Selvarajan Sandhiya

Emerging trends of nanomedicine - an overview

Nanotechnology is an emerging branch of science for designing tools and devices of size 1 to 100 nm with unique function at the cellular, atomic and molecular levels. The concept of using nanotechnology in medical research and clinical practice is known as nanomedicine. Nanoparticles possess some novel properties not seen with the macro molecules and they can be manipulated by attaching therapeutic components to help in diagnosis and treatment. They can also be used to probe cellular movements and molecular changes associated with pathological states. Nanodevices like carbon nanotubes to locate and deliver anticancer drugs at the specific tumour site are under research. Nanotechnology promises construction of artificial cells, enzymes and genes. This will help in the replacement therapy of many disorders which are due to deficiency of enzymes, mutation of genes or any repair in the synthesis of proteins. Currently nanodevices like respirocytes, microbivores and probes encapsulated by biologically localized embedding have a greater application in treatment of anaemia and infections. Thus in the present scenario, nanotechnology is spreading its wings to address the key problems in the field of medicine. Hence this review discusses in detail the applications of nanotechnology in medicine with more emphasis on drug delivery and therapy.

The dawn of hedgehog inhibitors: Vismodegib

Cancer, one of the leading causes of death worldwide is estimated to increase to approximately 13.1 million by 2030. This has amplified the research in oncology towards the exploration of novel targets. Recently there has been lots of interest regarding the hedgehog (Hh) pathway, which plays a significant role in the development of organs and tissues during embryonic and postnatal periods. In a normal person, the Hh signaling pathway is under inhibition and gets activated upon the binding of Hh ligand to a transmembrane receptor called Patched (PTCH1) thus allowing the transmembrane protein, smoothened (SMO) to transfer signals through various proteins. One of the newer drugs namely vismodegib involves the inhibition of Hh pathway and has shown promising results in the treatment of advanced basal-cell carcinoma as well as medulloblastoma. It has been granted approval by US Food and Drug Administrations (US FDA) priority review program on January 30, 2012 for the treatment of advanced basal-cell carcinoma. The drug is also being evaluated in malignancies like medulloblastoma, pancreatic cancer, multiple myeloma, chondrosarcoma and prostate cancer. Moreover various Hh inhibitors namely LDE 225, saridegib, BMS 833923, LEQ 506, PF- 04449913 and TAK-441 are also undergoing phase I and II trials for different neoplasms. Hence this review will describe briefly the Hh pathway and the novel drug vismodegib.

Belatacept: A worthy alternative to cyclosporine?

Renal transplant is the definitive therapy in patients with end-stage renal disease (ESRD) and offers the only solace for such patients who have no alternative other than frequent hemodialysis, a process which contributes to sufficient morbidity.[1] Recent developments in the field of renal transplant including novel drugs have contributed immensely to the improvement in 1-year graft survival rates which approach almost 90%.[2] The pharmacotherapy of organ transplantation for immunosuppression consists primarily of an induction regimen comprising a monoclonal antibody such as basiliximab followed by maintenance immunosuppression consisting of calcineurin inhibitors (CNI) like cyclosporine or tacrolimus, and antiproliferative agents (mycophenolate mofetil) and lowdose corticosteroids. Long-term benefits of these drugs have not been as satisfactory, with the 5-year graft survival falling as low as 72%. Allograft dysfunction is a common cause for allograft loss. Several factors contribute to allograft dysfunction such as interstitial fibrosis, tubular atrophy and chronic toxicity of CNIs.[3] By the end of 2 years as many as 50% of patients on CNIs develop nephrotoxicity. The increased incidence of cardiovascular diseases in these group of patients have also been attributed to CNI owing to the drugs propensity to worsen hypertension, diabetes and dyslipidemia.[4-7] An active search for a better alternative to alleviate the suffering of patients on long-term immunosuppressive post renal transplant has led to the development of a new drug belatacept, recently approved by USFDA in June 2011. mechanism of action

The impact of the educational intervention on knowledge, attitude, and practice of pharmacovigilance toward adverse drug reactions reporting among health-care professionals in a Tertiary Care Hospital in South India

Background: Knowledge, attitude, practice (KAP)-based educational intervention is an important tool to reduce underreporting of adverse drug reactions (ADRs). Hence, this study aimed to assess the KAP of doctors and nurses working in medicine and allied departments of Jawaharlal Institute of Postgraduate Medical Education and Research on spontaneous reporting of ADRs, following an educational intervention. The study also compared the quantity of ADRs reported before and after 1 year of introducing the educational intervention. Methodology: The study was a cross-sectional questionnaire-based study involving doctors and nurses working in a tertiary care hospital in South India. A predesigned structured questionnaire was prepared to suit our ADR monitoring center, validated and then distributed to doctors and nurses working in medicine and allied departments of the institute. The study participants were asked to fill KAP pretest questionnaire followed by interactive educational intervention and post-test questionnaire related to KAP after 1 year. The impact of educational intervention among doctors and nurses was evaluated by their response to the post-test questionnaire and the number of ADR reported after intervention. The appropriate statistical analysis was used through Graph Pad InStat version 3.0. Results: A total of 235 health-care professionals were involved in the pre-KAP questionnaire, an educational intervention, and post-KAP questionnaire. Among them, doctors were 39%, and nurses were 61%. The overall response rate among doctors and nurses following educational intervention was statistically significant (P < 0.0001). Following the educational intervention, the quantity of ADR reported became double compared to pre-intervention. Conclusion: The KAP of health-care professionals improved following educational interventional program on pharmacovigilance. Continued educational intervention may inculcate ADR reporting culture among health-care professionals.

Comparison of ranolazine and trimetazidine on glycemic status in diabetic patients with coronary artery disease - a randomized controlled trial.

INTRODUCTION Cardiovascular diseases have become the leading cause of death around the globe and diabetes mellitus (DM) is considered to be a coronary artery disease (CAD) risk equivalent. Ranolazine, an anti anginal drug has been found to reduce Glycated haemoglobin (HbA1c) in diabetes patients with chronic angina. However the effect of another antianginal drug trimetazidine, on glycemic status is not clear. AIM To compare the effect of ranolazine and trimetazidine on glycemic status in diabetic patients with CAD. SETTINGS AND DESIGN Patients diagnosed with CAD and diabetes mellitus attending Cardiology Out Patient Department (OPD), Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Puducherry, India were recruited for this randomized open label parallel arm trial. MATERIALS AND METHODS The study conducted from January-2012 to April-2013 had 47 eligible patients diagnosed with CAD and diabetes mellitus. They were randomized to receive either ranolazine 500 mg BD or trimetazidine 35 mg BD for 12 weeks. HbA1c levels, fasting blood glucose (FBG), lipid profile, QT and QTc intervals were measured at baseline and after 12 weeks. STATISTICAL ANALYSIS Unpaired t-test was used to compare the baseline characteristics of between the groups while comparison within the groups were done using Paired t-test. Wilcoxon and Mann Whitney U-tests were used for non parametric data. Graph pad instat version-3 was used for statistical analysis. Values were expressed as mean ± SD. A p < 0.05 was considered statistically significant. RESULTS The study could not find any change in HbA1c levels in both ranolazine and trimetazidine groups. The adverse effects reported from patients on ranolazine include angina, constipation, postural hypotension, headache, dizziness, nausea and weakness while patients on trimetazidine complained of constipation, weakness, palpitations, angina, dizziness, nausea, dyspepsia, headache, gastric discomfort, joint pain, etc. CONCLUSION In patients with chronic angina and diabetes mellitus Ranolazine 500mg BD and Trimetazidine 35mg BD did not show any effect on HbA1c and fasting blood glucose lebel.

Comparison of different methods for causality assessment of adverse drug reactions

Background The causality assessment of adverse drug reactions (ADRs) remains a challenge, and none of the different available method of causality assessment used for assessing adverse reactions has been universally accepted as the gold standard. Objective To examine the agreement and correlation among three broad approaches for causality assessment of ADRs viz. World Health Organization-Uppsala Monitoring Centre (WHO-UMC) system, Naranjo algorithm, and updated Logistic method. Setting ADR monitoring centre (AMC) of a tertiary care teaching hospital in India. Method A total of 230 cases of ADR from April 2017 to August 2017 were retrospectively analyzed by each of these three methods. The agreement among the different methods was calculated by Cohen’s kappa (κ), and Spearman’s correlation was used to find the correlation among these methods. Main outcome measures Cohen’s kappa value and Spearman’s correlation coefficient for comparison among the different methods. Results The Cohen’s κ used for analyzing the agreement between WHO-UMC system and Naranjo algorithm was 0.45, between WHO-UMC system and updated Logistic method was 0.405, and between Naranjo algorithm and updated Logistic method was 0.606. The Spearman’s correlation coefficient was 0.793 for Naranjo algorithm vs. updated Logistic method, 0.735 for WHO-UMC system vs. Naranjo algorithm, and 0.696 for WHO-UMC system vs. updated Logistic method. Conclusion Causality assessment based on objective measurements (scores and probabilities) like updated Logistic method and Naranjo algorithm are less prone to subjective variations compared to the WHO-UMC system which is based on expert judgement.

Drug induced diseases (DID): Need for more awareness & research.

Iatrogenic disease or drug induced disease (DID) is an ever enduring concern for patients, healthcare professionals and health administrators. In spite of being a major concern in clinical practice, DID has not been given the due attention it deserves. One of the reasons for this may be that DID causes apprehension among health care professionals making them uncomfortable as well as unwilling to be part of studies undertaken to reduce DID. In India, several individual case reports have been published related to specific iatrogenic disease but a comprehensive study on this problem is not yet published. The true incidence or prevalence of DID in our country is not known. The results of the study by Tandon et al1 in this issue provide information on DID in Indian setting. Although the study has a few limitations and overlap between adverse drug reactions (ADR) and DID, yet it flags an important issue which needs attention. The magnitude of adverse drug reactions which includes DID is huge. Considering its importance, the Central Drugs Standard Control Organisation (CDSCO), New Delhi, Government of India, had initiated a nation-wide Pharmacovigilance Programme of India (PvPI) in July 2010. The total number of Individual Case Safety Reports (ICSR) in PvPI database is 84,4702. In the US, it was reported that ADRs accounts for more than one lakh death each year and it is between the fourth and sixth leading cause of death3. In our country, we do not have statistics on DID but the total ADRs in PvPI database for the last few years are less than one lakh. This indicates the scenario of under reporting of ADRs in our country compared to United States of America3. A classic paper published in 1981 found that 36 per cent of 815 consecutive patients in general medical service of a tertiary care hospital had iatrogenic illness4. Likewise a prospective study from Portugal reported that 22.9 per cent of patients admitted in the department of internal medicine developed iatrogenic disease5. In the present study by Tandon and colleagues1, the reported incidence of DID is 38.8 per cent. However, contrary to previous studies, the present study was retrospective and the data were obtained from the ADRs reported to Adverse Drug Reaction Monitoring Center, functioning under PvPI. As this study methodology may not be considered as ideal, there is a need for prospective and well-designed epidemiological studies to be undertaken in this area. Further, future studies should also focus on elderly who are prone to have chronic illness, consulting multiple physicians and receive polypharmacy. Most of the published reports on DID are from tertiary care hospitals including the present one1. However, the epidemiology of ADR (including DID) occurring in primary care and in general practice remains uncertain. The various factors contributing to DID can be related to pharmacokinetic and pharmacodynamics of drugs, non-adherence to prescribed drug therapy as well as medication errors6. Concurrent diseases (e.g. liver and renal impairments), genetic polymorphisms in drug metabolizing enzymes and transporters, nutritional factors (hypo-albuminaemia may result in more free drug of highly protein bound drugs) and concomitantly administered drugs may also contribute to alteration in drug metabolism as well as target receptor activities of drugs. Hence in this era of personalized medicine, prescribers need to understand and update their knowledge on the rapidly transforming drug information. In the present study1, 99.3 per cent of the total DIDs were reported as Type A (predictable) reactions. As these reactions are anticipated extension of drugs known pharmacological action, the acquaintance of pharmacokinetic and pharmacodynamic knowledge of a drug can help to prevent the DID. Moreover, a good understanding of pharmaceutical formulations and their applications can help in reducing DID. Peyriere et al7 have reported that 57.9 per cent of drug related admissions in internal medicine or during hospitalization are preventable. These ADRs were associated with therapeutic errors namely inappropriate administration, drug-drug interactions, dosage error and continuation of drug despite the onset of ADRs7. Correspondingly, a report has suggested that nearly 73.8 per cent of iatrogenic events as a cause of intensive care unit admission are probably preventable8. Being on the front lines of patient care as well as pharmacotherapy, healthcare professionals need to be knowledgeable regarding the risk of drug-induced diseases, including methods of detection, prevention, and management. The published studies reveal that, to be more efficient, health care practitioners need to be skillful in patient consultation and education in addition to possessing knowledge on complex biomedical science. However, effectiveness in these roles requires lifelong learning to keep pace with rapidly changing information about drugs and their effects. In fact, the issue of drug safety in general is an excellent focus for interdisciplinary education in health care. The WHO-UMC (Uppsala Monitoring Centre) Global drug safety database9 for the year 2013 has 8.5 million ADR reports. In this, Indias contribution accounts for nearly 0.7 per cent of the global data base9. In the last 30 years, India has witnessed banning or withdrawal of nearly 90 drugs for manufacture and sale by CDSCO (Central Drugs Standard Control Organization)10. This forecasts the urgent need to expand the countrywide PvPI activities so as to implement safety decisions and policy at the regulatory levels in the interest of patient safety. Policy decisions regarding patient safety and medication errors can be achieved through promotion of population based surveillance of DIDs by PvPI in association with CDSCO. In addition, continuing medical educational programmes and training need to be imparted on the healthcare professionals to keep them updated about DIDs as well as on the measures taken to prevent them. The importance of spontaneous reporting of adverse drug reaction needs to be included in the curriculum of all healthcare professionals and the habit needs to be cultivated right from the undergraduate level. While doing so care should be taken to maintain confidentiality of the patients as well as reporting personals so as to encourage further reporting. Likewise during diagnosis as well as while teaching medical graduates, emphasis needs to be given on deliberation of DID as one of the causes of the disease. Basic and epidemiological researchers interested in evidence based medicine and personalized medicine can be motivated to contribute towards the detection, quantification and reduction of DIDs of the marketed drugs. In addition, carrying out systematic reviews as well as meta analysis to generate evidence towards the occurrence of DID can add required information to the armamentarium of pharmacovigilance11. Tools of personalized medicine such as pharmacogenomics, transcriptomics, proteomics, metabolomics, epigenomics, bioinformatics, systems biology, etc. can be used to identify individual patients suffering from DID due to genetic polymorphisms12. These details related to drugs as well as patients need to be compiled, correlated and to be made easily accessible to physicians using technology available in the hospitals. A few developed countries have integrated Electronic Medical Records into an electronic prescription module for their patients13. Similar systems can be introduced in our country after imparting training to the healthcare professionals on their use. Integrating Electronic Health Record (EHR) system with evidence driven decision support can be presented to the physicians, along with crucial evidence-based literature to promote timely and informed medical decision making. Further integration with a single platform solution that includes an electronic prescribing module provides the physician with objective, medication therapy decision support at the point of prescribing14. In addition, EHR may offer the benefit of analyzing related information across various patients thus providing a better source for detecting DIDs. Hence, including EHR system in the hospitals all over the country through PvPI could be a better option to pool all the data and get more information on DIDs at one place. DID could be a consequence of either anticipated effects as seen in the present study1 or else could also be due to unanticipated effects as seen in idiosyncratic adverse effects. In addition to pharmacokinetic changes contributing to DID in elderly and children, it could also result from drug-drug and food-drug interactions. Thus pharmacovigilance needs to be continuously under the vigil of regulatory authorities, drug manufacturers, healthcare professionals and the administrators of health care. Last but not the least, measures should be taken to inculcate the practice of physicians considering themselves as an integral part of PvPI, as reporting of ADR is not just an option but an obligation.