Dipeptide Derivatives of Primaquine as Transmission-Blocking Antimalarials: Effect of Aliphatic Side-Chain Acylation on the Gametocytocidal Activity and on the Formation of Carboxyprimaquine in Rat Liver Homogenates

Purpose. Dipeptide derivatives of primaquine (PQ) with reduced oxidative deamination to the inactive metabolite carboxypnmaquine were synthesized and evaluated as a novel class of transmission-blocking antimalarials. Methods. Antimalarial activity was studied using a model consisting of mefloquine-resistant Plasmodium berghei ANKA 25R/10, Balb C mice, and Anopheles stephensi mosquitoes. Metabolic studies were performed with rat liver homogenates, and the incubates were analyzed by HPLC. Results. All dipeptide derivatives and glycyl-PQ completely inhibited the appearance of oocysts in the midguts of the mosquitoes at 15 mg/ kg, while N-acetylprimaquine was not active at this dose. However, none of the title compounds were able to block oocyst production at 3.75 mg/kg, in contrast with primaquine. Exception for sarc-gly-PQ, all remaining compounds prevented sporozoite formation in the salivary glands of mosquitoes at a dose of 3.75 mg/kg. Simultaneous hydrolysis to primaquine and gly-PQ ocurred with the following order of V_max/ K_m: for primaquine formation, L-ala-gly-PQ > L-phe-gly-PQ > gly-gly-PQ; and for gly-PQ formation, L-phe-gly-PQ > L-ala-gly-PQ > gly-gly-PQ. In contrast, primaquine was not released from D-phe-gly-PQ, sarc-gly-PQ, and N-acetylprimaquine. Neither carboxyprimaquine nor 8-amino- 6-methoxy- quinoline were detected in any of the incubation mixtures. Conclusions. The title compounds prevent the development of the sporogonic cycle of Plasmodium berghei. Gametocytocidal activity is independent of the rate and pathway of primaquine formation. Acylation of the aliphatic side-chain effectively prevents the formation of Carboxyprimaquine, but the presence of a terminal amino group appears to be essential for the gametocytocidal activity.     

Ultra‐short heart rate variability recording reliability: The effect of controlled paced breathing

Background

Recent studies have reported that Heart Rate Variability (HRV) indices remain reliable even during recordings shorter than 5 min, suggesting the ultra‐short recording method as a valuable tool for autonomic assessment. However, the minimum time‐epoch to obtain a reliable record for all HRV domains (time, frequency, and Poincare geometric measures), as well as the effect of respiratory rate on the reliability of these indices remains unknown.

Methods

Twenty volunteers had their HRV recorded in a seated position during spontaneous and controlled respiratory rhythms. HRV intervals with 1, 2, and 3 min were correlated with the gold standard period (6‐min duration) and the mean values of all indices were compared in the two respiratory rhythm conditions.

Results

rMSSD and SD1 were more reliable for recordings with ultra‐short duration at all time intervals (r values from 0.764 to 0.950, p < 0.05) for spontaneous breathing condition, whereas the other indices require longer recording time to obtain reliable values. The controlled breathing rhythm evokes stronger r values for time domain indices (r values from 0.83 to 0.99, p < 0.05 for rMSSD), but impairs the mean values replicability of domains across most time intervals. Although the use of standardized breathing increases the correlations coefficients, all HRV indices showed an increase in mean values (t values from 3.79 to 14.94, p < 0.001) except the RR and HF that presented a decrease (t = 4.14 and 5.96, p < 0.0001).

Conclusion

Our results indicate that proper ultra‐short‐term recording method can provide a quick and reliable source of cardiac autonomic nervous system assessment.

     

Rhinoscleroma causing severe bilateral nasal obstruction

Rhinoscleroma is a chronic, infectious and granulomatous disease of the respiratory tract. There is often a delay in diagnosis due to unfamiliarity with the disease and also because culture is not always positive. We report a case in a 26-year-old woman with granular mass obstructing bilateral nasal cavities and causing breathing difficulty. Histopathological examination showed characteristic Mikulicz histiocytes containing numerous Gram-negative intracellular rod-shaped bacilli consistent with the diagnosis of rhinoscleroma. The patient was treated with gemifloxacin and tetracycline and remains asymptomatic over a year follow-up period. It is important to consider rhinoscleroma in cases of chronic nasal obstruction. As culture is not always positive, histopathological examination may be crucial to the diagnosis.     

FDG-PET/CT in large-vessel vasculitis: its diagnostic and follow-up role

Vasculitis is a disorder characterized by inflammation of blood vessels. Its clinical manifestations are diverse and depend on the size of the involved vessels and the organs affected by ischemia. In some cases the disease is manifested only with symptoms and signs of systemic inflammation (e.g. fever, night sweats, fatigue). Results of laboratory tests usually indicate only the inflammatory process. It is known that radiolabeled glucose analogue 18F-fluoro-deoxyglucose ([18F] FDG) used in positron emission tomography (PET) accumulates in both malignant and inflammatory tissue (Zhuang et al. in Radiol Clin North Am 43:121–134, 2005). We report a case of a patient with FDG-PET/CT findings of large-vessel vasculitis with follow-up results that convinced us to change the treatment.     

Combined Simulation and Experimental Study of Large Deformation of Red Blood Cells in Microfluidic Systems

We investigate the biophysical characteristics of healthy human red blood cells (RBCs) traversing microfluidic channels with cross-sectional areas as small as 2.7?×?3?μm. We combine single RBC optical tweezers and flow experiments with corresponding simulations based on dissipative particle dynamics (DPD), and upon validation of the DPD model, predictive simulations and companion experiments are performed in order to quantify cell deformation and pressure-velocity relationships for different channel sizes and physiologically relevant temperatures. We discuss conditions associated with the shape transitions of RBCs along with the relative effects of membrane and cytosol viscosity, plasma environments, and geometry on flow through microfluidic systems at physiological temperatures. In particular, we identify a cross-sectional area threshold below which the RBC membrane properties begin to dominate its flow behavior at room temperature; at physiological temperatures this effect is less profound.     

Combined rTPA and aspirin therapy for intracardiac thrombosis in neonates

We describe a case of a very low birth weight premature female twin with intracardiac thrombosis. Her condition was consistent with neonatal sepsis, and she was treated with advanced life support, antibiotic therapy, parenteral nutrition, blood transfusion, and central venous catheterization. Infective endocarditis was suspected, and a large intracavitary thrombus was detected by two-dimensional Doppler echocardiography. Surgical procedure was not only technically difficult but also highly lethal, being contraindicated in some cases. Consequently, the use of the thrombolytic recombinant tissue-plasminogen activator (rTPA) associated with aspirin was the treatment of choice, and complete dissolution of the thrombus was achieved without adverse effects.