The impact of propranolol on nitric oxide and total antioxidant capacity in patients with resistant hypertension-evidence from the APPROPRIATE trial.

OBJECTIVES: The objective was to assess the effect of propranolol on oxidative stress and anti-oxidant potential in patients with resistant hypertension as a secondary analysis of the APPROPRIATE trial. This randomized double blinded clinical trial recruited patients with resistant hypertension and allocated forty patients to propranolol and placebo in 1:1 ratio. The pro-oxidant state (nitrate and nitrite) was assessed using modified Griess assay. The total anti-oxidant capacity was measured using ABTS assay. RESULTS: Analysis was performed for 18 patients from the propranolol group and 15 from the placebo group. A decline in end point ambulatory blood pressure (p = 0.031) and greater mean reduction in office SBP (29.7 ± 13.0 mmHg, p = 0.021) was noted in the propranolol arm. Nitrate and nitrite levels were lower at the end of a 90 day follow up period in both arms, with a greater mean reduction with propranolol. A significant increase in the AOC was noted in both arms with higher incremental value with Propranolol. The findings of this study do not demonstrate a statistically significant effect of propranolol on the oxidative stress/antioxidant balance in patients with resistant hypertension. The observed trends merit further evaluation.

Translation and Validation of the Sinhalese Version of the Brief Medication Questionnaire in Patients with Diabetes Mellitus.

BACKGROUND: Adherence to long-term therapy for diabetes remains low. Accurately measuring adherence is the primary step in improving adherence. We translated and validated the Sinhalese version of the Brief Medication Questionnaire (BMQ) in patients with diabetes. METHODS: The study was conducted at the National Hospital of Sri Lanka between April and December 2017, including 165 patients with diabetes. BMQ was translated into Sinhalese using the translation-back translation method. The translated questionnaire validation included evaluation of internal consistency, temporal stability, and performance in regard to a gold standard (HbA1c). RESULTS: Mean age (±SD) was 60.6 ± 11.1 years, and 46.1% were males. Mean duration of diabetes in the participants was 13.4 ± 7.8 years. Mean HbA1c was 8.3 ± 1.7%, with poor glycaemic control (HbA1c ≥ 8.5%) identified in 41.8%. Medication adherence measured by the BMQ regimen, belief, and recall screens were 39.4%, 75.8%, and 18.8%, respectively. In the analysis of temporal stability, the overall BMQ and the regimen, belief, and recall screens demonstrated good concordance between test and retest with significant gamma correlation coefficients of r = 0.85 (p < 0.001), r = 0.81 (p < 0.001), r = 0.84 (p < 0.001), and r = 0.91 (p < 0.001), respectively. The overall BMQ had a Cronbach α coefficient of 0.65 (95% CI: 0.61-0.70). The questionnaire performance with regards to the gold standards for the overall BMQ AUC was 0.73 (95% CI 0.65-0.80), while the BMQ regimen screen AUC was 0.61 (95% CI 0.53-0.70). The overall BMQ score with a cutoff value of 2 presented better equilibrium between sensitivity and specificity for the gold standard. Those with low adherence had a significantly higher percentage of poor glycaemic control (HbA1c ≥ 8.5%). CONCLUSION: The translated questionnaire demonstrated good reliability (internal consistency), temporal stability (test-retest reliability), and validity when assessed using a gold standard for disease control. Using culturally validated tools to evaluate adherence may help clinicians to identify low adherence and institute corrective measures.

Spectrum of low-density lipoprotein receptor (LDLR) mutations in a cohort of Sri Lankan patients with familial hypercholesterolemia - a preliminary report.

BACKGROUND: Hypercholesterolemia is a major determinant of cardiovascular disease-associated morbidity and mortality. Mutations in the LDL-receptor (LDLR) gene are implicated in the majority of the cases with familial hypercholesterolemia (FH). However, the spectrum of mutations in the LDLR gene in Sri Lankan patients has not been investigated. The objective of this study was to report the frequency and spectrum of variants in LDLR in a cohort of Sri Lankan patients with FH. METHODS: A series of consecutive patients with FH, diagnosed according to Modified Simon Broome criteria or Dutch Lipid Clinic Network criteria at the University Medical Unit, Colombo, were recruited. Clinical data was recorded. DNA was extracted from peripheral blood samples. The LDLR gene was screened for genetic variants by Sanger sequencing. RESULTS: A total of 27 patients [13 (48%) males, 14 (52%) females; age range 24-73 years] were tested. Clinical features found among these 27 patients were: xanthelasma in 5 (18.5%), corneal arcus in 1 (3.7%), coronary artery disease (CAD) in 10 (37%), and a family history of hypercholesterolemia and/or CAD in 24 (88.9%) patients. In the entire cohort, mean total cholesterol was 356.8 mg/dl (±66.4) and mean LDL-cholesterol was 250.3 mg/dl (±67.7). Sanger sequencing of the 27 patients resulted in the identification of known pathogenic missense mutations in 5 (18.5%) patients. Four were heterozygotes for 1 mutation each. They were c.682G > C in 2 patients, c.1720C > A in 1 patient, and c.1855 T > A in 1 patient. One patient with severe FH phenotypes was a compound heterozygote for one known mutation, c.2289G > T, and another missense variant, c.1670C > G (p.Thr557Ser), with unknown functional impact. This latter variant has not been reported in any other population previously. CONCLUSIONS: The frequency of known mutations in the LDLR gene in this cohort of patients was markedly low compared to frequencies reported in other populations. This highlights the likelihood of a complex, polygenic inheritance of FH in Sri Lankan patients, indicating the need for a comprehensive genetic evaluation that includes the screening for mutations in other genes that cause FH, such as APOB, PCSK9, and LDLRAP1.

Study protocol: a randomised controlled trial of supervised resistance training versus aerobic training in Sri Lankan adults with type 2 diabetes mellitus: SL-DART study.

BACKGROUND: The prevalence of type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD) is rising globally. T2DM is particularly problematic in South Asia with an estimated 10-15% of Sri Lankans diagnosed with the disease. Exercise is known to improve blood glucose, lipid profiles, blood pressure and adiposity, key goals in the management of T2DM. However, much of the evidence to date has been gained from white Caucasians who have a different body composition and disease profile compared to South Asians. Similarly, the recreational exercise culture is new to Sri Lankans and the effects of exercise on T2DM has not been studied in this population. METHODS: The Sri Lanka Diabetes Aerobic and Resistance Training (SL-DART) Study will be comprised of 2 components. Component 1 is a 12-week randomized controlled trial (RCT) to compare the effects of a supervised progressive resistance exercise program (RT) and aerobic exercise program (AT) with standard treatment/control (CN). Sedentary Sri Lankan adults with T2DM (aged 35-65 years) and with no contraindications to exercise will be randomized into one of 3 groups (AT, RT, CN). Exercise sessions will be conducted 2 days/week for 3 months. Baseline and post-intervention biochemical (glycemic control, lipid and liver profiles, inflammatory markers), anthropometric (height, weight, body circumferences), body composition, physical fitness, food preference (liking and wanting food) and quality of life parameters will be measured and compared between groups. Component 2 will be a qualitative study conducted immediately post-intervention via in-depth interviews to assess the barriers and facilitators for adherence to each exercise program. DISCUSSION: SL-DART Study represents one of the first adequately powered methodologically sound RCTs conducted in South Asia to assess the effects of resistance and aerobic exercise in participants with T2DM. Triangulation of quantitative and qualitative outcomes will enable the design of a culturally appropriate therapeutic physical activity intervention for Sri Lankans with T2DM, and the initiation of a professionally driven and specialized clinical exercise prescription service. TRIAL REGISTRATION: Sri Lanka Clinical Trials Registry; SLCTR/2016/017 . Date registered 17.06.2016. Universal trial number U1111-1181-7561.

Addition of Propranolol in Resistant Arterial hypertension Treatment (APROPRIATE study): study protocol for a randomized double-blind placebo-controlled trial.

BACKGROUND: Resistant hypertension is defined as an uncontrolled blood pressure despite treatment at best-tolerated doses with at least three antihypertensive agents including a diuretic. It is an emerging public health problem. At present clinical trial data on management of resistant hypertension is limited. Management is largely based on observational studies and expert opinions. Propranolol is a nonselective beta blocker. Several studies have confirmed that propranolol has a significant hypotensive action, both when used alone and as an adjuvant therapy. At present there are no prospective, randomized, clinical studies evaluating the effectiveness of propranolol in patients with resistant hypertension. Therefore, we have designed a prospective randomized trial to evaluate the safety and efficacy of propranolol in patients with resistant hypertension. METHODS/DESIGN: The study will be conducted as a randomized, double-blind, placebo-controlled clinical trial for a period of 3 months. The study has been approved by the Ethics Review Committee of the Faculty of Medicine, University of Colombo. A total of 200 adults with resistant hypertension will be recruited for the study. They will be randomly assigned to the test and placebo groups on a 1:1 ratio. The test group will receive propranolol 40 mg three times a day and the control group will receive an identical placebo capsule. The study drugs will be double blinded to both investigators and subjects. The visits and the evaluations will be done as follows: screening (visit 0), 1 month (visit 1), 2 months (visit 2) and 3 months (visit 3). The primary outcomes of the study is to find a statistically significant difference between the fall in mean systolic and mean diastolic blood pressure measured by ABPM (ambulatory blood pressure monitoring) from baseline between the two groups. Data will be analyzed using SPSS v16. DISCUSSION: To our knowledge this is one of the first randomized controlled trials evaluating the effects of propranolol in resistant hypertension. This study will provide the necessary groundwork for future large-scale, multicentered clinical trials. The result, positive or negative, should provide a step change in the evidence guiding current and future policies regarding treatment of resistant hypertension. TRIAL REGISTRATION: Sri Lanka Clinical Trials Registry, identifier: SLCTR/2016/002 . Registered on 27 January 2016; Study protocol version 2.1.

Effects of Zinc supplementation on serum lipids: a systematic review and meta-analysis.

Zinc is a mineral that plays a vital role in many biological processes and plays an important role in insulin action and carbohydrate metabolism. It may also have a protective role in the prevention of atherogenesis. Numerous studies have evaluated the effects of Zinc supplementation on serum lipids in humans and have demonstrated varying results. We systematically evaluated the literature and performed a meta-analysis on the effects of Zinc supplementation on serum lipids. A five staged comprehensive search of the literature was conducted in the following databases; PubMed, Web of Science and SciVerse Scopus for studies published before 31st December 2014. All controlled clinical trial in humans, that included a Zinc supplement intervention, either alone or in combination with other micronutrients and evaluated effects on serum lipids (total cholesterol [TC], triglycerides [TG], LDL cholesterol [LDL-c] and HDL cholesterol [HDL-c]). A meta-analysis of selected studies was performed using RevMan v5.3. The Jaded scale was used to assess the methodological quality of the trials included in the systematic review. A total of 24 studies were included in Meta analysis, which included a total of 33 Zinc interventions, in a total of 14,515 participants in the Zinc intervention or control group. The duration of Zinc supplementation ranged from 1 month to 7.5 years. The dose of elemental Zinc supplemented ranged from 15-240 mg/day. The pooled mean difference for TC between Zinc supplemented and placebo groups from random effects analysis was -10.92 mg/dl (95 % CI: -15.33, -6.52; p < 0.0001, I(2) = 83 %), while for HDL cholesterol it was 2.12 mg/dl (95 % CI: -0.74, 4.98; p = 0.15, I(2) = 83 %). The pooled mean difference for LDL-c between Zinc supplemented and placebo group from random effect analysis was -6.87 mg/dl (95 % CI: -11.16,-2.58; p < 0.001, I(2) = 31) and for TG it was -10.92 mg/dl (95 % CI: -18.56, - 3.28; p < 0.01, I(2) = 69 %). In conclusion, Zinc supplementation has favourable effects on plasma lipid parameters. Zinc supplementation significantly reduced total cholesterol, LDL cholesterol and triglycerides. Therefore it may have the potential to reduce the incidence of atherosclerosis related morbidity and mortality.

Efficacy and safety of 'true' cinnamon (Cinnamomum zeylanicum) as a pharmaceutical agent in diabetes: a systematic review and meta-analysis.

AIMS: Diabetes is a leading cause of morbidity and mortality worldwide. Studies have frequently looked at dietary components beneficial in treatment and prevention. We aim to systematically evaluate the literature on the safety and efficacy of Cinnamomum zeylanicum on diabetes. METHODS: A comprehensive search of the literature was conducted in the following databases; PubMed, Web of Science, Biological Abstracts, SciVerse Scopus, SciVerse ScienceDierect, CINAHL and The Cochrane Library. A meta-analysis of studies examining the effect of C. zeylanicum extracts on clinical and biochemical parameters was conducted. Data were analysed using RevMan v5.1.2. RESULTS: The literature search identified 16 studies on C. zeylanicum (five in-vitro, six in-vivo and five in-vivo/in-vitro). However, there were no human studies. In-vitro C. zeylanicum demonstrated a potential for reducing post-prandial intestinal glucose absorption by inhibiting pancreatic α-amylase and α-glucosidase, stimulating cellular glucose uptake by membrane translocation of glucose transporter-4, stimulating glucose metabolism and glycogen synthesis, inhibiting gluconeogenesis and stimulating insulin release and potentiating insulin receptor activity. The beneficial effects of C. zeylanicum in animals include attenuation of diabetes associated weight loss, reduction of fasting blood glucose, LDL and HbA(1c) , increasing HDL cholesterol and increasing circulating insulin levels. Cinnamomum zeylanicum also significantly improved metabolic derangements associated with insulin resistance. It also showed beneficial effects against diabetic neuropathy and nephropathy, with no significant toxic effects on liver and kidney and a significantly high therapeutic window. CONCLUSION: Cinnamomum zeylanicum demonstrates numerous beneficial effects both in vitro and in vivo as a potential therapeutic agent for diabetes. However, further randomized clinical trials are required to establish therapeutic safety and efficacy.

Medium of language in discharge summaries: would the use of native language improve patients' knowledge of their illness and medications?

Sri Lankan inpatients receive a discharge summary in English known as a diagnosis card. The authors investigated whether supplementing the diagnosis summary with native language improved patients' knowledge of illness and medication. Participants were 130 newly diagnosed patients with noncommunicable chronic diseases (92 men, 70.8%; 38 women, 29.2%; M age = 55.4 years, SD age = 12.8 years) who were randomized to a control group receiving an English discharge summary and intervention group receiving a supplementary native language discharge summary. A questionnaire assessed knowledge of illness and prescribed medications at discharge and at 2 weeks. The groups were comparable for knowledge of diagnosis and prescribed medications at discharge. At 2 weeks, the intervention group had significantly higher scores than did the control group for knowledge on diagnosis, M = 81.41, SD = 34.63, versus M = 27.95, SD = 41.26, respectively, p < .001; and on medications, M = 54.48, SD = 33.91, versus M = 12.55, SD = 20.44, respectively, p < .001. The increase in scores was explained by the dichotomous variable, whether supplementary discharge summary was given or not (p < .001). A higher proportion in the intervention group read the discharge summary to gain knowledge of diagnosis (81.5%) and medication (80%) than in the control group (4.6% and 6.2%, respectively; p < .001). A total of 121 participants (92.1%) preferred a discharge summary in native language. This simple model may be useful to improve patient knowledge relating to illness in countries that predominantly use another language for medical communications, rather than a native language.

Brain targeted transcranial administration of diazepam and shortening of sleep latency in healthy human volunteers.

Application of medicated oils on scalp had been practiced for centuries in the Ayurvedic system of medicine in diseases associated with the central nervous system. It is possible that the effectiveness of the therapy may be a result of targeted delivery of active compounds to the brain transcranially. Evidence also comes from two previous studies with positive results on brain targeted transcranial delivery of methadone base and diazepam on rat models. Possibility of transcranial drug delivery was investigated in healthy human volunteers using electroencephalography techniques by assessing the ability of transcranially administered diazepam in bringing about ß activity in the electroencephalographic wave patterns and shortening of the sleep latency period. Non polar drug molecules dissolved in a non-aqueous sesame oil based vehicle is a significant feature in the transcranial dosage design. The study was under taken in two phases. In the Phase-I study scalp application of a single dose of 2 mg/3 ml of the oil was employed and in the Phase-II study repeat application of three doses 24 h apart were employed. Sleep latency changes were monitored with Multiple Sleep Latency Tests with 5 naps employing the standard electroencephalography, electroocculography and electromyography electrodes. Sleep onset was identified with the first epoch of any sleep stage non rapid eye movement 1, 2, 3, 4 or rapid eye movement using electroencephalography, electroocculography and electromyography criteria. In both phases of the study there was significant reduction in the sleep latencies. It was much more pronounced in the Phase-II study. None of the subjects however displayed beta activity in the electroencephalography. Sleep latency reduction following scalp application in both the phases are suggestive of transcranial migration of diazepam molecules to the receptor sites of the nerve tissue of the brain eliciting its pharmacological effect of sedation. Transcranial brain targeted dosage design is therefore feasible.

Prevalence of overweight and obesity in Sri Lankan adults.

The aim of the study was to determine the prevalence of overweight, obesity and abdominal obesity, and the underlying socio-demographic correlates among Sri Lankan adults. Data were from 4532 adults aged ≥18 years randomly selected for a national level study on diabetes and cardiovascular disease. Weight, height and waist circumference (WC) were measured and body mass index (BMI) calculated. The mean (95% confidence interval) BMI and WC were 21.1 kg m(-2) (20.9-21.3), 22.3 kg m(-2) (22.1-22.4) and 78.0 cm (77.5-78.6) and 77.5 cm (77.0-78.0) for males and females, respectively. According to the proposed World Health Organization cut-off values for Asians, the percentage of Sri Lankan adults in the overweight, obese and centrally obese categories were 25.2%, 9.2% and 26.2%, respectively. Based on the cut-offs for Caucasians, these were 16.8%, 3.7% and 10.8%. Our findings were compatible with prevalence of obesity in regional countries. In addition, female sex, urban living, higher education, higher income and being in the middle age were shown to be associated with overweight and obesity in Sri Lankans. In conclusion, we have documented a relatively high prevalence of overweight and obesity, particularly, abdominal obesity among adults in Sri Lanka which is a middle-income country. Urgent public health interventions are needed to control the problem at an early stage.

Prevalence and projections of diabetes and pre-diabetes in adults in Sri Lanka--Sri Lanka Diabetes, Cardiovascular Study (SLDCS).

AIMS: To determine the prevalence of diabetes mellitus and pre-diabetes (impaired fasting glucose and impaired glucose tolerance) in adults in Sri Lanka. Projections for the year 2030 and factors associated with diabetes and pre-diabetes are also presented. METHODS: This cross-sectional study was conducted between 2005 and 2006. A nationally representative sample of 5000 adults aged >or= 18 years was selected by a multi-stage random cluster sampling technique. Fasting plasma glucose was tested in all participants and a 75-g oral glucose tolerance test was performed in non-diabetic subjects. Prevalence was estimated for those > 20 years of age. RESULTS: Response rate was 91% (n = 4532), males 40%, age 46.1 +/- 15.1 years (mean +/- standard deviation). The age-sex standardized prevalence (95% confidence interval) of diabetes for Sri Lankans aged >or= 20 years was 10.3% (9.4-11.2%) [males 9.8% (8.4-11.2%), females 10.9% (9.7-12.1%), P = 0.129). Thirty-six per cent (31.9-40.1%) of all diabetic subjects were previously undiagnosed. Diabetes prevalence was higher in the urban population compared with rural [16.4% (13.8-19.0%) vs. 8.7% (7.8-9.6%); P < 0.001]. The prevalence of overall, urban and rural pre-diabetes was 11.5% (10.5-12.5%), 13.6% (11.2-16.0%) and 11.0% (10.0-12.0%), respectively. Overall, 21.8% (20.5-23.1%) had some form of dysglycaemia. The projected diabetes prevalence for the year 2030 is 13.9%. Those with diabetes and pre-diabetes compared with normal glucose tolerance were older, physically inactive, frequently lived in urban areas and had a family history of diabetes. They had higher body mass index, waist circumference, waist-hip ratio, systolic/diastolic blood pressure, low-density lipoprotein cholesterol and triglycerides. Insulin was prescribed to 4.4% (2.7-6.1%) of all diabetic subjects. CONCLUSIONS: One in five adults in Sri Lanka has either diabetes or pre-diabetes and one-third of those with diabetes are undiagnosed.

Management of acute myocardial infarction in general medical wards in Sri Lanka.

The study was designed to evaluate the management of acute myocardial infarction in the general medical wards of the National Hospital of Sri Lanka. All patients with acute myocardial infarction admitted from September 1996 to August 1997, were evaluated with regard to the time delay in admission and drug treatment. The facilities for monitoring and resuscitation were also assessed. A total of 259 patients were included in the study, 173 males and 86 females. The median time delay from the onset of the pain to admission at the out-patients department was 12 hours and that between out-patients department admission and ward admission was 20 minutes. The median delay in obtaining a 12-lead electrocardiogram when the patient was in the ward was 90 minutes. Review of the data showed that thrombolytic therapy, beta-blockers and angiotensin-converting enzyme inhibitors are underused. Complications were common. All the medical wards had adequate monitoring and resuscitation facilities. With adequate training of doctors and the availability of specialised cardiac nurses, thrombolytic therapy can be used effectively in medical wards.

Time delay to thrombolytic therapy--a Sri Lankan perspective.

Reducing the time delay in initiating thrombolytic therapy in acute myocardial infarction is critical in maximising the functional and survival benefit. We analysed 120 consecutive admissions for thrombolytic therapy to the Coronary Care Unit. The total delay was divided into prehospital, in-hospital and Coronary Care Unit stages, and the median delays were found to be 130, 70, and 15 minutes, respectively. The delay was significantly longer in patients who sought prehospital medical advice, and when the diagnosis was not made at the emergency treatment unit. Educating at-risk groups and modifying the admission system may help to minimise these delays, while the establishment of an emergency ambulance service with well-trained crew would also improve the prognosis after acute myocardial infarction in Sri Lanka.