Neurodegenerative disorders including Parkinson’s disease (PD), Huntington’s disease (HD) and the most frequent, Alzheimer’s disease (AD), represent one of the most urgent medical needs worldwide. Despite a significantly developed understanding of disease development and pathology, treatments that stop AD progression are not yet available. The recent approval of sodium oligomannate (GV-971) for AD treatment in China emphasized the potential value of natural products for the treatment of neurodegenerative disorders. Many current clinical studies include the administration of a natural compound as a single and combination treatment. The most prominent mechanisms of action are anti-inflammatory and anti-oxidative activities, thus preserving cellular survival. Here, we review current natural products that are either approved or are in testing for a treatment of neurodegeneration in AD. In addition to the most important compounds of plant origin, we also put special emphasis on compounds from algae, given their neuroprotective activity and their underlying mechanisms of neuroprotection.

No description available.

Schizophrenia is a severe mental disorder that can manifest in various ways and is often characterized by the appearance of positive symptoms (hallucinations, delusions), negative symptoms (social and attention impairment) and cognitive dysfunction (thought disorders, memory and executive function impairments). Traditional treatment methodologies involve blocking the dopamine receptor by binding to the same site as dopamine. These treatments are largely inadequate and lead to an array of adverse side effects. Side effects include weight gain, diabetes, and movement disorders; which critically limit the therapeutic value of antipsychotic drug treatment. Limited symptom control and severe adverse effects have led to poor drug adherence and a deprived quality of life for patients suffering from schizophrenia. The complex etiology of schizophrenia combined with a lack of effective translational models and tests to represent and assess the illness have hindered drug development. Evidently, there is a strong demand for a new generation of pharmaceuticals and an improved translational pipeline for the treatment of schizophrenia. The collection of studies presented here contribute to the advancement of translational tools for drug discovery, the establishment of pre-clinical models to embody the various symptoms, and the development of a novel drug candidate for schizophrenia. Allosteric modulation of G-protein coupled receptors is evolving as a new wave of therapy with promising implications for various CNS disorders. Allosteric compounds regulate binding without blocking the receptor. PAOPA, a dopamine D2 receptor allosteric modulator, prevents and treats schizophrenia-like symptoms in pre-clinical animal models of schizophrenia with no apparent adverse effects. The studies outlined in this thesis further categorize PAOPA as a novel therapeutic candidate for schizophrenia. Moreover, the findings presented here provide further insight into the potential therapeutic mechanism of action of PAOPA and set the foundation for the development of a new generation of antipsychotic drugs. These studies constitute an innovative approach to expanding research in the field of drug development for schizophrenia. / Thesis / Doctor of Philosophy (PhD)

No / Tenovin-6 (Tnv-6) is a bioactive small molecule with anti-neoplastic activity. Inhibition of the Sirtuin class of protein deacetylases with activation of p53 function is associated with the pro-apoptotic effects of Tnv-6 in many tumors. Here, we demonstrate that in chronic lymphocytic leukemia (CLL) cells, Tnv-6 causes non-genotoxic cytotoxicity, without adversely affecting human clonogenic hematopoietic progenitors in vitro, or murine hematopoiesis. Mechanistically, exposure of CLL cells to Tnv-6 did not induce cellular apoptosis or p53-pathway activity. Transcriptomic profiling identified a gene program influenced by Tnv-6 that included autophagy-lysosomal pathway genes. The dysregulation of autophagy was confirmed by changes in cellular ultrastructure and increases in the autophagy-regulatory proteins LC3 (LC3-II) and p62/Sequestosome. Adding bafilomycin-A1, an autophagy inhibitor to Tnv-6 containing cultures did not cause synergistic accumulation of LC3-II, suggesting inhibition of late-stage autophagy by Tnv-6. Thus, in CLL, the cytotoxic effects of Tnv-6 result from dysregulation of protective autophagy pathways.

No / Background Plasmodium falciparum drug resistance is a major public health challenge in sub-Sahara Africa. Many people are now resorting to the use of herbs in managing malaria due to the increasing treatment failures with the conventional drugs. In this study the ethanolic extract of Polyalthia longifolia (Sonn) Thw. var. pendula, a variety fondly used in folklore medicine in Ghana was investigated for potential antimalarial drug development. Method The ethanolic extract of P. longifolia (Sonn) Thw. var. pendula stem bark was screened against the multidrug resistant, K1 strain of P. falciparum by the parasite lactate dehydrogenase (pLDH) assay and a good antiplasmodial activity (IC50 22.04 ± 4.23 µg/ml) was observed which led to further chromatographic analysis in search for actives. Results Bioassay guided fractionation of the extract yielded; three clerodane diterpenes [16-hydroxycleroda-3,13-dien-16,15-olide (1), 16-oxocleroda-3,13E-dien-15-oic acid (2) and 3,16-dihydroxycleroda-4(18),13(14)Z-dien-15,16-olide (3)], a steroid [beta-stigmasterol (4)] and two alkaloids [darienine (5) and stepholidine (6)]. While compounds 4, 5 and 6 exhibited weak antiplasmodial activity (IC50 22–105 µg/ml), the clerodane diterpenes exhibited significantly potent (p<0.005) blood schizonticidal activity (IC50: 3–6 µg/ml). This is the first report of the antiplasmodial activity of compounds 2 and 3. In combination assay with chloroquine, compounds 1, 2, 3 and 5 antagonized the antiplasmodial activity of chloroquine while 4 and 6 demonstrated a synergistic action. Conclusion The potent antiplasmodial activity of the extract of P. longifolia (Sonn) Thw. var. pendula and compounds therein strongly suggests its usefulness as an antimalarial agent and supports its inclusion or exploitation in formulations of herbal remedies for malaria in Ghana.

Yes / Spurred by the enormous interest in co-crystals from the pharmaceutical industry, many novel co-crystals of active pharmaceutical ingredients have been discovered in recent years and this has in turn led to an increasing number of reports on polymorphs of co-crystals. Hence, a thorough characterization and understanding of co-crystal polymorphs is a valuable step during drug development. The purpose of this study is to perform in situ structural analysis and to determine thermodynamic stability of a dimorphic co-crystal system, 1:1 caffeine-glutaric acid (CA-GA, Forms I and II). We performed thermal and structural characterizations by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot-stage microscopy (HSM), slurry and in situ variable temperature X-ray diffraction (VTXRD). For completeness, we have also re-determined crystal structures of CA-GA Forms I and II at 180 K using single crystal X-ray diffraction. Our results revealed that Form II is stable and Form I is metastable at ambient conditions. Further, the results suggest that the dimorphs are enantiotropically related and the transition temperature is estimated to be 79 Celcius degrees. / This work was supported by Science and Engineering Research Council of A*STAR (Agency for Science, Technology and Research), Singapore.

Yes / Cocrystallization is an attractive approach to improving the physicochemical properties of active pharmaceutical ingredients (APIs), which have great potential in drug development. Accordingly, there is a growing need to understand the physicochemical changes that occur upon co-crystallisation. This work focuses on the combined use of spectroscopy and density functional theory (DFT) calculations to understand the molecular structure, hydrogen bond interactions and physicochemical properties of a pharmaceutical cocrystal. Solid-state NMR (ssNMR) spectroscopy can provide detailed molecular structure information on pharmaceutical cocrystals and complexes. It is non-destructive and usually provides deep structural insights that complement well with vibrational spectroscopy. In this work, a cocrystal of an antibiotic drug, nitrofurantoin (NF), with 4-hydroxybenzoic acid (4HBA) is examined to understand the capability of multiple spectroscopic techniques such as infrared (IR), Raman and solid-state NMR spectroscopies, and to confirm the molecular structure and hydrogen bonding of cocrystal systems. The results of IR and Raman spectroscopy showed that for the cocrystal formation, NF and 4HBA molecules interact through N–H⋯O–H interactions between the imide N–H of nitrofurantoin and the phenolic –OH of 4-hydroxybenzoic acid, and these interactions are also confirmed by natural bond orbital (NBO) and quantum theory of atoms in molecules (QTAIM) analyses. It is critical to understand whether a given cocrystal, upon conceiving a modified crystalline structure compared to that of its API, shows enhanced physical and chemical properties or not. Computationally, it is found that the NF–4HBA cocrystal shows softer (more reactive) behaviour in comparison to NF as its cocrystal, NF–4HBA, has a low band gap in comparison to the API, NF. These results demonstrate that the quantum chemical approach predicts accurately how to relate cocrystal with its physical and chemical properties. / BSR meritorious fellowship scheme. The Newton-Bhabha PhD placement award (2017). The Royal Society Seed Corn Research Grant (2018-19)

Thesis (MComm)--Stellenbosch University, 2001. / ENGLISH ABSTRACT: New products are indispensable to the growth of the modem business enterprise. Increased global and local competition, better informed consumers, rapidly changing technology and the short life span of products are typical of the reasons why it is necessary to develop new products. Traditionally new product development took place in accordance with a rigid new product development process where a next phase was dependent on the completion of preceding phases. The increased pressure to produce new products in shorter time spans has led to the development and application of less streamlined and rigid processes for the development of new products. The pharmaceutical industry has certain unique characteristics important for new product development. It spends more than five times than the average of all industries on research and development. New product development in the pharmaceutical industry largely depends on the discovery of new clinical entities and the development process is furthermore also highly regulated by governments. The focus of product evaluation in the pharmaceutical industry has also undergone a major shift. Traditionally the industry dealt with diseases which were defined broadly and as such the focus was on diseases and not individuals. The result was that consumer acceptance was virtually never evaluated. The shift is now to consumer acceptance because consumers become increasingly better informed and take part in decisions regarding their health and medical care. A further reason for the consumer focus lies in the genetic understanding of patients and this enable pharmaceutical companies to segment patients on the basis of pharmaco-genomic descriptions. The objectives of the study are twofold. In the first instance, the study assesses whether marketing practitioners in the South African pharmaceutical industry agree with the fundamental principles of new product development which are identified in academic literature. The responses from marketing personnel were obtained and analysed to establish their beliefs regarding new product development. The fundamental principles of new product development which form the focus of this study, were those that Calantone, Di Benedetto and Haggblom (1995) used in their research. The second objective of the study is to compare the findings in respect of the South African pharmaceutical industry with those of the study undertaken by Calantone, Di Benedetto and Haggblom in 1995. The purpose of the study is to establish whether the new product development principles taught in marketing management courses are relevant for the pharmaceutical industry. The method of investigation was divided into two sections, i.e. a literature overview and an empirical study. The literature study commenced with research on new product development in the South African Pharmaceutical Industry and other parts of the world. The Calantone, Di Benedetto and Haggblom (1995) questionnaire was also used in this study for data collection. The 91 pharmaceutical companies listed in Volume 34 of the 1999 MIMS Desk formed the population of the study. After contacting these companies a more accurate list was set up. After taking into account all the mergers that took place, 65 companies eventually constituted the population. Twenty nine of the questionnaires sent were returned and could be used. This represents a response rate of 44.6%. The organisations involved were responsible for 69.4% of the annual turnover of the total pharmaceutical industry in 1998 and their responses could therefore be regarded as representative of the pharmaceutical industry of South Africa. The questionnaire attended to the following principles of new product development: • Product innovation • New product development and launch tasks • Product diffusion • Interface between marketing, research and development • Organisational issues The information collected in respect of each pharmaceutical company was the following: • Annual turnover • Number of products manufactured and marketed • Number of employees • Number of new products launched during the past five years The findings of this study indicate that marketing staff in the South African pharmaceutical industry strongly agreed with those fundamental principles of new product development which were identified in academic literature. There was also a significant correlation between this study and the study undertaken by Calantone, Di Benedetto and Haggblom with respect to the percentage agreement on the various statements. It may thus be concluded that new product development principles taught in marketing managing courses are relevant for and are applied by marketing staff in the pharmaceutical industry in South Africa. / AFRIKAANSE OPSOMMING: Nuwe produkte is onontbeerlik vir die groei van die moderne sake-onderneming. 'n Toename in globale en lokale mededinging, beter ingeligte verbruikers, snel veranderende tegnologie en die kort lewensduur van produkte is tipies van die redes waarom dit belangrik is om nuwe produkte te ontwikkel. Tradisioneel het nuwe produk ontwikkeling volgens 'n rigiede nuwe produk ontwikkelingsproses plaasgevind waar 'n volgende fase afhanklik was van die voltooiing van voorafgaande fases. Die verhoogde druk om nuwe produkte in korter tye te vervaardig het tot die ontwikkeling en toepassing van minder stroombelynde en rigiede prosesse vir die ontwikkeling van nuwe produkte gelei. Die farmaseutiese bedryf het sekere unieke eienskappe wat belangrik is vir nuwe produk ontwikkeling. Die farmaseutiese bedryf bestee meer as vyfkeer die gemiddelde van alle bedrywe op navorsing en ontwikkeling. Nuwe produk ontwikkeling in die farmaseutiese bedryf is grootliks afhanklik van die ontdekking van nuwe kliniese entiteite en die ontwikkelingsproses word verder ook intensief gereguleer deur regerings. Die fokus van produkbeoordeling in die farmaseutiese bedryf het ook 'n verskuiwing ondergaan. Tradisioneel het die bedryf gehandel met siektes wat breed omskryf is en die fokus as sulks was op siektes en nie op individue nie. Die gevolg was dat verbruikersaanvaarding feitlik nooit beoordeel was nie. Die verskuiwing is nou na verbruikersaanvaarding omdat verbruikers toenemend beter ingelig word en deelneem aan besluite wat hulle gesondheid en mediese sorg raak. 'n Verdere rede vir die verbruikerfokus is daarin geleë dat pasiënte nou geneties verstaan kan word en dit maak vir farmaseutiese maatskappye moontlik om pasiënte op 'n farmakologies-genomiese basis te segmenteer. Die doelstellings van die studie is tweeledig. In die eerste instansie beoordeel die studie of bemarkingspersoneel werksaam in die die Suid-Afrikaanse farmaseutiese bedryf, saamstem met die fundamentele beginsels ten opsigte van nuwe produk ontwikkeling wat in die akademiese literatuur geïdentifiseer is. Die response van bemarkingpersoneel is verkry en ontleed om hulle oortuigings ten opsigte van nuwe produk ontwikkeling vas te stel. Die fundamentele beginsels van nuwe produk ontwikkeling wat die fokus van hierdie studie vorm, is dié wat Calantone, Di Benedetto en Haggblom (1995) in hulle navorsing gebruik het. Die tweede doelstelling van die studie is om die bevindings ten opsigte van die Suid-Afrikaanse farmaseutiese bedryf te vergelyk met dié van die studie onderneem deur Calantone, Di Benedetto en Haggblom in 1995. Die doel van die studie is om vas te stel of die nuwe produk ontwikkeling beginsels wat in bemarkingsbestuurkursusse onderrig word, relevant is vir die farmaseutiese bedryf. Die metode van ondersoek is onderverdeel in twee gedeeltes, naamlik 'n literatuuroorsig en 'n empiriese studie. Die literatuurstudie het begin met navorsing oor nuwe produk ontwikkeling in die Suid-Afrikaanse farmaseutiese bedryf en ander wêrelddele. Die Calantone, Di Benedetto en Haggblom (1995) vraelys is ook in hierdie studie vir die insameling van data gebruik. Die 91 farmaseutiese firmas wat in Volume 34 van die 1999 MIMS Desk gelys is, het die populasie van die studie gevorm. Na gesprekke met hierdie firmas en nadat alle samesmeltings in ag geneem is, is 'n meer akkurate lys opgestel en het die populasie uiteindelik uit 65 firmas bestaan. Nege en twintig van die vraelyste wat terugontvang is kon gebruik word. Hierdie verteenwoordig 'n responskoers van 44.6%. Die organisasies wat gereageer het was verantwoordelik vir 69.4% van die jaarlikse omset van die totale farmaseutiese bedryf in 1968 en die responses sou dus as verteenwoordigend van die farmaseutiese bedryf in Suid-Afrika beskou kon word. Die vraelys het aandag aan die volgende beginsels van nuweprodukontwikkeling gegee: • Nuweproduk ontwikkeling en loodstake • Produkdiffusie • Koppelvlakke tussen bemarking, navorsing en ontwikkeling • Organisatoriese kwessies Die inligting wat ten opsigte van elke farmaseutiese firma ingesamel is, is die volgende: • Jaarlikse omset • Aantal produkte vervaardig en bemark • Aantal werknemers • Aantal nuwe produkte wat gedurende die afgelope vyf jaar geloods is. Die bevindings van hierdie studie toon aan dat die bemarkingspersoneel in die Suid-Afrikaanse farmaseutiese bedryf sterk saamstem ten opsigte van die beginsels van nuwe produk ontwikkeling wat in die akademiese literatuur geïdentifiseer is. Daar bestaan ook 'n betekenisvolle korrelasie tussen hierdie studie en die Calantone, Di Benedetto en Haggblom studie ten opsigte van die persentasie wat saamgestem word oor die verskillende stellings. Die gevolgtrekking kan dus gemaak word dat die nuwe produk beginsels wat in bemarkingskursusse aangebied word, relevant is vir en toegepas word deur bemarkingspersoneel in die farmaseutiese bedryf in Suid- Afrika.

Despite significant advances in cancer treatment, clinical response remains suboptimal and there is a continued requirement for improved chemotherapeutics. The attrition rate for new therapies is high, due principally to lack of in vivo efficacy and poor pharmacodynamics. Consequently better systems are required to determine in vivo preclinical efficiency and drug-target interactions. Engineering of cancer cells to express fluorescent or bioluminescent proteins, either endogenously or under the control of specific gene promoters, and their detection by noninvasive optical imaging has the potential to improve preclinical drug development. In this study, a panel of colorectal cancer cell lines were engineered to express fluorescent and luminescent proteins either constitutively or under control of gene-promoters for the DNA damage response gene p53 or the cell cycle regulator p21, both important pharmacodynamic sensors. These cell lines were characterised for their potential as in vivo models of primary and metastatic tumour therapy response, several showing significant potential. In addition to the development of these models, this study also addressed the pharmacokinetics of different luciferase substrates and identified optimal temporal and dose characteristics for each. Furthermore, a new application for bioluminescent imaging was developed and validated for use in preclinical evaluation of vascular disrupting agents, a new generation of cancer therapeutic. This study demonstrates that despite the dynamic and variable nature of fluorescent and bioluminescent imaging, reproducible results can be obtained if appropriate precautions are taken. The models developed herein will expedite cancer drug development whilst reducing and refining the use of animals in research.

<p>A central aim in drug development is to ensure that the new drug is efficacious and safe in the intended patient population.</p><p>Mathematical models describing the pharmacokinetic-pharmacodynamic (PK-PD) properties of a drug are valuable to increase the knowledge about drug effects and disease and can be used to inform decisions. The aim of this thesis was to develop mechanism-based PK-PD-disease models for important safety and efficacy biomarkers used in anti-diabetic drug development. </p><p>Population PK, PK-PD and disease models were developed, based on data from clinical studies in subjects with varying degrees of renal function, non-diabetic subjects with insulin resistance and patients with type 2 diabetes mellitus (T2DM), receiving a peroxisome proliferator-activated receptor (PPAR) α/γ agonist, tesaglitazar.</p><p>The PK model showed that a decreased renal elimination of the metabolite in renally impaired subjects leads to increased levels of metabolite undergoing interconversion and subsequent accumulation of tesaglitazar. Tesaglitazar negatively affects the glomerular filtration rate (GFR), and since renal function affects tesaglitazar exposure, a PK-PD model was developed to simultaneously describe this interrelationship. The model and data showed that all patients had decreases in GFR, which were reversible when discontinuing treatment. </p><p>The PK-PD model described the interplay between fasting plasma glucose (FPG), glycosylated haemoglobin (HbA1c) and haemoglobin in T2DM patients. It provided a mechanistically plausible description of the release and aging of red blood cells (RBC), and the glucose dependent glycosylation of RBC to HbA1c. The PK-PD model for FPG and fasting insulin, incorporating components for β-cell mass, insulin sensitivity and impact of disease and drug treatment, realistically described the complex glucose homeostasis in the heterogeneous patient population. </p><p>The mechanism-based PK, PK-PD and disease models increase the understanding about T2DM and important biomarkers, and can be used to improve decision making in the development of future anti-diabetic drugs. </p>