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In the field of drug safety, causality assessment aims to determine the level of plausibility of the relationship between an adverse event and exposure to a particular product. It is after the causality assessment process that we will be able to point out a product adverse reaction. While regulators often require pharmaceutical companies to use a structured approach for assessing the causality of their products, the available methods are challenged by a number of procedural differences, even when drawing from the same domain of elements. To mitigate these inconsistencies, as well as the additional challenges associated with incomplete information and differences in the application of clinical judgments at the individual case level, this paper proposes a holistic framework for causality assessment that utilizes a combination of expert judgment/global introspection, evidence-based medicine, and probabilistic method. The goal of the presented approach is to provide a guide of clues to causality reminding medical safety assessors to seek and examine all available streams of evidence in totality and to assess this evidence in a qualitative, structured way.

The collection and assessment of individual case safety reports (ICSRs) is important to detect unknown adverse drug reactions particularly in the first decade after approval of new chemical entities. However, regulations require that these activities are routinely undertaken for all medicinal products, including older medicines such as generic medicinal products with a well-established safety profile. For the latter, the risk management plans no longer contain important risks, considered important safety concerns, on the basis that routine pharmacovigilance activity would not allow their further characterisation. Society assumes that unexpected adverse reactions causally related to pharmacological activity are very unlikely to be detected for such well-established medicines, but important risks can still occur. For these products, a change in the safety profile which is brand or source specific and usually local in nature, associated with failures with the adequate control of quality of manufacturing or distribution are important safety issues. These may be the consequence of manufacturing and pharmacovigilance quality systems that are not fully integrated over the product life cycle (e.g. inadequate control of quality defects affecting one or multiple batches; inadequate impact assessment of change/variation of manufacturing, quality control testing, storage and distribution processes; inadequate control over the distribution channels including the introduction of counterfeit or falsified products into the supply chain). Drug safety hazards caused by the above-mentioned issues have been identified with different products and formulations, from small molecules to complex molecules such as biological products extracted from animal sources, biosimilars and advanced therapy medicinal products. The various phases of the drug manufacturing and distribution of pharmaceutical products require inputs from pharmacovigilance to assess any effects of quality-related issues and to identify proportionate risk minimisation measures that often have design implications for a medicine which requires a close link between proactive vigilance and good manufacturing practice. To illustrate our argument for closer organisational integration, some examples of drug safety hazards originating from quality, manufacturing and distribution issues are discussed. Plain language summary Monitoring the manufacturing and quality of medicines: the fundamental task of pharmacovigilance Pharmacovigilance is the science relating to the collection, detection, assessment, monitoring, and prevention of adverse reactions with pharmaceutical products. The collection and assessment of adverse reactions are particularly important in the first decade after marketing authorisation of a drug as the information gathered in this period could help, for example, to identify complications from its use which were unknown before its commercialization. However, when it comes to medicines that have been on the market for a long time there is general acceptance that their safety profile is already well-established and unknown adverse reactions unlikely to occur. Nevertheless, even older medicines, such as generic drugs, can generate new risks. For these drugs a change in the safety profile could be the result of inadequate control of their quality, manufacturing and distribution systems. To overcome such an obstacle, it is necessary to fully integrate manufacturing and pharmacovigilance quality systems in the medicine life-cycle. This could help detect safety hazards and prevent the development of new complications which may arise due to the poor quality of a drug. Pharmacovigilance activities should indeed be included in all phases of the drugs’ manufacturing and distribution process, regardless of their chemical complexity to detect quality-related matters in good time and reduce the risk of safety concerns to a minimum.

International audience; L'infection pandémique par le coronavirus 2019 (COVID-19) qui se propage depuis la Chine génère un énorme flux d'informations et un point émergent est l'association fréquente de l'infection par le COVID-19 avec des anomalies hépatiques. Des études chinoises ont montré une augmentation des transaminases et d'autres enzymes hépatiques chez 14 à 53 % des patients infectés.

This is a joint statement from individual pharmacology and pharmaceutical professionals acting in their own capacity, including members of the Alliance for Clinical Research Excellence and Safety (ACRES) and the International Society of Pharmacovigilance (ISoP). By building on the extensive pharmacological and regulatory investigations that already take place, we are calling for a fuller and more robust systems‐based approach to the independent investigation of clinical research when serious incidents of harm occur, starting with first‐in‐human clinical trials. To complement existing activities and regulations, we propose an additional approach blending evidence derived from both pharmacological and organizational science, which addresses human factors and transparency, to enhance organizational learning and continuous improvement. As happens with investigations in other sectors of society, such as the chemical and aviation sector, this systems approach should be seen as an additional way to understand how problems occur and how they might be prevented in the future. We believe that repetition of potentially preventable and adverse outcomes during clinical research, by failing to identify and act upon all systematic vulnerabilities, is a situation that needs urgent change. As we will discuss further on, approaches based on applying systems theory and human factors are much more likely to improve objectivity and transparency, leading to better system design.

Much has changed in a relatively short period of time. There is a raging debate over the level of evidence expected to first introduce a treatment to patients based on smaller, more adaptive data sets. Some argue for less data followed by postapproval follow-up, others for more adaptive clinical trial designs and end-point modification driven by patient-focused drug development and use of real-world evidence. The transition in both the review and postmarketing regulatory framework is happening in front of our eyes in real time. To improve the ability of patients to receive high-quality, safe, effective, and timely care, better information via pharmacovigilance must be a priority as the world's many regulatory systems build the capacity to harness electronic health information to improve health, care quality, and safety. Globally, the widely variable ability of nations to build reliable regulatory systems (from precise review to robust pharmacovigilance) is a dangerous source of health care inequality. Developing validated tools and techniques for "predictive pharmacovigilance" will assist all health systems in better understanding the risks and benefits of the medicines they regulate by understanding what should be happening once a new medicine moves from risk-benefit regulatory efficacy to real-world risk-effectiveness. This will be of particular utility for smaller regulatory agencies with fewer resources. By comparing preapproval predictive pharmacovigilance data, developing regulatory authorities will be able to better understand the potential gap between what was predicted and what was actually measured (via more traditional pharmacovigilance methodologies). Predictive pharmacovigilance recognizes the value of understanding the imperfect reporting of real-world clinical use and that the absence of reporting is, in itself, an important postmarketing signal.

Objectives: To explore the challenges facing pharmacovigilance in Saudi Arabia and formulate recommendations to improve it from the perspective of healthcare professionals in Saudi Arabia. Methods: This was a qualitative study of 4 focus group discussions with pharmacists, physicians, and academicians held under the auspices of the King Saud University School of Pharmacy and the Center for Medicine in the Public Interest, Riyadh, Saudi Arabia. A total of 29 eligible healthcare professionals were invited to participate in the discussion. The predefined themes of the study were the current practice and major challenges facing pharmacovigilance in regulatory bodies, hospitals, the community, and academia, as well as recommendations to improve pharmacovigilance practice. Result: Of the 29 participants invited, 27 attended the discussion. Challenges facing regulatory bodies included complicated adverse drug reactions (ADR) reporting forms, lack of feedback on ADRs submitted to the Saudi Food and Drug Authority, lack of decisions from the local authority to withdraw medications, and lack of data on pharmacovigilance. The challenges to pharmacovigilance in hospitals included the lack of knowledge of the significance of ADR reporting, workload, blaming culture, and lack of collaboration between regulatory bodies and hospitals. However, challenges facing pharmaceutical industries included the lack of drug manufacturers in Saudi Arabia and lack of interest in pharmacovigilance. Recommendations to improve pharmacovigilance included the need for communication, stronger regulatory requirements, the need for research, the need for unified ADRs reporting, and continuous education and training. Conclusion: The study has identified the challenges facing pharmacovigilance in Saudi Arabia and made certain recommendations to overcome them. These recommendations might be helpful for regulatory bodies to enhance spontaneous reporting and promote pharmacovigilance.

Objectives: To assess completeness of reports in the Saudi Adverse Event Reporting System (SAERS), which is a part of the Saudi Food and Drug Authority pharmacovigilance system for monitoring the safety of medications. Methods: A cross-sectional study was conducted in Riyadh, Saudi Arabia using the reports that were received between December 2009 and June 2012 in the SAERS. The completeness was assessed by reviewing the components of the adverse drug reactions (ADRs) form, and how many fields were completed. Descriptive statistics are reported. Result: There were 14,783 reports during the study period. Eighty percent of these reports were spontaneous reports. Information related to the drug (99%) and adverse events (98%) of the reports were completed. While the patient’s demographic data were completed only in 38% of all reports, the least completed item in the ADRs form was the reporter information (15%). The most reported drug class was tumor necrosis factor inhibitors (7%), whereas events involving the respiratory organ system were the most frequently reported (4.5%). Conclusion: Although the SAERS is considered new, it has a high number of reports. More efforts are needed to improve the completeness of the SAERS to be a good source to assess the signals between events and suspected drugs, especially when there is a high number of reports. Saudi Med J 2015; Vol. 36 (7): 821-828 doi: 10.15537/smj.2015.7.11751

In an era when the number of expedited and conditional review pathways for newly available brand-name drugs and biosimilar medicines to treat serious and life-threatening diseases is increasing, defining pharmacovigilance has never been more crucial. 21st century pharmacovigilance is not merely about uncovering, reporting, and addressing adverse events associated with already approved and marketed agents, but can be described as the systematic monitoring of the process of pre-market review and post-market surveillance, which includes the use of medicines in everyday practice. Pharmacovigilance identifies previously unrecognised adverse events or changes in the patterns of these effects, the quality and adequacy of drug supply, and should ensure effective communication with the public, health-care professionals, and patients about the optimum safety and effective use of medicines. In this paper, the first in a Series of three about drug safety in oncology, we discuss evolving challenges in the purview, roles, and responsibilities of the US Food and Drug Administration and the European Medicines Agency with respect to pharmacovigilance efforts, with a special emphasis on oncology treatment.

The aim of this Round Table was to perform an initial assessment of the state of play of the impact of drugs on the environment. Demographic growth throughout the world and drug consumption which is constantly on the increase result in an ever increasing presence of medicinal substances in the various compartments (air, water, soil) with potential repercussions on the environment and on health. For the first time, the Giens pharmacology workshop have scheduled this topic outside the conventional sphere of action of Giens. A very high level of interest in this topic came forward both from the members of the round table and the listeners and it is certain that the round table opens the door to new initiatives for a subject about which there is still little knowledge. The following issues were therefore successively addressed: the fragmentation of the knowledge about the subject and its deficiencies concerning the impact on health, both of the wastes as a whole and that of specific drugs, the performances of the water treatment methods, the sources of pollution, the environmental impact, the lines of regulatory development, the impact on the environment and health and the training programmes to be set up among all protagonists, both professional and in the general public.

Resume L’objet de cette Table Ronde etait de faire un premier etat des lieux sur l’impact des medicaments sur l’environnement. La croissance demographique dans le monde, la demande de sante de plus en plus forte, la consommation de medicaments qui ne cesse de se developper, conduisent a une presence de plus en plus importante des substances medicamenteuses dans les differents compartiments (air, eau, sol) avec des repercussions potentielles sur l’environnement et la sante. Pour la premiere fois les Ateliers de Pharmacologie de Giens ont programme ce theme en dehors du champ d’action classique de Giens. Un interet tres important pour ce theme s’est degage tant des membres de la Table Ronde que des auditeurs, et il est certain que celle-ci ouvre la porte a de nouvelles initiatives pour un sujet encore mal connu. Ont donc ete abordes successivement : l’eclatement des connaissances sur le sujet, et leurs insuffisances concernant l’impact sanitaire aussi bien des rejets dans leur globalite que de certains medicaments particuliers, les performances des methodes de traitement des eaux, les sources de pollution, l’impact environnemental et l’impact sanitaire, les pistes d’evolution reglementaires et les formations a mettre en place aupres de tous les acteurs professionnel et grand public.

The objectives of this study are to assess the relevance of the medication error reporting system in a French teaching hospital, to enable the collection of medication error reports and to take corrective actions to reduce occurrence. This is a prospective pilot study based on blame-free reporting by healthcare professionals. The study setting is five medical/surgical departments in a French teaching hospital over a 6-month period. The main outcomes of this study are types, frequency, and consequences of medication errors reported. Over a 6-month period, 47 medication errors were reported. Twenty-eight (60%) were related to the prescription process, of which 17 were prescribing errors, 10 were because of data capture error and one was because of software malfunction. Ten medication errors (21%) were related to the dispensing process and eight (17%) to errors occurring during drug administration. Finally, one medication error (2%) was related to prescription, dispensing, and administration. The reporting process was accepted by most healthcare professionals who agreed to initiate medication errors reports upon assurance that data collection will be confidential. The reporting process led to several avoidance actions to minimize the medication error risk. Maintaining confidentiality embedded within a nonpunitive environment, this method was accepted by all participating personnel. Medication errors could be collected, reviewed, and corrective actions taken. This strategy can be a first step in a long-term ongoing process to prevent future medication errors in hospitals.

Resume Dans un contexte ou plusieurs vaccinations ont ete recemment recommandees en France, et ou de nombreux nouveaux vaccins sont en developpement, la Table Ronde a realise un etat des lieux des specificites du vaccin en France, que sont le developpement clinique, la modelisation medico-economique, l’evaluation et la communication. Dans chacun de ces domaines ont ete identifies les etapes et processus cles a ameliorer, assortis de propositions. Les principaux enjeux strategiques sont de favoriser le developpement des vaccins en France par l’acces a un suivi de populations caracterisees a large echelle, d’anticiper et coordonner l’evaluation des vaccins par les differents intervenants, d’accroitre la communication autour des strategies vaccinales, afin d’ameliorer la perception des vaccins, l’acceptabilite des vaccinations, et d’augmenter la couverture vaccinale. La Table Ronde a egalement propose la creation d’un groupe de travail qui s’assurera de la poursuite, du suivi et de la mise en œuvre des propositions formulees.

Resume L’utilisation des generiques est generatrice d’economies pour le budget de l’assurance maladie, et aucun acteur de sante ne pourrait en remettre serieusement en cause le principe. Le medicament generique d’une specialite de reference se definit comme un medicament ayant la meme composition qualitative et quantitative en principes actifs, la meme forme pharmaceutique et dont la bioequivalence avec cette specialite de reference a ete demontree par des etudes appropriees de biodisponibilite. C’est le droit de substitution accorde aux pharmaciens en 1999 qui est a l’origine du veritable essor de ces specialites sur le marche pharmaceutique francais. Neanmoins, pres de 10 apres, il apparait que le systeme en place n’offre pas toutes les securites necessaires en ce qui concerne la Pharmacovigilance, notamment s’agissant des produits a marge therapeutique etroite. En renforcant et/ou en completant le role joue par les professionnels de sante et les institutions concernes, il est tout a fait possible d’ameliorer la robustesse du systeme. De meme, l’arrivee recente en Europe des biosimilaires, molecules similaires mais non bioequivalentes aux produits biologiques entraine une situation specifique encore plus delicate, que celle des generiques du fait de leur nature, de la difficulte a les produire et du risque d’immunogenicite. Si la substitution n’est pas permise dans plusieurs pays europeens incluant la France, d’autres problemes peuvent apparaitre notamment en cas d’interchangeabilite necessitant la encore, le renforcement de certaines mesures. Les differents aspects sont abordes dans cet article avec des propositions concretes de securisation du systeme actuel, tant pour les generiques que les biosimilaires.

We investigated the antiischemic properties of a new compound, S-15176, in an experimental model of rat liver subjected to 120-min normothermic ischemia followed by 30-min reperfusion. Rats were divided into groups, pretreated with different doses of S-15176 (1.25, 2.5, 5 and 10 mg/kg/day by intramuscular injection) or solvent alone, and subjected to the ischemia--reperfusion process. Another group served as the sham-operated controls. Ischemia--reperfusion induced huge alterations of hepatocyte functions, namely, a decrease in ATP content and bile flow, and membrane leakage of alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT). These effects were associated with alterations in mitochondrial functions characterized by (1) a decrease in ATP synthesis, (2) a decrease in NAD(P)H levels and mitochondrial membrane potential, and (3) an increase in mitochondrial swelling reflecting the generation of permeability transition. Pretreatment of rats with S-15176 alleviated these deleterious ischemia--reperfusion effects at both the cellular and mitochondrial levels in a dose-dependent manner. The protection of mitochondrial functions was almost complete at a dosage of 10 mg/kg/day. In addition, in vitro, S-15176 totally abolished the swelling of isolated mitochondria induced by a calcium overload with an IC(50) value of 10 microM. These data demonstrate that S-15176 protects mitochondria against the deleterious effects of ischemia-reperfusion and suggest that this protective effect could be related to the inhibition of the mitochondrial permeability transition.

There are 3 main classes of systemic antifungals: the polyene macrolides (e.g. amphotericin B), the azoles (e.g. the imidazoles ketoconazole and miconazole and the triazoles itraconazole and fluconazole) and the allylamines (e.g. terbinafine). Other systemic antifungals include griseofulvin and flucytosine. Most drug-drug interactions involving systemic antifungals have negative consequences. The interactions of amphotericin B, flucytosine, griseofulvin, terbinafine and azole antifungals can be divided into the following categories: (i) additive dangerous interactions; (ii) modifications of antifungal kinetics by other drugs; and (iii) modifications of the kinetics of other drugs by antifungals. Amphotericin B and flucytosine mainly interact with other agents pharmacodynamically. Clinically important drug interactions with amphotericin B cause nephrotoxicity, hypokalaemia and blood dyscrasias. The most important drug interaction of flucytosine occurs with myelotoxic agents. Hypokalaemia can precipitate the long QT syndrome, as well as potentially lethal ventricular arrhythmias like torsade de pointes. Synergism is likely to occur when either QT interval-modifying drugs (e.g. terfenadine and astemizole) and drugs that induce hypokalaemia (e.g. amphotericin B) are coadministered. Induction and inhibition of cytochrome P450 enzymes at hepatic and extrahepatic sites are the mechanisms that underlie the most serious pharmacokinetic drug interactions of the azole antifungals. These agents have been shown to notably decrease the catabolism of numerous drugs: histamine H1 receptor antagonists, warfarin, cyclosporin, tacrolimus, digoxin, felodipine, lovastatin, midazolam, triazolam, methylprednisolone, glibenclamide (glyburide), phenytoin, rifabutin, ritonavir, saquinavir, nevirapine and nortriptyline. Non-antifungal drugs like carbamazepine, phenobarbital (phenobarbitone), phenytoin and rifampicin (rifampin) can induce the metabolism of azole antifungals. The bioavailability of ketoconazole and itraconazole is also reduced by drugs that increase gastric pH, such as H2 receptor antagonists, proton pump inhibitors, sucralfate and didanosine. Griseofulvin is an enzymatic inducer of coumarin-like drugs and estrogens, whereas terbinafine seems to have a low potential for drug interactions. Despite important advances in our understanding of the mechanisms underlying pharmacokinetic drug interactions during the 1990s, at this time they still remain difficult to predict in terms of magnitude in individual patients. This is because of the large interindividual and intraindividual variations in the catalytic activity of those metabolising enzymes that can either be induced or inhibited by various drugs. Notwithstanding these variations, increasing clinical experience is allowing pharmacokinetic interactions to be used to advantage in order to improve the tolerability of some drugs, as recently exemplified by the use of a fixed combination of ketoconazole and cyclosporin.

International audience; : In the recent past, concerns have raised regarding the potential risk of acute pancreatitis among type 2 diabetic patients using incretin-based drugs such as glucagon-like peptide 1 (GLP-1) analogs and dipeptidyl peptidase 4 (DPP-4) inhibitors. The aim of this study is to investigate the association between exposure to incretin-based drugs and the occurrence of pancreatitis reported in the French Pharmacovigilance Database. The case/non-case method was performed from serious adverse drug reactions (ADRs) involving antihyperglycemic agents (except insulin alone) reported to the French pharmacovigilance system between March 2008 (first marketing of an incretin-based drug in France) and March 2013. Cases were defined as reports of pancreatitis, and all other serious ADRs were considered non-cases. Disproportionality was assessed by calculating reporting odds ratios (ROR) adjusted for age, gender, history of pancreatitis, other antihyperglycemic drugs and other drugs associated with a higher risk of pancreatitis. Among 3,109 serious ADRs, 147 (4.7 %) reports of pancreatitis were identified as cases and 2,962 reports (95.3 %) of other ADRs as non-cases. Among the cases, 122 (83.0 %) involved incretin-based drugs. Disproportionality was found for all incretin-based drugs (adjusted ROR: 15.7 [95 % CI 9.8-24.9]), all GLP-1 analogs (29.4 [16.0-53.8]), exenatide (28.3 [12.8-62.3]), liraglutide (30.4 [15.4-60.0]), all DPP-4 inhibitors (12.1 [7.3-20.0]), sitagliptin (12.4 [7.3-21.0]), saxagliptin (15.1 [4.3-52.7]), and vildagliptin (7.4 [3.1-17.6]). Temporal analysis found disproportionality for incretin-based drugs since their first year of marketing in France. Compared with other antihyperglycemic agents, use of incretin-based drugs is associated with an increased risk of reported pancreatitis in France.

In a context where a number of vaccinations have recently been recommended in France, and where a large number of vaccines are under development, the Round Table has reviewed the specific features of vaccines in France, namely clinical development, medico-economic modelling, evaluation and communication. In each of these domains, the key stages and processes to be improved have been identified, and proposals made. The main strategic challenges are to promote the development of vaccines in France by access to the large-scale monitoring of populations, to look ahead and coordinate the evaluation of vaccines by the various parties involved, to widen communication about vaccination strategies, in order to improve the perception of vaccines and the acceptability of vaccinations, and to increase vaccination coverage. The Round Table has also proposed the creation of a working group to be responsible for pursuing, monitoring and implementing the proposals formulated.

ERMA; International audience; The use of generics results in savings for the budget of the health insurance, and no player of health could question seriously the principle. The generic drug of a reference medicinal product defines itself as a drug having the same qualitative and quantitative composition in active ingredients, the same dosage form and the bioequivalence with this reference medicinal product was demonstrated by appropriate studies of bioavailability. It is the right to switch granted to the pharmacists in 1999 that is at the origin of the real development of these specialties on the French pharmaceutical market. Nevertheless, about 10 years later, it seems that the system in place does not offer all the necessary securities with regard to pharmacovigilance, notably for the products with narrow therapeutic margin. By strengthening and/or by completing the role played by the health care professionals and the public institutions concerned, it is highly possible to improve the robustness of the system. Also, the recent arrival in Europe of the biosimilars, similar molecules but not bioequivalent to biological products, cause an even more tricky specific situation than that of the generics because of their nature, of the difficulty to manufacture them, and of the risk of immunogenicity. If the substitution is not permitted in several European countries including France, the other issues can appear especially in case of interchangeability requiring also, the reinforcement of certain measures.The various aspects are described in this article with concrete proposals on how the current system can be made safer, both for the generics and the biosimilars.

The purpose of this study was to investigate the possible effect of the trimetazidine derivative S-15176 on carnitine palmitoyltransferase1 (CPT-1) activity in rat heart and liver mitochondria. S-15176 was compared with the other antianginal agents amiodarone, perhexiline and trimetazidine, which do not show any hemodynamic effects and which are believed to exert their effects by switching the cellular metabolism towards glucose utilization at the expense of lipid metabolism, increasing the yield of oxygen utilization. S-15176 inhibited CPT-1 in vitro and was more effective in heart (IC 50 = 16.8 μ M) than in liver ( 50.8 ± 3.0 μ M). In the heart, its was less effective than the physiological inhibitor malonyl-CoA (IC 50 = 2.1 μ M), but it was more potent than amiodarone (IC 50 = 140 μ M). Kinetic experiments demonstrated a non-competitive inhibition of CPT-1 by S-15176 indicating that the two compounds did not share the same site of action. CPT-1 inhibition was also obvious ex vivo , in heart and liver tissues, after a 2 week treatment with S-15176. This inhibitory effect may shift heart and liver metabolism from fatty acid to glucose oxidation and contribute to the anti-ischemic effects of the drug.

S15176 and S16950 are trimetazidine derivatives that antagonize more strongly than the parent drug mitochondrial toxicity, which leads to cellular hypoxia and nephrotoxicity in kidneys experimentally exposed to cyclosporin A. We have investigated whether every derivative might interact or not with the inhibitory effect of Cyclosporin A on the proliferation of cultured human lymphocytes. S15176 significantly increased the antilymphoproliferative effect of Cyclosporin A, whereas S15176 by itself neither displayed any antilymphoproliferative effect, nor did it induce any apoptotic process in cultured human lymphocytes. The effect of S16950 was not significant.

The effects of hydrocortisone, triamcinolone, prednisolone and dexamethasone have been investigated in vitro using mitochondria isolated from rat brain. Respiratory control ratio (RCR), oxygen consumption, ATP synthesis, enzymatic activities of involved complexes and superoxide anion generation have been measured to assess the effects of these drugs. Our data showed that the decrease of RCR induced by glucocorticoids was due to a common inhibition of oxidative phosphorylation (State 3) and of complex V activity and a modification of the proton-fluxes through the mitochondrial inner membrane. These effects were quantitatively limited, since they occurred at concentrations lower than 2 nM. Dexamethasone was the only one able to induce a specific inhibition of complex I activity and to decrease the superoxide anion radical generation. Inhibition of complex V and partial reversion of uncoupling seem to be common properties of glucocorticoids. The theoretical consequence of these inhibitions could be the modulation of the mitochondrial function, oxygen consumption rate, ATP synthase activity and superoxide anion radical production, involved in many patho-physiological phenomena.