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C Jaquet

Publications and source records attributed to C Jaquet.

15 recordsLinked to original sources
PubMed1998

An assessment of drug-haematin binding as a mechanism for inhibition of haematin polymerisation by quinoline antimalarials.

Chloroquine is thought to exert its antimalarial activity by preventing the polymerisation of toxic haematin released during proteolysis of haemoglobin in the Plasmodium digestive vacuole. However, the molecular mechanisms by which this inhibition occurs and the universality of this mechanism for other quinoline antimalarials remain to be established. We demonstrate here a correlation for eight antimalarial quinolines between inhibition of haematin polymerisation in vitro and inhibition of P. falciparum growth in culture, confirming haematin polymerisation as the likely target of quinoline blood schizonticides. Furthermore, using isothermal titration microcalorimetry, a correlation was observed between the haematin binding constant of these compounds and their ability to inhibit haematin polymerisation, suggesting that these compounds mediate their activity through binding to haematin. It was also observed that the compounds bind primarily to the mu-oxo dimer form of haematin rather than the monomeric form. It is postulated that this binding inhibits haematin polymerisation by shifting the haematin dimerisation equilibrium to the mu-oxo dimer, thus reducing the availability of monomeric haematin for incorporation into haemozoin. These data reconcile the haematin polymerisation theory with the Fitch hypothesis, which states that chloroquine mediates its activity through binding to haematin.

Animals↗
PubMed1998

Gastric administration of recombinant 65 kDa heat shock protein delays the severity of type II collagen induced arthritis in mice.

OBJECTIVE: The 65 kDa heat shock protein (HSP) chaperonin is a highly conserved intracellular protein. HSP are involved in the pathogenesis of arthritis, but are not able to induce experimental arthritis. T cell clones recognizing the 180-188 amino acid sequence of 65 kDa HSP are present in inflamed synovium of both adjuvant arthritis and rheumatoid arthritis (RA). Oral administration of bovine collagen II or co-chaperonin 10 kDa HSP has been shown to induce an immune tolerance state to collagen induced arthritis (CIA). We investigate the effect of oral gavage with 65 kDa HSP on CIA. METHODS: We immunized 6-8-week-old DBA1 male mice with bovine type II collagen. A group of 25 mice were given oral recombinant mycobacterial 65 kDa HSP before immunization (30 microg in 200 microl phosphate buffered saline (PBS) at Days -7, -5, -2) while PBS alone was administered in 27 controls. A 3rd group was fed 65 kDa HSP according to the same protocol but was not immunized with collagen II (n = 8). The clinical arthritis score was recorded 3 times/week until Day 60. Antibodies to collagen II were determined by ELISA. RESULTS: The incidence of arthritis was comparable in the 2 groups (72 vs 70%). The onset of arthritis was not delayed in mice fed HSP. However, the severity of arthritis was lower 10 days after arthritis onset in animals fed 65 kDa HSP (clinical score 1.83 +/- 0.79 vs 2.74 +/- 1.1; p < 0.0001). No animals in Group 3 had arthritis. Serum IgG anti-type II collagen levels were decreased in HSP treated mice (optical density 0.33 +/- 0.21 vs 0.46 +/- 0.21; p < 0.0001). However, the ratio of IgG1/IgG2a antitype II collagen antibody response remained unchanged in the mice fed 65 kDa HSP. CONCLUSION: These results suggest that oral administration of 65 kDa HSP may diminish collagen induced arthritis.

Administration, Oral↗
PubMed1997

Antimalarial activity of the bisquinoline trans-N1,N2-bis (7-chloroquinolin-4-yl)cyclohexane-1,2-diamine: comparison of two stereoisomers and detailed evaluation of the S,S enantiomer, Ro 47-7737.

The S,S enantiomer of the bisquinoline trans-N1,N2-bis(7-chloroquinolin-4-yl)cyclohexane-1,2-diamine, Ro 47-7737, is significantly more potent against chloroquine-resistant Plasmodium falciparum than the R,R enantiomer and the previously described racemate. Both the enantiomers and the racemate are more potent inhibitors of heme polymerization than chloroquine, and their activities are probably mediated by inhibition of this parasite-specific process. The S,S enantiomer, Ro 47-7737, was studied in more detail and proved to be a potent antimalarial in the treatment of P. vivax ex vivo and P. berghei in vivo. Its suppression of P. berghei growth in a mouse model (50% effective dose, 2.3 mg/kg of body weight) was equal to that of chloroquine and mefloquine, and Ro 47-7737 was found to be more potent than these two drugs in the Rane test, in which the curative effect of a single dose is monitored. The dose at which 50% of animals were permanently cured (34 mg/kg) was markedly superior to those of chloroquine (285 mg/kg) and mefloquine (> 250 mg/kg). When administered orally at 50 mg/kg, Ro 47-7737 also showed a faster clearance of parasites than either chloroquine or mefloquine, and unlike the other two compounds, Ro 47-7737 showed no recrudescence. In a study to compare prophylactic efficacies of oral doses of 50 mg/kg, Ro 47-7737 provided protection for 14 days compared to 3 days for mefloquine and 1 day for chloroquine. The good curative and prophylactic properties of the compound can be explained in part by its long terminal half-life. The ability to generate parasite resistance to Ro 47-7737 was also assessed. With a rodent model, resistance could be generated over eight passages. This rate of resistance generation is comparable to that of mefloquine, which has proved to be an effective antimalarial for many years. Toxicity liabilities, however, ruled out this compound as a candidate for drug development.

Animals↗
PubMed1996

4-aminoquinoline analogs of chloroquine with shortened side chains retain activity against chloroquine-resistant Plasmodium falciparum.

We have synthesized several 4-aminoquinolines with shortened side chains that retain activity against chloroquine-resistant isolates of Plasmodium falciparum malaria (W. Hofheinz, C. Jaquet, and S. Jolidon, European patent 94116281.0, June 1995). We report here an assessment of the activities of four selected compounds containing ethyl, propyl, and isopropyl side chains. Reasonable in vitro activity (50% inhibitory concentration, < 100 nM) against chloroquine-resistant P. falciparum strains was consistently observed, and the compounds performed well in a variety of plasmodium berghei animal models. However, some potential drawbacks of these compounds became evident upon in-depth testing. In vitro analysis of more than 70 isolates of P. falciparum and studies with a mouse in vivo model suggested a degree of cross-resistance with chloroquine. In addition, pharmacokinetic analysis demonstrated the formation of N-dealkylated metabolites of these compounds. These metabolites are similarly active against chloroquine-susceptible strains but are much less active against chloroquine-resistant strains. Thus, the clinical dosing required for these compounds would probably be greater for chloroquine-resistant strains than for chloroquine-susceptible strains. The clinical potential of these compounds is discussed within the context of chloroquine's low therapeutic ratio and toxicity.

Aminoquinolines↗
PubMed1994

Ro 42-1611 (arteflene), a new effective antimalarial: chemical structure and biological activity.

The discovery of the natural peroxides qinghaosu (arteannuin A, artemisinin) (1) and yingzhaosu A (3) from traditional Chinese herbal medicines was a major advance in the search for new antimalarials (Fig. 1). Whereas qinghaosu can be produced from natural sources and has been well studied, yingzhaosu A has never been available for full evaluation as anti-malarial. We have designed a synthesis of the novel ring system present in yingzhaosu A, the 2,3-dioxabicyclo[3.3.1]nonane and prepared a series of yingzhaosu A analogues which were tested against Plasmodium berghei in mice. Structure-activity rules could be established and used for lead optimization. The best anti-malarial activity was observed for analogues having a keto group within the ring system and an aliphatic or aromatic lipophilic tail as ring substituent. The optimized analogues possessed activity comparable to qinghaosu. In spite of the presence of a peroxide ring, the new compounds were chemically stable against common reagents. In contrast to qinghaosu and its derivatives, they were also stable against hydrolytic decomposition and could therefore be expected to show improved pharmacokinetic properties. As one of the best compounds, Ro 42-1611 (arteflene) (26n, Fig. 2) was selected for detailed preclinical evaluation. Ro 42-1611 (arteflene) was found negative in a battery of mutagenicity tests. It had low acute toxicity after oral or subcutaneous administration. In a 4-week oral tolerance study in rats, doses of up to 400 mg/kg/day were well tolerated.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Antimalarial activity of the bicyclic peroxide Ro 42-1611 (arteflene) in experimental models.

The sesquiterpene peroxide Ro 42-1611 (arteflene), a synthetic derivative of yingzhaosu, was evaluated extensively against various drug-sensitive and drug-resistant lines of Plasmodium falciparum in vitro and P. berghei in vivo in mice. The potential therapeutic and prophylactic activities were studied comparatively with the standard antimalarials chloroquine, mefloquine and quinine, as well as qinghaosu and the derivatives artemether and artesunic acid. Experimentally arteflene proved to be a highly effective antimalarial drug. In vivo it is active at low doses against blood stages of P. berghei in mice after oral or parenteral administration. It has a rapid onset of drug action and a long lasting suppressive effect when given after infection, as well as a good potential for prophylactic activity when given before infection. The suppressive and prophylactic properties are comparable to chloroquine and superior to qinghaosu, artemether and artesunic acid. In vitro the compound showed no signs of cross-resistance with existing antimalarials. It was consistently rather more active against drug-resistant than against drug-sensitive strains of P. falciparum. Drug interaction studies in vitro and in vivo with chloroquine, mefloquine and quinine revealed an additive to synergistic effect with arteflene. Antagonism with these drugs was not observed. Compared with standard antimalarials the activity of arteflene in vitro is lower than would be expected from the in vivo results. This may be due to pharmacokinetic properties of the compound and the formation of an active metabolite which sustains the activity of arteflene in vivo.

Animals↗
PubMed1994

Tolerability and pharmacokinetics of Ro 42-1611 (arteflene) in man.

The safety, tolerability and pharmacokinetics of the antimalarial arteflene (Ro 42-1611) were evaluated in a single ascending dose, double-blind, placebo-controlled trial in healthy male volunteers. Six groups of 9 volunteers (6 active and 3 placebo) received single oral doses of 100, 300, 900, 1800, 2700 and 3600 mg as a drinking suspension in the fasted state. For pharmacokinetic evaluation serial plasma and urine samples were collected up to 48 h after drug intake. Samples were analyzed for unchanged drug and the 8-hydroxy-metabolite using a new HPLC assay with UV detection. Serial blood samples were also taken for pharmacodynamics (ex vivo inhibition of Plasmodium falciparum growth). No serious adverse events were reported and no withdrawals occurred. Laboratory parameters (haematology, blood chemistry, urinalysis), vital signs (blood pressure, heart rate, body temperature) and electrocardiograms revealed no clinically relevant changes. Highly significant inhibition of P. falciparum growth was observed in sera from subjects who received 300 mg or higher doses as early as 30 minutes and up to 8 h post dosing. Evaluation of the pharmacokinetics from the plasma concentration-time data showed that the mean Cmax and AUC values increased linearly with dose up to a dose level of 1800 mg. At higher doses a plateau was reached pointing to a saturation of absorption from the gastrointestinal tract. Maximum concentrations in plasma were reached 1.7 to 3.3 hours post-dose. The elimination half-lives were relatively short and ranged between 2 and 4 hours. In plasma, the 8-hydroxy-metabolite reached approximately 3 times the Cmax values of the unchanged substance.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

[Current drugs for the treatment of tropical malaria].

The occurrence in the early 60's of stable resistance to chloroquine among Plasmodium falciparum strains in the Amazonas and on the Thai-Cambodian border has been a shock for all malariologists. This led to the search for new antimalarials without cross resistance with chloroquine. For each new drug, one of the major concerns was to define how rapidly parasites would develop resistance to this compound. Drug combinations were taken into consideration so as to achieve a delay in the appearance of resistance. The decision to test a triple combination has led to the development of Fansimef, a fixed combination with tablets containing 250 mg mefloquine, 500 mg sulfadoxine and 25 mg pyrimethamine. A very relevant delay in the development of resistance was found both in-vivo--in the P. berghei model--and in-vitro using P. falciparum. Fansimef has also been under investigations for malaria. Controlled clinical trials were performed in Africa, South America and South East Asia. The documentation for this new indication will be submitted to registration authorities in 1991. A preference alternative to continuous chemoprophylaxis is stand-by malaria treatment for travellers to regions where the malaria risk is relatively low. Stand-by treatment is under investigations in France and in Switzerland. In the search for alternative remedies against drug resistant P. falciparum malaria our attention was directed to Yingzhaosu, a new sesquiterpene peroxide of plant origin from traditional Chinese medicine. A short and convenient synthesis of this ring system gave access to a variety of structural analogues of Yingzhaosu.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Decreased replication capacity of a duck hepatitis B virus mutant with altered distal pre-S region.

We have observed in a previous study that insertion, deletion and partial frameshift mutation in the distal pre-S region did not abolish replication capacity of the duck hepatitis B virus (DHBV) (Li et al., 1989, J. Virol. 63, 4965-4968). To compare further the relative replication capacity between the pre-S mutant and wild type virus, ducts were infected with either the wild type DHBV strain or a pre-S mutant (FS-17) characterized by a total change of nine consecutive amino acid codons in the distal pre-S region. Compared with the wild type virus, FS-17 exhibited decreased replication capacity whether in separate or mixed infection. The decreased viral replication was correlated with delayed appearance of supercoiled DNA and viral RNA in the hepatocytes. Besides, FS-17 induced persistent viremia when inoculated into 1-day-old ducklings; hence the transient viremia which had been observed in the previous study was probably due to the time delay needed to generate compensatory deletion mutation.

Amino Acid Sequence↗