The epidemiology of long-term benzodiazepine use

Recommendations for benzodiazepine (BZD) use suggest durations of no more than a few weeks, but studies report use for months, years, or even decades. This article examines the who (who are long-term users), why (why do they use BZD), what (what are patterns of long-term use) and how (how do they compare to all BZD users). The study population is from the National Population Health Survey in Canada which interviewed respondents four times at two-year intervals, asking about specific drugs use as well as demographic, lifestyle and health-related questions. Long-term BZD use was defined as BZD use for two successive cycles. Four percent of the Canadian population used BZD at any one time, half of whom also reported use in the previous cycle. Benzodiazepine users were more likely to be female, elderly, smokers, to prefer speaking a language other than English, to have insurance coverage for medication, and to have completed high school education. Almost none of these determinants predicted long-term use. Persons reporting BZD use in 2000 had an odds ratio (OR) of 38.6 for also using BZD in 1998, were more likely to use antidepressants (OR=8.5) and suffer from conditions such as poor health, stress, and pain. Most of these determinants had no association with long-term use or if they did at a considerably lower OR. Of the 395 BZD users in 2000, almost 48.4% also used BZD in the previous cycle and 17% in all three previous cycles. Benzodiazepine use in any previous cycle made BZD use in 2000 more likely, with use determined by how recent and the frequency of reported use, culminating in a very high OR of 83.3 for use in all three previous cycles. Continued use for any of the individual BZD tended to be largely for the same BZD. We conclude that: (1) the overriding determinant for BZD use was that of previous use; and (2) long-term use was not determined by the same factors as overall use, which is significant in developing approaches to dealing with long-term BZD use.     

Efficacy of combination therapy for systolic blood pressure in patients with severe systolic hypertension: the Systolic Evaluation of Lotrel Efficacy and Comparative Therapies (SELECT) study

Systolic hypertension is predominant among patients over 50 years of age, is a more important cardiovascular risk factor than diastolic blood pressure, and is more difficult to control than diastolic blood pressure. Consequently, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommends combination therapy as first-line treatment for patients with stage 2 hypertension. In the Systolic Evaluation of Lotrel Efficacy and Comparative Therapies (SELECT) study, 24-hour ambulatory blood pressure monitoring was used to identify patients with systolic hypertension and to determine the impact of 8 weeks of treatment with either amlodipine besylate/benazepril HCl 5/20 mg combination therapy (n=149), amlodipine besylate 5 mg (n=146), or benazepril HCl 20 mg (n=148). Combination therapy was significantly more effective in reducing systolic blood pressure and pulse pressure than either monotherapy (p<0.0001). Significantly greater percentages of patients in the combination group compared with either monotherapy achieved blood pressure control (p<0.0001). Adverse events were low in all three treatment arms, with less peripheral edema in the combination group than in the amlodipine-treated group. The combination of amlodipine besylate/benazepril HCl given to patients with stage 2 systolic hypertension resulted in significantly greater reductions in blood pressure and pulse pressure than those seen with monotherapy and was at least as well tolerated as the separate components. This data supports the recommendation of the JNC 7 for the use of combination therapy in patients with stage 2 hypertension.     

Estrogen modulates the sexually dimorphic synaptic connectivity of the ventromedial nucleus

Neurons in the ventrolateral division of the hypothalamic ventromedial nucleus (VMNvl) display a remarkable estrogen-dependent functional and structural plasticity, which is likely to be mediated, in part at least, by neuronal afferents. The present study was designed to determine whether the number of synapses per neuron and the size of individual synapses in the VMNvl vary across the estrus cycle and, also, whether they differ between the sexes. To accomplish this, the VMNvl of adult female rats at proestrus or diestrus day 1 and of age-matched male rats was analyzed using electron microscopy. We found that a single VMNvl neuron receives around 7,000 synapses during diestrus and approximately 10,000 during proestrus. This estrus cycle-related variation is accounted for by increases in the number of all types of synapses. In males, the number of synapses received by each VMNvl neuron is similar to that of diestrus rats (approximately 7,500). However, in males the number of axodendritic and axospinous synapses is smaller than in proestrus rats, whereas the number of axosomatic synapses is higher than in diestrus rats. In addition, we found that the size of the postsynaptic densities of axospinous and axosomatic synapses is consistently larger in males than in females. Our results show that the synaptic organization of the VMNvl is sexually dimorphic, with females having more dendritic synapses and males more somatic synapses. They also show that the synaptic plasticity induced by estrogen in the VMNvl is characterized by changes in the number, but not the size, of the synapses.     

N-domain angiotensin-converting enzyme isoform expression in tissues of Wistar and spontaneously hypertensive rats

BACKGROUND: Angiotensin I-converting enzyme (ACE) is a protein containing two active sites, called N- and C-domains, according to their position in the protein. AIM: The aim of the present study was to verify whether the expression of the N-domain ACEs detected in the urine of Wistar and spontaneously hypertensive (SHR) rats was restricted to the kidney. METHODS: Adrenal, aorta, heart, liver, lung, kidney and testicle tissue from Wistar rats and spontaneously hypertensive rats were homogenized in assay buffer and analyzed by gel filtration, Western blotting and radio-immunoassay. RESULTS: Two peaks (at 136 and 69 kDa) with ACE activity upon ZPhe-His-Leu were separated by gel filtration from homogenate tissues of Wistar rats, in contrast with the tissue from hypertensive rats, which showed ACE forms of 96 and 69 kDa. The bands detected by Western blotting for all studied tissue from Wistar and spontaneously hypertensive rats showed a correspondence with the two peaks containing ACE activity detected in the polyacrylamide gel slices. Angiotensin II levels were increased in hypertensive rat tissue when compared with Wistar rat tissues. In addition, captopril 3 micromol/l inhibited the enzymic activity, where the Km was in the order of mmol/l and micromol/l using hippuryl-His-Leu and Abz-Ser-Asp-Lys(Dnp)Pro-OH as substrates, respectively. All tissues from Wistar rats presented ACE with 136 kDa, similar to somatic ACE, and N-domain ACE with 69 kDa. In the same tissue of spontaneously hypertensive rats, 96 and 69 kDa N-domain ACEs were detected. CONCLUSIONS: Our results demonstrated that N-domain ACEs were not exclusively produced in the kidney and excreted in the urine; they were expressed in all tissue studied, suggesting that these enzymes could influence local angiotensin II production, contributing to organ-specific regulation.     

Effect of the renin--angiotensin system on the vessel wall: using ACE inhibition to improve endothelial function

Plasma renin activity and cardiovascular disease (CVD) incidence correlate closely in people with hypertension. The effects of angiotensin II (Ang II) on blood pressure (BP) are important in hypertensive patients; accumulating data suggest that the growth effects of Ang II in the cardiovascular system play a critical role in the development of atherosclerosis. Atherosclerosis development in hypertensive patients requires fundamental changes in endothelial structure and function. Key among the factors that may affect the endothelium is the renin--angiotensin--bradykinin system. Ang II, independent of other environmental and neurohormonal factors, mediates the vessel wall changes critical for the development of atherosclerotic disease. A strong correlation appears to exist between Ang II and CVD. Blockade of the renin-angiotensin system has a major impact on arterial structure and function independent of BP. Certain angiotensin-converting enzyme (ACE) inhibitors produce significant improvements in arterial compliance, which may yield a reduction in cardiovascular events. Blockade of the neurohormonal system may be a critical first-line approach to management of hypertension in an effort to prevent or reverse endothelial dysfunction. Moreover, the effects of ACE inhibition, in addition to its effect on BP, suggest that this therapeutic approach may be appropriate for managing patients at risk of CVD who do not yet have hypertension. The ideal antihypertensive agent should yield smooth, consistent BP control over the entire 24-hour period, both to avoid BP variability that places patients at increased risk of cardiovascular events and to offer protection during the vulnerable early morning hours when patients are well known to be at high risk.     

Antihypertensive utility of perindopril in a large, general practice-based clinical trial

The authors evaluated, in a community-based open-label trial, the effectiveness and safety of perindopril in 13,220 US hypertensive patients and studied how physicians adhere to hypertension treatment guidelines. Patients received perindopril 4 mg q.d. for 6 weeks. Based on physicians' perception of blood pressure response, the patient was either maintained on 4 mg or the dose was increased to 8 mg for an additional 6 weeks. From baseline to week 12, the mean sitting blood pressure significantly declined from 156.9/94.5 mm Hg to 139.2/84.0 mm Hg. Further dose titration resulted in a clinically significant reduction in blood pressure in all patients with inadequate response on 4 mg at week 6. Blood pressure control (<140/<90 mm Hg) was achieved at 12 weeks in 48.8% patients. The subpopulation analyses demonstrated that perindopril monotherapy was effective in both men and women, in patients of all ethnicities, and in patients <65 and ≤65 years of age. Perindopril was safe and well tolerated in all hypertensive subgroups including high-risk patients. Physicians were more attuned to controlling diastolic than systolic blood pressure, and their adherence to the treatment guidelines was found to be not optimal.     

Elective neck dissection in oral tongue cancer

Introduction

Treatment to the neck of patients with oral tongue cancer (OTC) without palpable nodes (cN0) is controversial. Elective neck dissection (END) could lead to over-treating more than 50% and follow-up indicates high regional recurrence. Decision to perform the surgery depends on the risk of hidden node metastases (NM).

Objective

The objective of this study was to assess the prevalence of hidden NM in cN0-OTC patients undergoing END.

Material and methods

Patients (n=22) with cN0-OTC were treated with partial glosectomy and END.

Results

Of these, 16 were free of node metastases (negative predictive value=73%) while the other 6 (27%) showed at least one NM. Risk was greater, although statistically not significant, in T3 than in T1-2. Overall survival was better in patients without NM having END (95% versus 38%).

Conclusions

cN0-OTC is associated with 27% of NM, which justifies END. It is necessary to select carefully the candidates for END so as to preclude over-treatment in 73% of patients. Perhaps lymph mapping and sentinel node biopsy will help the better identification of hidden NM.     

Habitats, dispersion and invasion of sylvatic Triatoma dimidiata (Hemiptera: Reduviidae: Triatominae) in Petén, Guatemala

Dispersion and invasion capacity of sylvatic populations of Triatoma dimidiata (Latreille) were investigated during 14 mo by means of experimental chicken coops installed in a nature reserve within the Maya Biosphere, Petén, Guatemala. In addition, palm trees, underground archeological holes (chultunes) and piles of limestones within the forest were inspected as potential sylvatic habitats of T. dimidiata. From the three types of sylvatic habitats we inspected, all served as shelter and breeding sites for T dimidiata. The natural infection of these bugs (n = 72) with Trypanosoma cruzi (Chagas) was high (25%) and represent a risk for humans who colonize the forest. T. dimidiata quickly invaded the experimental chicken coops installed in the primary forest, albeit at very low densities. However, only one adult bug was encountered in the chicken coops installed in a secondary forest. Dispersal of adult T. dimidiata was most apparent at the end of the dry season. Overall, our results indicate a potential risk for invasion by sylvatic T. dimidiata of domestic environments in this area, with a risk of T. cruzi transmission to humans. We suggest that a system of community-based surveillance should be developed to detect new infestations and organize prompt treatment of any new cases of acute Chagas disease that may result.     

AAV-mediated expression of vascular endothelial growth factor induces choroidal neovascularization in rat

PURPOSE: To develop a small-animal model of choroidal neovascularization (CNV) by injecting adeno-associated virus (AAV)-VEGF into the subretinal space (SRS) of rats. METHODS: An adeno-associated viral vector encoding human VEGF(165) was injected into the subretinal space (SRS) of Sprague-Dawley or Long Evans rats. Expression of VEGF was identified by RT-PCR and immunohistochemistry. Physiological and pathologic changes in the retina and choroid were evaluated by electroretinography, fluorescein angiography, light microscopy, and three-dimensional reconstruction of serial sections. RESULTS: Green fluorescent protein (GFP) and VEGF were expressed for at least 20 months in the retina and retinal pigment epithelium (RPE). Histologic sections showed extensive subretinal neovascularization, degenerating photoreceptors, and proliferating RPE at 5 weeks to 20 months after injection of AAV-VEGF. At 2 to 12 months after injection, leaking blood vessels were detected by fluorescein angiography. Electroretinogram a- and b-wave amplitudes were significantly decreased during this time. Three-dimensional reconstruction of serial sections demonstrated that choroidal blood vessels penetrated Bruch's membrane, one of them splitting into three branches in the SRS. In the current model, CNV was produced in 95% of the animals tested (19/20). It persisted for more than 20 months, a necessary requirement for modeling the development of CNV in age-related macular degeneration (AMD). CONCLUSIONS: In this study, a highly reproducible animal model of long-lasting CNV was developed. This model is being used to test antiangiogenic molecules to reduce or inhibit CNV and could be extended to primates.