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P Collart

Publications and source records attributed to P Collart.

At least 19 recordsLinked to original sources
PubMed2004

Comparative pharmacokinetics and metabolism of levetiracetam, a new anti-epileptic agent, in mouse, rat, rabbit and dog.

1: The pharmacokinetics and metabolism of 14C-levetiracetam, a new anti-epileptic agent, in mouse, rat, rabbit and dog after a single oral dose were investigated. Moreover, the in vitro hydrolysis of levetiracetam to its major carboxylic metabolite by rat tissue homogenates was investigated to identify tissues involved in the production of the metabolite. Data are also presented on the induction of the enzyme(s) involved in levetiracetam hydrolysis in the rat. 2: Levetiracetam was rapidly and almost completely absorbed. The unchanged drug accounted for a very high percentage of plasma radioactivity. Levetiracetam did not bind to plasma proteins. Although brain radioactivity concentrations were lower than those of whole blood at early time points, brain-to-blood ratios increased over time. The predominant route of elimination of total 14C was excretion via urine, accounting for about 81, 93, 87 and 89% of the dose in the mouse, rat, rabbit and dog, respectively. Consequently, levetiracetam was poorly metabolized. It was submitted in vivo to hydrolysis and/or oxidation. Hydrolysis of the amide function of levetiracetam produced the corresponding acid. However, levetiracetam could also be oxidized at positions 3 and 4 of the 2-oxopyrrolidine ring. Finally, the compound and the corresponding acid metabolite could be oxidized at position 5 of the 2-oxopyrrolidine ring and then hydrolysed with the opening of the ring. 3: All the investigated rat tissues (liver, kidney, lung, brain, small intestine mucosa) had the potential to produce the acid metabolite. By contrast, the acid was undetectable following incubation of levetiracetam with buffer alone or heat-denaturated liver fractions. 4: No marked species or sex differences were observed in the absorption, disposition and metabolism of levetiracetam. 5:The hydrolysis of levetiracetam is carried out by an enzymatic process characterized by a broad tissue distribution. In the rat, the enzyme system hydrolysing levetiracetam is not induced by phenobarbital, at least under the experimental conditions used herein, whereas the enzyme system(s) involved in the other metabolic pathways is induced.

Administration, Oral↗
PubMed2003

Discovery of orally bioavailable NK1 receptor antagonists.

Benzyloxyphenethylpiperazines are a new class of high affinity NK1 receptor antagonists. Oral bioavailability and selectivity can be fine tuned by the nature of the substituents on the basic nitrogen atom. Addition of substituents with a carboxylic acid group led to very selective and orally active NK1 antagonists free of interaction with L-type calcium channels.

Acylation↗
PubMed1999

In vitro inhibition of human liver drug metabolizing enzymes by second generation antihistamines.

Cetirizine, terfenadine, loratadine, astemizole and mizolastine were compared for their ability to inhibit marker activities for CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and for some glucuronidation isoenzymes in human liver microsomes. The most pronounced effects were observed with terfenadine, astemizole and loratadine which inhibited CYP3A4-mediated testosterone 6beta-hydroxylation (IC50 of 23, 21 and 32 microM, respectively) and CYP2D6-mediated dextromethorphan O-demethylation (IC50 of 18, 36 and 15 microM, respectively). In addition, loratadine markedly inhibited the CYP2C19 marker activity, (S)-mephenytoin 4-hydroxylation (Ki of 0.17 microM). Furthermore, loratadine activated the CYP2C9-catalyzed tolbutamide hydroxylation (ca. 3-fold increase at 30 microM) and inhibited some glucuronidation enzymes. Mizolastine appeared to be a relatively weak and unspecific inhibitor of CYP2E1, CYP2C9, CYP2D6 and CYP3A4 (IC50Ss in the 100 micromolar range). Cetirizine demonstrated no effect on the investigated activities. A comparison of the inhibitory potencies of cetirizine, terfenadine, loratidine, astemizole and mizolastine with their corresponding plasma concentrations in humans suggests that these antihistamines are not likely to interfere with the metabolic clearance of coadministered drugs, with the exception of loratidine, which appears to inhibit CYP2C19 with sufficient potency to warrant additional investigation.

Astemizole↗
PubMed1999

In vitro evaluation of potential drug interactions with levetiracetam, a new antiepileptic agent.

Levetiracetam and its carboxylic metabolite (AcL) were tested for their potential inhibitory effect on 11 different drug metabolizing enzyme activities using human liver microsomes. The following specific assays were investigated: testosterone 6beta-hydroxylation [cytochrome P-450 3A4 (CYP3A4)], coumarin hydroxylation (CYP2A6), (R)-warfarin hydroxylation (CYP1A2), (S)-mephenytoin hydroxylation (CYP2C19), p-nitrophenol hydroxylation (CYP2E1) tolbutamide hydroxylation (CYP2C9), dextromethorphan O-demethylation (CYP2D6), epoxide hydrolase and UDP-glucuronyltransferase (UGT) toward paracetamol (UGT1*6), ethinyloestradiol (UGT1*1), p-nitrophenol (UGT(pl 6.2)), and valproic acid. None of these activities were affected by levetiracetam or AcL added at concentrations up to 1 mM. Additionally, primary cultures of rat hepatocytes were used to assess a potential inducing effect of levetiracetam on CYPs. Phenobarbital (2 mM), beta-naphtoflavone (40 microM), dexamethasone (1 microM), and phenytoin (up to 300 microM) were tested as positive controls. When added to cells for 48 h, all the positive controls increased 7-ethoxycoumarin O-deethylase activity demonstrating the inducibility of CYPs in the present culture conditions. By contrast, levetiracetam did not affect the activity up to 1 mM. The highest levetiracetam concentrations examined in the above in vitro studies are well in excess of those measured in the plasma of patients receiving therapeutic doses. It is thus concluded that levetiracetam is unlikely to produce pharmacokinetic interactions through inhibition of CYPs, UGTs, and epoxide hydrolase. Furthermore, based on the in vitro assays with rat hepatocytes, it could be speculated that levetiracetam does not act as a CYP inducer.

Animals↗
PubMed1987

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.

Animals↗
PubMed1985

[Activity of thiamphenicol in the early stage of 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.

Animals↗
PubMed1984

[A method for evaluating the activity of antibiotics during the early phase of syphilitic infection].

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.

Animals↗
PubMed1982

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)

Adult↗
PubMed1981

[Critique of the basic elements on which various syphilis treatments are founded].

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.

Animals↗
PubMed1980

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.

Adult↗