Activity of Novel Tryptophan Analogs against Mammalian and Trypanosomal Monoamine Oxidases

Monoamine oxidases were assayed in live Trypanosoma brucei brucei and in trypanosomal homogenate using the oxygen electrode method. Serotonin and tryptamine were used as standard monomine oxidase A and B substrates, respectively. The ability of live trypanosomes to metabolize tryptamine and serotonin was also monitored by the more sensitive high performance liquid chromatography method. No measurable enzyme activity could be detected in either live trypanosomes or trypanosomal cell homogenates. These results obtained suggest that T. b. brucei do not possess monoamine oxidase activity. Thus trypanocidal tryptophan analogs that were previously thought to act through inhibition of monoamine metabolizing enzymes may be acting by a diferent mechanism. The activity of these tryptophan analogs against mammalian MAO was tested to establish their potential toxicity in man. Two compounds, 5-(1-benzenesulphonylindol-2-ylidene)-5-methoxy-3-ethyl-thiazolidene-2-thione and 5-(1-benzenesulphonylindol-2-ylidene)-3- methylthiazolidine-2-thione had significant activity against mammalian monoamine oxidase. The enzyme kinetics for the latter was also derived. Key words: Trypanosoma brucei brucei, monoamine oxidase, tryptophan metabolites. East and Central African Journal of Pharmaceutical Sciences Vol.6(2) 2003: 43-4

Evaluation of Anorectal Function in Perianal Crohn’s Disease: A Pilot Study

Background: Perianal Crohn’s disease is a disabling condition, with little known about anorectal function in healed/inactive perianal Crohn’s disease; Aim: To evaluate anorectal function in a cohort of patients with treated/healed perianal Crohn’s disease; Methods: Prospective cohort study, including high-resolution anorectal manometry, balloon expulsion test, and 3D-endoanal ultrasound in all patients; Results: Of the 16 patients studied (mean age ± SD, 42 ± 13 years), 12 (75%) were men. A laceration of the internal anal sphincter and/or anal scarring was seen in nine (56%) patients; there was no laceration of the external anal sphincter. Five (56%) of these nine patients had never experienced faecal incontinence. All had normal anal resting and squeeze pressures. Manometry suggested dyssynergia in 11 (69%) patients, with only one (6%) fulfilling the criteria for obstructed defecation. Hyposensitivity for at least one sensory parameter was seen in 11 (69%) patients and hypersensitivity in five (31%) patients; Conclusions: This study detected sphincter abnormalities in more than half of patients, many of whom were asymptomatic. Alterations in rectal sensation were frequently seen, more commonly with rectal hyposensitivity. Trial registration: ClinicalTrials.gov (NCT03819257)

High-resolution Br γ spectro-interferometry of the transitional Herbig Ae/Be star HD 100546: a Keplerian gaseous disc inside the inner rim

We present spatially and spectrally resolved Br γ emission around the planet-hosting, transitional Herbig Ae/Be star HD 100546. Aiming to gain insight into the physical origin of the line in possible relation to accretion processes, we carried out Br γ spectro-interferometry using AMBER/VLTI from three different baselines achieving spatial and spectral resolutions of 2–4 mas and 12 000. The Br γ visibility is larger than that of the continuum for all baselines. Differential phases reveal a shift between the photocentre of the Br γ line – displaced ∼0.6 mas (0.06 au at 100 pc) NE from the star – and that of the K-band continuum emission – displaced ∼0.3 mas NE from the star. The photocentres of the redshifted and blueshifted components of the Br γ line are located NW and SE from the photocentre of the peak line emission, respectively. Moreover, the photocentre of the fastest velocity bins within the spectral line tends to be closer to that of the peak emission than the photocentre of the slowest velocity bins. Our results are consistent with a Br γ-emitting region inside the dust inner rim ( ≲ 0.25 au) and extending very close to the central star, with a Keplerian, disc-like structure rotating counter-clockwise, and most probably flared (∼25°). Even though the main contribution to the Br γ line does not come from gas magnetically channelled on to the star, accretion on to HD 100546 could be magnetospheric, implying a mass accretion rate of a few 10−7 M⊙ yr−1. This value indicates that the observed gas has to be replenished on time-scales of a few months to years, perhaps by planet-induced flows from the outer to the inner disc as has been reported for similar systems

Screening a protein kinase inhibitor library against <i>Plasmodium falciparum</i>

Abstract Background Protein kinases have been shown to be key drug targets, especially in the area of oncology. It is of interest to explore the possibilities of protein kinases as a potential target class in Plasmodium spp., the causative agents of malaria. However, protein kinase biology in malaria is still being investigated. Therefore, rather than assaying against individual protein kinases, a library of 4731 compounds with protein kinase inhibitor-like scaffolds was screened against the causative parasite, Plasmodium falciparum. This approach is more holistic and considers the whole kinome, making it possible to identify compounds that inhibit more than one P. falciparum protein kinase, or indeed other malaria targets. Results As a result of this screen, 9 active compound series were identified; further validation was carried out on 4 of these series, with 3 being progressed into hits to lead chemistry. The detailed evaluation of one of these series is described. Discussion This screening approach proved to be an effective way to identify series for further optimisation against malaria. Compound optimisation was carried out in the absence of knowledge of the molecular target. Some of the series had to be halted for various reasons. Mode of action studies to find the molecular target may be useful when problems prevent further chemical optimisation. Conclusions Progressible series were identified through phenotypic screening of a relatively small focused kinase scaffold chemical library

Arsenic exposure and outcomes of antimonial treatment in visceral leishmaniasis patients in bihar, India:a retrospective cohort study

Funding: This work was supported by a Clinical PhD Fellowship to MRP (090665) and a Principal Research Fellowship to AHF (079838) from the Wellcome Trust (http://www.wellcome.ac.uk). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

In vitro activity of salinomycin and monensin derivatives against Trypanosoma brucei

Background: African trypanosomes are the causative agents of sleeping sickness in humans and nagana disease in livestock animals. As the few drugs available for treatment of the diseases have limited efficacy and produce adverse reactions, new and better tolerated therapies are required. Polyether ionophores have been shown to display anti-cancer, anti-microbial and anti-parasitic activity. In this study, derivatives of the polyether ionophores, salinomycin and monensin were tested for their in vitro activity against bloodstream forms of Trypanosoma brucei and human HL-60 cells. Results: Most polyether ionophore derivatives were less trypanocidal than their corresponding parent compounds. However, two salinomycin derivatives (salinomycin n-butyl amide and salinomycin 2,2,2-trifluoroethyl ester) were identified that showed increased anti-trypanosomal activity with 50% growth inhibition values in the mid nanomolar range and minimum inhibitory concentrations of below 1 μM similar to suramin, a drug used in the treatment of sleeping sickness. In contrast, human HL-60 cells were considerably less sensitive towards all polyether ionophore derivatives. The cytotoxic to trypanocidal activity ratio (selectivity) of the two promising compounds was greater than 250. Conclusions: The data indicate that polyether ionophore derivatives are interesting lead compounds for rational anti-trypanosomal drug development

Superparamagnetic properties of hemozoin

We report that hemozoin nanocrystals demonstrate superparamagnetic properties, with direct measurements of the synthetic hemozoin magnetization. The results show that the magnetic permeability constant varies from mu = 4585 (at -20 degrees C) to 3843 (+20 degrees C), with the values corresponding to a superparamagnetic system. Similar results were obtained from the analysis of the diffusion separation of natural hemozoin nanocrystals in the magnetic field gradient, with mu = 6783 exceeding the value obtained in direct measurements by the factor of 1.8. This difference is interpreted in terms of structural differences between the synthetic and natural hemozoin. The ab initio analysis of the hemozoin elementary cell showed that the Fe3+ ion is in the high-spin state (S = 5/2), while the exchange interaction between Fe3+ electron-spin states was much stronger than k(B)T at room temperature. Thus, the spin dynamics of the neighboring Fe3+ ions are strongly correlated, lending support to the superparamagnetism