Evaluation of synthetic substituted 1,2-dioxanes as novel agents against human leishmaniasis

The treatment of human leishmaniasis is currently based on few compounds that are highly toxic, expensive and have a high rate of treatment failure. A number of recent studies on new drugs focuses on natural or semi-synthetic compounds. Among them, the endoperoxide artemisinin, extracted from Artemisia annua, and some of its derivatives have shown leishmanicidal activity. In the present work, a series of structurally simple, fully synthetic 1,2-dioxanes were evaluated for in vitro antileishmanial activity against promastigotes of Leishmania donovani; the cytotoxicity for mammalian cells was also assessed. The six most promising compounds in terms of activity and selectivity were further investigated for their antileishmanial activity on the promastigote forms of L. tropica, L. major and L. infantum and against L. donovani amastigotes. The good performance in terms of potency and selectivity makes these six hits promising candidates for a preliminary lead optimization as antileishmanial agents

Towards a More Sustainable Photocatalyzed α-Arylation of Amines: Green Solvents, Catalyst Recycling and Low Loading

A more sustainable and efficient protocol for the photocatalytic α-amino arylation promoted by fac-Ir(ppy)3 was developed. Three noteworthy results were achieved: i) the replacement of toxic medium DMA with the greener solvents NBP and NHP, and the concurrent improvement of the process efficiency by lowering both the amine and the base amount; ii) the development of a recycling protocol for both the sustainable solvent NHP and the commercially available costly photocatalyst fac-Ir(ppy)3, achieving environmental and economic benefits. This approach to the photocatalyst recovery avoids very demanding catalyst structural modifications; iii) the protocol in green solvents proved to be scalable up to 10 mmol of limiting reagent, maintaining excellent performance also lowering the photocatalyst loading down to 0.05 mol%. This is the first example of photocatalytic α-arylation of amines promoted by such a low amount of catalyst. Lastly, the versatility of this approach was demonstrated by extending the use of the green solvent NBP to another photoredox process

Wolbachia, doxycycline and macrocyclic lactones: New prospects in the treatment of canine heartworm disease

Abstract Melarsomine dihydrochloride (Immiticide®, Merial) is the only approved adulticidal drug for the treatment of canine heartworm disease (HWD). However, in cases where arsenical therapy is not possible or is contraindicated, a monthly heartworm preventive along with doxycycline for a 4-week period, which targets the bacterial endosymbiont Wolbachia, might be considered. There are published reports on the efficacy of ivermectin and doxycycline in both experimentally and naturally infected dogs, but no data on the use of other macrocyclic lactones (MLs) with a similar treatment regime. Preliminary results of studies in dogs show that a topical formulation of moxidectin, the only ML currently registered as a microfilaricide, is also adulticidal when combined with doxycycline. It is not yet known if the efficacy of these combination therapies is due to pharmacokinetic synergism. A recent study showed that serum levels of doxycycline in dogs treated with the combination protocol were not statistically different compared to dogs treated with doxycycline alone. However, lungs from dogs treated with the combination therapy showed a marked reduction in T regulatory cells, indicating that treatment efficacy may be due to a heightened immune response against the parasite. Further studies are necessary to evaluate the long-term clinical outcome of combination protocols and to establish the most efficient treatment for HWD in dogs

Serum creatinine and urine protein : creatinine ratio in dogs affected by myxomatous mitral valve disease

Cardiac disease is often associated with worsening renal function, in humans. The cardiorenal syndromes (CRS) were defined as disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other. Five subtypes of the syndromes were identified; of these, CRS 2 indicates chronic abnormalities in cardiac function causing progressive and potentially permanent chronic kidney disease. Recent investigations support the role of central venous congestion, neurohormonal activation, anemia, oxidative stress and renal sympathetic activity as potential contributors to this complex syndrome. The main marker of kidney\u2019s disease in humans is considered the glomerular filtration rate. However, serum creatinine (sCr) and urine protein:creatinine ratio (UPC) are recognized as predictors of worsening renal function as well. The aim of this study was to investigate renal function in dogs with myxomatous mitral valve disease (MMVD) and cardiac remodeling (ACVIM stage 65B2) by measurement of sCr and UPC. This is an observational case-control study. Twenty dogs of various breeds, aged 7-15 years, affected by MMVD with hemodynamically signi\ufb01cant mitral regurgitation and cardiac remodeling (left ventricle internal diameter in diastole normalized according to allometric scaling 65 1.7 and/or LA/Ao ratio 65 1.6) were included in the study. Twenty healthy dogs of various breeds, aged 7-15 years were included as controls. Dogs with congenital or acquired cardiac disease other than MMVD, dogs with previous history or clinical signs at presentation of systemic, inflammatory or infectious disease, malignancies, hypertension (systolic blood pressure >160mmHg) or evidence of other organ dysfunction or hyperthermia were not included in the study. On each dog physical examination, echocardiography, ECG, RX, systemic blood pressure measurement, blood and urine analysis were performed in order to obtain a classification of MMVD (ACVIM consensus statement 2009) and chronic kidney disease (IRIS classification). Both dogs with MMDV and controls resulted IRIS class 1. The study revealed no statistically significant difference in sCr and UPC between dogs with MMVD (sCr: 0.76 mg/dl, 0.41 \u2013 1.21; UPC: 0.26, 0.00 \u2013 1.03) (mean; range) and controls (sCr: 0.74 mg/dl, 0.37 \u2013 1.21; UPC: 0.21, 0.03 \u2013 0.98) (mean; range). These results suggest that hemodynamically signi\ufb01cant mitral regurgitation with cardiac remodeling and expected neurohormonal system activation do not affect proteinuria and renal function. Nevertheless further studies are needed to confirm these findings

Collaterali aortico-polmonari associati a cardiopatie congenite

La presenza di comunicazioni anomale a carico della circolazione sistemica-polmonare \ue8 stata riportata nel cane come diagnosi differenziale del dotto arterioso pervio (PDA), in quanto il reperto caratteristico in letteratura \ue8 un soffio continuo ascellare sinistro. La diagnosi definitiva \ue8 stata effettuata in sede intraoperatoria (angiografia o visualizzazione diretta). I report pubblicati hanno sempre presentato questi difetti congeniti come singoli, a differenza della cardiologia pediatrica, dove sono segnalati in associazione a Tetralogia di Fallot (TdF) e atresia della polmonare

Vygotsky and its critics : philosophy and rationality

New enantiomerically pure 1,2,4-trioxepanes 10a,b/11a,b were synthesized from d-glucose. Their conformational behavior was studied by low-temperature NMR and substantiated by DFT calculations. On evaluation of in vitro antimalarial activity, the adamantyl derivative 11b showed IC50 values in the low micromolar range, particularly against the W2 chloroquine-resistant Plasmodium falciparum strain (IC50 = 0.15 \ub1 0.12 \u3bcM)

Preliminary Investigation of Cardiovascular–Renal Disorders in Dogs with Chronic Mitral Valve Disease

Background: Veterinary literature lacks data about cardiovascular\u2013renal disorders (CvRD) and cardiorenal-anemia syndrome (CRAS) in dogs. Hypothesis: A direct correlation exists between ACVIM class and IRIS stage; chronic kidney disease (CKD) complicates chronic mitral valve disease (CMVD) more often than does anemia in dogs. Animals: One hundred and fifty-eight client-owned dogs with CMVD. Methods: Signalment, physical examination findings, electrocardiography, thoracic radiographs, echocardiography, and blood analysis were retrospectively evaluated to assess the prevalence of CKD and anemia in dogs with CMVD and to investigate the relationships among ACVIM class, IRIS stage, and survival. Results: The prevalence of CKD and anemia in dogs with CMVD was significantly higher than in the general population of dogs. Dogs being treated for heart failure had a significantly higher prevalence of CKD than did dogs that had not received treatment. A statistically significant direct correlation was found between ACVIM class and IRIS stage. Severe heart disease, severe renal disease or both, furosemide administration, and advanced age at diagnosis of heart disease were associated with shorter survival time. Survival time of dogs affected by CvRD was statistically shorter than survival time of dogs affected by CMVD alone. Conclusion and Clinical Relevance: Chronic mitral valve disease is associated with increased prevalence of CKD and anemia in dogs. Treatment for medical management of heart failure may play a role in inducing CKD. Class of heart disease and IRIS stage were directly correlated. Cardiovascular\u2013renal disorders decrease survival time compared to the only presence of CMVD alone, whereas anemia does not play a central role in worsening heart function

Creating drag and lift curves from soccer trajectories

Trajectory analysis is an alternative to using wind tunnels to measure a soccer balls aerodynamic properties. It has advantages over wind tunnel testing such as being more representative of game play. However, previous work has not presented a method that produces complete, speed -dependent drag and lift coefficients. Four high-speed cameras in stereo-calibrated pairs were used to measure the spatial co-ordinates for 29 separate soccer trajectories. Those trajectories span a range of launch speeds from 9.3 m/s to 29.9 m/s. That range encompasses low-speed laminar flow of air over a soccer ball, through the drag crises where air flow is both laminar and turbulent, and up to high-speed turbulent air flow. Results from trajectory analysis were combined to give speed-dependent drag and lift coefficient curves for the entire range of speeds found in the 29 trajectories. Average root mean square error between measured and modelled trajectory was 0.028 m horizontally and 0.034 m vertically. The drag and lift crises can be observed in the plots of drag and lift coefficients respectively