6. Mean ADAS-cog score in older patients taking galantamine for 12 months remained above baseline. The score for patients taking placebo for 6 months before switching to galantamine did not differ significantly from baseline at 12 months but was lower than in patients receiving galantamine for 12 months. Incidence of adverse events in patients > 80 years was similar to that in the overall study population. Galantamine maintained cognitive and global function in patients > 80 years with mild to moderate AD for at least 5 to 6 months and cognitive efficacy for 12 months. Prescribing approved therapies such as galantamine for older patients with AD is recommended.     

An open-label extension trial of galantamine in patients with probable vascular dementia and mixed dementia

BACKGROUND: Alzheimer's disease (AD) and vascular dementia (VaD) are the most common types of dementia worldwide. Galantamine, an acetylcholinesterase inhibitor and allosteric nicotinic modulator, has shown broad clinical benefits in patients with mild to moderate dementia due to AD, probable VaD, or AD with cerebrovascular disease (CVD)-so-called mixed dementia. OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety profiles of galantamine 24 mg/d in patients with VaD or AD with CVD over the longer term (>6 months). METHODS: This was an open-label extension of a 6-month double-blind study of galantamine. Patients who had been randomized to receive galantamine 24 mg/d or placebo in the double-blind phase were eligible to continue open-label treatment with galantamine 24 mg/d for 6 months. The primary efficacy end point was change in cognition, based on scores on the 11-item Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog/11). Secondary measures included changes in functional ability (as measured on the Disability Assessment for Dementia [DAD]) and behavior (as measured on the Neuropsychiatric Inventory [NPI]). Safety and tolerability were also monitored. RESULTS: Four hundred fifty-nine patients (240 men, 219 women; mean [SE] age, 75.2 [0.33] years) entered the open-label phase. Of these patients, 195 (42.5%) had a diagnosis of probable VaD, and 238 (51.9%) had a diagnosis of AD with CVD; the remainder had an inconclusive diagnosis. At month 12 of the study, improvements from baseline (the start of the double-blind phase) in ADAS-cog/11 scores were observed in both the group that received placebo during the double-blind phase (placebo/galantamine group: -0.3 point; 95% CI, -1.64 to 1.06) and the group that received galantamine during the double-blind phase (galantamine/galantamine group: -0.9 point; 95% CI, -1.73 to 0.03). Improvement in functional ability was demonstrated by statistically significant mean (SE) changes from baseline in DAD score in both the placebo/galantamine group (-7.4 [1.68]; P < or = 0.001) and the galantamine/galantamine group (-3.6 [1.33]; P < or = 0.01). There was no significant change in mean (SE) NPI scores in either group (0.2 [0.98] and 0.1 [0.70], respectively). Galantamine treatment was well tolerated. CONCLUSIONS: In these patients with VaD and AD with CVD, galantamine treatment produced similar sustained benefits in terms of maintenance of or improvement in cognition (ADAS-cog/11), functional ability (DAD), and behavior (NPI) after 12 months.     

Endoprosthetic surface replacement of the head of the humerus

The concept of an endoprosthetic surface replacement of the humeral head differs from that of stemmed endoprostheses. It is the replacement of the destroyed joint surface with reconstruction of the normal anatomy and minimal bone resection. The aim of this prospective study was to evaluate the short-term results of a newly developed cup arthroplasty (Durom-Cup) for the humeral head. In a prospective study, 39 patients with 46 Durom-Cups were evaluated preoperatively and every 3 months postoperatively. The average follow-up was 15 +/- 9 months. The group included 28 shoulders with rheumatoid arthritis, 15 joints with osteoarthritis, and 3 humeral head necroses. The Constant-score and SAS-function score were used. The Constant-score increased from 20.25 +/- 9.06 points preoperatively to 46.62 +/- 14.05 at 3 months, to 48.11 +/- 14.49 at 6 months, and to 55.25 +/- 11.6 at 9 months postoperatively. The Constant-score stayed at this level during further follow-up and was 55.81 +/- 16.31 at 12 months postoperatively. The best results were seen in the group of humeral head necroses with a Constant-score of 71.0 +/- 12.2 compared to 54.66 +/- 13.89 in the group of osteoarthritis and 56.78 +/- 13.33 in patients with rheumatoid arthritis at 12 months postoperatively. The results with the Durom-Cup are encouraging so that cup arthroplasty seems to be a good alternative to stemmed prostheses. The main advantages of the humeral head resurfacing are the bone-preserving fixation and the relatively simple surgical technique.     

Prevention of recurrent bacterial urinary tract infections by intravesical instillation of hyaluronic acid.

OBJECTIVE: To evaluate the efficacy of vesical instillation of hyaluronic acid against recurrent urinary tract infections. METHODS: Twenty women with a history of recurrent urinary tract infections each received 9 intravesical instillations of hyaluronic acid over 6 months. Their status was assessed prospectively over 47.6 weeks and compared with a retrospective review of patient charts covering 36.2+/-6.2 weeks. RESULTS: The total numbers of urinary tract infections were 67 before and 10 after treatment (p<0.001). Thirteen patients (65%) were free of recurrences until the end of the study. One had a recurrence during treatment, and 6 (30%) during follow-up. The number of infections per year per patient was reduced from 4.99+/-0.92 to 0.56+/-0.82 (p<0.001). In women with recurrences, time to recurrence was 178.3+/-25.5 days, compared with 76.7+/-24.6 days before treatment (p<0.001). CONCLUSION: Intravesical instillation of hyaluronic acid is effective in preventing recurrent urinary tract infections.