A brief history of toxicology in France during the last two centuries (1789-1989).

The history of toxicology in France over the last two centuries has been marked by numerous authors who have progressively broadened the fields of investigation: initially concerned with criminal or accidental poisonings, they have also taken an interest in the environment, workers' health, doping and illicit products, the dangers of radioactivity or combat gases, the risks associated with drugs, etc. Often pharmacists, these toxicology experts were specialists in analytical chemistry and developed numerous methods to refine the detection and characterization of potentially toxic products, and to better understand the mechanisms of toxicity produced by these substances.

[Cannabis and safety of work. Evolution of its detection within the controls of narcotics since 2004 to the SNCF]. / Cannabis et sécurité du travail. Photographie de l'évolution de sa détection au sein des contrôles de stupéfiants depuis 2004 à la SNCF.

Fifteen to 20 % of fatal work-related accidents would be connected to the use of alcohol, psychotrops or narcotics. Many constraints restrain the systematic detection of addictive behaviour at work. The restraints can be financial, ethical, technical or laid down in the regulations. The occupational physician remains the main actor in the prevention of the risks caused by those behaviours. In 2004, the firm SNCF engaged a long-term action of drugs information and detection. It has been well-understood by the agents and all the firm's operators achieved in appropriated conditions, with a strict respect of the medical secret. In four years, the number of detected consumers decreased by half.

A critical review of the causes of death among post-mortem toxicological investigations: analysis of 34 buprenorphine-associated and 35 methadone-associated deaths.

AIMS: To assess the trends in the number, mortality and the nature of forensic cases involving toxicological detection of buprenorphine or methadone among toxicological investigations performed in Paris from June 1997 to June 2002. DESIGN: Retrospective, 5 year study with review of premortem data, autopsy, police reports, hospital data, and post-mortem toxicological analyses. SETTING AND PARTICIPANTS: 34 forensic cases of buprenorphine and 35 forensic cases of methadone detection among 1600 toxicological investigations performed at the Laboratory of Toxicology in the Medical Examiner's Office in Paris. MEASUREMENTS AND RESULTS: Therapeutic, toxic or lethal drug concentrations were defined based upon the results of blood analyses and the published literature. Drug concentrations were cross-referenced with other available ante- and post-mortem data. Subsequently, we classified a 'clear responsibility', 'possible responsibility' or 'not causative' role for buprenorphine or methadone in the death process, or 'no explanation of death'. Buprenorphine and methadone can be regarded as being directly implicated in, respectively, four of 34 death cases (12%) and three of 35 death cases (9%), and their participation in the lethal process is strongly plausible in eight (buprenorphine) and 11 (methadone) additional deaths. CONCLUSIONS: Analysis of causes of death reveals the difficulties in determining the role of substitution drugs in the death process, as many other factors may be involved, including circumstances surrounding death, past history, differential selection of subjects into either substitution modality and concomitant intake of other drugs (especially benzodiazepines and neuroleptics). The potential for synergistic or additive actions by other isolated molecules-particularly opioids, benzodiazepines, other psychotropes and alcohol-must be also considered.

Trends in opiate and opioid poisonings in addicts in north-east Paris and suburbs, 1995-99.

AIMS: (1). To assess the trends in the number, mortality and the nature of severe opiate/opioid poisonings from 1995 to 1999 in north-east Paris and adjacent suburbs and (2). to examine the effects of the introduction of high-dose buprenorphine on these parameters. DESIGN: Retrospective, 5-year study with review of pre-hospital, hospital and post-mortem data. SETTING AND PARTICIPANTS: Eighty patients from the toxicological intensive care unit (TICU) in north-east Paris, 421 patients from the pre-hospital emergency medical service in a north-east suburb of Paris (SAMU 93) and 40 deaths from the coroner's office in Paris. MEASUREMENTS AND RESULTS: We found that the number of pre-hospital opiate/opioid poisonings and deaths decreased over 5 years. During the same time frame, opiate/opioid poisoning admissions to our TICU remained steady, but the number of deaths declined. From 1995 to 1999, the detection of buprenorphine among opiate/opioid-poisoned TICU patients increased from two to eight occurrences per year while detection of opiates diminished from 17 to 10 occurrences per year. Increased buprenorphine detection correlated directly with increasing sales over this time period. In spite of the increased use of buprenorphine, the mortality associated with opiate/opioid poisonings has diminished in the pre-hospital environment from 9% in 1995 to 0% in 1999, and in the TICU from 12% in 1995 to 0% in 1997 and thereafter. We found a high frequency of multiple opiate/opioid use in severe poisonings, as well as the frequent association of other psychoactive drugs including ethanol. CONCLUSIONS: The number and the mortality of opiate/opioid poisonings appear to be stable or decreasing in our region. The association of multiple opiates/ opioids appears nearly as common as the association with other psychoactive drugs. The introduction of high-dose buprenorphine coincides with a decrease in opiate/opioid poisoning mortality. Further study will be necessary to clarify this observation.

[Chemical weapons: antidotes. View about the real means, perspectives]. / Armes chimiques: antidotes. Aperçu sur les moyens actuels, perspectives.

Chemical methods remain a credible threat in 1999. The doctrine for their use not only includes the battlefield but also domestic terrorism as was disclosed during the Tokyo metro attempt in 1995. International Treaties have not yet proven their efficacy. The arsenal of chemical weapons has changed little since the second World War but is now dispersed into many high-risk zones throughout the world. There has also been little change in antidotes: therapeutic prevention with pyridostigmine against organo-phosphorus compounds, protective treatment for seizure-induced brain lesions using anticonvulsants in association with oxime for acetylcholinesterase reactivation, and atropine are combined in a three-compartment syringe. Preventive measures against vesicants and other suffocating or toxic intracellular substances (CN, AsH(3), fluorocarbons.) can only be achieved with protective skin covering or protective breathing devices. There is no specific treatment and we often have to use symptomatic medications. Future perspectives include: phosphotriesterases as organo-phosphorus scavengers, huperzine as pretreatment and gacyclidine (GCK 11) which would effectively complete emergency multiple drug therapy against nerve agents. A new two-compartment syringe is now prepared with atropine, avisafone and HI6 or pralidoxine. A gel made of cyclodextrines for external and eventually internal use is under study.

Influence of free-to-total prostate specific antigen variability on the early diagnosis of prostate cancer: a comparative study of three immunoassays.

OBJECTIVE: To compare three immunoassays for total prostate specific antigen (tPSA), free PSA (fPSA), free-to-total PSA ratio (f/tPSA), and the f/tPSA thresholds for optimal differentiation between benign prostatic hypertrophy (BPH) and prostate cancer in 141 consecutive patients referred for prostatic disease. PATIENTS AND METHODS: The study included 43 patients with prostate cancer and 98 with BPH, all confirmed histologically. PSA levels were assessed using the following assay kits just before histological analysis of the prostate; Hybritech (Tandem-R PSA, normal values, NV, < 4 ng/mL, and Tandem-R free PSA), Cis Bio (PSA-RIACT, NV < 2.5 ng/mL and fPSA-RIACT) and Immunocorp (PSA-IRMA, NV < 4 ng/mL and Free PSA-IRMA). The results were assessed to determine the sensitivity, specificity and threshold values of the different assays to differentiate patients with BPH and cancer. RESULTS: The mean tPSA and f/tPSA ratio were statistically different in assays with different NVs. The mean fPSA values differed significantly between the Hybritech and Cis Bio, between the Hybritech and Immunocorp but not between the Cis Bio and Immunocorp assays. With receiver operator curve analysis, there were no statistically significant differences among the three immunoassays in f/tPSA (0.72 for Hybritech, 0.73 for Cis Bio and 0.64 for Immunocorp) or between the tPSA and fPSA curves for each manufacturer. With the sensitivity fixed at 90%, different f/tPSA thresholds were defined (0.22, 0.34 and 0.25 for Hybritech, Cis Bio and Immunocorp, respectively). The specificities (i.e. the percentage of unnecessary biopsies spared) were 22%, 21% and 31%, respectively (not significantly different). CONCLUSION: Each immunoassay could be used to distinguish prostate cancer and BPH at different f/tPSA thresholds, with 21-30% of unnecessary biopsies spared. There was no difference in overall performance among the different assays. Further studies are needed to better define the exact use of the f/tPSA ratio in the routine diagnosis of prostate cancer.

[The incidence of the variability of the free PSA/total PSA ratio on the early diagnosis of prostate cancer]. / Incidence de la variabilité du rapport PSA libre/PSA total sur le diagnostic précoce du cancer de prostate.

INTRODUCTION: In patients with moderate elevation of total PSA, the use of the Free PSA/Total PSa ratio (F+T PSA) has been shown to be useful in the diagnosis of impalpable prostatic cancer. However, the cut-off values proposed in the literature vary from study to study and according to the immunoassay kit used. Our prospective study was designed to compare 3 different kits (Tandem, Cis Bio and Immunocorp) on the same series of patients in order to determine on the basis of these results and a review of the literature, the optimal ratio for which prostatic biopsies should be indicated in the presence of an isolated elevation of Total PSA. MATERIAL AND METHODS: Serum samples from 141 patients (43 cancers and 98 cases of histologically confirmed BPH) were included. Assays were performed concomitantly with histological examination of the prostate, using Tandem, Cis Bio and Immunocorp kits. RESULTS: In the overall patient population, Total PSA and Free PSA assays were statistically different for the 3 kits (p < 0.001). The F/T PSA ratio was always statistically different between the cancer and benign prostatic hyperplasia groups (p < 0.002). The cut-off values defined by a sensitivity of 90% were of 0.22 for Tandem (specificity: 27.5%), 0.34 for Cis Bio (specificity: 19.4%) and 0.26 for Immunocorp (specificity: 26.5%). When the total PSA level was between 4.0 and 10.0 ng/ml, these cut-off values also differed: 0.23 for Tandem (specificity: 26.6%), 0.35 for Cis Bio (specificity: 17.2%) and 0.25 for Immunocorp (specificity: 29.7%). In patients with a non-suspicious digital rectal examination and a F/T PSA ratio less than 0.10, the cancer detection rate (number of biopsies required to diagnose 1 cancer) was 1.66 for Tandem, 1 for Cis Bio and 1.87 for Immunocorp versus 7.7 while, when the F/T PSA ratio was greater than 0.22, the cancer detection rate was infinity (no cancer beyond this limit), 12.5 and 23, respectively. CONCLUSION: The F/T PSA ratio increases the specificity of prostatic cancer detection in patients with a total PSA between 4 and 10.0 ng/ml with a non-suspicious digital rectal examination, therefore resulting in a reduction of the useless biopsy rate and defining more relevant indications for biopsies in the case of periodic follow-up. The systematic indication of this ratio in the screening context cannot be recommended, but it can be useful to demonstrate stage TIC tumours in order to avoid numerous useless biopsies.

[Value of free/total prostate specific antigen in the early diagnosis of prostate cancer (study of 105 patients)]. / Intérêt du rapport PSA libre/PSA total dans le diagnostic précoce du cancer de la prostate (etude de 105 patients).

INTRODUCTION: Prostate Specific Antigen (PSA) exists in the serum in several molecular forms which can be measured by immunoradiodetectable assays: free PSA and total PSA (which represent the sum of the free PSA and complexed PSA to alpha 1 antichymotrypsin). Recently, the proportion of free to total PSA could enhance the ability to distinguish benign histologic conditions from cancer. MATERIAL AND METHODS: Serum samples of 105 patients (31 histologically confirmed prostate cancers and 74 histologically confirmed untreated benign prostatic diseases) were included in this study. The total and free PSA levels were determined using the PSA immunoradioassay of Tandem-R PSA and Tandem - R free PSA. RESULTS: When all subjects were included, both total PSA and the proportion of free to total PSA significantly differentiated between patients with prostate cancer and patients with benign histologic conditions (p < 0.01 and p < 0.005). However, in men with total PSA values between 4.0 to 10.0 ng/ml, the proportion of free to total PSA significantly differentiated between the patients with benign and malignant histological conditions (p < 0.04). The most interesting was the ability of the proportion of free to total PSA to distinguish patients with total PSA value between 4.0 and 10.0 ng/ml and normal digital examination (p < 0.001). With these values of PSA-T, a free PSA cutoff of 0.23 detected at least 90.4% of cancers and would eliminate 19.4% of negative biopsies. CONCLUSION: Measurement of the free to total PSA level improves specificity of prostate cancer screening in selected men with elevated total serum PSA levels between 4.0 to 10.0 ng/ml and normal digital examination, and can reduce unnecessary prostate biopsies with minimal effects on the cancer detection rate.

[Is plasma lipoprotein (a) level a reliable indicator predicting restenosis after angioplasty?]. / Le taux plasmatique de lipoprotéine (a) permet-il de prédire la resténose après angioplastie?

Lipoprotein (a) [Lp(a)] is an independent genetically determined marker of coronary artery disease. It is present in the atheromatous plaque with a molecular structure similar to that of plasminogen. Its role in postangioplasty restenosis is a possibility but is controversial. A population of 103 coronary patients underwent angioplasty with control coronary angiography before the 6th month; there were 53 good results and 50 cases of restenosis. The Lp(a) was measured by immunonephelemetry (threshold value of 250 mg/l). A subgroup with Lp(a) concentrations > 250 mg/l was identified. The average concentrations of Lp(a) in the two groups without restenosis (368 +/- 350 mg/l) and with restenosis (418 +/- 434 mg/l) were not statisticaly different (p = 0.2). When cases with Lp(a) > 250 mg/l were considered alone, the tendency to higher average concentrations of Lp(a) in the group with restenosis (777 +/- 424 mg/l) compared with the group without restenosis (656 +/- 340 mg/l) was more clear-cut but did not achieve statistical significance (p = 0.08). The individual scatter of Lp(a) being very wide (83 to 1,450 mg/l in the group without restenosis and 90 to 1,740 mg/l in the group with restenosis), it is impossible to predict restenosis from this parameter in a given individual. No correlations were observed between the different lipid fractions and restenosis. The extension of the lesions and the angioplasty site did not correlate with restenosis in this study. The authors conclude: 1) that the Lp(a) concentration has no individual predictive value for restenosis; 2) individuals with Lp(a) concentrations > 250 mg/l have an increased risk of restenosis (NS); 3) these results confirm other recent publications; and 4) further research into the isoforms of Lp(a) in each group could provide interesting data.

[Evaluation of coronary risk: a new technique of measuring lipoprotein (a)]. / Evaluation du risque coronaire: une nouvelle technique de dosage de la lipoprotéine (a).

The aim of this study was to assess the reliability of immuno-nephelemetric assay (INA) of lipoprotein (Lp(a)) compared with immuno-radiometric (IRMA) and immuno-enzymologic (ELISA) assays in a coronary (P1) and a non-coronary (P2) populations. The serums of 66 coronary subjects (P1) with an average age of 61.5 +/- 10 years and 137 non-coronary subjects (P2) with an average age of 54 +/- 12 years were analysed by the 3 techniques. The technical characteristics of the INA were: negligeable interference with plasminogen (PLG) (< 1/100) for PLG < 375 mg/l; excellent repeatability and reproducibility at low, medium and high concentrations, respectively 12.3 and 7.5%. 1.2 and 1.2%, 1.3 and 1.1%, low dependance on sample conservation (stable 5 days at +4 degrees C), excellent practicability (simple and quick automised analysis: 10 min). The linear correlations with the concentrations of Lp(a) were: excellent with INA/IRMA P1 and P2: 0.99; very good with INA/ELISA P1: 0.88 and P2: 0.85; very good between IRMA/ELISA P1: 0.91 and P2: 0.87. The average values of Lp(a) were 386 mg/l (INA), 339 mg/l (IRMA), 316 mg/l (ELISA) for P1, and 231 mg/l (INA), 212 mg/l (IRMA) and 153 mg/l (ELISA) for P2, with a significant difference between P1 and P2 with all three techniques: 0.0138 (INA), 0.0207 (IRMA) and 0.0001 (ELISA). The authors concluded that measuring Lp(a) by INA is reliable with respect to IRMA and ELISA techniques, as accurate, quicker, automatised and cheaper, compensating for a lower sensitivity, a calculated risk of a non-specific reaction and the necessity of a shorter delay of analysis. The comparative results in two populations demonstrate it to be an excellent marker of coronary risk for epidemiological studies, independant of other risk factors.

[Necessity of radiopharmaceutical control and vigilance]. / De la nécessité du contrôle radiopharmaceutique et d'une radiopharmaco-surveillance.

A recent problem with radiopharmaceutics in Val-de-Grâce hospital proves the necessity of a control. Using of the 99mTc (Hydroxy-methylene diphosphonate [HMDP] skeletal image we got a kidney scintigraphic images instead of the expected skeleted. The investigation of the occurrences has rapidly shown no possible confusion: At the day of failed examination, only 99mTc microspheres (target: Lung), methoxy-isobutyl-isonitrile, MIBI (target: heart) and 99mTc Phytate (target: Reticulo-Endothelial System) were used. Radioactivity control of 99mTc generator was conformable and labelled efficiency of the whole of HMDP assays were satisfying. This test is only an approach of radiochemical purity and was not adequate here. The renal image had suggested a chelate use. Accordingly, we have realized the Pharmacopoeia identification of DTPA with dimethyl-glyoxime-Ni, HMDP standards, DTPA (diethylene-triamino pentacetate), and HMDP residues from the vials used on the incident's day. It has been shown that residues of HMDP contain, like DTPA, but not like HMDP standards, a nickel chelating system. This proves a substitution of compound unknown to medical users.

Radioimmunological determination of total thyroxin by antibodies immobilized on polystyrene tubes coated with styrene-maleic anhydride copolymers.

In this new technique for preparing activated polystyrene tubes for assay of human thyroxin (T4) we coated plastic with styrene-maleic anhydride copolymers. The quantity of antibodies immobilized on these tubes was considerably greater than on non-activated polystyrene tubes, and the time required for immobilization was shortened. Calibration curves were plotted, and determination of total T4 in 200 serum samples confirmed the expected increase in sensitivity as compared with a commercial (Gammacoat) method. The manufacturing procedure is simple and could easily be automated. Thus, such copolymer-coated tubes constitute an advantageous and reliable component in the assay of total T4 that can be used to improve the sensitivity of this and various other radioimmunological determinations.

Antibody immobilization on swollen polystyrene tubes for the radioimmunological determination of total human serum IgE.

A new technique for preparing activated polystyrene tubes was developed involving the controlled swelling of plastic. The quantity of antibodies immobilized on these tubes, and consequently the quantity of bound IgE, was considerably increased. Calibration curves were plotted and the determination of total IgE in 200 serum samples confirmed the expected increase in sensitivity compared to a standard method. The manufacturing procedure was simple and could easily be automated. Thus, swollen polystyrene tubes constitute an advantageous solid stage in the assay of total IgE, which can improve the sensitivity of various radioimmunological determinations.

[Biological markers and germinal tumors of the testis. Value and limitations of the assay of chorionic gonadotrophin hormone and alpha-fetoprotein]. / Marqueurs biologiques et tumeurs germinales du testicule. Intérêts et limites du dosage de l'hormone chorionique gonadotrope (HCG) et de l'alpha-foeto-protéine (AFP).

Between 1978 and 1985, 128 patients with germinal tumors of the testes were treated at the Val-de-Grâce Hospital; biological market levels--beta HCG and AFP--were determined before and after orchidectomy in the peripheral blood and during orchidectomy in testicular blood in 76 patients. HCG levels were elevated in 13% of seminomas and HCG and/or AFP levels were elevated in 76% of non seminomas; the sensitivity of the determination was greater in testicular blood. However, in our study, there was no parallelism between marker levels before orchidectomy and tumor stage or prognosis. The change in HCG and/or AFP levels appears to an index of the response to therapy: 4 patients with high HCG and/or AFP levels during chemotherapy died. The diagnosis of recurrence is not always documented by elevated marker levels and monitoring must always documented by elevated marker levels and monitoring must always include both determination of marker levels and imaging.

[Experimental coronary angioplasty using hematoporphyrin coloration simultaneously with a pulsed laser beam]. / Angioplastie coronaire expérimentale utilisant simultanément la coloration par l'hématoporphyrine et un rayon laser pulsé.

The setting up of a reliable method for angioplasty by laser irradiation is based. On the one hand, on the simultaneous control of the observed thermal, mechanical and photochemical effects within the atheromatous material and, on the other, on the demonstration of the absence of effects damaging to the arterial tunica. Theoretical modelling and experimental use have together proved the unique importance of pulsed emission, which strongly reduces thermal diffusion. Labelling of the atheromatous plaque by a hematoporphyrin derivative (HPD), as exemplified in the carcinological process, cancels the superficial reflectivity and strongly reduces the diffusion coefficient in the plaque. It confers on it a spectral absorption characteristic which is the basis of the exact physical coupling between the frequency of the exciting radiation and the absorption which generates vaporization in the pathological material. The preparation of chemically more homogeneous HPD and the spectrometric study of other colouring agents in vivo point to a further development of this technique of angioplasty.

[Comparative study of uric acid concentration in serum and saliva of healthy or hyperuricemic subjects]. / Etude comparative des concentrations d'acide urique dans le sérum et la salive chez les sujets sains ou hyperuricémiques.

In normal or hyperuricemic subjects, the average values of serum and salivary uric acid concentration are very similar in each group of subjects. After absorption of a uricosuric drug, benzbromarone, a study of the variations of uric acid concentrations in the serum and saliva shows that they are parallel, which shows the stricts dependence salivary excretion on plasma concentration.