An interlaboratory study to evaluate potential matrix reference materials for herbicides in water.

Matrix reference materials (MRM) are essential tools for the validation of analytical protocols. Nowadays, there are no such materials for the determination of herbicides in water. Pesticides stored in acetonitrile and stored on solid phase extraction (SPE) cartridges previously percolated with a water sample spiked with triazines and phenylureas have proven to be good candidates for reference materials because of their satisfactory stability under appropriate temperature conditions. To evaluate the behaviors of these materials containing pesticides and to be analyzed by liquid chromatography, a collaborative study including 15 laboratories has been organized. Observed reproducibility on candidate materials after the removal of extreme results was 16.1% for the vials with pesticides in acetonitrile (at around 0.125 mg/L) directly analyzed, 29.2% for a water sample spiked with the pesticides (at around 0.5 microg/L) analyzed after preconcentration on a cartridge and 26.7% for the cartridges previously percolated with a water containing the pesticides (250 mL at around 0.5 microg/L for each pesticide) analyzed after elution. Such dispersion values are quite compatible with the requirement of a further certification for such materials.

[In vivo study of the sensitivity of Treponema pallidum to ofloxacin]. / Etude in vivo de la sensibilité de Treponema pallidum à l'ofloxacine.

Treponema pallidum has not been yet cultivated. Hence any in vitro investigation is excluded, and it is owing to the experimental animal model, the rabbit, that we have studied the susceptibility of that germ to ofloxacin. This quinolone, owing to its pharmacokinetic and therapeutic properties, can specially be indicated in the treatment of Sexually Transmitted Diseases. Thus, its appeared to be of the utmost importance to know if the suggested schedule of treatment for STD, might not be susceptible to modify the course of a co-existing incubating syphilis by either delaying or inhibiting the apparition of the clinical features of primary syphilis. This study was undertaken at the incubation period, in syphilitic rabbits, using kinetic data obtained in man, after a given dosage of ofloxacin. Results were appraised upon converging data: lesions, bacteriology, and serology of the tested lot compared with two control batches of infected rabbits, the first one being untreated, the other having received the reference antibiotic treatment. From the data obtained and in the experimental settled conditions where this study was done, it results that ofloxacin has no effect on the course of the experimental syphilitic infection.

Syphilis in 1986.

Symptoms of syphilis have evolved over the ages. In the 16th century, they were essentially cutaneomucous ones. While the intensity of the symptoms decreased localization of the infection in the various organs--mainly those of the cardiovascular and nervous system--gradually appeared. Over a period of years following the introduction of penicillin therapy, the cutaneous and visceral stages became less common. Reminder of the chief serological reactions and of some aspects of the experimental syphilis in the rabbit, similar to certain forms of human syphilis--a strong but late penicillin therapy has been proven ineffective in humans as well as in animals. It is to be regretted that numerous methods of using penicillin (all over the world), had been, from the beginning--except in a few cases--of a purely empirical nature. The authors emphasize--with proof to support their opinion--the failure of antibiotic therapy, which can explain the recent reappearance of hepatic and nervous localizations that had disappeared for 30 years. Despite views to the contrary the authors conclude that penicillin has in no way resolved all the problems raised by the treatment of syphilis.

[Activity of thiamphenicol in the early stage of syphilis]. / Recherche sur l'activité du thiamphénicol au cours de la période précoce de la syphilis.

Possible activity of thiamphenicol on Treponema pallidum during single-dose treatment of gonococcal infection with 10 tablets of 0.250 mg each was investigated using a new, more accurate method. We found that, under the conditions of our study, thiamphenicol fails to kill T. pallidum, exhibiting only incomplete activity. Thus, thiamphenicol taken during incubation of syphilis may delay or inhibit the emergence of primary manifestations but fails to achieve bacteriologic sterilization of T. pallidum acquired concomitantly with gonococcus. Clinical and serologic evidence of syphilis should therefore be looked for routinely three and six months after treatment.

[A method for evaluating the activity of antibiotics during the early phase of syphilitic infection]. / Méthode pour juger de l'activité des antibiotiques au stade précoce de l'infection syphilitique.

The aim of our study is to evaluate the activity of antibiotics on Treponema pallidum (Tp) in the early stage of syphilis. Serum elimination kinetics for the antibiotic under study are first determined in rabbits. Four groups of seronegative rabbits are then submitted to intratesticular injection of a calibrated inoculum of Tp (Nichols virulent strain). The antibiotic is given simultaneously (TO), 3, 6 or 10 days after inoculation. Treated animals, as well as a control group of simultaneously infected untreated animals, are monitored for physical and serological changes for three months. Every animal is then tested according to the techniques of experimental rabbit syphilis to provide final conclusions. The technique investigates the direct activity on Tp of given serum concentrations of an antibiotic, and therefore the therapeutical effectiveness of an agent in a selected dosage. It also allows demonstration of sublethal activity on Tp of serum concentrations which are adequate for treating other concurrent infections (including STD) but not syphilis.

Is penicillin therapy always infallible in syphilis?

Penicillin is undoubtedly the antibiotic most effective on Treponema pallidum, but is it possible to prescribe it according to a standard regimen? Experimentation proves that such a uniform therapeutic plan cannot be determined for the following reasons: 1) Treponema pallidum may divide every 30 to 33 hours, but this concept is only established during the period of exponential growth in the initial lesion. Moreover, if Treponema pallidum are very quickly disseminated throughout the organism, then they do not divide at the same rate. In addition, we take into account a whole series of factors which can interfere with their rate of multiplication. 2) A penicillinemia of 0.03 U/ml may kill all the Treponema pallidum when they divide, but Dr. Eagle's data, although this would be a fairly active serum level, showed that the effective maximal serum concentration should be far higher, about 0.820 U/ml. The experimental data prove it is not possible to point out an accurate correlation between blood and tissue levels; thus, the penicillin levels in the cerebrospinal fluid are about 1/100 lower than those obtained in the serum. Among other factors it is necessary to take into account not only the age of the patient but also the penicillin complex chosen. Although the total of injected penicillin can be the same, the kinetics of serum levels are essentially variable, both regarding the increase of levels and duration according to the drug used. 3) As noted it follows that penicillinotherapy prescribed early with high and prolonged doses may allow a bacteriologic sterilization of primary syphilis.(ABSTRACT TRUNCATED AT 250 WORDS)

[Syphilis. An up-to-date physio-biological view of the main topics. IV.--The problem of the treatment by penicillin (author's transl)]. / La syphilis. Actualités physio-biologiques. IV.--Le problème de la pénicillinothérapie.

Can penicillin be considered as an infallible treatment for syphilis? Some practitioners have hoped and even believed that this antibiotic would be able to eradicate this infection. To support their thesis, they have put forward an uniform standard therapeutic plan capable of being applied to any stage of the disease and which is based upon the following syllogism: a) all T.p. would divide every 30-33 hours. b) a level of penicillinemia of 0.03 IU/ml would destroy all Treponema when they divide. c) thus, a penicillin therapy administered 3 times giving such levels in serum during a period of 33 hours would produce a bacteriological sterilization of the infected organism. But statistics have shown that these conceptions were wrong. As a matter of fact: 1) every biological research has clearly proved that it is wrong to assert such a rhythm of division for all T.p. Since this multiplication is submitted to a succession of factors that we know more or less well, thus, during the latency phase, T.p. vegetate inside the tissues without apparently multiplying so quickly. 2) For lack of being able to cultivate T.p., it is not possible to state which is the activity level of penicillin on this germ. 3) Finally, the kinetic elimination of penicillin varies extremely, particularly depending on the drug which is used with patients, and on the localization of these germs. All experimental and clinical studies agree and insist on the fact that penicillin therapy must be given early in the infection, at a prolonged and high dose; results having to be estimated on the serological answers, especially with repeated TPI and FTA tests. As far as the late phases of the disease are concerned, for lack of being able to cultivate T. pallidum and because we do not have any absolute criterion of any bacteriological sterilization, the serological answers being often positive, circumspection has always to be a rule: it is better to admit what we do not know rather than to assert without any proof.

[Syphilis. An up-to-date physio-biological view of the main topics. III -- The problem of immunity (author's transl)]. / La syphilis. Actualités physio-biologiques. III. -- Le problème de l'immunité.

The problem of immunity in Syphilis is a very complex problem which is tightly bound to healing. But for lack of being able to grow T. pallidum and as we are without any absolute criterion of bacteriological sterilization, the only method we have to be able to consider this study is to have recourse to experimentation upon animals. Two theories had been proposed to give an explanation about this phenomenon occurring during a late treated syphilis: on one side, for Kolle, Evers and Neisser, immunity in syphilis would be due to a premunition given by the only persistence in the organism of T.p. having still kept all their virulence. On the other hand, as far as Chesney and Kemp are concerned it would be a true immunity, obtained before the application of any therapeutic treatment, but which is not due to persistence of T.p. in tissues. However, recent works have proved, and this has been confirmed by several searchers, that a penicillin therapy, even at a high dose, given six months after the infection outset, is no longer able of destroying all T.p. Immunity in syphilis would then be due to a modification of tissular receptivity kept by the persistence of T.p. vegetating in the organism in a commensal state. As far as the nature of this immunity is concerned, all the present research would lead to prove that this refractory state would not be due to tumoral properties, but more likely to tissular properties and probably to cell mediated phenomena. Similar research carried out in man has created an opportunity to demonstrate these facts similar to those observed in experimentations upon animals. They particularly prove that a persistent serology over a long period is not due to a "cicatrice sérologique" (Serological marker) but to the keeping of T.p. in a quiescent state. However, it is a more or less relative immunity which is concerned, depending upon a very large number of factors that are far from being elucidated.

[Syphillis. An up-to-date physio-biological view of the main topics. II- The evolutive process of experimental syphilitic infection and a comparison with clinical symptoms in man (author's transl)]. / La syphilis. Actualités physio-biologiques. II. Processus évolutif de l'infection syphilitique expérimentale et humaine.

For lack of being able to grow Treponema pallidum, the only possibility that we have to study its biological behavior is to have recourse to experimentation upon animals. The stade comprising primary and secondary syphilis is characterized by visible "warning signals" which are not serious for the patient himself. But all their importance lies in the fact that they reveal the dissemination of T. pallidum inside the whole body. Thus, the healing alone or the disappearance of the lesion does not necessarily mean that it is cured. As a matter of fact, after that phase, infection may proceed "á bas bruit", as a chronic affection, which will come to light later, 10 to 15 years or more after the primary stage, as a visceral phase involving mainly cardiovascular or central nervous system. Those impairments cannot then be cured. Now, during that long period of latency, we are totally without any absolute criterion of "bacteriological sterilization", for we do not know precisely the physio-pathological meaning of these numerous serological reactions which are at out disposal and subsequently we are obliged to interpret them through divergent opinions because these techniques are not established on scientific method but are based upon empiric knowledges.

[Syphilis. Current physiobiological data. I. The bacteriological problem]. / La syphilis. Actualités physio-biologiques. I. Le problème bactériologique.

For lack of being able to grow Treponema pallidum, the only method which allows us to study the biology of this germ and the physiopathology of this infection lies in researches in experimental syphilis. After pointing out the different aspects of Treponema pallidum, either with light microscopy or electron microscopy, the authors review the different kinds of reproduction suggested by syphiligraphs, the recent trials to cultivate the treponema, and the processes of elimination. Then, they examine the biological properties and the antigenic structure of T.p. as it has been established by comparison with cultivable spirochetes. To end with, the authors show that both the TPI test and the FTA test are two very specific reactions; these tests mean nothing but the fact that the patient has been in contact with the antigens of Treponema pallidum and the quantitative tests cannot be considered as expressing the infectious potential capacity.

[Critique of the basic elements on which various syphilis treatments are founded]. / Crítica de los elementos de base en que se fundan ciertos tratamientos de la sífilis.

Certain basic treatments of syphilis depend on the following theories: 1) All treponema divide every 30 to 33 hours. Experiments have shown that this idea is only valid during the phase of exponential growth, i.e. it corresponds to the period lyinü between penetration of the germ into the organism and the onset of the initial lesion. One should also be reserved about a whole series of factors which may interfere with the rate of multiplication of treponema. 2) Blood penicillin levels of 0.03 U./ml. would destroy all treponema during cell division. It seems that the efficacy of penicillin mainly depends on levels, at the time of multiplication of the spirochetes. This level of 0.03 U./ml., according to Eagle, should be considered as an average serum concentration, the concentration of maximum efficacy is much higher, about 0.825 U./ml. In any case, it is not possible to obtain with a single dose, equal for all subjects, fixed and certain penicillin levels. For a given quantity injected, serum levels vary from one subject to another and, in the same individual, from one time to another. 3) The epidemiological results do not seem to confirm the optimistic forecasts of certain venereologists who thought that with a standard therapeutic method, it would be possible to eradicate syphilis.

Kinetic study of serum penicillin concentrations after single doses of benzathine and benethamine penicillins in young and old people.

In a comparative kinetic study of the serum concentrations of two penicillin complexes--medium-long-acting (benethamine penicillin) and long-acting (benzathine bipenicillin)--after a single injection in young adults and elderly people, the following results were confirmed statistically: (a) age was a major factor in the variations in serum penicillin concentrations and in their persistence in the serum; (b) the penicillin was absorbed faster in young than in elderly subjects even when a long-acting complex was used; (c) serum concentrations below the level regarded as lethal for treponemes appeared much earlier and more frequently in young than in old people; and (d) the bioequivalence between penicillin preparations could not be estimated solely for the number of units of the agent used but from the bioavailability of the chosen formulation. Thus a uniform and standard penicillin dosage allowing no safety margin may help in the superficial healing of a syphilitic chancre or the resolution of a roseola but it will certainly be insufficient to kill Treponema pallidum. It seems essential therefore to provide an antibiotic cover at high dosage over a long period of time.

Plasma cyclic AMP levels during a secretin-caerulein pancreatic function test in liver and pancreatic disease.

Plasma cyclic AMP levels were determined during a 40 minute secretin infusion (1 Cl.U kg-1h-1) followed by a 40 minute combined secretin (1 Cl.U kg-1h-1) caerulein (75 ng kg-1h-1) infusion. In nine healthy subjects, both secretin alone and secretin in combination with caerulein did not affect plasma cyclic AMP levels. The same was observed in six patients with chronic pancreatitis. By contrast, in patients suffering from liver disease (nine cases) or extrahepatic cholestasis (six cases), secretin elicited large increases in plasma cyclic AMP concentration; the mean values attained being, respectively, seven and four times higher than before the infusion. On the other hand, increases in plasma cyclic AMP 10 minutes after a bolus injection of glucagon (1 mg) were four times lower in the liver disease group as compared to the controls. The results reported here suggest that the liver plays a major role in the degradation of plasma cyclic AMP produced by target tissues responding to secretin, and in the release of cyclic AMP under glucagon. Liver disease reduce the capacity of the liver to clear cyclic AMP from the blood. The pancreas does not contribute significantly to the cyclic AMP in the blood.