Therapeutic Drug Classes Research Articles

Dual TTK/CLK2 inhibitor, CC‐671, selectively antagonizes ABCG2‐mediated multidrug resistance in lung cancer cells

One pivotal factor that leads to multidrug resistance (MDR) is the overexpression of ABCG2. Therefore, tremendous effort has been devoted to the search of effective reversal agents to overcome ABCG2‐mediated MDR. CC‐671 is a potent and selective inhibitor of both TTK (human protein kinase monopolar spindle 1 [hMps1]) and CDC like kinase 2 (CLK2). It represents a new class of cancer therapeutic drugs. In this study, we show that CC‐671 is an effective ABCG2 reversal agent that enhances the efficacy of chemotherapeutic drugs in ABCG2‐overexpressing lung cancer cells. Mechanistic studies show that the reversal effect of CC‐671 is primarily attributed to the inhibition of the drug efflux activity of ABCG2, which leads to an increased intracellular level of chemotherapeutic drugs. In addition, CC‐671 does not alter the protein expression or subcellular localization of ABCG2. The computational molecule docking analysis suggests CC‐671 has high binding affinity to the drug‐binding site of ABCG2. In conclusion, we reveal the interaction between CC‐671 and ABCG2, providing a rationale for the potential combined use of CC‐671 with ABCG2 substrate to overcome MDR.

Neuropsychiatric Properties of the ACE2/Ang-(1-7)/Mas Pathway: A Brief Review.

The current pharmacological strategies for the management of anxiety disorders and depression, serious conditions which are gaining greater prevalence worldwide, depend on only two therapeutic classes of mood-stabilizing drugs: Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs). Although first line agents with proven efficacy, their clinical success in the management of anxiety disorders and depression is still considered highly complex due to the multifaceted nature of such conditions. Several studies have shown a possible therapeutic target could be found in the form of the Angiotensin-Converting Enzyme [ACE] type 2 (ACE2), Angiotensin [Ang]-(1-7) and Mas receptor pathway of the Renin- Angiotensin System (RAS), which as will be discussed, has been described to exhibit promising therapeutic properties for the management of anxiety disorders and depression. In this article, the literature to describe recent findings related to the role of the RAS in anxiety and depression disorders was briefly revised. The literature used covers a time range from 1988 to 2019 and were acquired from the National Center for Biotechnology Information's (NCBI) PubMed search engine. The results demonstrated in this review are promising and encourage the development of new research for the treatment of anxiety and depression disorders focusing on the RAS. In conclusion, the ACE2/Ang-(1-7)/Mas pathway may exhibit anxiolytic and anti-depressive effects through many possible biochemical mechanisms both centrally and peripherally, and result in highly promising mental health benefits which justifies further investigation into this system as a possible new therapeutic target in the management of neuropsychiatric disorders, including any as of yet undescribed risk-benefit analysis compared to currently-implemented pharmacological strategies.

36-OR: Comparative Effectiveness of SGLT2 Inhibitors vs. GLP-1 Agonists

This retrospective cohort study compared sodium-glucose co-transporter-2 (SGLT2) inhibitor and glucagon-like peptide-1 (GLP-1) agonist therapeutic drug classes on cardiovascular (CV) outcomes, treatment persistence/discontinuation, healthcare utilization and costs. Using medical and pharmacy claims data from the Humana Research Database, new users of SGLT2 inhibitors or GLP-1 agonists from January 2015 to June 2017 were identified. Eligible patients were 19-89 years, enrolled in a Medicare Advantage Prescription Drug or fully-insured commercial health plan, with at least 12 months of continuous enrollment pre- and post-index date (i.e., date of first new prescription). Propensity score matching (1:1) was used to balance baseline characteristics. Cox proportional hazards models were used to compare CV outcomes and treatment discontinuation. Healthcare resource utilization and costs were compared using Wilcoxon signed rank test. A total of 5,507 patients were included in each treatment group. Patients indexed to use GLP-1 agonists were more likely to discontinue treatment (hazard ratio 1.15, 95% confidence interval 1.10-1.21) and more likely to encounter an inpatient hospitalization (14.4% vs. 11.9%, P<0.001) or emergency department visit (27.4% vs. 23.5%, P <0.001) compared to patients indexed on SGLT2 inhibitors. The risk of primary composite CV outcome (myocardial infarction or stroke or mortality) and secondary CV outcome (heart failure or death) was similar across cohorts. The average per-person per-month total cost ($1,796 vs. $1,617, P<0.001), medical ($904 vs. $834, P<0.001) and pharmacy costs ($891 vs. $783, P<0.001) were higher for the GLP-1 agonist cohort compared to the SGLT2 inhibitor cohort. Although differences in extra-glycemic CV benefits were not established, these findings may be useful to providers and payers, as this real-world data showed SGLT2 inhibitors were associated with longer treatment persistence and reduced healthcare utilization and costs relative to GLP-1 agonists. Disclosure I. Poonawalla: None. A. Bowe: Employee; Self; Humana. M. Tindal: None. Y.A. Meah: None. P. Schwab: Employee; Self; Humana. Employee; Spouse/Partner; Humana.

Quality of Evidence Supporting Major Psychotropic Drug‐Drug Interaction Warnings: A Systematic Literature Review

Among pharmacodynamic and pharmacokinetic drug-drug interactions (DDIs), psychotropic drug-drug interactions (pDDIs) are of particular interest because psychopharmacologic agents mark one of the fastest growing therapeutic drug classes over the past 2 decades, and prescribing multiple psychotropic drugs has become increasingly prevalent in clinical practice. However, the documentation of pDDIs across drug references has lacked consistency. Thus we set out to review the primary evidence directly supporting 58 pDDIs that were uniformly reported as "major" or "contraindicated" in three prominent drug references: Clinical Pharmacology, Micromedex, and Lexicomp. We identified 134 citations from Micromedex in December 2017 and 4251 citations from Medline in March 2018 involving any of the 58 pDDIs. The included articles directly observed a clinical adverse effect or effects on drug plasma concentrations from the concomitant use of the two listed drugs in each pDDI. These articles were classified as controlled studies (e.g., randomized controlled trials, clinical trials, or observational studies) or uncontrolled studies (case reports). A total of 124 studies with 2716 patients were included in this review. Commonly evaluated adverse effects related to the studied pDDIs included decreased effectiveness, central nervous system depression, neurotoxicity, QT-interval prolongation, and serotonin syndrome. Among the 58 pDDIs, 18 (31%) were not supported by any primary studies. Among the remaining 35 pDDIs supported by studies on clinical adverse effects, only 14 (40%) included evidence from controlled study designs. Only 7 (12.1%) of the 58 pDDIs had evidence from studies with a combined sample size of more than 100 patients. This literature review highlights the poor quality of evidence supporting major or contraindicated psychotropic DDI warnings. Most DDIs lacked support from controlled studies that evaluated clinically significant adverse effects, leaving uncertainty about the clinical relevance of the warning. More postmarketing studies are needed to evaluate the safety of psychotropic combination therapy.

IATC-FRAKEL: a simple multi-label web server for recognizing anatomical therapeutic chemical classes of drugs with their fingerprints only

Anatomical therapeutic chemical (ATC) classification system is very important for drug utilization and studies. Correct prediction of the 14 classes in the first level for given drugs is an essential problem for the study on such system. Several multi-label classifiers have been proposed in this regard. However, only two of them provided the web servers and their performance was not very high. On the other hand, although some rest classifiers can provide better performance, they were built based on some prior knowledge on drugs, such as information of chemical-chemical interaction and chemical ontology, leading to limited applications. Furthermore, provided codes of these classifiers are almost inaccessible for pharmacologists. In this study, we built a simple web server, namely iATC-FRAKEL. This web server only required the SMILES format of drugs as input and extracted their fingerprints for making prediction. The performance of the iATC-FRAKEL was much higher than all existing web servers and was comparable to the best multi-label classifier but had much wider applications. Such web server can be visited at http://cie.shmtu.edu.cn/iatc/index. The web server is available at http://cie.shmtu.edu.cn/iatc/index. chen_lei1@163.com. Supplementary data are available at Bioinformatics online.

Heavy chain dimers stabilized by disulfide bonds are required to promote in vitro assembly of trastuzumab

BackgroundMonoclonal antibodies (mAbs) and their derivatives have become one of the most important classes of therapeutic drugs. Their multiple applications increased the interest for understanding their complex structure. In vivo, animal cells are able to fold mAbs correctly (Song et al, J Biosci Bioeng 110:135-40, 2010), whereas previous in vitro approaches were scarce and mostly unsuccessful.ResultsIn this work, we compared in vitro assembly characteristics of trastuzumab, produced either by A) physical separation and refolding of its sub-units or B) direct joining of individually produced heavy and light chains. Native and denatured structures of trastuzumab were determined by SEC-HPLC, HIC-HPLC and SDS-PAGE.ConclusionsOur results demonstrate the requirement of correctly folded HC, forming disulfide-bonded dimers, in order to form a fully functional mAb. Otherwise, the unfolded HC tend to precipitate. We were able to assemble trastuzumab in this fashion by only mixing them to LC in pH-buffered conditions, while monomeric HC structure was too unstable to render a functional mAb. This approach has been used in the generation of homogeneous ADC, with results pending to be published.

Adverse drug reactions: An analysis of spontaneous reports

Background: Adverse drug reactions (ADRs) are among the top causes of morbidity and mortality in both hospitalized and ambulatory patients worldwide. The Pharmacovigilance Programme of India was initiated with the goal that the benefits of drugs should outweigh the risks. Aim and Objective: The purpose of this study was to analyze and evaluate the incidence and the patterns of ADRs from reports collected at our ADR monitoring center (AMC). Materials and Methods: A total of 187 suspected ADR forms which were submitted to our AMC were evaluated for demographics, reporting department, causative drug(s), and organ system involvement. Causality, severity, and preventability assessments were also carried out. Results: Most ADRs (43.31%) were found in the 31–60 years age group, with health centers (63) reporting the maximum number followed by the dermatology department (34). The leading causal therapeutic class of drugs was anti-infective agents (36.73%) followed by antiparasitic products (14.79%). Skin and subcutaneous tissue disorders (47.39%) and gastrointestinal disorders (26.04%) were the organ systems with most ADRs. In causality assessment, the probable cases had a higher incidence (78.57%) than the possible (21.42%) ones. Based on the severity, most of the reactions were categorized as moderate (83.95%), 14.97% were mild, and only 1.06% were severe. Most of the ADRs were not preventable (99.5%). Conclusion: Despite most ADRs being not preventable, regular awareness programs should be conducted and a system of rewarding those who consistently report ADRs may be implemented. This will increase reporting and also improve patient safety.

Role of medicinal chemistry in the current scenario

Medicinal chemistry is defined as an interdependent mature science, a combination applied medicine and basic chemistry that involves discovering, developing, identifying andinterpreting the biologically active compounds. It plays major role in drug research and development by taking advantage of recent technique with advanced knowledge of different branches of related sciences. Since it can be seen as a melting pot of organic chemistry with molecular pharmacology further emphasizes the study of the relationship of drug molecules structural activity so it requires knowledge of chemical and pharmacology concepts. The source of medicinal chemistry lies in all branches of biology and chemistry, which started its journey in the war against various diseases in Ehrlich's hands, who dreamed of a "magic bullet" to combat various infectious diseases. ADMET assessment of therapeutic drug classes influence on therapeutic decision. Top-flight medicinal chemists can play greater roles in improving drug-creation efficiencies and clinical success rates, thereby increasing the overall cost-effectiveness of the enterprise and, in turn, more quickly satisfying unmet medical needs.

Identification of novel compounds against Tat-mediated human immunodeficiency virus-1 transcription by high-throughput functional screening assay

Trans-activator (Tat)-mediated human immunodeficiency virus type 1 (HIV-1) transcription is essential for the replication of HIV-1 and is considered a potent therapeutic target for HIV-1 inhibition. In this study, the Library of Pharmacologically Active Compounds (LOPAC1280) was screened using our dual-reporter screening system for repositioning as Tat-inhibitory compounds. Consequently, two compounds were found to be potent, with low cytotoxicity. Of these two compounds, Roscovitine (CYC202) is already known to be a Tat inhibitor, while gemcitabine has been newly identified as an inhibitor of Tat-mediated transcription linked to viral production and replication. In an additional screening using the ribonucleoside analogues of gemcitabine, two analogues (2′-C-methylcytidine and 3-deazauridine) showed a specific Tat-inhibitory effect linked to their anti-HIV-1 activity. Interestingly, these compounds did not affect Tat protein directly, while the mechanism underlying their inhibition of Tat-mediated transcription was linked to pyrimidine biosynthesis, rather than to alteration of the dNTP pool, influenced by the inhibition of ribonucleotide reductase.Taken together, the proposed functional screening system is a useful tool for the identification of inhibitors of Tat-mediated HIV-1 transcription from among a large number of compounds, and the inhibitory effect of HIV-1 transcription by gemcitabine and its analogues may suggest a strategy for developing a new class of therapeutic anti-HIV drugs.

Medication Reconciliation Improvement Utilizing Process Redesign and Clinical Decision Support

Despite years of attention, hospitals continue to struggle to implement successful medication reconciliation. This study aimed to increase the percentage of hospital admission medication reconciliation (AdmMedRec) completion to ≥ 95% in 12 months at a large academic children's hospital. A quality improvement (QI) project was initiated in April 2017 by an interdisciplinary team of physicians, nurses, pharmacists, and analysts, co-led by a pediatric hospitalist and chief medical information officer. Interventions were implemented through sequential Plan-Do-Study-Act cycles. Process maps, fishbone diagrams, and failure mode and effects analysis were used to identify AdmMedRec failures. Baseline data from 12,481 admission encounters July 2016-April 2017 were analyzed. Interventions included electronic health record (EHR) workflow redesign, clarification of clinicians' responsibilities, targeted training, Best Practice Advisory alert, and weekly reporting of specialty- and physician-specific performance data. Data from 13,082 postintervention period admission encounters were examined. Reconciliation by therapeutic drug classes was calculated as a proxy for quality. AdmMedRec completion rate increased from a baseline of 73% to 95% within 7 months from the start of this project and was sustained at 94% during the postintervention period. Psychiatry and hospital medicine demonstrated the largest improvements, with rates increasing from 17% to 88% and 76% to 98%, respectively. Percentages of reconciled medications in all 13 therapeutic classes, including high-risk drugs, improved significantly (p < 0.05). Using an interdisciplinary team and interventions focused on process and culture changes, this QI initiative was successful at increasing AdmMedRec rates and reducing omission errors across all therapeutic drug classes.

IATC-NRAKEL: an efficient multi-label classifier for recognizing anatomical therapeutic chemical classes of drugs.

The anatomical therapeutic chemical (ATC) classification system plays an increasingly important role in drug repositioning and discovery. The correct identification of classes in each level of such system that a given drug may belong to is an essential problem. Several multi-label classifiers have been proposed in this regard. Although they provided satisfactory performance, the feature extraction procedures were still rough. More refined features may further improve the predicted quality. In this article, we provide a novel multi-label classifier, called iATC-NRAKEL, to predict drug ATC classes in the first level. To obtain more informative drug features, we employed the drug association information in STITCH and KEGG, which was organized by seven drug networks. The powerful network embedding algorithm, Mashup, was adopted to extract informative drug features. The obtained features were fed into the RAndom k-labELsets (RAKEL) algorithm with support vector machine as the basic classification algorithm to construct the classifier. The 10-fold cross-validation of the benchmark dataset with 3883 drugs showed that the accuracy and absolute true were 76.56 and 74.51%, respectively. The comparison results indicated that iATC-NRAKEL was much superior to all previous reported classifiers. Finally, the contribution of each network was analyzed. The codes of iATC-NRAKEL are available at https://github.com/zhou256/iATC-NRAKEL.

Primary nonadherence to medication and its drivers in Poland: findings from the electronic prescription pilot analysis.

Primary nonadherence to medication occurs when a patient does not fill a prescription and often leads to suboptimal patient outcomes, lost productivity, and increased net costs. Pilot introduction of electronic prescriptions (e‑prescriptions) in Poland took place in 2018, enabling nationwide assessment of primary nonadherence. To determine the prevalence and drivers of primary nonadherence in Poland. This retrospective analysis included data from all e‑prescriptions issued in Poland in 2018. Primary nonadherence was defined as not filling a prescription within 1 month from the date of issuing. Out of all 119 880 e‑prescriptions issued in Poland in 2018, 94 913 were filled, thus the primary nonadherence rate reached 20.8%. Although no differences in primary nonadherence were observed between sexes, age was found to have a significant effect, with older groups showing lower rates of primary nonadherence. In addition, slightly lower rates of primary nonadherence (17.0%) were found for e‑prescriptions issued for selected drugs of key importance (n = 47 492). Multivariable analysis performed within this subset showed that those aged ≥75 years had the lowest odds for nonadherence (odds ratio, 0.55; 95% CI, 0.48-0.64). Differences in primary nonadherence rates were observed across therapeutic areas (lowest value in antibiotics, 14.3%), drug classes (lowest value in sulfonylureas, 13.2%), and individual drugs. Primary nonadherence rates were lower for drugs covered by the "Leki 75+" program, which makes them free of charge for those aged 75 years or older. A high percentage of prescriptions issued in Poland are never filled. E‑prescriptions allow the identification and analysis of drivers of this phenomenon. Our findings may help designing national health and medicine policies.

Development and validation of a new analytical RP-HPLC method for simultaneous determination of Glibenclamide and Atenolol in bulk

A new, simple, reliable, fast, sensitive and economical RP-HPLC method was developed and validated for simultaneous estimation of two fixed-dose combinations frequently prescribed in coexisted chronic diseases such as diabetes (GLB) and hypertension (ATN) in bulk for the first time. The mobile phase used for the chromatographic runs consisted of 0.01N potassium dihydrogen ortho phosphate (pH 4.8) and acetonitrile (55:45, v/v). The separation was achieved on column (BDS C18 250 x 2.1mm, 1.6m) using isocratic mode. Drug peaks were well separated and were detected by a UV detector at 235.0 nm. The method was linear at the concentration range 2.5-15µg/ml for Glibenclamide (GLB) and 6.25-37.5µg/ml for Atenolol (ATN), respectively. The method has been validated according to ICH guidelines with respect to system suitability, specificity, precision, accuracy and robustness. The method was validated for system suitability, linearity, accuracy, precision, detection, quantification limits and robustness and was found it is acceptable in the range of 2.5–15 µg/ml for GLB and 6.25–37.5 µg/ml for ATN. The LOD and LOQ of GLB was found to be 0.48 µg/ml and 1.47µg/ml and for ATN was found to be 0.72µg/ml and 2.20 µg/ml, respectively. The method was applied to drug interaction studies of GLB with ATN to illustrate the scope and application of the methods to manage two different therapeutic classes of drugs, as they may co-administered in concurrent diseases.

Инсулиномиметически активные макромолекулярные металлокомплексы ванадия на основе поли-N-винилпирролидона. Часть 1. Синтез макромолекулярного металлокомплекса ванадия и оценка его острой пероральной токсичности

Diabetes mellitus (DM) is a severe chronic disease affecting virtually all kinds of metabolic processes in the human body. As incidence and prevalence of DM are increasing worldwide, WHO estimates the number of people living with diabetes to be as high as half a billion and still rising. Long-term health complications of DM, such as diabetic nephropathy, retinopathy, neuropathy, and cardiovascular pathology, although preven-table in most cases, are known to be severe, potentially life-threatening and often irreversible, which makes the search for new effective antidiabetic drugs a research priority and one of the most pressing issues in health care today. To date, the insulin-mimetic properties of vanadium compounds have been the subject of quite a significant number of studies. In vivo experiments have shown that vanadium, acting in an insulin-like fashion, takes part in the regulation of glucose and lipid metabolism. In particular, vanadium stimulates glucose uptake and metabolism in insulin target tissues, increases the intensity of glycogen and lipid biosynthesis, and inhibits that of gluconeogenesis, glycogenolysis, and lipolysis. Organic vanadium complexes are known to be less toxic than its inorganic salts, which are characterized by a number of potentially serious adverse effects, mainly but not exclusively on the central nervous system and the kidneys; in addition to lower toxicity, organic vanadium compounds have been found to have higher bioavailability when to compared to those of inorganic nature. Such observations clearly hold promise for the development of an entirely novel therapeutic class of antidiabetic drugs. The aims of this study are to obtain new polymeric vanadyl(VO2+) derivatives based on poly-N-vinylpyrrolidone (PVP) that would exert hypoglycemic effect in vivo, and to explore the possibilities of using such compounds or formulations derived thereof for type 2 DM prophylaxis and/or treatment. This work gives a method of obtaining and isolation of an oxovanadium(IV)-polymer metallocomplex, and describes the structural features of said compound, confirmed experimentally. The results of the acute oral toxicity study revealed that the newly synthesized compound is of low toxicity, having a median lethal dose (LD50) that is at a level well above those typical of inorganic vanadium salts.

PREDICTORS ASSOCIATED WITH ADVERSE DRUG REACTIONS AMONG GERIATRIC PATIENTS IN AN OUTPATIENT CLINIC

Objective: The process of aging involves an individual’s structural and functional depravity of their organ systems often results in compromised pharmacological principles of the prescribed drugs. Multimorbidity and polypharmacy along with change in pharmacokinetic and pharmacodynamic responses of drugs predispose the elderly to adverse drug reactions (ADRs). The present study was aimed to identify and report the characteristics and incidence of ADRs among geriatrics in an outpatient clinic.&#x0D; Methods: This was a 6-month prospective hospital-based observational study among patients of either sex aged 60 years and above visiting an outpatient clinic at the study site. The suspected ADRs were categorized according to the Will’s and Brown classification system. Causality of these ADRs was verified by applying the WHO-UMC criteria and the Naranjo’s scale. Severity and preventability of the ADRs were classified using the modified Hartwig and Siegel scale and modified Schumock and Thornton scale, respectively. Multivariate logistic regression was used to determine the risk factors for developing ADRs.&#x0D; Results: Among the 365 patients monitored, 57 (15%) patients experienced 60 ADRs. Therapeutic classes of drugs frequently associated with ADRs were the drugs used in hypertension (27 [45%]). Patients presenting with amlodipine (9 [15%]) induced pedal edema were observed with the highest frequency of ADRs. Polypharmacy (OR: 1.619, 95% confidence interval: 0.957−2.741, p=0.021) was observed as the influential risk factor for ADRs.&#x0D; Conclusion: Pharmacist’s services and involvement in geriatric patient’s centered care can be associated with their improved health, quality of life and economic outcomes, a reduction in medicine-related adverse events, and limiting the morbidity and mortality in this age band.

Study of drug prescription pattern in ischemic heart disease patients

Background: Drug utilization pattern studies helps to screen, assess and propose appropriate modifications in prescription practices, this would help to make patient care rational and cost effective. Study was intended to analyse the drug prescribing pattern for treatment of Ischemic heart disease using WHO indicators.Methods: This is a cross sectional observational study conducted on ischemic heart disease patients admitted at inpatient department of medicine in a tertiary care teaching hospital. The study consisted of analysis of drug utilization pattern of prescribed drugs.Results: IHD was more commonly seen in males (70.06%) than females (29.94%). IHD was most commonly seen in patients of age group of 61-70 year. Drugs prescribed to patients belong to various therapeutic classes ranging from anti-platelets, anticoagulants, anti-anginal, antithrombin, thrombolytic, hypolipidemics. The most commonly prescribed therapeutic class of drugs was antiplatelet (86.26%) followed by hypolipidemic (82.25%) and ACE inhibitors drugs (46.60%). Average number of drugs per encounter was 7.70. Drugs were prescribed by their generic names were 29.99%. Out of total study group 22.06% patients were prescribed at least one antibiotic. Injections were prescribed only in 1392 (27.86%) out of 4995 drugs. Of total drugs 3270 (65.45%) of drugs were from National List of Essential Medicines-2016 (NLEM -2016) and 2774 (55.53%) drugs prescribed were from WHO-EML-2016.Conclusions: Risk of artery disease increased with increasing age. IHD was more common in males than females. The most commonly prescribed drug classes in Ischemic heart disease were anti-platelet drugs followed by hypolipidemic agents.

Drug utilization pattern in a neonatal intensive care unit at tertiary care hospital attached to a medical college in Southern Karnataka, India

Background: Neonates and in particular preterm neonates belongs to the most vulnerable population. A neonatal intensive Care Unit (NICU) is a highly specialized unit that provides high quality skilled care to critically ill new newborn, premature or low birth weight babies. Apart from facilities for continuous clinical and biochemical monitoring, NICU management involves the use of wide range of medications. Irrational prescription of drug is common in clinical practice, important reason being lack of knowledge about drug prescription. Developing countries have limited funds available for health care and drugs so it becomes very important to prescribe drugs rationally. The present study was done to find out the drug utilization pattern and improve the rational use which aids in the improvement of neonatal care. Methods: The study was retrospective study in NICU of tertiary care hospital attached to MIMS, Mandya for a duration of 6 months. Data extraction sheet were used to collect the information regarding demographic details, maternal and delivery details, indication for admission, final diagnosis and medications administered. Data collected were evaluated for the category of prescribed, based on World Health Organization Anatomical Therapeutic Committee (WHO classification system and were analyzed using SPSS. WHO drug utilization core indicators were also evaluated.Results: Among 400 neonates admitted in NICU during the study period, 53.7% were males and 46.2% were females. There were 29.7% preterm born neonates. The maximum number of neonates were admitted in early neonatal period (87.25%). Neonatal sepsis (37.9%) and Birth asphyxia (11.6%) were the most common indications for admission. The total number of drugs prescribed was 1428 and the average number of drugs per neonate was 3.57. Preterm (&lt;37weeks) and low birth weight (&lt;2.5Kg) were exposed to significantly higher number of drugs. The most frequently prescribed therapeutic class of drugs was anti-infectives (60.36%), followed by drugs of central nervous system (7. 84%). Among the anti-infectives, the most commonly prescribed drugs were Ampicillin (59%), followed by gentamycin (42.5%). High end antibiotics like carbapenems, colistin’s and linezolid were used in less than 5% of cases.Conclusions: Drug use in neonates should be minimal and focus on the importance of therapeutic treatment guidelines establishment in hospital to control the over usage of antibiotics.

The study of adverse drug reactions of antihypertensive medicines in essential hypertension patients in Hi-Tech Medical College and Hospital, Bhubaneswar, Odisha, India

Background: Every drug has the potentiality to cause an adverse drug reaction (ADR). ADRs are a major problem in drug therapy .The aim of this study was to assess the incidence and causality of ADRs to antihypertensive agents used for the essential hypertensive patients attending at the general medicine out patients departments of Hi-Tech Medical College and Hospital, Bhubaneswar Odisha, during the time period of November 2016 to October 2018.Methods: This prospective-observational study was carried out in general medicine outpatient department of Hi-Tech Medical College and Hospital, Bhubaneswar, Odisha.Results: Out of 254 patients, 78 (30.71%) patients were developed ADRs to antihypertensive drugs. 51 (65.38%) were female and 27 (34.62%) were male. Calcium channel blockers were the commonest therapeutic class of antihypertensive drugs associated with ADRs (n = 50, 64.10%). According to WHO causality assessment scale most of the ADRs were “probable” 41 (52.56%), followed by “possible” 21 (26.92%), unclassifiable 13 (16.67%) and unlikely 3 (3.85%).Conclusions: The results of this study concluded that antihypertensive drugs able to induce the development of adverse drug reactions, which were significant cause of increase burden on health care system and decrease the quality of life, the health care professionals should take care about the rational use of antihypertensive agents. Thus, to minimize the incidence of adverse drug reaction and to increase the quality of life.

Abstract B136: Optimized messenger RNA immunolipoplexes for cancer immunotherapy: Balancing immunogenicity and adjuvancy

Abstract Messenger RNA has garnered a lot of attention as a new therapeutic drug class for vaccination (1). Particularly for cancer immunotherapy, mRNA encoding tumor antigens has the potential to design personalized and effective cancer vaccines (2). However, the major challenge remains to directly deliver the mRNA to (professional) antigen presenting cells (APCs), evoking safe and effective antitumor immunity. The mRNA vaccines that are currently being evaluated in first-in-human clinical trials depend on the self-adjuvant effect of mRNA and subsequent signaling via type I IFN (3-4). We and others have reported that type I IFNs have the downside of inducing anti-mRNA (anti-viral) innate responses, which makes it challenging to strike a balance between evoking innate immunity and obtaining adequate levels of mRNA expression (5-6). In addition, high levels of IFN-α are known to cause adverse effects (e.g., flu-like symptoms and autoimmune sequelae) (7).To overcome these issues, we developed a nanoparticle platform which protects mRNA against degradation while successfully delivering mRNA to APCs in vivo (6). In this platform, we choose to minimize the mRNA-based immune recognition using a nucleoside-modified (“immune-silent”) mRNA construct, but instead to co-package clinically-approved immune adjuvants (e.g., MPLA) to achieve strong and controllable immunogenicity. The vaccine potential of mRNA lipid nanoparticles with different immune adjuvants was evaluated by performing biodistribution and immunogenicity studies after systemic delivery in mice. The preclinical antitumor efficacy was assessed in an EG7-OVA lymphoma and B16-OVA melanoma model. In addition to evaluating overall survival, experiments were performed where tumors were isolated after immunization and screened for effector responses (e.g., antigen-specific CD8+ T-cells and NK cells) and suppressive mechanisms that could impact the therapeutic outcome (e.g., immune checkpoints, myeloid derived suppressor cells [MDSCs] and tumor-associated macrophages [TAMs]). To tackle adaptive resistance to activated T-cells, we evaluated a combinatory therapy of the mRNA vaccine with anti-PDL1 antibodies (8). Upon i.v. injection in mice, these particles are mainly detected within APCs (macrophages and dendritic cells) in lungs and spleen. Importantly, this resulted in high mRNA expression as well as functional activation of the particle-loaded immune cells, marked by cytokine production of IL-12p70 and IFN-γ. We were able to optimize a formulation of adjuvanted-nanoparticles with modified mRNA, which resulted in 6 to 7 times higher numbers of tumor-infiltrating antigen-specific T-cells compared to unmodified mRNA particles. In addition to CD8+ T-cell responses, we also observed a 2- to 3-fold increase in intratumoral NK cells, compared to untreated mice. Furthermore, these mice exhibited reduced immune suppression at the tumor site: low numbers of MDSCs whereas TAMs displayed proinflammatory M1-like changes in phenotype. Moreover, we observed clear synergistic antitumor effects between the mRNA nanoparticles and anti-PDL1 checkpoint blocking antibodies. Taken together, we have developed a flexible and versatile mRNA nanoparticle platform, that presents an attractive way of initiating antitumor immunity by targeting and activating immune cells directly in vivo. Importantly, by combining immune-silent mRNA with immune-adjuvants in a single particle, a safe, effective and controllable immune response can be evoked, which can be strengthened by rational combination with state-of-the-art clinically approved immunotherapies.

Bioconjugated Oligonucleotides: Recent Developments and Therapeutic Applications.

Oligonucleotide-based agents have the potential to treat or cure almost any disease, and are one of the key therapeutic drug classes of the future. Bioconjugated oligonucleotides, a subset of this class, are emerging from basic research and being successfully translated to the clinic. In this Review, we first briefly describe two approaches for inhibiting specific genes using oligonucleotides-antisense DNA (ASO) and RNA interference (RNAi)-followed by a discussion on delivery to cells. We then summarize and analyze recent developments in bioconjugated oligonucleotides including those possessing GalNAc, cell penetrating peptides, α-tocopherol, aptamers, antibodies, cholesterol, squalene, fatty acids, or nucleolipids. These novel conjugates provide a means to enhance tissue targeting, cell internalization, endosomal escape, target binding specificity, resistance to nucleases, and more. We next describe those bioconjugated oligonucleotides approved for patient use or in clinical trials. Finally, we summarize the state of the field, describe current limitations, and discuss future prospects. Bioconjugation chemistry is at the centerpiece of this therapeutic oligonucleotide revolution, and significant opportunities exist for development of new modification chemistries, for mechanistic studies at the chemical-biology interface, and for translating such agents to the clinic.