Preclinical Drug Development

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The basics of preclinical drug development for neurodegenerative disease indications

The basics of preclinical drug development for neurodegenerative disease indications

Metabolism studies are also recommended by the FDA. These studies can be useful to evaluate the potential for drug-drug interactions and cytochrome P 450 inhibition and to generate drug metabolite profiles for different spe- cies, including humans. Metabolism studies are typically conducted using in vitro methods for exposing hepatic microsomes, cytosolic fractions, hepatocyte cultures, or other applicable test systems to the drug. Using a bioana- lytical method, any metabolites are described as a frac- tional percent of parent-drug peak. Any metabolite occurring at a significant level (for example, accounting for 10% or more of parent drug level, particularly when using test systems derived from primary human tissues) likely represents a significant metabolic pathway for the drug and may require further investigation, including elu- cidation of metabolite identity and biological activity. In vitro metabolism studies are frequently the first glimpse into the effects of human metabolic pathways on a drug and may reveal considerable metabolic differences between humans and preclinical species. In the event of significant interspecies metabolite profile differences, investigators may compare these with the human metab- olite profile to identify which species, if any, most closely matches the humans, and then select this species for the pivotal safety and toxicology studies. Because of the importance of these interspecies results for understanding the potential disposition of the drug in humans, many development plans begin these studies about the same time as the first animal PK studies.
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“A Review of Preclinical Drug Development Models Utilised in Antiobesity Research” by Gautam Arora, Sumeet Gullaiya, Shyam Sunder Aggrawal, India.

“A Review of Preclinical Drug Development Models Utilised in Antiobesity Research” by Gautam Arora, Sumeet Gullaiya, Shyam Sunder Aggrawal, India.

As the obesity is a global health problem, resulting from an energy imbalance caused by an increased ratio of caloric intake and expenditure, now effect over 500 million individual worldwide. Obesity is abnormal or excessive fat accumulation that presents risk to health. The body mass index (BMI) of a person is 25-30 kg/m 2 indicates overweight and above 30 kg/m 2 represents obesity. Lifestyle and behavioural interventions aimed at reducing calorie intake or increase expenditure have limited long term effectiveness. Implementing and maintaining the lifestyle changes associated with weight loss but challenging for many patient. Surgical treatment for obesity, although highly effective are unavailable or unsuitable for majority of an individual with excess adiposity. Accordingly few effective treatment options are available to most individual with obesity. Although a number of pharmacological approaches for treatment of obesity have been investigated but only few are safe. Currently approved long term and short term antiobesity drugs, continuously has been monitored for efficacy and safety concern. Furthermore, evaluation of antiobesity drugs in children and elderly populations require long term postmarketing surveillance to fully elucidate its effects and mechanism. However, much emphasis now a days has been placed on reduced food intake /or body weight that made the pharmacological management of obesity at an exciting crossroads. Polytherapeutic strategies as well as new therapy targets led to identification and characterisation of specific obese subpopulations that allow for the tailor-made development and appropriate use of personalised medicines for successful development and discovery of patent and safe drugs for the treatment and prevention of obesity. Therefore the choice of the model depends upon the characteristics of the research. 50
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Preclinical assessment of CNS drug action using eye movements in mice

Preclinical assessment of CNS drug action using eye movements in mice

The drug development process for CNS indications is hampered by a paucity of preclinical tests that accurately predict drug efficacy in humans. Here, we show that a wide variety of CNS-active drugs induce characteris- tic alterations in visual stimulus–induced and/or spontaneous eye movements in mice. Active compounds included sedatives and antipsychotic, antidepressant, and antiseizure drugs as well as drugs of abuse, such as cocaine, morphine, and phencyclidine. The use of quantitative eye-movement analysis was demonstrated by comparing it with the commonly used rotarod test of motor coordination and by using eye movements to monitor pharmacokinetics, blood-brain barrier penetration, drug-receptor interactions, heavy metal toxicity, pharmacologic treatment in a model of schizophrenia, and degenerative CNS disease. We conclude that eye- movement analysis could complement existing animal tests to improve preclinical drug development.
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EMA401: an old antagonist of the AT2R for a new indication in neuropathic pain

EMA401: an old antagonist of the AT2R for a new indication in neuropathic pain

putative analgesic drugs acting via this system. The University of Queensland, Aus- tralia, filed a patent in 2004 based on the work of Drs Maree Smith and Bruce Wyse from the Centre for Integrated Preclinical Drug Development for a number of AT2R antagonists as analgesics for neuropathic pain (the so-called “use patent”, claiming a new use for an old drug). One specific racemate (EMA400; Figure 1) was especially promising in preclinical studies. Its S-enantiomer, EMA401, has a binding affinity in the nanomolar range for the murine and human AT2R. 3 Among others based on this high
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Repurposing of anticancer drugs: in vitro and in vivo activities against Schistosoma mansoni

Repurposing of anticancer drugs: in vitro and in vivo activities against Schistosoma mansoni

the equivalent volume of drug-free DMSO (0.3 %) served as control. NTS were evaluated 24, 48, and 72 h after incubation via microscopic read out (80–120× magnification; Zeiss; Germany), using a scoring scale from 3 (normal viability, morphology, and granularity) to 0 (no motility, changed morphology, and granularity). Drugs with an activity of ≥ 50 % after 24 h, and/or 90 % after 72 h, and a drug effect on adult schistosomes of ≥ 80 % after 24 h and/or 90 % after 72 h at 33.3 μM, were tested at six differ- ent concentrations ranging from 0.14 to 33.3 μM using a 3- fold dilution series for IC 50 determination. All assays were
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Effective visualization of integrated knowledge and data to enable informed decisions in drug development and translational medicine

Effective visualization of integrated knowledge and data to enable informed decisions in drug development and translational medicine

The Knowledge Plot was applied retrospectively and prospectively in selected projects within or across multiple therapeutic disease areas. In the retrospective analysis, preclinical and clinical key biomarkers and endpoints were selected i) for candidate drug selection, benchmarking and differentiation by utilizing all available knowledge on refer- ence compounds and competitors, ii) to identify which data were used at each milestone for decision making, iii) to compare endpoints used in different subpopulations iv) back translation of clinical data to build translational con- tinuum and understand the predictability of preclinical models and assays, v) evaluation of different compounds with different mechanism of actions aiming for the same patient population and vi) evaluate different dose sched- ules. The first example using the Knowledge Plot concept demonstrates the relative differences between two com- pounds (Compound A and B) by comparing their inte- grated profiles, supporting either candidate drug selection or benchmarking or differentiation with reference com- pound or competitor (Figures 4 and 5). The data included are: in vitro assays; target engagement; in vivo efficacy; safety pharmacology; and tolerability in early clinical stud- ies. Each line represents the behavior of a specific end- point with increasing exposure in different dose groups. The efficacy endpoint in the rat was calculated using two different methods (blue stars). Both methods gave similar profiles and reached the 100-line, e.g. the targeted or Meaningful Effect level. Target engagement in monkey and human (yellow circles and triangles) are similar and appears in both Figures 4 and 5. The difference between the two compounds is clearly demonstrated in the safety
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“De-addictives: Evaluation Methods and its Choice of Remedies from Various System of Medicines’’ – an Update” by Kalashanti R Pyngrope, Anbu J, Radhika M N, Komala M, India.

“De-addictives: Evaluation Methods and its Choice of Remedies from Various System of Medicines’’ – an Update” by Kalashanti R Pyngrope, Anbu J, Radhika M N, Komala M, India.

Addiction is a characteristic psychological and physiological dependence on a substance or practice that is beyond professional control. It is a chronic brain disorder that causes obsessive substance use despite harmful consequences. Addiction causes major destructive effect to human being along with its social consequence. Abrupt withdrawal of any addicted substances produces psychological disorder. Natural substances have various effect on the body, even though many of them can lead to addiction, others have long been used in the treatment and detoxification. In this review, the methods of evaluation and various modalities of treatment for de-addiction are discussed. Some of the laboratory method for finding various de-addictive drugs in animals’ model, different form of treatments with herbals such as – Ginseng, Tabernanthe iboga and Voacanga africana, l-THP, Datura, Nigella sativa etc; synthetic drugs (Methadone, Buprenorphine, Naltrexone, Disulfiram, Acamprosate) and therapies (Acupuncture, Aromatherapy, Yoga, Nutritional and Horticulture therapy) were reviewed and found to have significant effect in substance dependence. Refined preclinical model such as CPP, drug self-administration and cue induced paradigm or models etc, are used to understand the neurobiological effect of addictive substances in the brain and its different form of treatment can be used depends on the symptoms and severity of the condition with appropriate system of medicine.
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Comparative Evaluation of  Anti-Depressant Activity of GlycyrrhizaGlabra and Piper Nigrum Combination with  Individual Drugs Effects and Standard Drug Imipramine in Mice

Comparative Evaluation of Anti-Depressant Activity of GlycyrrhizaGlabra and Piper Nigrum Combination with Individual Drugs Effects and Standard Drug Imipramine in Mice

combination. The anti-depressant effect of combination of Glycyrrhizin glabra and Piper nigrum was more as compared to individual drug effects. Force swim test and tail suspension test are the most common and the accepted paradigms for the depression study. In FST, when the mice are forced to swim in a restricted space from from which they can not escape are escape are induced to characteristic behaviour of immobility. This behaviour of immobility shows a state of despair which can be reduced by several anti-depressants which are also therapeutically effective in humans. In TST, the immobility behaviour shown by rodents, when they are put into an unavoidable and inescapable stress reflect behavioural despair which is reduced by some clinically effective anti- depressants. These anti-depressants reduce the immobility that mice display after active and unsuccessful attempts to escape when suspended by tail.
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Preclinical and clinical study of siddha drugs “Rajaelathy Chooranam” (Internal) and “Nathai Choori Ennai” (External) in the treatment of “Kumbavaatham” (Periarthritis)

Preclinical and clinical study of siddha drugs “Rajaelathy Chooranam” (Internal) and “Nathai Choori Ennai” (External) in the treatment of “Kumbavaatham” (Periarthritis)

First group treated as vehicle control and second, third and fourth groups were treated with Rajaelathy chooranam Low dose (180 mg), Mid dose (900 mg) and High dose (1800 mg) respectively. The animals were dosed with Rajaelathy chooranam by oral for 90 days and is monitored for behavioural parameters for the first 4 hours after drug administration. Body weight of the animal was be monitored at weekly intervals. The animals that die within this period was be subjected to necropsy. Remaining animals was be weighed and sacrificed under the injuction of Pentathal Sodium on the on the 91 st day of the study. Blood will be collected from the anesthetized animals from Abdominal aorta and the following investigations like Haematology, Biochemical analysis and Histopathology are done.
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Chemotherapy resistance in metastatic breast cancer: the evolving role of ixabepilone

Chemotherapy resistance in metastatic breast cancer: the evolving role of ixabepilone

In addition to P-gp and β-tubulin alterations, other mechanisms have been implicated in breast cancer drug resistance. Alterations in enzymes that are involved in DNA repair or that aff ect drug sensitivity can also aff ect drug resistance. Topoisomerase II is a critical enzyme that is involved in DNA replication and repair, in which reduced topoisomerase II expression or function can contribute to resistance to agents such as anthracyclines and epipodophyllotoxins [7,53]. Th e loss of DNA- mismatch repair activity – which mediates damage repair from many drugs including alkylating agents, platinum com pounds, and anthracyclines – has also been impli- cated in drug resistance [54]. In breast cancer, altered DNA-mismatch repair is associated with micro satellite instability. Th e loss of function of the DNA-mismatch repair proteins MSH2 and MLH1 resulted in resistance to the topoisomerase II inhibitors epirubicin, doxo- rubicin, and mitoxantrone, but not to taxanes [55]. Th e reduced expression of MLH1, following neoadjuvant chemotherapy for node-positive breast cancer, predicted poor disease-free survival [56], and in a study of sporadic invasive ductal carcinoma it was associated with resistance to the adjuvant cyclophosphamide, metho- trexate, and fl uorouracil [57]. In general, the loss of hetero zygosity or microsatellite instability can contribute Table 1. Mechanisms of drug resistance in breast cancer [24,25]
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Ramucirumab: preclinical research and clinical development

Ramucirumab: preclinical research and clinical development

Abstract: Ramucirumab (IMC-1121B, LY3009806), a fully humanized monoclonal antibody directed against the extracellular domain of vascular endothelial growth factor receptor 2 (VEGFR-2), is a new therapeutic option that selectively inhibits the human VEGFR-2 with a much greater affinity than its natural ligands. Based on the promising results of both preclinical and early clinical studies, ramucirumab has been tested in different tumor types either alone or in combination with chemotherapy. While it has recently been granted its first US Food and Drug Administration approval for use as a single agent in patients with advanced or metastatic gastric cancer or gastroesophageal junction carcinoma, its role for metastatic breast cancer or advanced non-small-cell lung cancer is still debated. The aims of this review are to recall and discuss the most significant preclinical and clinical studies that led to the development of ramu- cirumab and to present the results of the randomized clinical trials that have tested its efficacy in different malignancies, including gastric and lung cancer.
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Schottelius, Arndt
  

(2018):


	Molekulare Mechanismen der Entzündung: Pro- und anti-inflammatorische Faktoren und deren Bedeutung für die Pathophysiologie und Therapie entzündlicher Erkrankungen.


Habilitationsschrift, LMU München: Medizinische Fakult

Schottelius, Arndt (2018): Molekulare Mechanismen der Entzündung: Pro- und anti-inflammatorische Faktoren und deren Bedeutung für die Pathophysiologie und Therapie entzündlicher Erkrankungen. Habilitationsschrift, LMU München: Medizinische Fakultät

 Established strong preclinical data for human antibody directed against CD38 (MOR202) in multiple myeloma and brought into Phase I/IIa leading to highly attractive co-development partnership with Celgene. Advanced program to robust clinical proof-of-concept. Leading efforts to design and implement pivotal combination study for anti-CD38 mAb program in multiple myeloma. Championed efforts to develop anti-CD38 in autoimmune disease.

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Development of cordycepin formulations for preclinical and clinical studies

Development of cordycepin formulations for preclinical and clinical studies

Effects of filter sterilisation on concentrations of PBS-based cordycepin formulations mean ± SD, n = 4 Cordycepin concentration mg/mL Formulation... LEGENDS TO FIGURES.[r]

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Clinical development of new drug-radiotherapy combinations.

Clinical development of new drug-radiotherapy combinations.

Before designing an early-phase clinical study, investi- gators must define the proposed treatment in instances of unmet need, and select a registerable end point that the clinical study will pursue. This will inform on the tissue type and end point for the models used in the preclini- cal phase. For example, if the standard of clinical care is cisplatin- based chemoradiotherapy, preclinical model- ling should ensure that antagonism does not occur when the new drug is added to cisplatin-based chemo- radiation. While in vitro studies should initially be used to examine drug–radiotherapy combinations, in vivo tumour models are likely to be more informative. There has been interest in using mouse models that might be more molecularly diverse or possess more complex stroma, such as patient-derived xenografts (PDX) or genetically engineered mouse models (GEMs) 79,80 . These
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Ten years of biosimilars in Europe: development and evolution of the regulatory pathways

Ten years of biosimilars in Europe: development and evolution of the regulatory pathways

Abstract: A biosimilar is defined by the European Medicines Agency as a biological medicine that is similar to another biological medicine that has already been authorized for use. A science-based regulatory framework to ensure high-quality biosimilars has been established in Europe since 2005 and is monitored and updated on an ongoing basis. The guiding principle of a biosimilar development program is to establish similarity between the biosimilar and the reference medicine by the best possible means, ensuring that the previously proven safety and efficacy of the reference medicinal product also applies to the biosimilar. Development of a biosimilar is underpinned by state-of-the-art analytical techniques to characterize both reference medicines and biosimilars. The extent and nature of the nonclinical in vivo studies and clinical studies to be performed depend on the level of evidence obtained in the previous step(s), including the robustness of the physicochemical, biological, and nonclinical in vitro data. Extrapolation is an important element of the biosimilarity concept. When biosimilar comparability has been demonstrated in one indication, extrapolation of the data package to other indications of the reference medicine could be acceptable, but needs to be scientifically justified and considered in light of the demonstrated level of sameness by all analytical, nonclinical, and clinical data. The credibility of the scientific basis behind the biosimilar concept, and quality of regulatory decision-making, is demonstrated by the successful approval and clinical use of 20 biosimilar medicines since 2006 when Omnitrope ® was the first biosimilar to be approved. The regulatory
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Tissue engineering and regenerative approaches to improving the healing of large bone defects

Tissue engineering and regenerative approaches to improving the healing of large bone defects

Synthetic scaffold design involves a series of design trade-offs, which present inherent challenges for large bone defect healing. For example, scaffolds require optimised mechanical properties for a particular clinical approach, but must also provide adequate porosity for cell infiltration and tissue formation and degradability over a timeframe that scales with the timing of new bone formation (Hollister, 2005). In addition, scaffold design parameters such as µm-scale and nm-scale geometry have become increasingly appreciated as critical regulators of osteogenesis. In particular, nm-scale pillars and fibres have been associated with enhanced osteogenic differentiation of bone-forming stem cells in vitro (Dalby et al., 2007), as well as increased osteogenesis in vivo (Ingavle and Leach, 2013). The diversity of existing and emerging parameters that appear to be important for large bone defect healing will call for efficient – and perhaps high throughput – screening strategies to identify optimal scaffold materials. It is noteworthy that one reason why scaffold materials developed to date have been composed of similar base materials relates to the relatively complex regulatory path for novel bone scaffolding materials. Materials comprising new combinations of clinically established base materials typically provide a more rapid route to regulatory approval and clinical applications. In particular, while combinations of existing, FDA approved materials may only require one to demonstrate substantial equivalence to an existing “predicate device”, novel scaffold materials often require substantial preclinical studies and one or more clinical studies prior to regulatory approval. The adaptable features of commonly used scaffold materials coupled with the relatively complex regulatory path of novel materials limits innovation.
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The impact of a self-development coaching programme on medical and dental students’ psychological health and academic performance: a randomised controlled trial

The impact of a self-development coaching programme on medical and dental students’ psychological health and academic performance: a randomised controlled trial

We would like to thank Dr. Mohammed Beyari, Dr. Anmar Nassir, Dr. Waheeb Alharbi, Abdulwahed Homsi, Ashjan Almasoudi, Bayan AL-maimani, Ahmad Saleh Alghamdi, Doaa Melebari, Lujain Kurdi, Rehab Fallatah, Seddig Fallatah, Wafaa Almalki, and Danya Turkistani for helping data acquisition. We would like also to thank the other team members who helped in conducting the intervention on site. This study was funded by Queensland University of Technology (QUT) and Umm al-Qura University (UQU). The funding was part of the PhD candidature at QUT, and part of the PhD scholarship by UQU. The funders had no role in the study design, data collection, analyses, publication or manuscript development.
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EFFECTS OF THERAPEUTIC NUTRITION WITH THE APITHERAPEUTIC PRODUCT APITER IN DOGS AND CATS IN RICKETS DISEASE

EFFECTS OF THERAPEUTIC NUTRITION WITH THE APITHERAPEUTIC PRODUCT APITER IN DOGS AND CATS IN RICKETS DISEASE

In order to create the product APITER the researches were carried out in the Institute for Beekeeping Research and Development - Bucharest and the product was preclinical and clinical tested in the Medical Clinic of the Veterinary Medicine Faculty from Bucharest.The increasing interest in internationally context for non- conventionally therapies and especially for the apitherapy and phitotherapy used in veterinary purpose determined us to study the effects of such therapies in bone diseases (rickets) in dogs and cats using a new product -Apiter.The clinical experiments were done in the period - October 2004 – February 2006 using a lot of 70 individuals (dogs and cats), of different ages between 6 weeks and 7 years with osteo-articulars disorders of rickety type for young individuals and osteomalacia (adult rickets), in treatment series of 10 and 30 days.The clinical investigations were completed by radiological exams and biochemical determinations (Ca, Mg, P and alkaline phosphatase), the resulted values being registered before and after treatment.The obtained results shown us that the tested methods with the new product APITER, applied on dogs and cats with rickets disease were as efficiently as the classic nutrition methods.The therapeutic efficiency of the new product was proved by the increased values of Calcium - from 4 mg/dl to 9,2-11,5 mg/dl, Phosphor –from 1,6-3,81 mg/dl to 4,1-5,7 mg/dl, the normalization of the Mg values (2,5-3 mg/dl), the decreasing of alkaline phosphatase (116-443 UI/l la 77-187 U/I) concomitantly with the normalization of hepatic tests (ALT, GGT, AP, TBIL).
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A Study on Valikanam

A Study on Valikanam

Siddha system of medicine is the most ancient medical science which is propounded and practised by eminent spiritual scientists called Siddhars. Siddhars are those who lived and maintained their bodies as they desired best. They had realised that, the body though transient was one and only instrument for attaining success in the spiritual development and growth and so worked out to attain the eight super natural powers the Ashtamasiddhi, essential for their goal.

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Mapping knowledge translation and innovation processes in Cancer Drug Development: the case of liposomal doxorubicin

Mapping knowledge translation and innovation processes in Cancer Drug Development: the case of liposomal doxorubicin

It has been pointed out by various authors that there is a disproportion between the number of papers published and the amount of nanodrugs readily available in the market [10]. Indeed, there exist thousands of papers as compared to just 247 confirmed commercial products in a preclinical, clinical or commercial stage [12]. The question then arises on how TI is structured when a nanodrug is approved, that is, when an innovation truly emerges. The approach we offer herein to answer that question consists in mapping the aforementioned pro- cesses in the scientific literature network for a case example, namely liposomal doxorubicin. Liposomes are micro- and nano-scaled lipid bilayered “bubbles” that can be used in a plethora of therapeutic strategies. The therapeutic use of liposomes ranges from drug carriers and drug delivery systems to multiplex with antibodies, optical contrast, genetic material and others [13]. Liposo- mal doxorubicin was chosen as an illustrative case study, with a historical relevance, since a PEGylated liposomal doxorubicin, Doxil, was the first nanodrug approved by the United States Food and Drug Administration (FDA) in 1995 [14]. The proposed approach aims to understand how scientific research evolves and gets re-organized when a technological change process is taking place. Moreover, this approach is aimed to provide insight towards building more effective innovation policies in health-oriented nanotechnologies.
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