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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.

In the first phase III efficacy trial of the malaria vaccine SPf66 in Africa, MOIs in SPf66- and placebo-vaccinated children were analyzed by polymerase chain reaction-restriction fragment length polymorphism of the Plasmodium falciparum merozoite surface antigen 2 (MSA2). MOIs were significantly reduced in asymptomatic vaccine recipients compared with those in asymptomatic placebo recipients; however, no differences were observed among symptomatic children in the vaccine and control groups. These results show that immunization with SPf66 modulates the course of naturally occurring infections, as reflected by reduced MOIs. In placebo recipients, however, there was a significant negative correlation between numbers of infecting genotypes, as identified by MSA2, and morbidity. Asymptomatic placebo recipients had an average of 5 concurrent infections, whereas children with clinical cases had an average of 3.4 infections. These data provide further evidence that premunition from concurrent infections is important in immunity against clinical malaria. No such effect of multiple infections was found in the vaccinated group.

Selective activation of peripheral cannabinoid CB1 receptors has the potential to become a valuable therapy for chronic pain conditions as long as central nervous system effects are attenuated. A new class of cannabinoid ligands was rationally designed from known aminoalkylindole agonists and showed good binding and functional activities at human CB1 and CB2 receptors. This has led to the discovery of a novel CB1/CB2 dual agonist, naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone (13), which displays good oral bioavailability, potent antihyperalgesic activity in animal models, and limited brain penetration.

The observed ability of HAART during early asymptomatic HIV infection to initiate rapid reversal of disease-induced T-cell activation and maturation abnormalities, while preserving pretherapy levels of immune function, supports the concept that therapeutic advantage is to be gained by commencing early aggressive antiretroviral therapy.

The long-term response of 10 asymptomatic, antiretroviral therapy-naive HIV-1-infected patients to potent combination antiretroviral therapy was characterized by monitoring levels of HIV-1 RNA in plasma, peripheral blood mononuclear cells (PBMC), and lymphoid tissue using highly sensitive HIV-1 RNA assays. Although plasma viral loads were continuously suppressed to levels below 50 HIV-1 RNA copies/ml for up to 2.5 years (60-128 weeks), HIV-1 RNA was still detectable at very low levels (1 to 49 HIV-1 RNA copies/ml) in 25% of the samples. In corresponding PBMC specimens, residual HIV-RNA was detectable in as much as 91% of samples tested (1 to 420 HIV-1 RNA copies/microg total RNA). Similarly, HIV-1 RNA levels in lymphoid tissue also remained detectable at a high frequency (86%). A highly significant correlation was demonstrated between therapy-induced change in PBMC HIV-1 RNA levels and change in plasma HIV-1 RNA levels (r2 = 0.69; p = 0.003). These findings support the concept that measurement of HIV-1 RNA in the easily accessible PBMC compartment is relevant for evaluating the potency of current and future antiretroviral therapies. Short CommunicationResidual HIV-RNA Levels Persist for Up to 2. ABSTRACTThe long-term response of 10 asymptom atic, antiretroviral therapy-naive HIV-1-infected patients to potent combination antiretroviral therapy was characterized by monitoring levels of HIV-1 RNA in plasma, peripheral blood mononuclear cells (PBMC), and lymphoid tissue using highly sensitive HIV-1 RNA assays. Although plasma viral loads were continuously suppressed to levels below 50 HIV-1 RNA copies/ml for up to 2.5 years (60-128 weeks), HIV-1 RNA was still detectable at very low levels (1 to 49 HIV-1 RNA copies/ml) in 25% of the samples. In corresponding PBMC specimens, residual HIV-RNA was detectable in as much as 91% of samples tested (1 to 420 HIV-1 RNA copies/m g total RNA). Similarly, HIV-1 RNA levels in lymphoid tissue also remained detectable at a high frequency (86% ). A highly significant correlation was demonstrated between therapy-induced change in PBMC HIV-1 RNA levels and change in plasma HIV-1 RNA levels (r 2 5 0.69; p 5 0.003). These findings support the concept that measurement of HIV-1 RNA in the easily accessible PBMC compartment is relevant for evaluating the potency of current and future antiretroviral therapies.

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