Bakgrund Läkemedelsupplysningen (LMU) är en upplysningstjänst som svarar på allmänna frågor kring användning av läkemedel där en viktig del av arbetet är att fånga upp informationsbehov om läkemedel. Sedan 2015 dokumenteras var tionde samtal med hjälp av ett webbaserat formulär och flera av frågorna handlar om vaccin. Vaccination är något som rekommenderas av både myndigheter och sjukvårdspersonal. Anledningen till att vaccinera sig är dels för att skydda individen i sig och för att inte sprida smitta till personer som av olika anledningar inte kan vaccineras. Det kan ses en trend med oroade föräldrar som väljer att inte vaccinera sina barn och tvekan till vaccin är rankat som ett av de tio största hoten mot global hälsa av WHO. Syfte Syftet är att analysera frågor som kommit in till LMU för att öka förståelsen för de kunskapsluckor, oro och behov som allmänheten besitter om vacciner. Metod En kvalitativ analys har gjorts av samtalen som kommit in till LMU som handlar om vaccin mellan åren 2015 och 2018 med hjälp av webbaserade formulär. Det som inkluderats i studien är frågor om influensavaccin, hepatitvaccin, TBE vaccin, resevacciner och barnvaccinationsprogrammet. En validering gjordes även genom att kontrollera hur många samtal om vaccin som hamnat under fel ATC kod. Resultat Samtal som handlar om vaccin motsvarade 2% av alla frågor som kommit in till LMU och det vaccin som efterfrågades mest var influensavaccin. Det kan ses en trend med ett ökande antal samtal angående vaccin de senaste fyra åren. Slutsats Media och internet påverkar människors syn om vaccin men även levnadsvanor kan påverka. Det största informationsbehovet om vaccin verkar vara om biverkningar, dosering, behandling/effekt och interaktioner.

This master thesis explores the launch process of new pharmaceuticals in Sweden. The path of a pharmaceutical from idea to innovation is a long and arduous process with only few new products actually reaching the patients in the end. Seeing as the drug development is also an expensive process, it is of importance that the products that get approval meet their expected revenue. New pharmaceuticals can also be life changing for the patient, and thus it is important that once approval is received the patients gain access to the new treatments. This study focuses on the post regulatory approval processes in Sweden, as well as activities carried out by the companies that affect the adoption of a new product. By utilizing a qualitative study, this thesis aims to describe the internal and external factors that affect the pharmaceutical launch process in Sweden. As well as exploring what future initiatives and possible changes that might affect it. Ten interviews with different company representatives as well as six interviews with governmental and regional stakeholders were analysed using grounded theory to answer what factors affect the adoption of new pharmaceuticals. Factors that were found to be important were: Utilisation of cross-functional teams, clear and simple strategy that includes the whole organisation, communicating with national and regional authorities, and get feedback from these, communicate with patient representatives and organisations as well as developing utility services for the product. From a couple of these factors a trend towards the servicification of the pharmaceutical industry was discovered.

by Cheung Yiu-ming. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1990. / Includes bibliographies. / ACKNOWLEDGMENT / ABSTRACT / Chapter CHAPTER 1 --- GENERAL INTRODUCTION --- p.1 / Chapter 1.1 --- REVIEW OF GAS-LIQUID CHROMATOGRAPHY --- p.1 / Chapter 1.2 --- APPLICATION OF GAS-LIQUID CHROMATOGRAPHY IN DRUG ANALYSIS --- p.8 / Chapter 1.3 --- AIMS OF THE PRESENT WORK --- p.9 / REFERENCES --- p.11 / Chapter CHAPTER 2 --- GAS-LIQUID CHROMATOGRAPHIC DETERMINATION OF ACTIVE INGREDIENTS IN COUGH-COLD SYRUP FORMULATIONS --- p.12 / Chapter 2.1 --- INTRODUCTION --- p.12 / Chapter 2.2 --- EXPERIMENTAL --- p.16 / Chapter 2.3 --- RESULTS AND DISCUSSION --- p.22 / Chapter 2.4 --- CONCLUSION --- p.73 / REFERENCES --- p.74 / Chapter CHAPTER 3 --- "GAS-LIQUID CHROMATOGRAPHIC DETERMINATION OF ATROPINE SULFATE/HYOSCYAMINE SULFATE, HOMATROPINE HYDROBROMIDE AND HYOSCINE HYDROBROMIDE IN PHARMACEUTICAL PREPARATIONS" --- p.75 / Chapter 3.1 --- INTRODUCTION --- p.75 / Chapter 3.2 --- EXPERIMENTAL --- p.79 / Chapter 3.3 --- RESULTS AND DISCUSSION --- p.85 / Chapter 3.4 --- CONCLUSION --- p.126 / REFERENCES --- p.127 / APPENDIX --- p.128 / Chapter A.1 --- INTRODUCTION --- p.128 / Chapter A.2 --- EXPERIMENTAL --- p.129 / Chapter A.3 --- RESULTS AND DISCUSSION --- p.132 / Chapter A.4 --- CONCLUSION --- p.147 / REFERENCE --- p.147 / LEGENDS FOR FIGURES / LEGENDS FOR TABLES

<p> <b>BACKGROUND:</b> The 2009 Health Information Technology for Economic and Clinical Health (HITECH) Act created meaningful use (MU) incentive program to promote the nationwide adoption of certified electronic health record (EHR) systems. Computerized physician order entry (CPOE) system is a part of the EHR system and a cornerstone of the MU incentive program, which helps to reduce prescribing errors and enhance care coordination for treatment between providers. </p><p> <b>OBJECTIVES:</b> The main objective of this study was to investigate trends in the adoption of CPOE system for medication orders and determine factors associated with meeting the meaningful use criteria for health information technology. </p><p> <b>METHODS:</b> A cross-sectional analysis was conducted using 10 years of data from the 2006&ndash;2015 National Ambulatory Medical Care Survey (NAMCS), 10 years of 2006&ndash;2015 data from the National Hospital Ambulatory Medical Care Survey (NHAMCS)&mdash;emergency department (ED) component, the 2016 American Hospital Association (AHA) Annual Survey Database, and the 2016 AHA Annual Survey Information Technology (IT) Supplement. The outcomes of the study included the adoption of CPOE for medication orders, drug-drug interaction alerts (DDI), guideline reminders, electronic prescribing (eRx), health information exchange (HIE), and compliance with the MU criteria. Descriptive statistics were calculated for all study variables. Bivariate analysis using the chi-square test was used to determine if there is a significant relationship between the adoption of CPOE for medication orders and timing (pre-post meaningful use). Chi-square test for trend was used to determine the significance of the change in the adoption of several EHR functionalities between 2006 and 2015. Logistic regression analyses were performed to identify factors that influence the adoption of several EHR functionalities. All analyses were performed using SAS 9.3 at an alpha of 0.05. </p><p> <b>RESULTS:</b> In NAMCS 2006&ndash;2015, the weighted surveyed physicians&rsquo; responses were weighted to represent 325,070 ambulatory based physicians throughout the U.S. The majority (66%) of respondents worked in group practices, and 34% worked as solo practitioners. The overall AHA annual survey sample had 6,239 hospitals. Of these, a total of 3,656 hospitals responded to the AHA IT supplement survey, representing a response rate of 59%. Primary care physicians&rsquo; adoption of CPOE systems for medication orders was significantly higher than specialists (p &lt; 0.0001). The adoption of CPOE for medication orders was higher in the Post-MU incentive payments period (2012&ndash;2015) compared to pre-MU incentive payments period (2006&ndash;2011) in both the ambulatory care and ED settings (p &lt; 0.0001). From 2006 through 2015 there was a statistically significant increase in the percent of ambulatory care practices adopting CPOE medication ordering system with clinical decision support (CDS) tools and eRx in the ambulatory care setting (p-trend &lt; 0.001). In the same period, group practices compared to solo practices were significantly more likely to adopt these EHR functionalities (p &lt; 0.0001). From 2013 to 2015, physician offices that generated > 50% of their revenue from Medicaid in the ambulatory care setting were less likely to adopt EHR systems that meet the MU criteria compared those generate &le; 50% (p &lt; 0.01). </p><p> <b>CONCLUSION:</b> Findings indicate that physician specialty, practice size, and percentage of revenue from Medicaid are significantly associated with the adoption of selected EHR functionalities. The CPOE for medication orders adoption rates significantly increased post-MU incentive payments. No significant association was found between for-profit hospitals and sending electronic notification to the patient&rsquo;s primary care physician upon ED visit. These results may be important to design interventions to improve EHR adoption.</p><p>

<p> The overarching goal of my thesis work was to utilize the combination of mathematical and experimental models towards an effort to resolve chemotherapy-induced peripheral neuropathy (CIPN), one of the most common adverse effects of cancer chemotherapy. In chapter two, we have developed quantitative-structure toxicity relationship (QSTR) models using machine learning algorithms that enable the prediction of peripheral neuropathy incidence solely from a chemicals molecular structure. The QSTR models enable the prediction of clinical neurotoxicity, which could be potentially useful in early drug discovery to screen out compounds that are highly neurotoxic and identify safer drug candidates to move forward into further development. The QSTR model was used to suggest modifications to the molecular structure of bortezomib that may reduce the number of patients who develop peripheral neuropathy from bortezomib therapy. In the third chapter, we conducted a network-based comparative systems pharmacology analysis of proteasome inhibitions. The concept behind this work was to use <i>in silico</i> pharmacological interaction networks to elucidate the neurotoxic differences between bortezomib and carfilzomib. Our theoretical results suggested the importance of the unfolded protein response in bortezomib neurotoxicity and that the mechanisms of neurotoxicity by proteasome inhibitors closely relate to the pathogenesis of Guillian-Barr&eacute; syndrome caused by the Epstein-Barr virus. In chapter four we have written a review article to introduce the concept of Boolean network modeling in systems pharmacology. Due to the lack of knowledge about parameter values that govern the cellular dynamic processes involved in peripheral nerve damage, the development of a quantitative systems pharmacology model would not be feasible. Therefore, in chapter five, we developed a Boolean network-based systems pharmacology model of intracellular signaling and gene regulation in peripheral neurons. The model was used to simulate the neurotoxic effects of bortezomib and to identify potential treatment strategies for proteasome-inhibitor induced peripheral neuropathy. A novel combinatorial treatment strategy was identified that consists of a TNF? inhibitor, NMDA receptor antagonist, and reactive oxygen species inhibitor. Our subsequent goals were aimed towards translating this finding with the endeavor to hopefully one-day impact human health. Initially we had proposed to use three separate agents for each of these targets, however the clinical administration of three agents to prevent the neurotoxicity of one is likely unfeasible. We then came across a synthetic cannabinoid derivative, dexanabinol, that promiscuously inhibits all three of these targets and was previously developed for its intended use to treat traumatic brain injury. We believe that this drug candidate was worth investigating due to the overlapping pharmacological activity with suggested targets from network analyses, previously established favorable safety profile in humans, notable <i>in vitro/vivo</i> neuroprotective properties, and rising popularity for the therapeutic potential of cannabinoids to treat CIPN. In chapter six we assessed the efficacy of dexanabinol for preventing the neurotoxic effects of bortezomib in various experimental models. Due to the limited translatability of 2D cell culture techniques, we investigated the pharmacodynamics of dexanabinol using a microphysiological model of the peripheral nerve. Bortezomib caused a reduction in electrophysiological endpoints, which were partially restored by dexanabinol. In chapter 7 we evaluated the possible interaction of dexanabinol on the anti-cancer effects of bortezomib. We observed no significant differences in tumor volume between bortezomib alone and in combination with dexanabinol in a multiple myeloma mouse model. Lastly, we are currently investigating the efficacy of dexanabinol in well-established rat model of bortezomib-induced peripheral neuropathy. We believe that positive results would warrant a clinical trial. In conclusion, the statistical and mechanistic models of peripheral neuropathy that were developed could be used to reduce the overall burden of CIPN through the design of safer chemotherapeutics and discovery of novel neuroprotective treatment strategies.</p><p>

Bakgrund: Det finns många orsaker till ofrivillig barnlöshet men tack vare nya tekniker har det blivit möjligt att få barn för många. Först och främst är det in vitro fertilisering (IVF)- / Intracytoplasmatisk spermieinjektion (ICSI)-behandlingar genom kontrollerad ovariestimulering (COS) av gonadotropiner som har ökat möjligheten att få flera ägg för att öka chansen att få en lyckad graviditet. Under de senaste årtiondena har en markant utveckling gjorts inom gonadotropins område från urin extraherade gonadotropiner till rekombinanta gonadotropiner. De två välstuderade och mest använda gonadotropinerna för COS vid IVF/ICSI är högrenat humant menopausalt gonadotropin (HP-hMG) och rekombinant humant follikelstimulerande hormon (r-hFSH, follitropin alfa). Syfte: Syftet med föreliggande arbete var att jämföra effektivitet och farmakologiska skillnader på Menopur ® (HP-hMG) och GONAL-f ® (r-hFSH) för COS vid IVF/ICSI-behandling. Metod: Denna litteraturstudie byggde på vetenskapliga artiklar, som söktes fram via PubMed, Webb of Science. Fem kliniska studier, vilka främst fokuserade på effektiviteten och farmakologiska skillnader av två gonadotropinpreparat (r-hFSH och HP-hMG) för COS vid IVF/ICSI, granskades närmare. Resultat: Granskningen visade att resultatet med avseende på pågående graviditetsgrad är jämförbart mellan HP-hMG och follitropin alfa oavsett fast eller flexibel dos både med GnRH-agonist- och antagonistprotokoll. Resultat med avseende på farmakologiska skillnader för COS visade att antalet erhöllna oocyter och progesteronnivån var signifikant högre hos r-hFSH-gruppen. Däremot var serum E2-nivån signifikant högre hos HP-hMG-gruppen medan serum LH-nivån var liknande i båda grupperna. Slutsats: Utifrån denna litteraturstudie demonstrerades icke-inferioritet med avseende på den pågående graviditeten för HP-hMG jämfört med r-hFSH. Men det fanns tydligt farmakologiska skillnader för COS mellan dessa två gonadotropinpreparat exempelvis serum E2-nivå, progesteronnivå och antal erhöllna oocyter. Detta skulle kunna bero på att LH-aktivitet spelade en viktig roll både för att optimera kvalitet och utvecklingspotential hos oocyterna. r-hFSH är rekombinant och därmed kan tillverkas oberoende av tillgång på humant material. Detta bör på längre sikt innebära att tillverkningskostnaderna minskar och att preparatet blir billigare samt mera tillgängligt för patienterna. Då effekten mellan preparaten i denna studie inte tycks skilja sig åt i någon högre utsträckning kanske framtida investeringar skulle sikta på att försöka utveckla effektivare r-hFSH-preparat. Dessutom bör större kunskap om betydelsen av de olika farmakologiska profilerna av dessa två gonadotropiner med avseende på reproduktiva resultat utredas genom ytterligare undersökningar i större effektstudier. Ur ett kliniskt perspektiv bör mer forskningsfokus läggas på att undersöka behandlingsprotokoll som förbättrar oocytkvaliteten och kliniska utfall istället för att maximera antalet erhållna oocyter.

Employee Engagement is a critical business issue for the pharmaceutical industry especially owing to the highly competitive nature of this industry. This research postulates that factors can be identified that promote employee engagement in the pharmaceutical manufacturing industry. The purpose of the study is to research the factors that contribute to employee engagement in the pharmaceutical industry and to make recommendations in line with the results obtained that may be appropriate and significant to assist the pharmaceutical industry / Graduate School of Business Leadership / (M.B.A.)

<b>Background:</b> Sustained elevations in catecholaminergic signaling, mediated primarily through β-adrenergic receptor (β-AR) stimulation, are a hallmark neurohormonal alteration in heart failure (HF) that contribute to pathophysiologic cardiac remodeling. An important pathophysiological change during sustained β-AR stimulation is functional inhibition of the slow delayed rectifier potassium current, IKs, which has been demonstrated to prolong action potential duration (APD) and increase ventricular arrhythmogenesis in HF. Though functional inhibition of IKs has been consistently reproduced in cellular, animal, and limited human studies of HF, the mechanisms that mediate IKs inhibition during HF remain poorly understood.<div><br></div><div>In addition, HF results in aberrant calcium handling that is known to contribute to the disease. HF has been demonstrated to increase the expression and function of calcium/calmodulin-dependent protein kinase II (CaMKII), a key regulator of calcium homeostasis and excitation-contraction coupling in cardiomyocytes. Enhanced CaMKII signaling has been consistently demonstrated to contribute to increased arrhythmogenesis in a number of cardiac diseases, including HF. CaMKII is a known pathological regulator of many cardiac ion channels resulting in APD prolongation and the development of arrhythmias.<br></div><div><br></div><div><b>Objective:</b> This investigation aims to assesses the potential for CaMKII regulation of KCNQ1 (pore-forming subunit of IKs) during sustained β-AR stimulation and to characterize the potential functional implications on IKs. Furthermore, this investigation seeks to elucidate the mechanism underlying CaMKII-mediated IKs inhibition during sustained β-AR stimulation.<br></div><div><br></div><div><b>Methods: </b>Phosphorylation of KCNQ1 was assessed using a tandem liquid chromatography- mass spectrometry/ mass spectrometry (LCMS/MS) approach during sustained β-AR stimulation via treatment with 100 nM isoproterenol (ISO) for 4-24 hours and during co-expression with KCNE1. Whole-cell, voltage-clamp patch clamp electrophysiology experiments were performed in HEK 293 cells transiently co-expressing wild-type (WT) or mutant KCNQ1 (mutations conferring mimics of dephosphorylation and phosphorylation were introduced at phosphorylation sites identified by LCMS/MS) and KCNE1 (auxiliary subunit) during ISO treatment, treatment with CaMKII or protein kinase A (PKA) inhibitors, or during lentiviral δCaMKII overexpression. A robotic peptide synthesizer was used to create fifteen residue peptide fragments on a nitrocellulose membrane corresponding to KCNQ1 intracellular domains and the KCNQ1 residues identified via LCMS/MS; membranes were incubated with activated CaMKII or PKA in the presence of radiolabeled ATP to identify potential sites of phosphorylation. Bimolecular fluorescence complementation (BiFC) experiments were performed in HEK 293 cells to assess the impact of CaMKII-mediated KCNQ1 phosphorylation on the interaction of KCNQ1 and KCNE1 subunits. Protein immunoblot experiments were performed to (1) assess CaMKII activation during ISO treatment and (2) to assess plasma membrane expression of KCNQ1 and KCNE1 subunits with mimics of differential KCNQ1 phosphorylation following a membrane protein biotinylation procedure.<br></div><div><br></div><div><b>Results:</b> In Aim 1, we investigated the regulation of the KCNQ1 carboxyl terminus during sustained β-AR stimulation and assessed the associated functional implications on IKs. An LCMS/MS approach identified five novel KCNQ1 carboxyl terminal sites that demonstrated basal phosphorylation, with T482 and S484 having enhanced phosphorylation during treatment with 100 nM ISO for 24 hours (p<0.01 at both sites). Using patch clamp electrophysiology, we demonstrated that treatment with 100 nM ISO for 12-24 hours reduced IKs current density (p=0.01) and produced a depolarizing shift in the voltage dependence of activation (p<0.01) relative to vehicle. Mimics of phosphorylation (mutations to aspartic acid; Triple-D KCNQ1) at S457, T482, and S484 in combination, meanwhile, reduced IKs activation current density relative to dephosphorylation (mutations to alanine; Triple-A KCNQ1) mimics (p=0.02) but did not affect the voltage dependence of activation (p=0.66). Functional assessment of these sites individually revealed that phosphorylation mimics at S457 (p=0.02) and S484 (p=0.04), but not at T482 (p=0.53), reduced IKs current density relative to mimics of dephosphorylation. Similarly, the voltage dependence of activation was right-shifted with phosphorylation mimics at S457 (p=0.03) and S484 (p=0.02), but not at T482 (p=0.99), relative to mimics of dephosphorylation.<br></div><div><br></div><div>The focus of Aim 2 was to assess the potential for CaMKII signaling to regulate increased KCNQ1 phosphorylation and reduced IKs function during sustained β-AR stimulation. Peptide fragments corresponding to the KCNQ1 carboxyl terminal sites demonstrating basal phosphorylation via LCMS/MS analysis were synthesized on a nitrocellulose membrane and exposed to activated δCaMKII. Only peptide fragments corresponding to S484 demonstrated CaMKII phosphorylation. Patch clamp experiments demonstrated that CaMKII inhibition via the chemical inhibitor KN-93 (p=0.02) and the peptide inhibitor CN21 (p<0.01) reversed ISO-treatment associated inhibition of IKs activation current density relative to appropriate controls (KN-92 and CN21-Alanine, respectively). Inhibition with KN-93 and CN21 (p<0.01 for both) also reversed ISO-treatment associated right shifts in the voltage dependence of activation relative to appropriate controls. The ability of ISO treatment to activate CaMKII in HEK 293 cells was confirmed via protein immunoblot wherein T287 phosphorylation (CaMKII residue conferring constitutive activity) was increased during ISO treatment (p<0.05). Lentiviral overexpression of δCaMKII inhibited IKs activation current density with WT IKs (p=0.01) but not with Triple-A IKs (p=0.20) relative to lentiviral control. Inhibition of IKs activation current density during δCaMKII overexpression was attenuated with S484A IKs (p=0.04) but not with S457A (p=0.99) relative to WT IKs during δCaMKII overexpression. The voltage dependence of activation was also right-shifted during δCaMKII overexpression relative to lentiviral control (p=0.03). PKA inhibition with the peptide inhibitor PKI did not reverse ISO-treatment associated inhibition of IKs activation current density (p=0.51), and PKA did not phosphorylate peptide fragments corresponding to any of residues identified via LCMS/MS.<br></div><div><br></div><div>Aim 3 investigated the mechanism through which CaMKII-mediated phosphorylation at KCNQ1 S484 inhibits IKs function. To assess whether interaction with KCNE1 affects KCNQ1 phosphorylation, we performed LCMS/MS experiments during expression of KCNQ1 alone and during co-expression with KCNE1. Phosphorylation at S484 was reduced during co-expression with KCNE1 relative to expression of KCNQ1 alone (p<0.01). In addition, mimics of phosphorylation at S484 (S484D) did not affect activation current density (p=0.96) or the voltage dependence of activation (p=0.51) relative to dephosphorylation mimics (S484A). Based on these results, we hypothesized that S484 phosphorylation affected the interaction between KCNQ1 and KCNE1 subunits; accordingly, we assessed the KCNQ1-KCNE1 interaction using BiFC experiments in HEK 293 cells. In accordance with our hypothesis, Venus fluorescent intensity (corresponding to KCNQ1-KCNE1 interaction) was reduced during ISO treatment relative to vehicle (p<0.05) and with S484D KCNQ1 relative to S484A (p<0.01). The role of CaMKII in mediating this disruption of KCNQ1-KCNE1 interaction was demonstrated BiFC experiments that showed co-treatment with ISO and KN-93 attenuated reduced Venus intensity during co-treatment with ISO and KN-92 (p<0.01). These results were corroborated by BiFC experiments with Long QT Syndrome Phenotype 1 (LQT1) mutations that demonstrated that an LQT1 mutation predicted to disrupt CaMKII phosphorylation at S484 (R481I) attenuated reduced Venus intensity during ISO treatment relative to an LQT1 mutations predicted to not affect CaMKII regulation of S484 (S484T; p<0.01). The ability of S484 phosphorylation to affect KCNQ1 and/or KCNE1 trafficking was assessed via protein immunoblot experiments to detect KCNQ1 and KCNE1 following a biotinylation procedure to isolate plasma membrane-bound proteins. Biotinylation experiments demonstrated that KCNQ1 and KCNE1 plasma membrane expression were reduced by ~15% and ~33%, respectively, with S484D KCNQ1 relative to S484A (p<0.05 for both).<br></div><div><b><br></b></div><div><b>Conclusion: </b>CaMKII phosphorylates KCNQ1 S484 during sustained β-AR stimulation to inhibit IKs function. S484 phosphorylation inhibits IKs function by disrupting the interaction between KCNQ1 and KCNE1 subunits and by reducing the plasma membrane expression of KCNQ1 and KCNE1. Pathological regulation of KCNQ1 by CaMKII (and subsequent inhibition of IKs) during sustained β-AR stimulation may contribute to increased arrhythmogenesis during physiologic states of chronically increased catecholaminergic tone, such as during HF.<br></div>

This thesis investigates the 25-year transitional process of the Korean pharmaceutical industry from its initial focus on the imitative production of generic drugs to the development of new drugs. The catch-up dynamics of latecomer countries in science-intensive industries, such as the pharmaceutical industry, is an overlooked research topic in existing literature on innovation studies. This thesis provides an in-depth analysis of Korea's science-intensive catch-up and applies an ‘exploration and exploitation' framework to a latecomer setting and in a novel institutional and market context of the transitional phase. This thesis argues that the rate of change in the transition from imitating drugs to developing new drugs depends on the institutional and organisational mechanisms that enable a new form of technological learning, termed ‘exploratory learning'. This form of learning is often unfamiliar to firms in latecomer countries, whereas it is necessary for producing innovative drugs. That is, latecomers' institutional and organisational promotion of exploratory learning is related to a ‘pattern change' in the previously established institutional and organisational routines associated with imitative learning. The findings show that the rate of industrial transition in this sector was constrained by the problematic operation of S&T policies promoting key characteristics of exploratory learning, such as high-risk long-term learning as well as dense interactions between a diverse number of innovation actors. The findings also illuminate some latecomer firms' initial difficulties in managing the new mode of technological learning, and in strategically applying that mode of learning to overcome the barriers to moving through the transitional phase towards producing competitive innovation. The thesis also suggests that the nature of drugs as integral products, deeply grounded in science, makes it difficult to effectively promote institutional and organisational transformations in favour of exploratory learning.

Considering the importance of nitrogen-rich heterocycles in drug discovery, a novel strategy towards heterocycle synthesis was envisioned using cyanamide chemistry. Synthesis which involve mild conditions, avoids multi-step sequence and non-toxic reagents are desirable for generation of large combinatorial libraries of drug molecules. We envisaged that the NCN linkage of the cyanamide as well as the concomitant use of the nucleo-and electrophilic centres of the cyanamide could provide a novel synthetic route towards nitrogen heterocycles. The first part (Ch-2) constitute the bulk of the thesis and it focuses on the generation of cyanamide ion and its cyclisative capture with a 1,3-dipole – nitrile oxide in situ. The cycloadduct -1,2,4-oxadiazol-5(4H)-imine was obtained in good yields, which was further transformed into pharmacologically important cores like oxadiazolone and amidines. A library of the different heterocyclic cores was generated, which tolerated a wide variety of functional groups in good to excellent yields. In the second part (Ch-3), we developed a novel protocol for the synthesis of 1,2,4-triazol-3-imine via a formal 1,3-dipolar cycloaddition of in situ generated nitrile imines and cyanamide ion. Further hydrolysis furnished with 1,2,4-triazol-3-one, which is an important core from medicinal chemistry point of view. The concomitant generation and reaction of two reactive species- 1,3-dipoles and cyanamide ion was achieved in a single pot in situ to provide a route towards novel and pharmaceutically important heterocyclic cores. The present work provides a platform for the development of cyanamide derivatives as a ‘single-reagent—diverse-scaffolds’ strategy for time efficient library delivery of structurally diverse molecules.