Biomedical subjects

Jacques Descotes

Publications and source records attributed to Jacques Descotes.

At least 19 recordsLinked to original sources

PubMed2006

Cardiotoxicity of 5-fluorouracil in 1350 patients with no prior history of heart disease.

To show the nature and magnitude of EKG anomalies subsequent to 5-fluorouracil (5FU) administration and determine whether the onset is dependent on a pre-existing cardiovascular pathological condition. 1,350 patients were treated by 5FU between 1995 and 2000. EKG were recorded in all patients before each administration of 5FU. All cases of 5FU related cardiotoxicity were analyzed and recorded by the Lyon Pharmacovigilance Center. Clinical symptoms included chest pain in 10 patients with an infarct-like pattern in 2 (including one death), and heart failure in one. Three patients suffered from anginal pain without EKG changes and two had electrocardiographic changes without clinical symptoms. Coronary disorders resolved completely on cessation of 5FU therapy, except in one patient who died two months later of heart infarct. The patient with heart failure required specific treatment. Based on both the clinical and electrocardiographic changes, the causative role of 5FU is highly likely. The incidence of cardiotoxicity was 1.2% among these patients, which is close to previous data from the literature. These 16 case reports confirm the cardiotoxic potential of 5FU and argue for the need of a careful cardiac monitoring of 5FU treated cancer patients. The mechanism of 5FU cardiotoxicity is not elucidated. Coronary spasm is the most commonly suspected hypothesis, but further studies are warranted to seek for toxic inflammatory lesions of the myocardium (apoptosis, necrosis, fibrosis).

Adult↗

PubMed2006

The effects of ropivacaine at clinically relevant doses on myocardial ischemia in pigs.

A major risk associated with bupivacaine during myocardial ischemia is ventricular fibrillation. We investigated the influence of ropivacaine on cardiac contractility and the propensity to ventricular fibrillation before and after myocardial ischemia in a placebo-controlled pig study. Anesthetized domestic pigs were administered 1 mg.kg(-1) of ropivacaine intravenously over 1 min and then 0.03 mg.kg(-1).min(-1) as a 30-min infusion, or saline. The following endpoints were measured before and after ropivacaine administration: (1) the ventricular fibrillation threshold (VFT) before and during myocardial ischemia induced by total transient ligation of the anterior interventricular artery and (2) electrophysiological (sinus heart rate, duration of QRS and QT intervals) and hemodynamic (blood pressure, the time derivative of left ventricular pressure [peak LV dP/dt]) parameters. Ropivacaine induced no changes in sinus heart rate, QRS, and or QT before or during ischemia. In contrast, there was a mild increase in the VFT before ischemia, which was drastically and significantly reduced during ischemia. The reduction of peak LV dP/dt during ischemia was further increased by ropivacaine. We also found that the effect of ropivacaine on the VFT was coronary blood flow-dependent, with a markedly decreased threshold in the presence of ischemia. Similar effects have been observed in humans with several other local anesthetics, as well as with class I antiarrhythmic drugs. The results of this study should be taken into account by anesthesiologists when administering ropivacaine to coronary patients.

Amides↗

PubMed2006

Acute occupational poisoning by octogen: first case report.

BACKGROUND: Octogen (HMX) is a polynitramine explosive closely related to hexogen, a known occupational toxin in military munitions plants. No acute human poisoning with octogen has ever been reported. CASE REPORT: A 28-year-old man with no history of epilepsy was admitted to the Emergency Department for seizures that had developed during the night after a full working day when he manually sieved large amounts of dry octogen. On admission, the clinical examination was normal and all other examinations could not substantiate the development of essential or secondary epilepsy. Elevated octogen concentrations were measured in his plasma, which confirmed occupational exposure to the explosive. CONCLUSION: The rarity of acute human poisonings by octogen is due to the infrequent use of this explosive and, more importantly, its very low oral bioavailability. However, acute poisoning can occur, but should be easily avoided by implementing adequate preventive measures.

Acute Disease↗

PubMed2006

Evaluation of a surgical procedure to measure drug biliary excretion of rats in regulatory safety studies.

A surgical procedure was evaluated to allow bile collection from the freely moving male Sprague-Dawley rats for the assessment of drug biliary excretion during regulatory safety studies. A catheter was implanted into the bile duct to divert the bile flow via an exteriorized loop. Following recovery from the surgery and verification of normal hepatic function, the exteriorized catheter was sectioned to allow collection of the bile and replacement with a commercial bile salt solution. Approximately 80% of the catheterized animals (10 females and 10 males) had normal serum liver enzyme levels 2 days after surgery. Then, the effect of acute or repeated administrations of the immunosuppressant tacrolimus on the biliary excretion of 14C diazepam was studied to validate the technique. A first group of 12 rats received an intravenous injection of 10 mg/kg 14C-diazepam and the total and sequential amounts of diazepam excreted in the bile were measured over 72 h. Biliary excretion accounted for 80% of diazepam elimination. These rats were then given an oral administration of 3 mg/kg tacrolimus on days 7 and 8 followed by the same intravenous dose of 14C-diazepam. Another group of 10 catheterized rats was given 21 daily oral doses of 3 mg/kg tacrolimus followed by a single intravenous administration of 14C-diazepam. No significant changes in diazepam biliary excretion were observed following either acute or repeated administration of tacrolimus. This study demonstrates the feasibility of drug biliary excretion investigations under Good Laboratory Practices conditions as a complement to regulatory acute or repeated dose safety studies.

Animals↗

PubMed2006

Methods of evaluating immunotoxicity.

Immunotoxicology is an important aspect of the safety evaluation of drugs and chemicals. Immunosuppression, (unspecific) immunostimulation, hypersensitivity and autoimmunity are the four types of immune-mediated adverse effects. However, the nonclinical assessment of immunotoxicity is at present often restricted to animal models and assays to predict unexpected immunosuppression. There is, however, no general consensus that a variety of assays can be considered depending on the compound to be tested. A major issue is whether histological examination of the thymus, spleen, lymphoid organs and Peyer's patches is a reliable predictor of immunosuppression or whether immune function should also be assessed. A T-dependent antibody response assay, either the plaque-forming cell assay or anti-keyhole limpet haemocyanin enzyme-linked immunosorbant assay, is recommended as a first-line assay. A variety of assays, including lymphocyte subset analysis, natural killer-cell activity, lymphocyte proliferation, delayed-type hypersensitivity, cytotoxic T-lymphocyte activity and macrophage/neutrophil function assays, can also be used. In certain circumstances, host resistance assays can be considered. With the exception of contact sensitisation, very few animal models and assays can reliably predict the potential for (unspecific) immunostimulation, hypersensitivity or autoimmunity. A major limitation of immunotoxicity risk assessment is the lack of human data. Immunological end points and clinical criteria to be included in clinical trials and epidemiological studies have to be carefully standardised and validated.

Animals↗

PubMed2005

Toxicovigilance: a new approach for the hazard identification and risk assessment of toxicants in human beings.

The concept of toxicovigilance encompasses the active detection, validation and follow-up of clinical adverse events related to toxic exposures in human beings. Poison centers are key players in this function as poisoning statistics are essential to define the cause, incidence and severity of poisonings occurring in the general population. In addition, the systematic search for unexpected shifts in the recorded causes of poisonings, e.g., following the introduction of a new product, or change in the formulation or recommended use of an old product, allows for a rapid detection of potential adverse health consequences and the implementation of preventive or corrective measures. However, toxicovigilance is genuinely a medical and not only a statistical approach of human toxicity issues. In contrast to epidemiology, toxicovigilance is based on the in-depth medical assessment of acute or chronic intoxications on an individual basis, which requires detailed information that poison centers can rarely obtain via emergency telephone calls and that epidemiologists cannot collect or process. Validation of this medical information must primarily be based on toxicological expertise to help identify causal links between otherwise unexplained pathological conditions and documented toxic exposures. Thus, toxicovigilance can contribute to hazard identification and risk assessment by providing medically validated data which are often overlooked in the process of risk assessment. So far, very few structured toxicovigilance systems have been set up and hopefully national and international initiatives will bridge this gap in our knowledge of the toxicity of many chemicals and commercial products in human beings.

Female↗

PubMed2005

Immunotoxicology: role in the safety assessment of drugs.

The immunotoxic effects of drugs are divided into immunosuppression, immunostimulation, hypersensitivity and autoimmunity. The major adverse consequences of immunosuppression are infectious complications and virus-induced malignancies. Flu-like reactions, more frequent autoimmune diseases and hypersensitivity reactions to unrelated allergens, and inhibition of drug-metabolising enzymes are the adverse effects related to immunostimulation. Hypersensitivity reactions are the most frequent immunotoxic effects of drugs. They include immune-mediated ('allergic') and non immune-mediated ('pseudoallergic') reactions. Drug-induced autoimmune reactions, either systemic or organ-specific, are seemingly rare. A review of drug-induced immunotoxic effects demonstrates that immunotoxicity is a significant cause of morbidity and even mortality. As immunotoxicologists have long focused on immunosuppression, the nonclinical immunotoxicity safety assessment of unexpected immunosuppression is based on a number of relatively well standardised and validated animal models and assays. However, there is no general consensus regarding the minimal requirement for this assessment. Many different assays can be used to extend the assessment case by case. Few animal models and assays have been validated for use in the nonclinical safety assessment of unexpected immunostimulation. The situation is worse regarding the prediction of hypersensitivity and autoimmune reactions. Our limited understanding of the molecular and cellular mechanisms of immunotoxicity accounts, at least partly, for this situation. Recent guidelines for the immunotoxicity safety assessment of drugs, even though conflicting on several points, will serve as an impetus not only to refine current animal models and assays, but also to search for better alternatives. The new data generated will have to be interpreted and extended to animal species other than just rodents. Likewise, animal results will have to be compared with findings in humans. The search for immunological endpoints that can be used in several animal species and in humans will therefore become essential. Specific endpoints and clinical criteria that can be included in clinical trials to further investigate the potential for immunotoxicity of new drugs will have to be defined. Because immunotoxicity plays a key role in drug-induced adverse effects, the role of immunotoxicology in drug safety assessment is indisputable and the systematic nonclinical as well as clinical immunotoxicity assessment of every new drug is deemed essential.

Animals↗

PubMed2004

Cytokine release does not improve the sensitivity and specificity of the direct popliteal lymph node assay.

The popliteal lymph node assay (PLNA) is being considered as a tool to predict the potential of drugs for inducing systemic autoimmune and hypersensitivity reactions. Despite the use of different technical approaches and the evaluation of over 130 compounds, the sensitivity and specificity of the PLNA are still debatable due to many false positive and negative responses. In this study, cytokine production was assessed as a possible endpoint to improve the direct (primary) PLNA. Diclofenac, imipramine, hydralazine, glafenin and minocycline were tested using the classical procedure. TH1 cytokines (IL-2 and IFN-gamma), TH2 cytokines (IL-4 and IL-5) and pro-inflammatory cytokines (IL-6, TNF-alpha, monocyte chemoattractant protein-1 (MCP-1), IL-12p70 and IL-10) were measured in the serum and in suspensions of popliteal lymph node cells of female Balb/c mice by flow cytometry 7 days after drug administration. Only diclofenac and imipramine induced a cellularity index above 5 (considered as a positive response). Of the five tested drugs, only diclofenac induced a slight increase in TH1 cytokines, but there were no effects on TH2 cytokine production whatever the drug tested. Diclofenac increased the production of pro-inflammatory cytokines, whereas the production of MCP-1 was increased by minocycline and decreased by imipramine. No changes in serum cytokine levels were evident. These results suggest that measuring cytokine release is unlikely to improve the sensitivity and specificity of the direct PLNA.

Animals↗

PubMed2004

Popliteal lymph node responses to acetone and ethanol differ from those induced by streptozotocin.

The popliteal lymph node (PLN) assay was proposed to detect the potential of immunotoxicants for inducing systemic autoimmune-like reactions, but also xenobiotics that are sensitizing or exert immunostimulatory properties. Results on over 100 chemicals, mostly pharmaceuticals, are available with the PLN assay and show many correlations between rodent data and the clinical experience. A major issue is that the mechanisms involved have not been fully elucidated. In order to provide mechanistic clues to improve the predictability of the PLN assay, the effects of streptozotocin (STZ) were compared to those of ethanol and acetone in normal C57Bl/6 mice as well as mice depleted in CD4+ or CD8+ T-cells by treatment with specific monoclonal antibodies. STZ, ethanol and acetone gave similar positive responses in normal mice. Neither CD4+ nor CD8+ T-cell depletion influenced the PLN responses to ethanol or acetone, whereas CD8+ in contrast to CD4+ T-cell depletion abolished the response to STZ. There was an increase in the production of IL-6 and IFN-gamma mRNAs measured by RT-PCR in STZ-, but not in ethanol- or acetone-treated normal mice. The production of TNFalpha, IL-1alpha, IL-1beta, IL-2R and IL-12 mRNAs was increased whatever the treatment, but increases were 2- to 3-fold greater after STZ than ethanol or acetone. These results suggest that PLN responses to primary irritants such as ethanol and acetone essentially reflect non-specific inflammation, whereas PLN responses to an autoimmunogenic compound such as STZ involve CD8+ T lymphocytes and the production of IFN-gamma and IL-6. These findings may prove useful to improve the predictability of the PLN assay.

Acetone↗

PubMed2004

Importance of immunotoxicity in safety assessment: a medical toxicologist's perspective.

The clinical data accumulated so far unequivocally demonstrate that immunotoxicity is associated with significant morbidity. Immunotoxic effects are divided into four categories: immunosuppression, immunostimulation, hypersensitivity and autoimmunity. Each category is associated with distinct adverse effects. Even though concern primarily focused on immunosuppression, hypersensitivity and immunostimulation are also key issues, especially with pharmaceuticals. Histology of the lymphoid organs is not sufficient to reliably predict immunosuppression and at least one immune function assay is recommended. It is not known whether function assays used to predict immunosuppression are applicable to the prediction of immunostimulation. Specific assays can be helpful. Most available animal models and assays are not valid to assess the potential for hypersensitivity, and autoimmunity is not predictable at all. Conflicting guidelines and the lack of human data contribute further to this situation. Several critical factors deserve consideration. Dose-response relationships are often atypical and this should impact on the study design. Due to the redundancy of the immune system, a single change is not necessarily sufficient evidence for immunotoxicity so that a global assessment of all preclinical findings is advisable. Genetic factors play a major role in immune responses. As wide inter-individual variability is unavoidable, sufficient numbers of animals, a cautious comparison with both study and historical controls, and the possible use of inbred or genetically modified animals are to be considered. Marked interspecies differences in the immune system should lead to use more than one animal species and to confirm animal data during clinical trials. The inclusion of certain immune endpoints applicable to animals and man is therefore essential. The optimal timing of immunotoxicity studies is debated, but early studies are recommended. Despite significant progress, quite a few issues are still pending. Nevertheless, due to the many adverse effects reported in man, the immunotoxicity potential of every new molecular entity should be systematically and specifically evaluated.

Adjuvants, Immunologic↗

PubMed2004

Clinical and histopathological progression of lesions in lupus-prone (NZB x NZW) F1 mice.

This study was conducted to review the progression with age of renal and other changes in (NZB x NZW) F1 females obtained from a commercial colony, housed under SPF conditions. Sixty-two mice were given food and water ad libitum and sacrificed at intervals up to 47 weeks of age. Routine haematology and urinalysis were performed at regular intervals. The serum levels of IgA, IgG, IgM and antinuclear antibody levels were monitored along with urinary protein. Major organs and tissues from all animals were preserved and examined. Special attention was paid to the kidneys: in addition to routine 4-microm paraffin sections, 1-microm resin sections were prepared and examined. Positive levels of urinary protein (> 1 g/L) were only found in 50% of the animals, even at 32 weeks of age. Histopathologically, the expected type of glomerular damage was present; but the incidence and severity of the change were low, with only 33% of the mice affected at 32 weeks of age. Most mice had fatty vacuolation in the liver. At 24 weeks of age, 50% of the mice sacrificed had haemorrhagic degeneration of the liver. This was not seen at later time points. Only two mice survived until 47 weeks of age. In summary, these findings were of the expected type, but at a much lower incidence and severity than formerly reported. The background of the strain and the experimental conditions are of great importance in the progress of these renal lesions. The lack of homogeneity of the renal changes would make it difficult to determine any influence of xenobiotics on the progress of autoimmune diseases.

Age Factors↗

PubMed2004

Hidden cardiac lesions and psychotropic drugs as a possible cause of sudden death in psychiatric patients: a report of 14 cases and review of the literature.

OBJECTIVE: To confirm the hypothesis that psychotropic drugs, especially neuroleptics, lithium, and antidepressants, are implicated as a cause of unexpected sudden death in psychiatric patients because of their cardiotoxicity, especially when hidden cardiac lesions are present. METHOD: We performed a full pathological examination of 14 psychiatric patients who unexpectedly and suddenly died between 1980 and 1999. RESULTS: Neuroleptics were involved in 13 instances, antidepressants in 9, and anxiolytics in 5. Psychotropic drugs were combined in all but a single patient. In all 14 patients, toxicological analyses discarded drug overdose as cause of death. At postmortem examination, the brain and abdominal organs were normal. In 13 patients, the following lesions were found in the heart and lungs: dilated cardiomyopathy (6 patients), left ventricular hypertrophy (2 patients, 1 of which was associated with mitral prolapse and anomalies of His bundle), arrhythmogenic cardiopathy of the right ventricle (1 patient), pericarditis (1 patient), mitral prolapse (1 patient), muscular bridge on the anterior interventricular artery (1 patient), and Mendelsons syndrome (1 patient). In 1 case, no changes were seen. Most of the drugs that were taken immediately prior to death can induce arrhythmias either by prolonging the QT interval, potentially resulting in torsades de pointes, or by widening QRS complexes, possibly leading to reentry and ventricular fibrillation. CONCLUSION: Our findings suggest that the arrhythmogenic effects of psychotropic drugs can be exacer bated when preexisting hidden cardiac lesions are present and can result in sudden death. Patients should be systematically evaluated for cardiac lesions prior to starting any treatment with psychotropic drugs; the minimal effective dosage should be used.

Adult↗

PubMed2004

Low dose methotrexate in the first trimester of pregnancy: results of a French collaborative study.

OBJECTIVE: To assess the risk of major malformations in pregnant women with chronic inflammatory disorders treated with low dose methotrexate (MTX) during the first trimester of pregnancy. Secondary outcomes included the rate of miscarriage, birth weight, and gestational age at delivery. METHODS: Data from the French network of 31 pharmacovigilance centers and 2 teratology information services were analyzed. The outcome of pregnancy was prospectively assessed in women exposed during the first trimester of pregnancy. Data on maternal history and drug exposure were collected at the initial inquiry, and on the outcome of pregnancy at followup. RESULTS: Twenty-eight cases were available for analysis. MTX exposure ended before 8 weeks of gestation in 26 patients. Miscarriages occurred in 4 patients and 5 had elective termination of pregnancy. There were 19 live births, among whom 3 were premature. Birth weights in full-term children were within the expected range. One child exposed until 8.5 weeks of gestation had only minor anomalies (metatarsus varus and eyelid angioma). CONCLUSION: Although no definitive conclusion can be drawn, our results and the analysis of the literature support the conclusion that no strong teratogenic risk is associated with low dose MTX provided that the drug is discontinued as early as possible in pregnant women.

Abnormalities, Drug-Induced↗

PubMed2003

Effects of two pediatric vaccines on autoimmune diabetes in NOD female mice.

The induction or exacerbation of autoimmune diseases is a potential adverse effect of immunostimulating drugs. Vaccines have been suspected of such actions. Epidemiological studies, however, have so far failed to demonstrate any causal relationship between vaccination and autoimmune diseases, including insulin-dependent diabetes mellitus (IDDM). In this study, autoimmune diabetes-prone non-obese diabetic (NOD) mice were treated with two multivalent diphtheria, tetanus, pertussis, poliomyelitis and haemophilus vaccines (diphtheria, tetanus, acellular pertussis, inactivated polio (DTaP-IVP) or DTaP-IVP/Haemophilus influenza type b (Hib)) intraperitoneally at each of 10, 12 and 14 weeks of age. Although non-statistically significant, the incidence of autoimmune diabetes was slightly reduced by the DTaP-IVP vaccine. Blood glucose levels were actually significantly reduced in the mice treated with the DTaP-IVP vaccine relative to the untreated control mice. A slight decrease in blood glucose levels amongst the mice given the DTaP-IVP/Hib vaccine was also noted. Therefore this study does not support previous claims that children's vaccination might be associated with acceleration or exacerbation of IDDM.

Animals↗

PubMed2003

From clinical to human toxicology: linking animal research and risk assessment in man.

Since the 1960s, clinical toxicologists have primarily focused on acute poisonings. This proved very successful as the prognosis markedly improved with the use of resuscitation methods, evidence-based management and new antidotes. This latter area was the first major instance linking animal research and clinical toxicology, as illustrated with N-acetyl-cysteine or specific antibodies. Simultaneously the evolution of poison centers was a critical turning point as '2nd generation' centers are increasingly involved in risk assessment and toxicovigilance. Human toxicology is a broader area in that it is also involved in the toxicity evaluation of xenobiotics with the resulting need to link animal research and risk assessment to match the results of preclinical studies with clinical observations. However, this is not an easy task as experimental and clinical toxicologists seldom share ideas and expertise. Immunotoxicology is an example of this situation. Most of the available data on immunosuppression was obtained in animals and not in man, whereas allergic reactions have been extensively investigated in man, but overlooked in animals until recently. One of the major challenges facing toxicology is to bridge the gap between animal research and risk assessment in man. Human toxicology is expected to play a role in taking up this challenge.

Animals↗

PubMed2003

Immunosuppressive drugs and cancer.

Among the many adverse effects induced by immunosuppressive drugs, cancers are a major cause of morbidity and mortality. This review is based on the most recent clinical data. Epidemiological studies and cancer registries have consistently shown an increased risk of malignancies in transplant patients although the calculated risk (4-500-fold increase) differs markedly between studies essentially because of differences in methodologies and selection of patients. Skin and lip cancers, lymphomas and Kaposi's sarcomas are the main types of cancer in these patients. A number of risk factors have been identified, such as latent viral infections, the treatment regimen and the level of immunosuppression. The increasing use of immunosuppressive drugs in nontransplant patients is useful to delineate more accurately the consequences of mild-to-moderate immunosuppression.

Animals↗

PubMed2003

NK-cell activity in immunotoxicity drug evaluation.

NK-cell activity as a tool for detection of immunotoxic effects of new human drugs has gained further attention when the recent European note for guidance CPMP/SWP/1042/99 was adopted. The inclusion of NK-cell activity plus distribution of lymphocyte subsets were suggested as an alternative to the primary antibody response to a T-cell dependent antigen. Either of the two test alternatives should be included as a routine parameter in at least one repeated dose-toxicity study, rats or mice being the species of choice. The standard procedure for measuring NK-cell activity is the 51Cr-release assay. However, a new flow-cytometric assay, adapted for rat peripheral blood, does not require dedicated groups of animals, offers the possibility of repeated testing, and shows at least as sensitive as the conventional 51Cr-release assay.

Animals↗

PubMed2003

Ropivacaine combined with various anti-arrhythmic drugs results in mild alterations in myocardial contractility in pigs.

PURPOSE: The present study was undertaken following the observation of a marked decrease in myocardial contractility after ropivacaine in a patient on amiodarone, in order to investigate the cardiovascular effects of combining ropivacaine with anti-arrhythmic drugs (AARD). METHODS: Anesthetized domestic pigs were treated with disopyramide, flecainide, atenolol, amiodarone, diltiazem or nicardipine at a dose leading to blood levels obtained in treated patients, then received 1 mg*kg(-1) ropivacaine. Blood pressure (BP), left venticular (LV) dP/dt max, sinus heart rate, and intraventricular conduction time were measured before and following the administration of AARD, and following ropivacaine at different time points. RESULTS: All tested AARD induced the expected hemodynamic and electrophysiologic effects. Following ropivacaine, a 20 to 35% decrease in LV dP/dt max of prolonged duration was observed with amiodarone only. A brief 10 to 20% decrease in mean BP was observed in all animals, except those treated with nicardipine who sustained an important and prolonged decrease in BP. All other variables were not significantly affected. DISCUSSION: The combination of ropivacaine with AARD was always associated with a slight drop in LV dP/dt max. The effect on mean BP was slight, except with nicardipine. Clinicians should be aware of the interactions of ropivacaine with AARD, especially amiodarone and nicardipine.

Amides↗