Amphiphilic Antimony(V) Complexes for Oral Treatment of Visceral Leishmaniasis

The need for daily parenteral administration is an important limitation in the clinical use of pentavalent antimonial drugs against leishmaniasis. In this study, amphiphilic antimony(V) complexes were prepared from alkylmethylglucamides (L8 and L10, with carbon chain lengths of 8 and 10, respectively), and their potential for the oral treatment of visceral leishmaniasis (VL) was evaluated. Complexes of Sb and ligand at 1:3 (SbL8 and SbL10) were obtained from the reaction of antimony(V) with L8 and L10, as evidenced by elemental and electrospray ionization-tandem mass spectrometry (ESI-MS) analyses. Fluorescence probing of hydrophobic environment and negative-staining transmission electron microscopy showed that SbL8 forms kinetically stabilized nanoassemblies in water. Pharmacokinetic studies with mice in which the compound was administered by the oral route at 200 mg of Sb/kg of body weight indicated that the SbL8 complex promoted greater and more sustained Sb levels in serum and liver than the levels obtained for the conventional antimonial drug meglumine antimoniate (Glucantime [Glu]). The efficacy of SbL8 and SbL10 administered by the oral route was evaluated in BALB/c mice infected with Leishmania infantum after a daily dose of 200 mg of Sb/kg for 20 days. Both complexes promoted significant reduction in the liver and spleen parasite burdens in relation to those in the saline-treated control group. The extent of parasite suppression (>99.96%) was similar to that achieved after Glu given intraperitoneally at 80 mg of Sb/kg/day. As expected, there was no significant reduction in the parasitic load in the group treated orally with Glu at 200 mg of Sb/(kg day). In conclusion, amphiphilic antimony(V) complexes emerge as an innovative and promising strategy for the oral treatment of VL.     

Grief responses of pediatric house officers to a patient's death

Abstract

Twenty-five pediatric house officers were surveyed (14 M; 11 F) to assess their behavioral and psychophysiologic responses to patient death. Vignettes about the deaths of two pediatric patients were included as part of a self-administered questionnaire. The vignettes were followed by 14 behavioral and 20 psychophysiologic responses to the deaths depicted, and physicians were asked to indicate the expected occurrence of these reactions for themselves and for an ideal physician. Reported reactions were found to be similar to grief responses experienced with the death of a loved one. Significant differences were found between the responses of female and male house officers to patient death. Additionally, differences were found between the manner in which the physicians personally responded to a patient's death in comparison to the way they considered an ideal physician would respond. Practical suggestions are given, based on these data, for inclusion of information in death education courses for physicians.     

The mean fluorescence intensities of anti‐HLA antibodies detected using micro‐bead flow cytometry predict the risk of platelet transfusion refractoriness

There are no accepted methods to predict the development of platelet transfusion refractoriness (PTR) due to human leucocyte antigen (HLA)‐alloimmunization. Hence, matched platelets are usually given only to patients demonstrating PTR, necessarily resulting in some ineffective random donor platelets (RDPLT) transfusions. To assess its utility in predicting PTR, we retrospectively tested samples from 387 patients receiving chemotherapy for acute leukaemia or autologous transplantation using a micro‐bead flow cytometry assay. The average of the mean fluorescence intensities (avgMFI) of the class I beads in the screening assay was correlated with outcomes of RDPLT transfusions during a 2 week period. Antibodies were detected in 57 patients; 66 developed PTR, of whom 28 were alloimmunized. avgMFI usefully predicted the development of PTR (area under the receiver operating curve 0·87, 95% confidence interval: 0·77–0·96). A logistic regression model estimated the probability of PTR to be >90% when avgMFI >5440. These results indicate that micro‐bead flow cytometry assays could inform a risk‐adapted strategy for managing thrombocytopaenic HLA allo‐immunized patients.     

Cannabis/Cannabinoids for Treating COVID-19 Associated Neuropsychiatric Complications

COVID-19 epidemic has resulted in devastating mortality and morbidity consisting of socioeconomic and health effects that have included respiratory/pulmonary, cardiovascular, mental health and neurological consequences such as anxiety, depression, and substance use. Several effective vaccines have been developed and extensive efforts are underway to develop therapeutics to treat COVID-19. Cannabis and/or its product-cannabidiol (CBD) are being advertised for the treatment of COVID-19 associated mental/neurological complications and substance use disorders. However, research reviewed shows that there is insufficient data from clinical studies to support the use of cannabis or CBD for the treatment of COVID-19 associated mental health and neurological complications. Additional basic and clinical research is suggested to develop cannabis or cannabidiol for the treatment of mental health problems associated with coronavirus infection and or substance use disorders. In the meantime, it is important that the addiction physician/psychiatrist must caution while prescribing or recommending cannabis or CBD for treating such clinical indications.

Graphical abstract

Research shows that currently there is no clinical evidence to support the use of cannabis or any of its compounds including CBD for treating any of the neuropsychiatric complications of COVID-19. Thus, it is important that the addiction physicians/psychiatrists caution their patients from using cannabis or cannabis products for treating any such complications.

     

Cross GTPase-activating protein (CrossGAP)/Vilse links the Roundabout receptor to Rac to regulate midline repulsion

The regulators of the Rho-family GTPases, GTPase-activating proteins (GAPs) and guanine exchange factors (GEFs), play important roles in axon guidance. By means of a functional genomic study of the Rho-family GEFs and GAPs in Drosophila, we have identified a Rho-family GAP, CrossGAP (CrGAP), which is involved in Roundabout (Robo) receptor-mediated repulsive axon guidance. CrGAP physically associates with the Robo receptor. Too much or too little CrGAP activity leads to defects in Robo-mediated repulsion at the midline choice point. The CrGAP gain-of-function phenotype mimics the loss-of-function phenotypes of both Robo and Rac. Dosage-sensitive genetic interactions among CrGAP, Robo, and Rac support a model in which CrGAP transduces signals downstream of Robo receptor to regulate Rac-dependent cytoskeletal changes.     

High‐frequency vibration for the recanalization of guidewire refractory chronic total coronary occlusions

Background: Recanalization of coronary chronic total occlusions (CTOs) remains a clinical challenge, particularly when standard guidewire attempts fail. Objectives: We sought to determine the safety and efficacy of a novel method that used high‐frequency (20 kHz) vibration to fragment occlusive fibrous tissue and facilitate guidewire crossing into the distal vessel. Methods: A total of 125 patients with CTO, who failed at attempts of conventional guidewire recanalization after more than 5 min of fluoroscopy time, were enrolled in the study. The primary efficacy endpoint was the advancement of the CROSSER? catheter through the occlusion and attainment of coronary guidewire positioning in the distal coronary lumen. The primary safety endpoint was the occurrence of death, myocardial infarction, clinical perforation, or target vessel revascularization within the first 30 days. Results: The average fluoroscopy time while delivering the CROSSER catheter was 12.4 min. CROSSER‐assisted guidewire recanalization was achieved in 76 (60.8%) procedures and a final diameter stenosis <50% was obtained in 68 (54.4%) of cases. Major adverse events occurred in 11 (8.8%) patients, lower than the predefined objective performance criteria. Angina frequency and quality of life were improved in patients with successful guidewire recanalization. Conclusions: We conclude that high‐frequency vibration using the CROSSER catheter is a safe and effective therapy for patients with CTO, which are refractory to standard guidewire recanalization. © 2008 Wiley‐Liss, Inc.     

Growth hormone and low dose estrogen in Turner syndrome: results of a United States multi-center trial to near-final height

A cardinal clinical feature of Turner syndrome (TS) is linear growth failure resulting in extreme short stature: the median adult height of untreated women with TS is 143 cm, 20 cm (8 in.) below that of the general female population. In the largest multicenter, randomized, long-term, dose-response study conducted in the United States, 232 subjects with TS received either 0.27 or 0.36 mg/kg.wk of recombinant human GH with either low dose ethinyl E2 or oral placebo. The study was placebo-controlled for both GH and estrogen for the first 18 months and remained placebo-controlled for estrogen for its duration. The near-final height of the 99 subjects whose bone age was at least 14 yr was 148.7 +/- 6.1 cm after 5.5 +/- 1.8 yr of GH started at a mean age of 10.9 +/- 2.3 yr; this represents an average increase of 1.3 +/- 0.6 SD scores from baseline (TS standard). Height was greater than 152.4 cm (60 in.) in 29% of subjects compared with the expected 5% of untreated patients. Mean near-final heights of subjects who received the lower GH dose, with or without estrogen, were 145.1 +/- 5.4 and 149.9 +/- 6.0 cm, respectively; those who received the higher GH dose with or without estrogen achieved mean near-final heights of 149.1 +/- 6.0 and 150.4 +/- 6.0 cm, respectively. Factors that most impacted outcome were younger age, lower bone age/chronological age ratio, lower body weight, and greater height SD score at study entry. This study demonstrates significant GH-induced improvement in height SD score, with correction of height to within the normal channels for a significant number of patients, and provides evidence of a GH dose-response effect. These data also indicate that early administration of estrogen, even at relatively low doses, does not improve gain in near-final height in patients with TS.     

Effects of sustained-release bupropion among persons interested in reducing but not quitting smoking

PURPOSE: To determine whether sustained-release bupropion promotes smoking reduction leading to smoking cessation among persons who wish to reduce their amount of smoking, but who are unwilling to quit or who perceive themselves as being unable to quit. METHODS: Current smokers were assigned randomly to receive either sustained-release bupropion (150 mg twice daily) or matching placebo. During an initial 6-month smoking reduction phase, those who were willing to quit entered a 7-week cessation phase, during which study medication was continued. RESULTS: Four-week continuous abstinence rates were 14% (41/295) in the bupropion group and 8% (25/299) in the placebo group (P = 0.02) during treatment. However, this benefit did not continue after treatment was stopped; subsequent continuous abstinence rates were 7% (20/295) in the bupropion group and 5% (16/299) in the placebo group (P = 0.50). Similar proportions of subjects entered the cessation phase in both treatment groups (38% [n = 113] of those in the bupropion group and 34% [n = 101] of those in the placebo group), although the time until a cessation attempt was shorter for those taking bupropion (median, 64 days vs. 118 days, P = 0.008). The extent of smoking reduction (measured by urinary cotinine concentrations) among the 327 subjects who did not enter the cessation phase was significantly greater (P <0.05) in those treated with bupropion during the reduction treatment phase, but not during the month 12 follow-up visit (P = 0.25). CONCLUSION: Sustained-release bupropion, when used in smokers initially not willing to make a cessation attempt, can help sustain smoking reduction while subjects are on active medication, reduce the time until the next cessation attempt, and increase short-term abstinence rates. However, these benefits were modest and not sustained after bupropion was discontinued.