Dispiro- 1,2,4,5-tetraoxanes: A New Class of Antimalarial Peroxides

Dispiro-l,2,4,5tetraoxanes2 -4 were synthesized as potential peroxide a n t h a l a* d drugs. They had curative activity against Plasmodium berghei in vivo at single doses of 320 and 640 mg/kg which confirms earlier unpublished data Moreover, artemisinin (1) and 4 had equivalent ED”s against P. berghei in vivo in the multiple-dose Thompson tat; neither showed any evidence of acute toxicity at total doses of more than 12 g/kg. Dispiro-l,2,4,5-tetraoxane 4 had IC50’s comparable to those of 1 against Plasmodium falciparum clones in vitro. These results confirm the potential of dispiro-l,2,4,5-tetraoxanes as a new class of inexpensive peroxide antimalarial drugs

Synthesis and Antimalarial Activity of Sixteen Dispiro-1,2,4,5-tetraoxanes: Alkyl-Substituted 7,8,15,16-Tetraoxadispiro[5.2.5.2]hexadecanes

Sixteen alkyl-substituted dispiro-1,2,4,5-tetraoxanes (7,8,15,16-tetraoxadispiro[5.2.5.2]hexadecanes) were synthesized to explore dispiro-1,2,4,5-tetraoxane SAR and to identify tetraoxanes with better oral antimalarial activity than prototype tetraoxane 1 (WR 148999). The tetraoxanes were prepared either by peroxidation of the corresponding cyclohexanone derivatives in H2-SO4/CH3CN or by ozonolysis of the corresponding cyclohexanone methyl oximes. Those tetraoxanes with alkyl substituents at the 1 and 10 positions were formed as single stereoisomers, whereas the five tetraoxanes formed without the stereochemical control provided by alkyl groups at the 1 and 10 positions were isolated as mixtures of diastereomers. Three of the sixteen tetraoxanes were inactive (IC50’s \u3e 1000 nM), but five (2, 6, 10, 11, 12) had IC50’s between 10 and 30 nM against the chloroquine-sensitive D6 and chloroquine-resistant W2 clones of Plasmodium falciparum compared to corresponding IC50’s of 55 and 32 nM for 1 and 8.4 and 7.3 nM for artemisinin. We suggest that tetraoxanes 13, 16, and 17 were inactive and tetraoxanes 4 and 7 were weakly active due to steric effects preventing or hindering peroxide bond access to parasite heme. Tetraoxanes 1, 10, 11, and 14, along with artemisinin and arteether as controls, were administered po b.i.d. (128 mg/kg/day) to P. berghei-infected mice on days 3, 4, and 5 post-infection. At this dose, tetraoxanes 10, 11, and 14 cured between 40% and 60% of the infected animals. In comparison, artemisinin and tetraoxane 1 produced no cures, whereas arteether cured 100% of the infected animals. There was no apparent relationship between tetraoxane structure and in vitro neurotoxicity, nor was there any correlation between antimalarial activity and neurotoxicity for these seventeen tetraoxanes

Methyl-Substituted Dispiro-1,2,4,5-tetraoxanes: Correlations of Structural Studies with Antimalarial Activity

Two tetramethyl-substituted dispiro-1,2,4,5-tetraoxanes (7,8,15,16-tetraoxadispiro[5.2.5.2]- hexadecanes) 3 and 4 were designed as metabolically stable analogues of the dimethylsubstituted dispiro-1,2,4,5-tetraoxane prototype WR 148999 (2). For a positive control we selected the sterically unhindered tetraoxane 5 (7,8,15,16-tetraoxadispiro[5.2.5.2]hexadecane), devoid of any substituents. Tetraoxanes 3 and 4 were completely inactive in contrast to tetraoxanes 2 and 5. We hypothesize that the two inactive tetraoxanes possess sufficient steric hindrance about the tetraoxane ring due to the two additional axial methyl groups to prevent their activation to presumed parasiticidal carbon radicals by inhibiting electron transfer from heme or other iron(II) species. For each of the tetraoxanes 2-4, the tetraoxane and both spirocyclohexyl rings are in a chair conformation and the bond lengths and angles are all quite normal except for the C1-C2 bond which is slightly lengthened. Comparison of the modeled and X-ray structures for tetraoxanes 2-5 reveals that molecular mechanics (MMX and MM3) and 3-21G* calculations each gave accurate structural parameters such as bond lengths, bond angles, and dihedral angles. In contrast, semiempirical methods such as AM1 gave poor results

Lymphatic filariasis in the Democratic Republic of Congo; micro-stratification overlap mapping (MOM) as a prerequisite for control and surveillance

<p>Abstract</p> <p>Background</p> <p>The Democratic Republic of Congo (DRC) has a significant burden of lymphatic filariasis (LF) caused by the parasite <it>Wuchereria bancrofti</it>. A major impediment to the expansion of the LF elimination programme is the risk of serious adverse events (SAEs) associated with the use of ivermectin in areas co-endemic for onchocerciasis and loiasis. It is important to analyse these and other factors, such as soil transmitted helminths (STH) and malaria co-endemicity, which will impact on LF elimination.</p> <p>Results</p> <p>We analysed maps of onchocerciasis community-directed treatment with ivermectin (CDTi) from the African Programme for Onchocerciasis Control (APOC); maps of predicted prevalence of <it>Loa loa</it>; planned STH control maps of albendazole (and mebendazole) from the Global Atlas of Helminth Infections (GAHI); and bed nets and insecticide treated nets (ITNs) distribution from Demographic and Health Surveys (DHS) as well as published historic data which were incorporated into overlay maps. We developed an approach we designate as micro-stratification overlap mapping (MOM) to identify areas that will assist the implementation of LF elimination in the DRC. The historic data on LF was found through an extensive review of the literature as no recently published information was available.</p> <p>Conclusions</p> <p>This paper identifies an approach that takes account of the various factors that will influence not only country strategies, but suggests that country plans will require a finer resolution mapping than usual, before implementation of LF activities can be efficiently deployed. This is because 1) distribution of ivermectin through APOC projects will already have had an impact of LF intensity and prevalence 2) DRC has been up scaling bed net distribution which will impact over time on transmission of <it>W. bancrofti </it>and 3) recently available predictive maps of <it>L. loa </it>allow higher risk areas to be identified, which allow LF implementation to be initiated with reduced risk where <it>L. loa </it>is considered non-endemic. We believe that using the proposed MOM approach is essential for planning the expanded distribution of drugs for LF programmes in countries co-endemic for filarial infections.</p

Medical science publication.

Mode of access: Internet.Issued by: Army Medical Service Graduate School, Walter Reed Army Medical Center, 1953-1954 ; by: Walter Reed Army Institute of Research, 1955

The determination of internally deposited radioactive isotopes in the Marshallese people by excretion analysis /

"Work done in conjunction with the Division of Biology and Medicine, AEC, and sponsored jointly by the Surgeon General, United States Army, and Defense Atomic Support Agency."Includes bibliographical references (page 8).Mode of access: Internet

Immunological Response of Three Mouse Strains to Typhoid Vaccine and Vi Antigen

Vi-agglutinin, active cutaneous anaphylaxis and protective responses (ed(50)) of three mouse strains (CFW, NIH, and Balb/cAnN) to acetone-inactivated typhoid vaccine and soluble Vi antigen were compared. Seven days after immunization with either typhoid vaccine or Vi antigen the three strains of mice differed with respect to Vi-antibody titers. Significant differences were observed in the protective responses. Each mouse strain was significantly better protected by the intraperitoneal than by subcutaneous route of immunization. Active cutaneous anaphylaxis was more pronounced in showing strain differences in response to Vi antigen. The serological responses to Vi antigen of the strains of mice did not correlate with their protective response