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Two new Pudicinae (Trichostrongylina, Heligmosomoidea, Heligmonellidae) coparasites of Proechimys longicaudatus(Caviomorph rodent) from Bolivia are described: Pudica ginsburgi n.sp. is differentiated from all the other species of the genus by the great length of the spicules and of the vestibule and by a different ratio of the length of the spicules on the length of the body. Heligmostrongylus chiaraen.sp. has very developed rays 4, strongly divergent from rays 5 as occurs in three other species, H. almeidai(Durette-Desset & Tcheprakoff, 1969), a parasite of Trichomys apereoides(= Cercomys cunlcularius) from Brazil,H. squamastrongylus(Travassos, 1937), a parasite of Proechimysoris from Brazil and H. proechimysiDurette-Desset, 1970, a parasite of Proechimys semispinosusfrom Columbia. The specimens from Bolivia are differentiated from the three species by the division of the dorsal ray (anterior half versus posterior half) and by a different ratio of the length of the spicules on the length of the body.

The aim of this preliminary study was to investigate the potential use of the transdermal route for primaquine administration in the treatment of malaria. Thus the activity of this drug on asexual blood forms of two rodent malaria parasites (P. v. petteriand P. y. nigeriensis) was evaluated following a single TTS patch application. Sustained plasma concentration values wete observed for about 60 hours. The results obtained from a prepotency test showed that primaquine was more active towards P. v.petterithan P. y. nigeriensis. This preliminary study showed that the transdermal route for primaquine administration may be a promising strategy for improving the treatment of malaria in both causal prophylactic and prevention of relapses infection.

A merozoite of Plasmodium yoelii nigeriensiswas observed, by transmission electron microscopy, associated with the surface of a dendritic leucocyte, in the cortical zone of a renal lymph node from a heavily infected mouse.

The biological rhythms of Plasmodium vinckei vinckei, P. v. lentumand P. yoelii yoeliii.e. synchronicity, duration of the erythrocytic cycle, timing of the schizogony and of the penetration of merozoites into red blood cells, were studied in the Swiss white mouse. Two different methods of synchronisation were used: the freezing-thawing of parasitized blood and the inoculation of a single parasitic stage, separated from the other stages by centrifugation through a Percoll® -Glucose gradient. The duration of the schizogonic cycle of P. v. vinckeiand P.v. lentum, two highly synchronous subspecies, was 24 hours. With P. v. vinckeithe timing of the schizogony was independent of the circadian rhythm of the host and was set by the time of inoculation. With P. v. lentumthe timing of the schizogony and merozoites penetration into red blood cells depended both, on the hosts rhythm and the time of inoculation of frozen-thawed blood : schizogony occurred at 18:00 if the inoculum was injected at 06:00 or 12:00, and at 06:00 if injected at 18:00 or 00:01 . P. y. yoeliia naturally asynchronous parasite was synchronized by means of a Percoll® Glucose gradient. The duration of its intraerythrocytic cycle was found to be 18 hours, similar to that of the other subspecies of P. yoelii.

Experiments were performed with P. chabaudi chabaudito investigate the relationship between the development of the parasite and the circadian rhythm of the host. Blood was taken from a donor mouse at 10.00 hours, when it contained mainly young stages and inoculated to receptor mice, either immediately or after 8 hours at +4°C. The inoculum was diluted in order to obtain a more or less extended prepatent period. Thus, by using successively the different mice, parasitemias could be followed during 12 days before the crisis. When parasitemias reached 1%, from day 1 (D1) to D7, depending on the dilution, the parasitic patterns were studied every 6 hours during 2 or 3 days. In mice inoculated at 10.00 hours the rhythm remained unmodified. In mice inoculated at 18.00 hours the infection was at first synchronous (from D1 to D4) but the schizogony occurred between 06.00 and 12.00 hours instead of midnight. From day 4 to day 7 the infection became asynchronous. At day 10 the normal rhythm was resumed and the schizogony occurred around midnight.

ABSTRACTWe report the isolation and identification of a new quassinoid named simalikalactone E (SkE), extracted from a widely used Amazonian antimalarial remedy made out of Quassia amaraL. (Simaroubaceae) leaves. This new molecule inhibited the growth of Plasmodium falciparumcultured in vitro by 50%, in the concentration range from 24 to 68 nM, independently of the strain sensitivity to chloroquine. We also showed that this compound was able to decrease gametocytemia with a 50% inhibitory concentration sevenfold lower than that of primaquine. SkE was found to be less toxic than simalikalactone D (SkD), another antimalarial quassinoid from Q. amara, and its cytotoxicity on mammalian cells was dependent on the cell line, displaying a good selectivity index when tested on nontumorogenic cells. In vivo, SkE inhibited murine malaria growth of Plasmodium vinckei petteriby 50% at 1 and 0.5 mg/kg of body weight/day, by the oral or intraperitoneal routes, respectively. The contribution of quassinoids as a source of antimalarial molecules needs therefore to be reconsidered.

Methylene blue (MB) is the oldest synthetic antimalarial. It is not used anymore as antimalarial but should be reconsidered. For this purpose we have measured its impact on both chloroquine sensitive and resistant Plasmodiumstrains. We showed that around 5 nM of MB were able to inhibit 50% of the parasite growth in vitroand that late rings and early trophozoites were the most sensitive stages; while early rings, late trophozoites and schizonts were less sensitive. Drug interaction study following fractional inhibitory concentrations (FIC) method showed antagonism with amodiaquine, atovaquone, doxycycline, pyrimethamine; additivity with artemether, chloroquine, mefloquine, primaquine and synergy with quinine. These results confirmed the interest of MB that could be integrated in a new low cost antimalarial combination therapy.

Abstract: Chabirenia cayennensis n. g., n. sp. (Nematoda: Rhabdiasidae) is described from the teiid lizard Ameiva ameiva. A total of 139 worms were recovered, all females, from the mucous glands of the buccal cavity. The worm has a free-living phase in a homogonic life-cycle. Infective larvae are enclosed in a sheath with chequered ornamentation and composed of two exuviae. The new genus is distinct from the five known genera of the family, Pneumonema Johnston, 1916, Acanthorhabdias Pereira, 1927, Entomelas Travassos, 1930, Rhabdias Stiles & Hassall, 1905 and Neoentomelas Hasagawa, 1989, in the following characters: helical habitus, longitudinal cuticular crests, very tiny buccal cavity without thick walls and three oesophageal onchia. Several characters of this new rhabdiasid suggest the Strongylida.

Baelmans, R., Deharo, E., Mun˜oz, V., Sauvain, M., and Ginsburg, H. 2000. Experimental conditions for testing the inhibitory activity of chloroquine on the formation of β-hematin. Experimental Parasitology96, 242–248. Some antimalarial drugs act by inhibiting the process of ferriprotoporphyrin IX polymerization which protects the parasite against the noxious effect of this product of host cell hemoglobin digestion. As the quest for new drugs with a similar mode of action continues, high-throughput screening methods are needed. We demonstrate herein that such a recently described screening technique (Basilico et al., J. Antimicrob. Chemother. 42, 55–60, 1998) is considerably disturbed by certain ions. Thus, at the assay's pH 2.6, the phosphate ions are responsible for the inhibitory activity of chloroquine phosphate, rather than chloroquine itself. Using a combination of solubility tests and Fourier transform infrared spectrometry we also show that two alternative methods using higher pH's are also prone to salt effects and demonstrate that these can be minimized by extensive washing of the product with DMSO.

Vesicles containing apparently healthy merozoites from mature schizonts were observed in the spleen and lymph nodes of mice parasitized by Plasmodium yoelii nigeriensis. They differed from all parasitic stages undergoing digestion by the macrophage and from mature schizonts of the blood. Up to 40 merozoites from three mature schizonts may be seen in the same compartment. They ate thought to be accumulations of latent merozoites.

Abstract: A high level of drug resistance was obtained with a line of Plasmodiumchabaudi maintained under intense chloroquine selection pressure according to the protocols established for P. berghei. The main objective of this work was to verify if the characteristic asynchronous schizogonic rhythm of naturally resistant rodent malaria parasites was also found when the drug resistance was induced experimentally. The degree of resistance was evaluated through the use of the “2% delay test” (DT) and the schizogonic rhythm, by reference to the synchronicity index (SI). The strain had originally a DT of 4.26 and an SI of 0.52. Following the application of 80 mg/kg chloroquine at each passage, as early as at the 8th passage the parasites rapidly became resistant and asynchronous. At the 17th passage the DT was 3.32 and the SI, 0.20. In the drug-resistant line the original indices, both the DT and the SI, were restored after deep-freezing, sporogony, or passage through a Percoll gradient, or simply by repeated intravenous subinoculations of blood. The clear correlation between asynchronicity and drug resistance is easily explained by the action of chloroquine, which favours the schizogonic cycles initiated by latent merozoites.

Following the demonstration of the antimalarial effect of the long chain saturated alcohol n-hentriacontanoi ((CH2)29CH2OH), isolated from the Bolivian endemic solanaceous plant Cuatresiasp., we have tested the effect of the C18 fatty acids oleic, elaidic, linoleic, and linoleic on malaria parasites. These fatty acids inhibited the parasitemic development in mice infected with Plasmodiurn vinckei petterior with Plasmodium yoelii nigeriensisin a 4-day suppressive test. To gain a deeper discernment of the antimalarial mode of action, the effects of these compounds were evaluated on Plasmodiun falciparumgrowth in culture. Whereas n-hentriacontanol did not show any inhibition of this parasite, on the contrary, the C18 acids displayed a considerable inhibitory activity at ≤ 200 μg/ml both in intact infected cells and in free parasites. In order to understand the mechanism of their antimalarial action, several tests were performed. No hemolysis of infected cells could be observed up to 500 μg/ml. No effect on the lipid peroxidation, ATP levels, transport through the parasite-induced permeabiIity pathways, or on the phagocytosis of the infected cells could be observed. The cytotoxic effect of the fatty acids was very rapid: full inhibition of nucleic acids and protein syntheses was observed in less than 30 min. This inhibition was not relieved by the addition of deferrioxamine or FeCl3, indicating that fatty acids (FA) do not act by facilitating the transport of iron. Inhibition was relieved in neither the presence of erotic acid or its methyl ester, indicating that FA do not act at the mitochondrial level of pyrimidine synthesis. Inhibition was not relieved when cells were incubated in high potassium medium, implying that FA did not act by depleting the parasite of this physiologically important cation. Vitamin E had no protective effect and no evidence for Lipid peroxidation could be obtained, suggesting that the inhibitory effect of FA was not due to lipid peroxidation. These results suggest that octadecenoic acids may have a specific target(s) inside the parasite. Further investigations are warranted since soybean lipid emulsions used for parenteral nutrition show similar inhibition of parasite propagation in vivoand in culture.

Nitric oxide (NO), a highly diffusible cellular mediator involved in a wide range of biological effects, has been indicated as one of the cytotoxic agents released by leukocytes to counteract malaria infection. On the other hand, NO has been implicated as a mediator of the neuropathological symptoms of cerebral malaria. In such circumstances NO production has been thought to be induced in host tissues by host-derived cytokines. Here we provide evidence for the first time that human red blood cells infected by Plasmodium falciparum (IRBC) synthesize NO. The synthesis of NO (measured as citrulline and nitrate production) appeared to be very high in comparison with human endothelial cells; no citrulline and nitrate production was detectable in noninfected red blood cells. The NO synthase (NOS) activity was very high in the lysate of IRBC (while not measurable in that of normal red blood cells) and was inhibited in a dose-dependent way by three different NOS inhibitors (L-canavanine, NG-amino-L-arginine, and NG-nitro-L-arginine). NOS activity in P. falciparum IRBC is Ca++ independent, and the enzyme shows an apparent molecular mass < 100 kD, suggesting that the parasite expresses an isoform different from those found in mammalian cells. IRBC release a soluble factor able to induce NOS in human endothelial cells. Such NOS-inducing activity is not tissue specific, is time and dose dependent, requires de novo protein synthesis, and is probably associated with a thermolabile protein having a molecular mass > 100 kD. Our data suggest that an increased NO synthesis in P. falciparum malaria can be directly elicited by soluble factor(s) by the blood stages of the parasite, without necessarily requiring the intervention of host cytokines.

Stearylamine, oleic acid, phosphatidylserine and dicetylphosphate have been studied to determine their capacity to induce electric charge on non-ionic submicron emulsions containing halofantrine and mefloquine.The in-vivo antimalarial activity of drug-loaded emulsions, evaluated in mice, was affected by the nature of the additives used. In particular, the electric-charge inducers markedly affected the pharmacological activity of mefloquine, but not of halofantrine. After subcutaneous administration ED50 values (the doses affording 50% protection) were 3 and 15 mg kg−1, respectively, for halofantrine and mefloquine emulsions without charge inducers. The mefloquine-loaded emulsions with charge inducers were active at 10 mg kg−1for dicetylphosphate, 17 mg kg−1for phosphatidylserine, 23 mg kg−1for oleic acid and 27 mg kg−1for stearylamine, again after subcutaneous administration.This work has enabled the formulation of stable emulsions, incorporating drugs with high antimalarial activity, which are proposed for parenteral delivery of these fairly soluble drugs.

Stearylamine, oleic acid, phosphatidylserine and dicetylphosphate have been studied to determine their capacity to induce electric charge on non‐ionic submicron emulsions containing halofantrine and mefloquine.

Varicella zoster virus (VZV) causes varicella (chickenpox), establishes latency in ganglia and reactivates decades later to produce zoster in the elderly. Clinical, pathological, immunological and virological features of simian varicella virus (SVV) infection of primates parallel human VZV infection. Primary SVV infection of primates, cause varicella, after which virus becomes latent in ganglionic neurons and reactivates upon social and environmental stress. Five rhesus macaques were infected intrabronchially with 4.0x105pfu of SVV. Two weeks later, the monkeys developed varicella rash. Twenty months later four of the monkeys were treated once with a 50mg/kg of anti-CD4 antibody. All 5 monkeys developed zoster rash, 7–55 days after the treatment. Punch biopsies of the skin rash were analyzed for the presence of SVV antigens by immunohistochemistry and immunofluorescence. SVV ORF 63 protein and glycoproteins gH and L were detected in sweat glands in skin from all 5 monkeys. Presence of SVV in the β-3-tubilin-positive nerve endings in affected skin suggested possible route of skin infection during zoster.

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ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.