Activity of oxantel pamoate monotherapy and combination chemotherapy against Trichuris muris and hookworms : revival of an old drug

BACKGROUND: It is widely recognized that only a handful of drugs are available against soil-transmitted helminthiasis, all of which are characterized by a low efficacy against Trichuris trichiura, when administered as single doses. The re-evaluation of old, forgotten drugs is a promising strategy to identify alternative anthelminthic drug candidates or drug combinations. METHODOLOGY: We studied the activity of the veterinary drug oxantel pamoate against Trichuris muris, Ancylostoma ceylanicum and Necator americanus in vitro and in vivo. In addition, the dose-effect of oxantel pamoate combined with albendazole, mebendazole, levamisole, pyrantel pamoate and ivermectin was studied against T. muris in vitro and additive or synergistic combinations were followed up in vivo. PRINCIPAL FINDINGS: We calculated an ED50 of 4.7 mg/kg for oxantel pamoate against T. muris in mice. Combinations of oxantel pamoate with pyrantel pamoate behaved antagonistically in vitro (combination index (CI) = 2.53). Oxantel pamoate combined with levamisole, albendazole or ivermectin using ratios based on their ED50s revealed antagonistic effects in vivo (CI = 1.27, 1.90 and 1.27, respectively). A highly synergistic effect (CI = 0.15) was observed when oxantel pamoate-mebendazole was administered to T. muris-infected mice. Oxantel pamoate (10 mg/kg) lacked activity against Ancylostoma ceylanicum and Necator americanus in vivo. CONCLUSIONSIGNIFICANCE: Our study confirms the excellent trichuricidal properties of oxantel pamoate. Since the drug lacks activity against hookworms it is necessary to combine oxantel pamoate with a partner drug with anti-hookworm properties. Synergistic effects were observed for oxantel pamoate-mebendazole, hence this combination should be studied in more detail. Since, of the standard drugs, albendazole has the highest efficacy against hookworms, additional investigations on the combination effect of oxantel pamoate-albendazole should be launche

Orally active antischistosomal early leads identified from the open access malaria box.

BACKGROUND: Worldwide hundreds of millions of schistosomiasis patients rely on treatment with a single drug, praziquantel. Therapeutic limitations and the threat of praziquantel resistance underline the need to discover and develop next generation drugs. METHODOLOGY: We studied the antischistosomal properties of the Medicines for Malaria Venture (MMV) malaria box containing 200 diverse drug-like and 200 probe-like compounds with confirmed in vitro activity against Plasmodium falciparum. Compounds were tested against schistosomula and adult Schistosoma mansoni in vitro. Based on in vitro performance, available pharmacokinetic profiles and toxicity data, selected compounds were investigated in vivo. PRINCIPAL FINDINGS: Promising antischistosomal activity (IC50: 1.4-9.5 µM) was observed for 34 compounds against schistosomula. Three compounds presented IC50 values between 0.8 and 1.3 µM against adult S. mansoni. Two promising early leads were identified, namely a N,N'-diarylurea and a 2,3-dianilinoquinoxaline. Treatment of S. mansoni infected mice with a single oral 400 mg/kg dose of these drugs resulted in significant worm burden reductions of 52.5% and 40.8%, respectively. CONCLUSIONS/SIGNIFICANCE: The two candidates identified by investigating the MMV malaria box are characterized by good pharmacokinetic profiles, low cytotoxic potential and easy chemistry and therefore offer an excellent starting point for antischistosomal drug discovery and development

In vitro antischistosomal activity of Artemisia annua and Artemisia afra extracts

Background Schistosomiasis, a neglected tropical disease, imposes substantial health and economic burdens on impoverished groups living in predominantly rural areas. Praziquantel (PZQ) is the only drug available for treatment, and it is not completely efficacious. Artemisia annua and Artemisia afra infusions were proposed to possess antischistosomal activities in a recently retracted publication of a clinical trial, leading to our investigation in vitro. Objective The objective was to identify the main components of the infusions and evaluate the in vitro antischistosomal activities of traditionally prepared infusions as well as hexane and dichloromethane (DCM) extracts of the infusions of A. afra and A. annua. Methods Infusions of A. afra and A. annua were submitted to liquid-liquid partitioning with n-hexane and DCM to provide samples for in vitro bioassays using newly transformed schistosomulas (NTS) and adult Schistosoma mansoni worms obtained from infected mice. The viability of the NTS and adult S. mansoni was visually scored via microscopic readout. Results Nine phytochemicals comprising coumarins and organic acids were identified. A. afra and A. annua infusions and extracts possess potent in vitro antischistosomal activities against NTS, at 100 μg/ml. However, the A. afra infusions exhibited better activities against NTS than the A. annua infusion. The A. afra hexane- and DCM extracts presented IC50 values that are similar to PZQ (1.5 μg/ml) and approximately five times lower than the comparison drug artesunate (11.6 μg/ml) against NTS. Low IC50 values for both these extracts were also obtained in phenotypic assays with adult S. mansoni. Conclusion A. afra shows greater antischistosomal potential than A. annua. Thus, further studies are necessary to identify the active molecule(s) responsible for the notable antischistosomal activity of A. afra

Composite tube cracking in kraft recovery boilers: A state-of-the-art review

Beginning in the mid-1960s, increasing energy costs in Finland and Sweden made energy recovery more critical to the cost-effective operation of a kraft pulp mill. Boiler designers responded to this need by raising the steam operating pressure, but almost immediately the wall tubes in these new boilers began to corrode rapidly. Test panels installed in the walls of the most severely corroding boiler identified austenitic stainless steel as sufficiently resistant to the new corrosive conditions, and discussions with Sandvik AB, a Swedish tube manufacturer, led to the suggestion that coextruded tubes be used for water wall service in kraft recovery boilers. Replacement of carbon steel by coextruded tubes has solved most of the corrosion problems experienced by carbon steel wall tubes, however, these tubes have not been problem-free. Beginning in early 1995, a multidisciplinary research program funded by the US Department of Energy was established to investigate the cause of cracking in coextruded tubes and to develop improved materials for use in water walls and floors of kraft recovery boilers. One portion of that program, a state-of-the-art review of public- and private-domain documents related to coextruded tube cracking in kraft recovery boilers is reported here. Sources of information that were consulted for this review include the following: tube manufacturers, boiler manufacturers, public-domain literature, companies operating kraft recovery boilers, consultants and failure analysis laboratories, and failure analyses conducted specifically for this project. Much of the information contained in this report involves cracking problems experienced in recovery boiler floors and those aspects of spout and air-port-opening cracking not readily attributable to thermal fatigue. 61 refs

Praziquantel meets Niclosamide: a dual-drug antiparasitic cocrystal

In this paper we report a successful example of combining drugs through cocrystallization. Specifically, the novel solid is formed by two anthelminthic drugs, namely praziquantel (PZQ) and niclosamide (NCM) in a 1:3 molar ratio, and it can be obtained through a sustainable one-step mechanochemical process in the presence of micromolar amounts of methanol. The novel solid phase crystallizes in the monoclinic space group of P2(1)/c, showing one PZQ and three NCM molecules linked through homo- and heteromolecular hydrogen bonds in the asymmetric unit, as also attested by SSNMR and FT-IR results. A plate-like habitus is evident from scanning electron microscopy analysis with a melting point of 202.89 °C, which is intermediate to those of the parent compounds. The supramolecular interactions confer favorable properties to the cocrystal, preventing NCM transformation into the insoluble monohydrate both in the solid state and in aqueous solution. Remarkably, the PZQ - NCM cocrystal exhibits higher anthelmintic activity against in vitro S. mansoni models than corresponding physical mixture of the APIs. Finally, due to in vitro promising results, in vivo preliminary tests on mice were also performed through the administration of minicapsules size M

Manganese pigmented anodized copper as solar selective absorber

The study concerns the optical and structural properties of layers obtained by a new efficient surface treatment totally free of chromium species. The process is made up of an anodic oxidation of copper in an alkaline solution followed by an alkaline potassium permanganate dipping post-treatment. Coatings, obtained at the lab and pilot scales, are stable up to 220 °C in air and vacuum, present low emissivity (0.14 at 70 °C) and high solar absorptivity (0.96), i.e. a suitable thermal efficiency (0.84 at 70 °C)

Role of retardation in 3-D relativistic equations

Equal-time Green's function is used to derive a three-dimensional integral equation from the Bethe-Salpeter equation. The resultant equation, in the absence of anti-particles, is identical to the use of time-ordered diagrams, and has been used within the framework of $\phi^2\sigma$ coupling to study the role of energy dependence and non-locality when the two-body potential is the sum of $\sigma$-exchange and crossed $\sigma$ exchange. The results show that non-locality and energy dependence make a substantial contribution to both the on-shell and off-shell amplitudes.Comment: 17 pages, RevTeX; 8 figures. Accepted for publication in Phys. Rev. C56 (Nov. 97

Quantum measurement problem and cluster separability

A modified Beltrametti-Cassinelli-Lahti model of measurement apparatus that satisfies both the probability reproducibility condition and the objectification requirement is constructed. Only measurements on microsystems are considered. The cluster separability forms a basis for the first working hypothesis: the current version of quantum mechanics leaves open what happens to systems when they change their separation status. New rules that close this gap can therefore be added without disturbing the logic of quantum mechanics. The second working hypothesis is that registration apparatuses for microsystems must contain detectors and that their readings are signals from detectors. This implies that separation status of a microsystem changes during both preparation and registration. A new rule that specifies what happens at these changes and that guarantees the objectification is formulated and discussed. A part of our result has certain similarity with 'collapse of the wave function'.Comment: 31 pages, no figure. Published versio

Signals for Lorentz Violation in Post-Newtonian Gravity

The pure-gravity sector of the minimal Standard-Model Extension is studied in the limit of Riemann spacetime. A method is developed to extract the modified Einstein field equations in the limit of small metric fluctuations about the Minkowski vacuum, while allowing for the dynamics of the 20 independent coefficients for Lorentz violation. The linearized effective equations are solved to obtain the post-newtonian metric. The corresponding post-newtonian behavior of a perfect fluid is studied and applied to the gravitating many-body system. Illustrative examples of the methodology are provided using bumblebee models. The implications of the general theoretical results are studied for a variety of existing and proposed gravitational experiments, including lunar and satellite laser ranging, laboratory experiments with gravimeters and torsion pendula, measurements of the spin precession of orbiting gyroscopes, timing studies of signals from binary pulsars, and the classic tests involving the perihelion precession and the time delay of light. For each type of experiment considered, estimates of the attainable sensitivities are provided. Numerous effects of local Lorentz violation can be studied in existing or near-future experiments at sensitivities ranging from parts in 10^4 down to parts in 10^{15}.Comment: 46 pages two-column REVTeX, accepted in Physical Review