Il corso ha l’obiettivo di fornire allo studente le conoscenze necessarie relative agli obiettivi della Farmacovigilanza, in particolare la valutazione del rischio connesso all’assunzione dei farmaci e la stima dell’incidenza delle loro reazioni avverse. Attraverso lo studio dell’organizzazione del Sistema di Farmacovigilanza, lo studente comprenderà come tali obiettivi siano raggiungibili attraverso i seguenti passaggi fondamentali: 1) individuare il più rapidamente possibile nuove reazioni avverse da farmaci (ADR); 2) migliorare ed allargare le informazioni su ADR sospette o già note; 3) valutare i vantaggi di un farmaco su altri o su altri tipi di terapia; 4) disseminare tali informazioni per rendere più corretta e adeguata la pratica clinica terapeutica. Tali conoscenze permetteranno allo studente di acquisire capacità professionali specifiche, correlate al monitoraggio di effetti indesiderati associati ad un trattamento farmacologico. Durante il corso, lo studente sarà stimolato a formulare giudizi e ad esercitare il senso critico relativamente alle problematiche studiate.
Il corso è articolato in lezioni frontali al fine di consentire l'acquisizione delle conoscenze, di sviluppare le capacità comunicative ed il linguaggio tecnico attraverso l'interazione in aula con il docente su argomenti inerenti al corso e a problematiche correlate. L'approccio critico del corso permetterà allo studente di sviluppare l'autonomia di apprendimento, utile ai fini degli studi successivi o per l'auto-aggiornamento.
The course of Toxicology aims to provide students with the qualifying knowledge about the toxicological effects and the mechanism of action of physical and chemical agents on mammals and environment, and about the possible protective/preventive strategies to apply for the toxicity risk management. The student will acquire knowledge about the principles of general toxicology (toxicodynamic, toxicokinetic, mutagenesis, cancerogenesis and teratogenesis), the risk assessment procedures, and about some topics of systemic toxicology, food toxicology and ecotoxicology. This knowledge will allow the student to acquire the suitable professional skills related to environmental, drug, cosmetic and food safety. During the course, the student will be stimulated to critically evaluate the challenges and problems about the topic under study, particularly the toxicity power of some natural compounds whose toxicity risk is often underperceived due to their natural origin or the low exposure levels. The course is based on lectures aimed at developing communication skills and technical language through the classroom interaction with the lecturer about the toxicology and the related challenges. Taking advantage of the lecturer support, the student could explore specific topics of toxicology, through looking up medical and scientific databases, which will be further discussed in the classroom. The course will also allow the student to develop communication skills and autonomy of learning, useful to perform subsequent studies or for the self-updating.
SILVIA DI GIACOMO Teacher profile
The program of the course is divided into two main sections, namely Pharmacovigilance and Toxicology, organized as follows.
The Pharmacovigilance section is divided into two parts: in the first part (10 h) the general aspects of the teaching are examined, particularly with regard to the process that leads to drug development, to the adverse reactions drug-induced and finally to the assessment of the causal link between the adverse reaction and drug consumption (point 1); in the second part (12 h), the methodologies used in Pharmacovigilance are studied in depth, with particular reference to spontaneous reporting and the modalities with which it must be performed, and to both epidemiological and clinical studies that allow to identify an adverse reaction to a drug (point 2). The second part of the program also includes classroom exercises in which cases of adverse drug reactions will be analyzed (2h). This will allow the student to apply the acquired knowledge and to exercise the critical sense regarding the problems studied.
The Toxicology section is divided into two parts: in the first part (16 h) the general aspects of Toxicology are examined, particularly with regard to the factors responsible for the manifestation of the toxic reaction, the routes of exposure and the analysis of the toxicological risk (point 1); in the second part (32 h), toxicity mechanisms are investigated with particular reference to cellular toxicity, genotoxicity, carcinogenesis, teratogenesis and the role of the absorption, distribution, metabolism and excretion processes in the manifestation of the toxic effect (point 2). Furthermore, in the second part, specific examples of toxic compounds and their toxicological profile will be included.
1. Introduction to pharmacovigilance
Historical background and aim of Pharmacovigilance. Drug iter: pre- and post-marketing studies. Information provided by pre-marketing studies; advantages and limitations of pre-marketing studies.
Adverse drug reactions (ADR): definitions of side effect, adverse event, adverse reaction.
Classification of adverse reactions: factors that make it difficult to identify ADR. Severity of ADR (levels I, II, III, IV, VI, VII).
Causality assessment: temporal relationship, dechallenge and rechallenge, literature data, Naranjo algorithm and WHO.
2. Pharmacovigilance methodologies
Passive pharmacovigilance: spontaneous reporting. Potential of spontaneous reports. Criteria to be followed in reporting an adverse reaction. Factors that influence the reliability of an alert. Stress of under-reporting and over-reporting. Factors to be considered for each ADR report: randomness, reporting documentation, frequency of reports, severity of adverse reactions, potential for risk, mechanism of drug action, pre-clinical studies, clinical trials and epidemiological studies. Iter of a report. Card for reporting an adverse reaction. Case report and Case series.
Active pharmacovigilance: epidemiological studies. Factors to consider when using a drug: efficacy, safety, economy, appropriateness, risk / benefit ratio. Evolution of pharmacovigilance systems over time: analysis of risk factors (identification, evaluation, quantification), management of risk factors, sources of risk in the use of drugs. The main measures for studying phenomena in populations: epidemiological studies; case-control studies, cohort studies, meta-analysis, Randomized Controlled Trial (RCT), Prescription Event Monitoring (PEM), PEM Organizational Scheme.
Data banks; General Practice Research Database (GPRD).
Pharmacovigilance legislation: new Italian legislation, Community directives on Pharmacovigilance, organization of Pharmacovigilance system at Italian, European and world level.
1. General principles of Toxicology
Toxicology interest areas. Definition of toxicity and toxic agent. Classification of toxic agents. Types of adverse effects and characteristics: target, latency period, persistence. Exposure characteristics: pathways and sites, duration and frequency of exposure. Adverse reactions: definition and types. Allergic reactions, idiosyncrasy, immediate and delayed, reversible, irreversible, local, systemic toxicity. Interactions between xenobiotics: additive effect, synergism, potentiation, antagonism, tolerance.
Dose concept. Dose-response relationship: gradual, quantal, hormonal response. Normal distribution of the response. Expression of results in percentage graph and in probit (doses in logarithmic scale). Effective doses and toxic doses: LC50, LD50, therapeutic index, safety margin.
Evaluation of toxicological risk
Concept of toxicological risk and hazard. REACH (Regulation, Evaluation, Authorization of Chemicals) and Regulatory Bodies. Procedures for toxicological risk analysis: hazard identification, risk assessment, management and communication. Methods applied to risk analysis and toxicological protocol. OECD guidelines for acute, sub-acute and chronic toxicity studies. Carcinogenicity studies. Evaluation of the dose-response curve: LOEL, LOAEL, NOEL, NOAEL. Determination of acceptable risk and margin of safety. Definition of Rfc, ADI, TDI, PDE and Benchmark dose. Threshold of toxicological concern (TTC) concept. Calculation of ADI. Safety factors. Degree of uncertainty due to extrapolation from animal species to humans. Corrective factors: duration of exposure, inter-individual variability, severity of the toxic effect.
Absorption, distribution and excretion of toxic substances. Biotransformation of xenobiotics: Phase I and Phase II reactions. Cytochrome CYP450 system. Induction and enzymatic inhibition. Genetic polymorphisms and their role in the expression of toxicity. Ethanol metabolism and toxicity. Examples of toxic xenobiotics activated following biotransformation.
Types of cell damage and responses. Mitochondrial damage. Depletion of ATP. Lipid peroxidation and membrane damage. Oxidative stress and reactive oxygen and nitrogen species: cellular defense mechanisms. Cell adaptation. Cell death: necrosis, apoptosis.
Mechanisms of genetic damage. Point and chromosomal mutations. Clastogenic and aneuploidogenic effect. Effects of mutations. Mutagenesis and carcinogenesis. Measurement of genotoxic damage: genotoxicity tests, applications and regulatory guidelines. In vitro, in vivo and in silico genotoxicity studies. Genotoxicity test in ecotoxicology and epidemiology. Ames test: general principles, methods, bacterial strains for genotoxicity studies, exogenous metabolic activator. Micronucleus test: general and methodical principles. Comet test
Features of the carcinogenic process. Mechanisms of action and classification of chemical carcinogens (genotoxic and epigenetic carcinogens, co-carcinogens). IARC Classification. Carcinogenicity studies. Evaluation of the carcinogenic potential of a xenobiotic: cancer slope factor. Examples of carcinogens and their toxicity mechanisms. Direct carcinogens: alkylating agents. Indirect carcinogens: benzo [a] pyrene, polycyclic aromatic hydrocarbons, aflatoxin B1. asbestos fibers. Epigenetic carcinogens: polychlorinated aromatic compounds (dioxins and furans), phenobarbital, asbestos fibers, ROS.
Developmental toxicity and teratogenesis
Toxicity on the reproductive system. General principles of teratogenesis. Types of teratogenic agents. Principles of teratology. Developmental toxicology: critical phases of susceptibility, blastogenesis, embryogenesis, fetogenesis. Maternal factors influencing development: placental barrier. Teratogenic agents: FDA classification. Examples of teratogenic agents: thalidomide, diethylstilbestrol, retinoids, ethanol. International guidelines for the study of reproductive toxicology.
It is recommended the didactic material presented in the lectures, as well as the consultation of the site www.agenziafarmaco.gov.it
- Balduini W., Costa Lucio G. Tossicologia generale e applicata ai farmaci. Edra, 2015.
- Casarett and Doull (a cura di Hrelia P. e Cantelli Forti G.) - Elementi di Tossicologia. Casa Editrice Ambrosiana, Milano, 2013.
Consultation texts for specific parts
- Casarett and Doull’s - Tossicologia - I fondamenti dell’azione delle sostanze tossiche (traduzione italiana della VII edizione), EMSI, Roma, 2010.
- Corsini E, Marinovich M, Galli C.L. Tossicologia. III Ed., Piccin.
To effectively follow and study the topics covered in the course and to achieve the learning objectives provided by the course, it is essential that the student possess knowledge of basic subjects, in particular with regard to physiology, biochemistry, pharmacology and pharmacognosy.
Lectures, PowerPoint presentation and guided exercises in the classroom.
The final exam is based on an oral test during which the knowledge acquired by the student will be assessed in relation to the topics included in the examination program and carried out during the lessons.
The exam can be passed if the score is greater than or equal to 18/30. To achieve the minimum score, the student must demonstrate that he has acquired sufficient knowledge of the general problems of toxicology (toxic effects and mechanisms of action of chemical and physical agents; possible protective / preventive measures to be followed for the management of toxicological risk) and of pharmacovigilance (assessment of the drug-associated risk and estimating the incidence of their adverse reactions).
To achieve a score of 30/30 cum laude, the student must instead demonstrate that excellent knowledge of all the topics covered during the course and logical abilities have been acquired.
Assessment methods and criteria are the same for attending and non-attending students.
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- Academic year: 2019/2020
- Curriculum: INFORMAZIONE SCIENTIFICA SUL FARMACO
- Year: Third year
- Semester: Second semester
- SSD: BIO/14
- CFU: 9
- Attività formative caratterizzanti
- Ambito disciplinare: Discipline Biologiche
- Lecture (Hours): 24
- CFU: 3
- SSD: BIO/14
- Attività formative affini ed integrative
- Ambito disciplinare: Attività formative affini o integrative
- Lecture (Hours): 48
- CFU: 6
- SSD: BIO/14