Markos Klonizakis

Effectiveness of non-benzodiazepine hypnotics in treatment of adult insomnia: meta-analysis of data submitted to the Food and Drug Administration

Objectives To investigate the effectiveness of non-benzodiazepine hypnotics (Z drugs) and associated placebo responses in adults and to evaluate potential moderators of effectiveness in a dataset used to approve these drugs. Design Systematic review and meta-analysis. Data source US Food and Drug Administration (FDA). Study selection Randomised double blind parallel placebo controlled trials of currently approved Z drugs (eszopiclone, zaleplon, and zolpidem). Data extraction Change score from baseline to post-test for drug and placebo groups; drug efficacy analysed as the difference of both change scores. Weighted raw and standardised mean differences with their confidence intervals under random effects assumptions for polysomnographic and subjective sleep latency, as primary outcomes. Secondary outcomes included waking after sleep onset, number of awakenings, total sleep time, sleep efficiency, and subjective sleep quality. Weighted least square regression analysis was used to explain heterogeneity of drug effects. Data synthesis 13 studies containing 65 separate drug-placebo comparisons by type of outcome, type of drug, and dose were included. Studies included 4378 participants from different countries and varying drug doses, lengths of treatment, and study years. Z drugs showed significant, albeit small, improvements (reductions) in our primary outcomes: polysomnographic sleep latency (weighted standardised mean difference, 95% confidence interval −0.57 to −0.16) and subjective sleep latency (−0.33, −0.62 to −0.04) compared with placebo. Analyses of weighted mean raw differences showed that Z drugs decreased polysomnographic sleep latency by 22 minutes (−33 to −11 minutes) compared with placebo. Although no significant effects were found in secondary outcomes, there were insufficient studies reporting these outcomes to allow firm conclusions. Moderator analyses indicated that sleep latency was more likely to be reduced in studies published earlier, with larger drug doses, with longer duration of treatment, with a greater proportion of younger and/or female patients, and with zolpidem. Conclusion Compared with placebo, Z drugs produce slight improvements in subjective and polysomnographic sleep latency, especially with larger doses and regardless of type of drug. Although the drug effect and the placebo response were rather small and of questionable clinical importance, the two together produced to a reasonably large clinical response.

Comparison of laser speckle contrast imaging with laser Doppler for assessing microvascular function

OBJECTIVE To compare the inter-day reproducibility of post-occlusive reactive hyperaemia (PORH) and sympathetic vasomotor reflexes assessed by single-point laser Doppler flowmetry (SP-LDF), integrating-probe LDF (IP-LDF) and laser speckle contrast imaging (LSCI), and the spatial variability of PORH assessed by IP-LDF and LSCI. We also evaluated the relationship between IP-LDF and LSCI perfusion values across a broad range of skin blood flows. METHODS Eighteen healthy adults (50% male, age 27 ± 4 years) participated in this study. Using SP-LDF, IP-LDF and LSCI, indices of skin blood flow were measured on the forearm during PORH (1-, 5- and 10-min occlusions) and on the finger pad during inspiratory gasp and cold pressor tests. These tests were repeated 3-7 days later. Data were converted to cutaneous vascular conductance (CVC; laser Doppler flow/mean arterial pressure) and expressed as absolute and relative changes from pre-stimulus CVC (ΔCVC(ABS) and ΔCVC(REL), respectively), as well as normalised to peak CVC for the PORH tests. Reproducibility was expressed as within-subjects coefficients of variation (CV, in %) and intraclass correlation coefficients. RESULTS The reproducibility of PORH on the forearm was poorer when assessed with SP-LDF and IP-LDF compared to LSCI (e.g., CV for 5-min PORH ΔCVC(ABS)=35%, 27% and 19%, respectively), with no superior method of data expression. In contrast, the reproducibility of the inspiratory gasp and cold pressor test responses on the finger pad were better with SP-LDF and IP-LDF compared to LSCI (e.g., CV for inspiratory gasp ΔCVC(REL)=13%, 7% and 19%, respectively). The spatial variability of PORH responses was poorer with IP-LDF compared to LSCI (e.g., CV ranging 11-35% versus 3-16%, respectively). The association between simultaneous LSCI and IP-LDF perfusion values was non-linear. CONCLUSION The reproducibility of cutaneous PORH was better when assessed with LSCI compared to SP-LDF and IP-LDF; probably due to measuring larger skin areas (lower inter-site variability). However, when measuring sympathetic vasomotor reflexes on the finger pad, reproducibility was better with SP-LDF and IP-LDF, perhaps due to the high sensitivity of LSCI to changes in skin blood flow at low levels.

Reproducibility of cutaneous thermal hyperaemia assessed by laser Doppler flowmetry in young and older adults

OBJECTIVES The primary objective of this study was to assess the inter-day reproducibility of cutaneous thermal hyperaemia, as assessed using integrating-probe laser Doppler flowmetry (LDF), in young and older men. A secondary objective was to identify the most reproducible form of data expression. METHODS Cutaneous thermal hyperaemia was assessed on the forearm in 14 young (25±1 year) and 14 older (65±1 year) men, using integrating-probe LDF. The test was repeated 7-14 days later. The baseline, initial peak, and plateau phases of the data traces were identified and expressed as raw cutaneous vascular conductance (CVC), CVC normalised to baseline (%CVC(BL)), and CVC normalised to 44°C vasodilatation (%CVC(MAX)). Reproducibility was assessed using the coefficient of variation (CV) and intraclass correlation coefficient (ICC) statistics. RESULTS The inter-day reproducibility was dependent on how the data were expressed. The reproducibility of the initial peak and plateau was equally acceptable in both young and older adults when data were expressed as %CVC(MAX) (e.g., CVs ranging from 4 to 11%). However, the baseline phase was poorly reproducible in both groups irrespective of the data presentation method used (e.g., CVs ranging from 25 to 35%). Furthermore, expressing data as raw CVC or as %CVC(BL) generally showed poor reproducibility for both groups and all phases of the test (e.g., CVs ranging from 15 to 39%). CONCLUSION Integrating-probe LDF is a reproducible technique to assess cutaneous thermal hyperaemia on the forearm when data are expressed as %CVC(MAX) in healthy young and older adults without history of hypertension or taking system drugs.

Mediterranean diet- and exercise-induced improvement in age-dependent vascular activity

The aging effect on microvascular integrity, marked by endothelial dysfunction and reduction in exercise tolerance, is a major cause of CVD (cardiovascular disease). Improved dietary habits, known to reduce morbidity and mortality, are also known to attenuate those aging effects. The present study investigated the effects of combined MD (Mediterranean diet) and exercise intervention on lower- and upper-limb cutaneous microvascular functions in an older healthy population. A total of 22 sedentary healthy participants (age, 55±4 years) underwent cardiopulmonary exercise tolerance test, and were assessed for their upper- and lower-limb vascular endothelial CVC (cutaneous vascular conductance) using LDF (laser Doppler fluximetry) with endothelium-dependent [ACh (acetylcholine chloride)] and -independent [SNP (sodium nitroprusside)] vasodilation. Participants were then randomized into two groups: MD and non-MD, and followed an 8-week intervention programme, which included discontinuous treadmill running based on each individuals exertion, twice per week. Exercise training improved CVC in both groups (e.g. 0.42±0.19 compared with 1.50±1.05 and 0.47±0.26 compared with 1.15±0.59 at 1000 μCb for MD and non-MD respectively; P<0.001). This was also combined by improvement in the exercise tolerance indicated by increased VT (ventilatory threshold) in both groups [12.2±2.8 compared with 14.8±2.8 ml·(kg of body weight)(-1)·min(-1) and 11.7±2.7 compared with 14.6±3.2 ml·(kg of body weight)(-1)·min(-1) for MD and non-MD groups respectively; P<0.05]. However, the MD group showed greater improvement in endothelium-dependent vasodilation than non-MD [ANCOVA (analyses of co-variance), P=0.02]. The results of the present study suggest that compliance with MD, combined with regular moderate exercise, improves age-provoked microcirculatory endothelial dysfunction and increases exercise tolerance, both responsible for reducing cardiovascular risk in this age group.

Role of sensory nerves in the rapid cutaneous vasodilator response to local heating in young and older endurance‐trained and untrained men

The ability to increase skin blood flow (SkBF) rapidly in response to local heating is diminished with advanced age; however, the mechanisms are unclear. The primary aim of this study was to investigate the role of sensory nerves in this age‐related change. A secondary aim was to investigate the effect of aerobic fitness on sensory nerve‐mediated vasodilatation in young and aged skin. We measured SkBF (using laser Doppler flowmetry) in young and older endurance‐trained and untrained men (n = 7 in each group) at baseline and during 35 min of local skin heating to 42°C at two sites on the ventral forearm. One site was pretreated with topical anaesthetic cream to block local sensory nerve function. Cutaneous vascular conductance (CVC) was calculated as SkBF divided by mean arterial pressure and normalized to maximal values (CVCmax) achieved during local heating to 44°C. At the untreated site, the rapid vasodilatation during the first ∼5 min of local heating (initial peak) was lower in the older untrained group (68 ± 3%CVCmax) compared with all other groups (young trained, 76 ± 4%CVCmax; young untrained, 75 ± 5%CVCmax; and older trained, 81 ± 3%CVCmax; P < 0.05). Sensory nerve blockade abolished these differences among the groups (P > 0.05). The contribution of sensory nerve‐mediated vasodilatation was lower in the older untrained group compared with all other groups (P< 0.05). Our results suggest that the age‐related decline in the rapid vasodilator response to local heating in human skin is explained by diminished sensory nerve‐mediated vasodilatation. These findings also indicate that this age‐related change can be prevented through participation in regular aerobic exercise.

Aging and aerobic fitness affect the contribution of noradrenergic sympathetic nerves to the rapid cutaneous vasodilator response to local heating

Sedentary aging results in a diminished rapid cutaneous vasodilator response to local heating. We investigated whether this diminished response was due to altered contributions of noradrenergic sympathetic nerves by assessing 1) the age-related decline and 2) the effect of aerobic fitness. Using laser-Doppler flowmetry, we measured skin blood flow (SkBF) in young (24 ± 1 yr) and older (64 ± 1 yr) endurance-trained and sedentary men (n = 7 per group) at baseline and during 35 min of local skin heating to 42°C at 1) untreated forearm sites, 2) forearm sites treated with bretylium tosylate (BT), which prevents neurotransmitter release from noradrenergic sympathetic nerves, and 3) forearm sites treated with yohimbine + propranolol (YP), which antagonizes α- and β-adrenergic receptors. SkBF was converted to cutaneous vascular conductance (CVC = SkBF/mean arterial pressure) and normalized to maximal CVC (%CVC(max)) achieved by skin heating to 44°C. Pharmacological agents were administered using microdialysis. In the young trained group, the rapid vasodilator response was reduced at BT and YP sites (P < 0.05); by contrast, in the young sedentary and older trained groups, YP had no effect (P > 0.05), but BT did (P > 0.05). Neither BT nor YP affected the rapid vasodilator response in the older sedentary group (P > 0.05). These data suggest that the age-related reduction in the rapid vasodilator response is due to an impairment of sympathetic-dependent mechanisms, which can be partly attenuated with habitual aerobic exercise. Rapid vasodilation involves noradrenergic neurotransmitters in young trained men and nonadrenergic sympathetic cotransmitters (e.g., neuropeptide Y) in young sedentary and older trained men, possibly as a compensatory mechanism. Finally, in older sedentary men, the rapid vasodilation appears not to involve the sympathetic system.

Long-term effects of an exercise and Mediterranean diet intervention in the vascular function of an older, healthy population

BACKGROUND Preserving endothelial function and microvascular integrity is suggested to reduce cardiovascular disease risk. It was recently shown that the age-dependent decline in endothelial and microvascular integrity may be reversed when combining exercise with Mediterranean diet (MD) in an 8-week intervention. The present study investigates whether the risk-reduction improvement in microcirculatory and cardiorespiratory functions are sustained in this age-group after a 1-year follow-up. DESIGN AND METHODS Twenty sedentary healthy participants (age, 55±4years) from the original study underwent cardiopulmonary exercise tolerance test and were assessed for their upper- and lower-limb vascular endothelial cutaneous vascular conductance (CVC) using laser Doppler fluximetry (LDF) with endothelium-dependent [ACh (acetylcholine chloride)] and endothelium-independent [SNP (sodium nitroprusside)] vasodilation, 1year after completing the intervention. RESULTS Both MD and exercise groups appeared to have an improved microvascular responses, in comparison to baseline as far as ACh is concerned. Exploring the interactions between the time point and the original group, however, revealed a stronger improvement in the MD group in comparison to the exercise group, for ACh (p=0.04, d=0.41). In the upper body, the time point and group interaction for ACh, indicated a better improvement for MD, without however statistical significance (p=0.07, d=0.24). Additionally, cardiorespiratory improvement in ventilatory threshold was maintained, 1year after (12.2±3.0 vs. 13.2±3.2ml∙kg(-1)∙min(-1), p<0.05). CONCLUSIONS The original improvements from an 8-week exercise and MD intervention were still evident, particularly in the microcirculatory and cardiorespiratory assessments, 1year after the initial study. This suggests that a brief intervention combining MD with exercise in this high-risk group promises long-term health benefits.

Assessment of Lower Limb Microcirculation: Exploring the Reproducibility and Clinical Application of Laser Doppler Techniques

Purpose of Study: Non-invasive laser Doppler fluximetry (LDF) and laser Doppler imaging (LDI), combined with iontophoresis, have been used to study the microcirculation in a range of clinical conditions including lower limb venous disease. A prerequisite for an accurate measurement tool is that it is reproducible. However, there is currently no literature with respect to the reproducibility of LDF and LDI combined with iontophoresis in the lower limb (in general) and in the upright position (in specific). Furthermore, the two techniques have been used interchangeably by researchers and the association between these two different measurement methods has not been explored, nor have the factors that affect them been well described. Thus the aim of this study was to determine the reproducibility of LDF and LDI with iontophoresis in the lower limb and investigate factors that influence their clinical application. Procedures: Cutaneous microvascular responses in the lower limb were measured in the supine and standing positions using LDF and LDI combined with iontophoretic administration of endothelial-dependent (acetylcholine, ACh) and -independent (sodium nitroprusside) vasodilators in 25 patients with uncomplicated isolated superficial venous incompetence (ISVI) and 26 healthy controls. Results: Maximum perfusion had the best reproducibility assessed by LDF (CV 20.5–24.3%) and LDI (15.8–17.6%). Both techniques were positively influenced by iontophoretic dose (e.g. p = 0.0001 for LDF) and the use of vasodilator agents (e.g. p = 0.0001 for LDF), but negatively influenced in the standing position and/or in the presence of ISVI (p = 0.0016 and 0.045, respectively, for LDF). There was a statistically significant positive relationship between the two techniques, for example ACh maximum perfusion versus LDF ACh maximum perfusion (r = 0.404, p = 0.016). Conclusions: Both techniques are reproducible, in line with similar studies undertaken in other areas of the human body, and provide useful information for the study of the lower-limb microcirculation. Direct comparison between techniques based on absolute numbers should be avoided and the technique choice should be based on individual study needs.

Effects of exercise training and Mediterranean diet on vascular risk reduction in post-menopausal women

This study tested the potential risk-reduction benefits of Mediterranean Diet (MD) and regular exercise training on microvascular activity and cardiorespiratory capacity in postmenopausal women. Fifteen sedentary postmenopausal participants (age = 54.6 ± 3.6) were randomised into either exercise training or exercise combined with following MD for eight-weeks, and were assessed for their cardiorespiratory capacity, and upper- and lower-limb endothelial cutaneous vascular conductance (CVC) test using Laser Doppler Fluximetry (LDF), coupled with measuring endothelium-dependent Acetylcholine Chloride (Ach) and -dependent Sodium Nitropurruside (SNP) vasodilators. Exercise training improved cardiorespiratory capacity as indicated by ventilatory threshold (11.5 ± 2.1 vs. 14.0 ± 3.0 ml·kg-1·min-1, p < 0.05) and improved the microcirculatory perfusion results of CVC for both vasodilators Ach (p < 0.001, d = 0.65) and SNP (p = 0.003, d = 0.53) in the lower-limb and ACh (p = 0.01, d = 0.41) and SNP (p = 0.03, d = 0.48) in the upper-limb, all (p < 0.05). However, combining exercise with MD showed a stronger improvement in Ach (p = 0.02, d = 0.36) of the lower limb, than in exercise alone group. The results suggest that regular moderate exercise improves microcirculatory vascular function and increases exercise tolerance, both are responsible for reducing cardiovascular risk in postmenopausal women. However, combining MD with exercise suggests additional microvascular vasodialiatory improvement, suggesting an effective strategy for further cardiovascular risk-reduction in this high-risk group.

Implementing a Mediterranean diet intervention into a RCT: Lessons learned from a non-Mediterranean based country

ObjectivesTo examine the participant experiences regarding perceived barriers and facilitators which impact on consuming the Mediterranean diet in the East of England.DesignQualitative methodology with focus groups.SettingA healthy, middle-aged population situated in the East of England. Intervention: An 8-week Mediterranean dietary intervention trial.ParticipantsEleven participants (including three co-habiting partners) in three focus groups, ranging between 50-65yrs with a mean age of 54.3yrs (±4.0)ResultsThematic analysis from the focus groups revealed that participants considered that the MD intervention had introduced a better quality of food, widening the food-horizon and allowed them to re-define cultural eating habits. They also reported several physical benefits from adapting to this diet and found the experience as positive. Whilst claiming that the MD was an enjoyable and pleasurable, the participants did express difficulty adapting to the eating pattern, finding difficulty in purchasing food items, an increase in food costs and found work, stress and time pressures undermining adherence.ConclusionThe participants’ experiences suggested that the MD was an encouraging dietary change with a middle aged non-Mediterranean based population group. Future MD interventions should tailor interventions and support participants closely, particularly with the necessary planning, organisation and purchasing involved with implementing this diet in non-Mediterranean countries. Secondly, researchers should also challenge any erroneous assumptions regarding the consumption of Mediterranean food, which may hinder implementation.