Sandhiya Selvarajan

Globalization of Clinical Trials – Where are We Heading?

The last decade has witnessed a greater transparency in clinical research with the advent of clinical trial registries. The aim of the study was to describe the trends in the globalization of clinical trials in the last five years. We performed an internet search using the WHO International clinical trials registry platform (WHO ICTRP) to identify the clinical trials conducted from January 2007 to December 31, 2011 among 25 countries. Among the 25 countries, the United States, Japan and Germany occupy the top positions in the total number of clinical trials conducted. Clinical trials in the US (36312) constituted 31.5% of the total number of trials performed during this period. However over a period of five years both US and Western Europe appear to show a decline, while the emerging countries show a rise in clinical trials registered. Among the emerging countries China, India and Republic of Korea are most active regions involved in clinical trials. Cancer, diabetes and respiratory diseases were most widely researched areas overall. Although the study confirms the transition in the clinical trials research towards emerging countries, the developed regions of the world still contribute to more than 70% of the trials registered worldwide.

Clinical trials in India: Where do we stand globally?

Aims: To evaluate the trend of clinical trials in India over the last 4 years compared to the well-established countries using clinical trial registries since the advent of clinical trial registry of India (CTRI). Materials and Methods: The data of clinical trials registered in India, United States (US), and European Union (EU) were obtained from websites of CTRI, clinicaltrial.gov and EU clinical trial registry, respectively from July 20, 2007 to August 29, 2011 for a period of 4 years. Trials registered in Australia, Canada, China, and Japan were obtained from WHOs international clinical trial registry platform for the same period. We used search words for the common diseases such as diabetes, hypertension, etc., Results: The total number of clinical trials registered during the study period was 67,448 across seven study nations. Clinical trials from India constituted only 2.7% of the total number of trials carried out, compared to US constituting 47% of the total number of trials registered, followed by 18% from EU and 11% from Japan. However, India, China, and Japan have been found to show an increase of 3.7%, 5.1%, and 13.1% increase in the number of trials registered in 2011 compared to 2007. In contrast, US and EU showed a decline of 11.3% and 11.95% respectively in the total number of trials registered in 2011 compared to 2007. Conclusions: Although India shows gradual increase in trials registered since the advent of CTRI, still it continues to lag behind established countries in clinical research.

Effect of Vitamin D supplementation on vascular functions and oxidative stress in type 2 diabetic patients with Vitamin D deficiency

Background: Vitamin D levels are reported to have an inverse liaison with the risk of cardiovascular diseases. Hence, we aimed to evaluate the effect of Vitamin D supplementation on changes in vascular functions and oxidative stress in type 2 diabetic patients with Vitamin D deficiency. Subjects and Methods: One hundred and three patients with type 2 diabetes attending endocrinology outpatients department in a tertiary care hospital were screened for Vitamin D deficiency. Patients with serum 25-hydroxy Vitamin D levels <20 ng/ml were considered as deficient and were administered 60,000 IU of oral Vitamin D3 weekly for 8 weeks. In these patients, parameters of vascular functions (carotid-femoral pulse wave velocity, brachial-ankle pulse wave velocity, and arterial stiffness index) and oxidative stress (serum malondialdehyde levels and total antioxidant status) were measured at baseline and after 8 weeks of oral Vitamin D supplementation. Results: Among 103 patients with type 2 diabetes, 75 (72.82%) were found to have Vitamin D deficiency. Amidst these patients, carotid-femoral pulse wave velocity (991.6 ± 161.82 vs. 899.29 ± 151.86, P< 0.001), right brachial-ankle pulse wave velocity (1446.16 ± 204.33 vs. 1350.8 ± 178.39, P< 0.001), and left brachial-ankle pulse wave velocity (1493.81 ± 219.65 vs. 1367.61 ± 220.64, P< 0.001) showed a significant reduction following Vitamin D supplementation. Further, these patients were found to have significant fall in serum malondialdehyde levels with rise in total antioxidant status ensuing Vitamin D supplementation. Conclusion: The present study shows that oral Vitamin D supplementation of 60,000 IU/week for 8 weeks significantly improves vascular functions and reduces oxidative stress in type 2 diabetic patients with Vitamin D deficiency.

Effect of metformin on exercise capacity in metabolic syndrome

OBJECTIVE Metabolic syndrome is a constellation of risk factors with increased predilection towards occurrence of cardiovascular diseases. Currently physical exercise and management with metformin are the prevailing treatment modalities for metabolic syndrome. Patients with metabolic syndrome have been found to have reduced exercise capacity over a period of time. Likewise metformin has been shown to decrease exercise capacity among healthy volunteers. Hence this study aims to evaluate the effect of metformin on the exercise capacity of patients with metabolic syndrome. DESIGN Prospective study with 6 weeks follow up. METHODS Newly diagnosed patients with metabolic syndrome and to be started on Table Metformin 500mg twice a day were recruited for the study after obtaining written informed consent. Cardiopulmonary Exercise Testing (CPET) was done at baseline before the subjects were started on metformin and after 6 weeks of treatment using cardiopulmonary exercise testing apparatus (ZAN600). RESULTS Fifteen treatment naïve patients with metabolic syndrome completed six weeks of therapy with metformin. In these patients oxygen uptake [VO2] showed statistically significant decrease from 1.10±0.44 at baseline to 0.9±0.39 (l/min) after six weeks of treatment with metformin [mean difference of -0.20 (-0.31 to -0.09); P=0.001]. Similarly oxygen uptake/kg body weight [VO2/Kg] showed a significant decrease from 14.10±4.73 to 11.44±3.81 (mlkg-1min-1) at the end of six weeks of treatment [mean difference of -2.66 (-4.06 to -1.26); P=0.001]. CONCLUSION Six weeks of treatment with metformin significantly decreases exercise capacity in newly diagnosed patients with metabolic syndrome.

Looking into the Crystal Ball—Upcoming Drugs for Dyslipidemia

Dyslipidaemia is a critical risk factor for the development of cardiovascular complications such as ischemic heart disease and stroke. Although statins are effective anti-dyslipidemic drugs, their usage is fraught with issues such as failure of adequate lipid control in 30% of cases and intolerance in select patients. The limited potential of other alternatives such as fibrates, bile acid sequestrants and niacin has spurred the search for novel drug molecules with better efficacy and safety. CETP inhibitors such as evacetrapib and anacetrapib have shown promise in raising HDL besides LDL lowering property. Microsomal triglyceride transfer protein (MTP) inhibitors such as lomitapide and Apo CIII inhibitors such as mipomersen have recently been approved in Familial Hypercholesterolemia but experience in the non-familial setting is pretty much limited. One of the novel anti-dyslipidemic drugs which is greatly anticipated to make a mark in LDL-C control is the PCSK9 inhibitors. Some of the anti-dyslipidemic drugs which work by PCSK9 inhibition include evolocumab, alirocumab and ALN-PCS. Other approaches that are being given due consideration include farnesoid X receptor modulation and Lp-PLA2 inhibition. While it may not be an easy proposition to dismantle statins from their current position as a cholesterol reducing agent and as a drug to reduce coronary and cerebro-vascular atherosclerosis, our improved understanding of the disease and appropriate harnessing of resources using sound and robust technology could make rapid in-roads in our pursuit of the ideal anti-dyslipidemic drug.

Systematic review on vitamin D level in apparently healthy Indian population and analysis of its associated factors

Background: Vitamin D which is involved in the maintenance of bone mineral homeostasis has been found to portray various pleiotropic effects. Although it has been widely accepted that serum 25-hydroxy Vitamin D level above 30 ng/ml is considered optimal for the biological actions of Vitamin D, there is a need to explore the levels of Vitamin D reported among Indians from various regions of the country. Hence, this systematic review aims to appraise the status of Vitamin D levels reported from apparently healthy Indians across various parts of India. Methodology: A comprehensive literature search was carried out to identify the range of Vitamin D levels among apparently healthy individuals from various parts of India, with the search term “Vitamin D and India” in the search portals of PubMed, Google Scholar, Indmed, and ScienceDirect. A total of 2998 articles were retrieved by the above search strategy, of which only forty studies fulfilled the criteria to be included in the systematic review. Studies done in various states were compiled under the respective zones based on the classification of Indian zones as specified in Zonal maps of India. Results: The level of Vitamin D from all the forty included studies ranged from 3.15 ± 1.4 to 52.9 ± 33.7 ng/ml. The effect size of Vitamin D level was higher in the South Zone compared to other zones. Conclusion: The present study shows that Vitamin D deficiency is prevalent among apparently healthy Indians living in different regions of India, irrespective of their exposure to sunlight.

End points in heart failure—are we doing it right?

PurposeHeart Failure (HF) continues to be associated with high mortality and morbidity. We attempted to identify the most common end points used in phase 3 clinical trials of heart failure and discuss their merits and demerits.MethodsLiterature evaluation was done using the databases PubMed and Clinicaltrials.gov from January 2010 to December 2016 to identify randomised clinical trials (RCTs) evaluating the effect of therapeutic drugs on heart failure. Following the literature search, the data on the primary end points were extracted from each of the selected trials. The most recurrent and important end points of Phase III clinical trials for HF over the last six years were identified for further discussion.ResultsFrom our search, it was observed that the most common end points used in trials with acute heart failure (AHF) were composite end point, dyspnea, CV death and most common end points used in trials with chronic heart failure (CHF) were composite end point, 6 minute walk test (6MWT), CV death or HFH, Vo2 max, all cause mortality, left ventricular ejection fraction (LVEF), and dyspnea.ConclusionChoosing the appropriate end points is a critical step in the study design that could turn the tide in the beleaguered drug development pipeline of HF, resulting in the right molecule reaching the HF community.

Acenocoumarol as an alternative anticoagulant in a patient with warfarin‐related nephropathy

Warfarin‐related nephropathy.

Oyster shell calcium induced parotid swelling

A 59 year old female consumer was started on therapy with oyster shell calcium in combination with vitamin D3 and she presented with swelling below the ear, after two doses. She stopped the drug by herself and the swelling disappeared in one day. She started the drug one day after recovery and again she developed the swelling. She was advised to stop the drug with a suggestion to take lemon to enhance parotid secretion and the swelling subsided. Calcium plays major role in salivary secretion and studies have shown reduced parotid secretion in rats, deficient of vitamin D. But in humans involvement of calcium and vitamin D3 in parotid secretion is unknown. However, the patient had no history of reaction though she had previously taken vitamin D3 with calcium carbonate which was not from oyster shell. Hence, we ruled out vitamin D3 in this reaction and suspecting oyster shell calcium as a culprit. This adverse drug reaction (ADR) was assessed using World Health Organization (WHO) causality assessment, Naranjos and Hartwig severity scales. As per WHO causality assessment scale, the ADR was classified as “certain”. This reaction was analyzed as per Naranjos algorithm and was classified as probable. According to Hartwigs severity scale the reaction was rated as mild. Our case is an example of a mild but rare adverse effect of oyster shell calcium carbonate which is widely used.

Prophylactic Use of Steroids and Antibiotics in Acute Hydrocarbon Poisoning in Children

Ingestion of hydrocarbons is a common cause of childhood poisoning in low and middle-income countries. Although mild ingestions are usually devoid of complications, the morbidity and mortality associated with such poisoning are primarily related to pulmonary aspiration. Subsequent complications, most importantly, secondary bacterial infections can worsen the clinical condition. Standard treatment protocol for acute accidental hydrocarbon poisoning does not advocate routine use of steroids or antibiotics. However, some studies have demonstrated beneficial effects of prophylactic steroid and antibiotic to prevent chemical pneumonitis. In this article, we have summarized the findings of the clinical studies from literature, which have evaluated the advantages of early administration of steroids and antibiotics to prevent chemical pneumonitis in acute hydrocarbon poisoning in children. From these studies, we have found that there is no convincing evidence for initiating steroid and antibiotic to improve outcome in these children.