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MS applications for rapid opioid detection
Medicilon’s toxicology department has professional teams with rich experience in toxicology studies. We offer high-quality data and rapid turnaround period to support drug discovery and development. Our toxicological studies are conducted in various animal species. The toxicological evaluation from dose design, in-life studies to histology and pathology testing along with toxicokinetics studies are all compliant with GLP or NON-GLP standards. Our study platform is certified as one of the Shanghai Public Service Research Platforms.
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The studies presented herein were born through the observations of the challenges that are faced by forensic toxicology study laboratories. While these challenges were first observed in the forensic toxicology field, they are common across clinical, workplace drug testing, and pain management laboratories alike. The challenge is how to increase efficiency without sacrificing quality. Current drug screening protocols such as immunoassays (IA), gas chromatography mass spectrometry (GC/MS), and liquid-liquid chromatography tandem mass spectrometry (LC/MS/MS) are robust but inefficient and limited, with some analyses providing only class information. These analyses when coupled require up to four days to complete for a confirmed, reportable finding. Long analysis times contribute to the backlogs faced by many clinical and toxicological laboratories. In the study presented here, desorption ionization mass spectrometry (DIMS) or, more specifically, Direct Analysis in Real Time mass spectrometry, DART™ MS, as a potential analysis platform for increasing analysis efficiency. DART™ enabled mass spectrometers are capable of providing specific analyte information in minutes. Therefore, this dissertation was designed to provide proof-of-concept that DART™ MS can be developed as a high throughput, cost effective, and highly selective platform for the analysis of select opioids in ante- and post-mortem biological specimens (i.e. blood, urine, and vitreous humor). This study focused on seven opioids analytes commonly encountered in drug testing laboratories in the three commonly submitted matrices. The selected analytes included: hydrocodone, methadone, morphine, 6-monoacetylmorphine (6MAM), morphine-6-β-glucuronide, oxymorphone and tapentadol. The selected matrices were whole blood, urine, and vitreous humor. Three key areas were evaluated as part of this dissertation: instrument selection/method development, comparison of sample processing techniques, and protocol verification. Two DART™ enabled mass spectrometers were selected: a DART™ enabled time of flight (TOF) mass spectrometer, was used for screening and a DART™ enabled triple quadrupole linear ion trap (QTRAP) mass spectrometer, used for confirmation. Both instruments rely on the mass spectrometer for separation rather than chromatography allowing for data acquisition with 2.0 and 2.5 minute methods, respectively. Acquisition methods were designed through optimization of each analyte, used to analyze fortified samples prepared for each matrix, and processed through a series of protocols. Results of this study indicated that the “best” protocol for each matrix to be dependent upon the instrument sensitivity, the analyte chemistries, and the matrix composition. For whole blood, a liquid-liquid extraction protocol utilizing a dichloromethane/chloroform extraction solvent provided the best coverage of selected toxicology study analytes with the highest overall responses. This protocol was utilized to validate the designed DART™ QTRAP™ MS methods. Successful validation resulted in highly selective and specific methods for hydrocodone, methadone, tapentadol, and oxymorphone at therapeutic and sub-therapeutic concentrations. Therefore, we present DI-MS instruments such as the DART™ MS as a complementary platform for analysis of select opioids in biological specimens.
The genetic toxicology of carcinogenic compounds
Medicilon’s toxicology department has professional teams with rich experience in toxicology studies. We offer high-quality data and rapid turnaround period to support drug discovery and development. Our toxicological studies are conducted in various animal species. The toxicological evaluation from dose design, in-life studies to histology and pathology testing along with toxicokinetics studies are all compliant with GLP or NON-GLP standards. Our study platform is certified as one of the Shanghai Public Service Research Platforms.
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This thesis involved the development of a range of assay systems for the detection of environmental mutagens and carcinogens. Initially a protocol was optimised for the induction of mitotic gene conversion in stationary-phase cultures of the yeast Saccharomyces cerevisiae, strain JD1 following exposure to compounds which require exogenous metabolic activation, which involved an initial incubation at 37oC for 2 hours followed by a 16 hour incubation at 28oC. This protocol was found to be effective for the detection of cyclophosphamide and sterigmatocystin. In two separate studies, the activities of a total of 14 different compounds were then investigated in yeast using this, and other protocols involving exponential-phase cultures. In the first study, benzidine and diaminoterphenyl were detected, although, despite being structural analogues, their metabolic requirements differed. Dimethylaminoazobenzene and cyanodimethylaniline could not be detected under any of the conditions examined. In the second of these studies 8 carcinogens and 2 non-carcinogens were examined.
Only one of the carcinogens, Acrylonitrile, was detected. The inactivity of the other 7 carcinogens was considered to be due to their ineffectiveness at inducing mitotic gene conversion. A third study indicated that respiratory status of the yeast strain used, had both quantitative and qualitative effects on the detection of sterigmatocystin, benzidine and diaminoterphenyl. Further studies were performed on two additional assays, chromosomal aberration induction and mammalian cell transformation, as these endpoints had proved very successful for detecting chemicals which were not readily detected in assays for other genetic endpoints. BZD was found to induce chromosomal abberrations in peripheral human lymphocyte cultures, in the absence of S9, which was in contrast to the activity detected in the yeast system in toxicology studies. It was suggested that this was due to metabolic competence of the human lymphocyte cells. Studies on the stepwise transformation of Syrian hamster dermal cells, led to the suggestion of a model for the occurrence of aneuploidy events during this process, and their fixation at completion of transformation. The significance of this with respect to the observed occurrence of aneuploidy with cancer is discussed.
Hybrid Computational Toxicology Models for Regulatory Risk Assessment
Medicilon’s toxicology department has professional teams with rich experience in toxicology studies. We offer high-quality data and rapid turnaround period to support drug discovery and development. Our toxicological studies are conducted in various animal species. The toxicological evaluation from dose design, in-life studies to histology and pathology testing along with toxicokinetics studies are all compliant with GLP or NON-GLP standards. Our study platform is certified as one of the Shanghai Public Service Research Platforms.
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Computational toxicology study is the development of quantitative structure activity relationship (QSAR) models that relate a quantitative measure of chemical structure to a biological effect. In silico QSAR tools are widely accepted as a faster alternative to time-consuming clinical and animal testing methods for regulatory risk assessment of xenobiotics used in consumer products. However, different QSAR tools often make contrasting predictions for a new xenobiotic and may also vary in their predictive ability for different class of xenobiotics. This makes their use challenging, especially in regulatory applications, where transparency and interpretation of predictions play a crucial role in the development of safety assessment decisions. Recent efforts in computational toxicology involve the use of in vitro data, which enables better insight into the mode of action of xenobiotics and identification of potential mechanism(s) of toxicity. To ensure that in silico models are robust and reliable before they can be used for regulatory applications, the registration, evaluation, authorization and restriction of chemicals (REACH) initiative and the organization for economic co-operation and development (OECD) have established legislative guidelines for their validation.
This dissertation addresses the limitations in the use of current QSAR tools for regulatory risk assessment within REACH/OECD guidelines. The first contribution is an ensemble model that combines the predictions from four QSAR tools for improving the quality of predictions. The model presents a novel mechanism to select a desired trade-off between false positive and false negative predictions. The second contribution is the introduction of quantitative biological activity relationship (QBAR) models that use mechanistically relevant in vitro data as biological descriptors for development of computational toxicology models. Two novel applications are presented that demonstrate that QBAR models can sufficiently predict carcinogenicity when QSAR model predictions may fail.
The third contribution is the development of two novel methods which explore the synergistic use of structural and biological similarity data for carcinogenicity prediction. Two applications are presented that demonstrate the feasibility of proposed methods within REACH/OECD guidelines. These contributions lay the foundation for development of novel mechanism based in silico tools for mechanistically complex toxic endpoints to successfully advance the field of computational toxicology study.
Multiplex Microsphere Assays for High-Throughput
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Proteases are of great interest as possible drug targets, because they regulate many physiological processes including infection, cell growth and death, fertilization, inflammation, allergic reactions, bone remodeling, tumor growth and blood clotting. Bacterial proteases are critical to the toxicity of many pathogens as they commonly target host pathways that lead to the death of the host organism. Therefore, the development of novel drugs and antibiotics that target bacterial protease is of great importance. At present, there are five catalytic types of bacterial proteases that have been recognized. Four are based on the type of amino acid found at the active site (serine, threonine, cysteine, or aspartate), while the fifth type coordinates a metal ion in its active site. These metalloproteases (MPRs) are specific proteases use coordinated metal ions to attack the peptide bond to cleave proteins. The metal ion is usually zinc, cobalt, or manganese. Generally, MPRs are divided into two groups depending on how many metal ions are required in the catalytic mechanism. So far, most MPRs are one-metal-iondependent proteases, with the exception of some exopeptidases that require two catalytic metal ions for efficient cleavage. MPRs are widely used by bacteria and play various pathogenic roles in infection. For example, some bacteria use MPRs to process enterotoxin (e.g. cholera toxin) to their active state. Other bacteria use proteases as part of their toxins, which is the case for the Botulinum neurotoxins (BoNT) and Tetanus neurotoxins (TeNT) that use MPRs to directly cleave target host proteins. For these reasons, MPRs are important targets for compound screening.
Most MPRs are zinc-dependent proteases and are integral to virtually all aspects of metabolism.The consensus binding motif for zinc-containing metalloproteases is HEXXH, in which two histidine residues coordinate zinc divalent cationic binding. This zinc-binding motif has been found in the light chain of Clostridium Botulinum neurotoxins, Bacteroides fragilis enterotoxin, and Bacillus anthracis lethal factor. These light chain proteases require the presence of zinc for activity. Of specific interest to this work, Botulinum neurotoxin (BoNT) light chains cleave one of three soluble Nethylamaleimide-sensitive factor-attachment protein receptor (SNARE) proteins that are components of the neuroexocytosis machinery. Cleavage of these proteins leads to the blockade of neurotransmitter release and consequent paralysis. The light chain of Bacillus anthracis lethal toxin, known as lethal factor (LF) cleaves the mitogen-activated protein kinase-kinases (MAPKKs) at their amino-terminus. Though the toxicity of many bacterial toxins are due to the Zn metalloproteases activity, the Zn coordinating active site is highly conserved across many families of zinc metalloproteases. This makes it difficult to target the active site of toxin MPRs, as the numerous cellular Zn metalloproteases, such as matrix metalloprotease (MMPs) and metalloproteases with a disintegrin domain (ADAM) are critical for cell processes. Therefore, understanding the structure-activity relationships of these enzymes would be beneficial for the development of potential inhibitors. In addition, a further understanding of the mechanism of these enzymes will offer great opportunity for compound screening or create new and useful protease compounds that specifically target toxin MPRs.
Expression, purification, and assay development for recombinant expressed tryptophan synthase from Escherichia coli
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The emergence of antibiotic resistant bacteria has been a global concern for numerous decades. Bacteria are able to attain resistance to many current antibiotics due to high mutation rates and the ability to share genomic DNA with other bacterial species. New pathways need to be exploited for drug design studies, not only to limit the spread of resistance but also to generate a greater diversity in antimicrobial mechanisms. Tryptophan is an essential amino acid that is synthesized from enzymes found only in plants and bacteria. The lack of any enzyme homologues for humans makes this pathway an ideal target for inhibition studies. We have previously shown in laboratory studies that bacterial mutants lacking the tryptophan gene are unable to grow in tryptophan deprived media, further demonstrating the potential for drug design studies against it. E. coli Tryptophan synthase (TrpS), the enzyme catalyzing the last two steps in the biosynthetic pathway of tryptophan, was chosen for inhibitor compound screeningstudies. TrpS consists of two distinct subunits (TrpS-α and TrpS-β), each able to catalyze their own reaction. TrpS-α and TrpS-β protein were separately cloned, expressed and purified to >90% purity using recombinant-expression techniques. Assays were developed for the TrpS-α and TrpS-β enzymes to assess their catalytic activity and the TrpS-β assay was converted to a 96-well plate format for initial inhibitor screening. In vitro and in silico screens using a first generation library of compounds generated against IGPS, the enzyme just prior to TrpS in the tryptophan biosynthetic pathway, resulted in several potential inhibitors for future lead compound screening development. The results of this study demonstrate the potential to develop a new class of inhibitors against E. coli TrpS.
toxicology study of bromidichloroaetic acid
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The National Toxicology Program (NTP) is an interagency program within the Public Health Service (PHS) of the Department of Health and Human Services (HHS) and is headquartered at the National Institute of Environmental Health Sciences of the National Institutes of Health (NIEHS/NIH). Three agencies contribute resources to the program: NIEHS/NIH, the National Institute for Occupational Safety and Health of the Centers for Disease Control and Prevention (NIOSH/CDC), and the National Center for Toxicological Research of the Food and Drug Administration (NCTR/FDA). Established in 1978, the NTP is charged with coordinating toxicological testing activities, strengthening the science base in toxicology study, developing and validating improved testing methods, and providing information about potentially toxic substances to health regulatory and research agencies, scientific and medical communities, and the public.
The Technical Report series began in 1976 with carcinogenesis studies conducted by the National Cancer Institute. In 1981, this bioassay program was transferred to the NTP. The studies described in the Technical Report series are designed and conducted to characterize and evaluate the toxicology study, including carcinogenic activity, of selected substances in laboratory animals (usually two species, rats and mice). Substances selected for NTP toxicity and carcinogenicity studies are chosen primarily on the basis of human exposure, level of production, and chemical
structure. The interpretive conclusions presented in NTP Technical Reports are based only on the results of these NTP studies. Extrapolation of these results to other species, including characterization of hazards and risks to humans, requires analyses beyond the intent of these reports. Selection per se is not an indicator of a substance’s carcinogenic potential.
The NTP conducts its studies in compliance with its laboratory health and safety guidelines and FDA Good Laboratory Practice Regulations and must meet or exceed all applicable federal, state, and local health and safety regulations. Animal care and use are in accordance with the Public Health Service Policy on Humane Care and Use of Animals. Studies are subjected to retrospective quality assurance audits before being presented for public review.
Toxicology study of drugs and chemicals
Medicilon’s toxicology department has professional teams with rich experience in toxicology studies. We offer high-quality data and rapid turnaround period to support drug discovery and development. Our toxicological studies are conducted in various animal species. The toxicological evaluation from dose design, in-life studies to histology and pathology testing along with toxicokinetics studies are all compliant with GLP or NON-GLP standards. Our study platform is certified as one of the Shanghai Public Service Research Platforms.
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Toxicology study is the study of the harmful effects of substances on living organisms: humans, plants and animals. Toxicological testing evaluates the biological response of living organisms to different routes and durations of exposure to a substance. Nonhuman primates wereused because OP-1 is a recombinant human protein. Guinea pigs and rabbits were used asstandard species for dermal sensitization and developmental toxicology studies,respectively.
Modern toxicology contributes to clinical, legal, occupational and veterinary medicine and plays a key role in the development of drugs, food additives, home products, cosmetics, industrial chemicals, agrochemicals, pesticides, etc. Paracelsus, a 16th Century Swiss physician recognized as the "father of toxicology," is noted for his principle that all substances are poisons if the dose is sufficiently high – “the dose makes the poison.” He understood that the relationship between dose and response are inseparable. At very low doses, even notorious toxins such as arsenic will not cause harm. Conversely, at very high doses, essential substances such as water will harm or kill.
There are two different related areas in the measurement of toxicants and toxicity in food: 1) actual measurements of the effects of toxicants in different models ranging from in vitro biochemical systems, cell-based in vitro systems, animal in vivo models to clinical settings analyzing systemic or organ-specific toxicity and 2) assessment and/or predictions of potential toxicants in food. These two are interrelated since the mechanistic knowledge gained by the actual assessment of the effects of toxicants can lead to the identification of other potential toxicants in food. The majority of assessment systems for food toxicology study were developed in the field of pharmacology. Pharmacology and nutritional science share common roots since many of the world's most commonly used drugs are derived from natural products .
Mechanisms of Action: Knowledge of Toxicity
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Toxicology examines the chemical origins of adverse effects in biological systems. The scope of toxicology is broad covering investigations of dose response effects, exposure routes, biological targets, pathways, and biochemical processes. All these fields are united through interpretation based on knowledge of molecular mechanisms of action.
In other words, the series of processes leading from exposure to outcome including uptake, distribution, metabolism, biological transformation, and accumulation. We use the results of molecular toxicology study to refine our knowledge of chemical-endpoint relations. Knowledge of mechanism of action allow us to interpret results (e.g. dose response curves], limit scope of investigations (e.g. examine specific biological targets), and identify novel interactions. We elucidate these mechanisms by uncovering relations between chemical and endpoints, identifying biological targets, and determining system level effects of chemical exposure. Developing relations between chemical and endpoint provides information on how and why a chemical is toxic. Toxicity endpoints refer to observations regarding a specific disease, symptom, or sign related to toxicity. The goal is to establish a relationship between dose and effect. These relationships are specific to the test system used, in vitro, in vivo, and how the chemical is exposed such as exposure site and dosageorganism. Knowledge of endpoint relations is used to guide investigations examining chemical interaction with specific biological targets. Further statistical analysis of data can refine chemical endpoint relationships to the individual contributions of chemical substructure. Using chemical or substructure-endpoint relations we can determine the fate and effect of a chemical as it moves through an Understanding how a chemical interacts with a biological target provides information to the mechanistic workings of toxicity. A chemical can interact at multiple levels of an organism, such as alter gene transcription and/or protein stability. Investigations may involve measuring the effects of individual gene transcription rate changes in response to chemical exposure. The data produced from these investigations provides information as to the targets a chemical works through to produce an outcome. For an organism, the final level mechanisms of actions are uncovered is at the level of the system. A system level of investigation seeks to understand how the entire biological system interacts due to chemical perturbation. Investigations on the system typically fall under the category of 'omics: proteomics, genomics, or metabolomics. Each seeks to understand the effect on the system at the protein, gene, and metabolite level respectively. The data from these experiments help uncover the overall system patterns reflected by chemical toxicity. These changes may be the result of individual or multiple mechanisms of action. The analysis and interpretation of systems level investigation relies on knowledge of chemical-endpoint and molecular toxicity relations. Mechanism of action is the knowledge linking the diverse scope and purpose of toxicology study. This knowledge is complied from separate investigations examining a small part of the overall toxic process. Each type of investigation produces data that uncovers a facet of chemical toxicity. Any insight to be gained from these investigations depends on how we struc 10 ture, store, and share information to allow examination of the complete picture. The greater the detail and integration of captured data the higher the chance of developing useful predictive patterns.
Uncovering Patterns in Toxicity: Data Mining
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Data mining is the process of finding patterns in data. It is about uncovering the underlying rules and trends that are inherent in data . By uncovering patterns we characterize raw data into useful information by providing context and meaning. We find these rules and trends using a combination of statistics, machine learning, computer science, and information theory. In the field of toxicology study and risk assessment there is a need to move away from in vitro and in vivo testing, As such, there is a move towards in silico methods, such as data mining, to characterizing potential toxicity, Predictive models can be generated based on data driven or expert based systems. In data driven systems patterns are automatically or semiautomatically extracted to build models with predictive outcome (linear models, decision trees, and bayesian networks]expert decision logic formulated by a domain expert. The patterns expressed are those learned by a domain expert to make decision regarding interpretation of data. Both these systems can take the form of rule based models. One such rule based model found in toxicology is decision trees. Data driven systems can be used to uncover chemical bioactivity relationships and experimentally derive outcomes such as phenotype. These models are validated based on their ability to correctly classify data according to the specified outcome. A second type of system are those representing human decision logic or knowledge. Expert based systems are representations of Decision trees represent a 'divide and conquer' approach to learning and representing data patterns. Each tree is made up of nodes and paths. Nodes represent tests of specific attrib utes contained in the data and paths are the test result. In toxicology study, decision trees were first established by Cramer and Cramer in 1976 to estimate potential toxicity. Since their introduction, decision trees have been accepted as a representation for predictive models of data driven and expert based systems. Decision trees represent an interpretable model capable of handing mixed data types[e.g numerical and nominal) but are limited to categorical output. However, a disadvantage with decision trees, and all predictive models, is the format we capture the model affects how and what they can be used for. The logic behind the model, rules and descriptors, are not easily shared or compared between applications due to lack of shared model standards and vocabulary. If we could represent the meaning of a model we could derive logical explanations of classification. The semantics would also enable comparison of derived models based on similarity. Knowing how models differ would allow us to identify relevant models from a collection.
Bioanalytical methods study of Protein
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A quantitative method for the determination of proteins in complex bioloanalysis studies has been developed based on the selectivity of antibodies for sample purification followed by proteolytic digestion and quantitative mass spectrometry. An immunosorbent of polyclonal anti-bovine serum albumin (BSA) antibodies immobilized on CNBR agarose is used in the on-line mode for selective sample pretreatment. Next, the purified sample is trypsin digested to obtain protein specific peptide markers. Subsequent analysis of the peptide mixture using a desalination procedure and a separation step coupled, on-line to an ion-trap mass spectrometer, reveals that this method enables selective determination of proteins in biological matrices like diluted human plasma.
This approach enhances substantially the selectivity compared to common quantitative analysis executed with immunoassays and colorimetry, fluorimetry or luminescence detection. Hyphenation of the immunoaffinity chromatography with on-line digestion and chromatography–mass spectrometry is performed and a completely on-line quantification of the model protein BSA in bovine and human urine was established. A detection limit of 170 nmol/l and a quantification limit of 280 nmol/l is obtained using 50 μl of either standard or spiked biological matrix. The model system allows fully automated absolute quantitative mass spectrometric analysis of intact proteins in biological matrices without time-consuming labeling procedures.
Protein phosphorylation catalyzed by protein kinase is one of the most important post-translational modifications and plays a significant regulatory role in many vital bioloanalysis studies. Aberrant protein-phosphorylation states and kinase activity are closely associated with many human diseases. Monitoring the kinase activity and its inhibition is essential for fundamental biochemical research and kinase-targeted drug discovery. Nanomaterial-based kinase assays provide a promising toolkit for exploring protein kinase functions, which have attracted growing interest in academic research, biomedical diagnosis, and pharmaceutical discovery. The recent advances in the development of the protein kinase activity assays based on various nanomaterials, classifies these methods by different analytical techniques, summarizes the general design strategies, and offers perspectives on future developments.
Uncovering Patterns in Toxicity: Data Mining
Medicilon’s toxicology department has professional teams with rich experience in toxicology studies. We offer high-quality data and rapid turnaround period to support drug discovery and development. Our toxicological studies are conducted in various animal species. The toxicological evaluation from dose design, in-life studies to histology and pathology testing along with toxicokinetics studies are all compliant with GLP or NON-GLP standards. Our study platform is certified as one of the Shanghai Public Service Research Platforms.
Website: www.medicilon.com E-mail: Marketing@medicilon.com.cn
Data mining is the process of finding patterns in data. It is about uncovering the underlying rules and trends that are inherent in data . By uncovering patterns we characterize raw data into useful information by providing context and meaning. We find these rules and trends using a combination of statistics, machine learning, computer science, and information theory. In the field of toxicology study and risk assessment there is a need to move away from in vitro and in vivo testing, As such, there is a move towards in silico methods, such as data mining, to characterizing potential toxicity, Predictive models can be generated based on data driven or expert based systems. In data driven systems patterns are automatically or semiautomatically extracted to build models with predictive outcome (linear models, decision trees, and bayesian networks]expert decision logic formulated by a domain expert. The patterns expressed are those learned by a domain expert to make decision regarding interpretation of data. Both these systems can take the form of rule based models. One such rule based model found in toxicology is decision trees. Data driven systems can be used to uncover chemical bioactivity relationships and experimentally derive outcomes such as phenotype. These models are validated based on their ability to correctly classify data according to the specified outcome. A second type of system are those representing human decision logic or knowledge. Expert based systems are representations of Decision trees represent a 'divide and conquer' approach to learning and representing data patterns. Each tree is made up of nodes and paths. Nodes represent tests of specific attrib utes contained in the data and paths are the test result. In toxicology study, decision trees were first established by Cramer and Cramer in 1976 to estimate potential toxicity. Since their introduction, decision trees have been accepted as a representation for predictive models of data driven and expert based systems. Decision trees represent an interpretable model capable of handing mixed data types[e.g numerical and nominal) but are limited to categorical output. However, a disadvantage with decision trees, and all predictive models, is the format we capture the model affects how and what they can be used for. The logic behind the model, rules and descriptors, are not easily shared or compared between applications due to lack of shared model standards and vocabulary. If we could represent the meaning of a model we could derive logical explanations of classification. The semantics would also enable comparison of derived models based on similarity. Knowing how models differ would allow us to identify relevant models from a collection.
Txicological studies of recombinant factor VIII Fc fusion protein in animals
Medicilon’s toxicology department has professional teams with rich experience in toxicology studies. We offer high-quality data and rapid turnaround period to support drug discovery and development. Our toxicological studies are conducted in various animal species. The toxicological evaluation from dose design, in-life studies to histology and pathology testing along with toxicokinetics studies are all compliant with GLP or NON-GLP standards. Our study platform is certified as one of the Shanghai Public Service Research Platforms.
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The toxicological studies effects of rFVIIIFc were measured through observations of in-life parameters (clinical observations, body weight, food consumption, and ophthalmic examination), laboratory evaluations (hematology, serum chemistry, and coagulation parameters), and post-mortem evaluation (gross necropsy, organ weights, and histopathology) in all studies. Cardiovascular evaluations were also performed for monkeys in the repeat-dose toxicology study. Electrocardiograms (ECGs) were recorded for all monkeys prior to dosing and on Day 23, as well as in the week prior to the scheduled core cohort necropsy (Day 26) and all recovery monkeys during the week prior (Day 54) to the recovery cohort necropsy; ECGs were analyzed qualitatively by a board-certified veterinary cardiologist. Heart rates were calculated from the ECG tracings. Local tolerance was evaluated through gross and microscopic evaluation of the intravenous infusion site in the repeat-dose studies in both rats and monkeys.
For the repeat-dose studies, assessments of in-life parameters, clinical pathology, and post-mortem evaluations were analyzed statistically when the number of animals was 3 or greater. Data were analyzed for effects of rFVIIIFc through an analysis of variance. For data with variances that were homogeneous across test groups, as determined by Bartlett’s test for homogeneity at the 0.05 level, tests for differences between experimental and control groups were made using Dunnett’s test. For non-homogenous data, tests for pair-wise differences between experimental and control groups were made using Cochran and Cox’s modified 2-sample t test. Statistical significance was set at the 0.05 level for all comparisons.
Rats and monkeys were pharmacologically relevant species for toxicological studies, as the coagulation cascade is well conserved across species and rFVIIIFc is able to bind to FcRn in both species (unpublished data). The route of administration (intravenous) and formulations of rFVIIIFc used in this study were consistent with those used in clinical studies; the lyophilized formulation used in the repeat-dose monkey study was representative of the formulation intended for commercial use. Dosing frequency in the repeat-dose studies (every other day) was based on an elimination half-life of approximately 13 hours in both species. The doses of rFVIIIFc used in these studies (50-1000 IU/kg in the repeat-dose studies and 3000-20,000 IU/kg in the high-dose study) were greater than those indicated for use in humans.
rFVIIIFc was well tolerated in 2 relevant animal species, rats and monkeys. An adequate safety margin of 10-fold was demonstrated, based on a NOAEL of 1000 IU/kg in the repeat-dose toxicology studies compared with a highest anticipated clinical dose of 100 IU/kg. The nonclinical safety profile of rFVIIIFc shown here supported the observed clinical safety profile of rFVIIIFc [9] and. Furthermore, the A-LONG phase 3 clinical study demonstrated that rFVIIIFc was well tolerated and efficacious for the prevention and treatment of bleeding episodes in previously treated subjects with severe hemophilia.
A Xenobiotic can Cause Adverse Side Effects
Medicilon’s toxicology department has professional teams with rich experience in toxicology studies. We offer high-quality data and rapid turnaround period to support drug discovery and development. Our toxicological studies are conducted in various animal species. The toxicological evaluation from dose design, in-life studies to histology and pathology testing along with toxicokinetics studies are all compliant with GLP or NON-GLP standards. Our study platform is certified as one of the Shanghai Public Service Research Platforms.
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Xenobiotics are foreign chemicals that are either not found normally in the human body or not produced naturally. Common xenobiotics include pharmaceutical drugs, environmental pollutants and pesticides. Every day, we are exposed to a wide variety of xenobiotics that are used in consumer products, ranging from pharmaceuticals and food additives to agricultural products and cosmetics. Even though these products are useful, they may be associated with undesirable side effects in humans as a response to xenobiotic exposure. For example, aspirin (chemical acetylsalicylic acid) is a relatively safe over-the-counter analgesic that is taken by people all over the world. However, chronic use of aspirin can cause serious side effects on the gastric mucosa, and it is fatal at a dose of about 0.2 to 0.5 g/kg. Another example is kohl (black eyeliner), a commonly used eye cosmetic, that is often contaminated with lead. Absorption of lead or lead poisoning is considered to be the most important environmental disease and is known to cause juvenile delinquency, behavioral problems and renal problems.
The word “toxicity” describes the extent to which a xenobiotic can cause adverse side effects. Toxicology study is the branch of science that is concerned with the study of adverse or toxic effects of chemical, physical or biological agents on living organisms and the ecosystem, including the prevention and amelioration of such adverse effects. A toxic endpoint is a specific toxic response to a toxic agent, e.g. skin sensitivity. Toxicity is the leading cause of failure of new medical devices and pharmaceutical drugs. The success of a medicinal product, pharmaceutical drug or a medical device depends not only on its efficacy but also on its chemical composition. Xenobiotic exposure through pharmaceutical drugs happens directly by oral consumption. Medical devices, on the other hand, cause indirect exposure because of leaching and migration of chemicals from the device material to the human body. Pharmaceutical drugs and medical devices, therefore, need to undergo a rigorous regulatory risk assessment procedure before they obtain marketing approval. Chemical risk assessment or evaluation of the extent of toxic effects associated with xenobiotic exposure is, therefore, necessary for protection of human and environmental health.
The extent of risk exerted by a xenobiotic is determined by its absorption, distribution, metabolism, elimination and toxicological, commonly referred to as the ADMET profile. Absorption is the process of transfer of drug from the site of administration into the systemic circulation. Distribution is the process of reversible transfer of drug from blood to different parts of the body and its transportation to the site of action. Xenobiotic distribution is dependent on several factors like physicochemical properties of the xenobiotic (e.g. solubility), physiological factors (e.g. permeability of tissue membranes) and xenobiotic interactions in the blood and tissues (e.g. binding to carrier proteins). Metabolism, also referred to as biotransformation, is the process of transformation of the xenobiotic inside the body into an easily excrete-able form. Sometimes it may also involve biochemical transformation of an inactive xenobiotic into an active metabolite. The process of metabolism usually takes place in the liver. Elimination is the process of irreversible removal of the xenobiotic and the metabolites from the body. Elimination can happen by metabolism and excretion. The knowledge of ADME parameters is useful in predicting xenobiotic concentration in the body at any point of time and its potential side-effects. It is a fine optimization of a chemical’s potency and its ADMET properties that ultimately leads to the selection and clinical development of chemical components of a potential medicinal product. Chemical risk assessment early in the pharmaceutical or device development is, therefore, important in understanding human biological response to a xenobiotic in Toxicology study.
