Effect of Opaganib on Supplemental Oxygen and Mortality in Patients with Severe SARS-CoV-2 Pneumonia

RationaleThere are few treatment options for severe COVID-19 pneumonia. Opaganib is an oral treatment under investigation. ObjectiveEvaluate opaganib treatment in hospitalized patients with severe COVID-19 pneumonia. MethodsA randomized, placebo-controlled, double-blind phase 2/3 trial was conducted in 60 sites worldwide from August 2020 to July 2021. Patients received either opaganib (n=230; 500mg twice daily) or matching placebo (n=233) for 14 days. Main Outcome MeasurementsPrimary outcome was the proportion of patients no longer requiring supplemental oxygen by day 14. Secondary outcomes included changes in the World Health Organization Ordinal Scale for Clinical Improvement, viral clearance, intubation, and mortality at 28- and 42-days. Main ResultsPre-specified primary and secondary outcome analyses did not demonstrate statistically significant benefit (except for time to viral clearance). Post-hoc analysis revealed the fraction of inspired oxygen (FiO2) at baseline was prognostic for opaganib treatment responsiveness and corresponded to disease severity markers. Patients with FiO2 levels at or below the median value ([≤]60%) had better outcomes after opaganib treatment (n=117) compared to placebo (n=134). The proportion of patients with [≤]60% FIO2 at baseline that no longer required supplemental oxygen ([≥]24 hours) by day 14 of opaganib treatment increased (76.9% vs 63.4%: p-value =0.033). There was a 62.6% reduction in intubation/mechanical ventilation (6.84% vs 17.91%; p-value=0.012) and a clinically meaningful 62% reduction in mortality (5.98% vs 16.7%; p-value=0.019) by day 42. No new safety concerns observed. ConclusionsPost-hoc analysis supports opaganib benefit in COVID-19 severe pneumonia patients that require lower supplemental oxygen ([≤]60% FiO2). Further studies are warranted. Trial registration numberNCT04467840

The interplay between reactive oxygen species and antioxidants in cancer progression and therapy: a narrative review.

OBJECTIVE: To unveil the role of reactive oxygen species (ROS) and antioxidants in signaling and involvement in cancer progression and therapy. BACKGROUND: Cancer is considered one of the main causes of mortality in developed countries and expected to be more in developing countries as well. Although some cancers may develop at young age, yet almost all types of cancers are an accumulation of genetic and epigenetic cell damages. Cancer is considered a diverse collection of diseases on a cellular level rather than a single disease; and each disease has a different cause as well. ROS have been seen as harmful toxic molecules; however, they are recognized for cellular signaling capabilities. Elevated levels of ROS have protumorigenic activities; they induce cancer cell proliferation, and adaptation to hypoxia in addition to other effects like DNA damage and genetic instability. They are produced excessively by cancer cells to hyperactivate cellular transformation meanwhile increasing antioxidant capacity to avoid cell death. METHODS: We discussed peer reviewed published research work from 1987 to 2021. In this paper, we review the role of antioxidants as defensive barrier against excessive ROS levels for maintaining oxidation-reduction (redox) balance; however, antioxidant can also strive in tumor cells with their scavenging capacities and maintain protumorigenic signaling and resist the cancer cell oxidative stress and apoptosis. High doses of antioxidant compounds could be toxic to cells as they are capable of reacting with the physiological concentrations of ROS present for normal cellular processes and signaling. CONCLUSIONS: Maintaining cellular redox homeostasis is vital for healthy biological system. Therefore, therapeutic modalities for cancer including antioxidants and ROS management should be used at certain doses to target specific redox pathways involved in cancer progression without disrupting the overall redox balance in normal cells.

The dynamics of ultrastructural changes during Entamoeba invadens encystation.

Entamoeba histolytica infection causes amoebiasis, which is a global public health problem. The major route of infection is oral ingestion of E. histolytica cysts, cysts being the sole form responsible for host-to-host transmission. Cysts are produced by cell differentiation from proliferative trophozoites in a process termed 'encystation'. Therefore, encystation is an important process from a medical as well as a biological perspective. Previous electron microscopy studies have shown the ultrastructure of precysts and mature cysts; however, the dynamics of ultrastructural changes during encystation were ambiguous. Here, we analysed a series of Entamoeba invadens encysting cells by transmission electron microscopy. Entamoeba invadens is a model for encystation and the cells were prepared by short interval time course sampling from in vitro encystation-inducing cultures. We related sampled cells to stage conversion, which was monitored in the overall population by flow cytometry. The present approach revealed the dynamics of ultrastructure changes during E. invadens encystation. Importantly, the results indicate a functional linkage of processes that are crucial in encystation, such as glycogen accumulation and cyst wall formation. Hence, this study provides a reference for studying sequential molecular events during Entamoeba encystation.

Stented versus Non-Stented Snodgrass Urethroplasty for Distal Hypospadia Repair.

BACKGROUND: Hypospadia is one of the most common congenital anomalies in children. Patients with distal hypospadias can be treated successfully with a tubularized incised plate (TIP) urethroplasty, usually with a postoperative urethral stent to divert urine into the diaper or a urine bag for approximately 1 week. However, these stents have their own morbidity and complications. We therefore tried to determine the safety of distal penile hypospadias repair without the use of a postoperative stent. PATIENTS AND METHOD: Fifty patients with distal penile hypospadias were prospectively assessed from May 2016 to August 2018. All patients underwent Snodgrass urethroplasty by the same surgeon. Half of the patients had a postoperative stent for 1 week. The other half had no stent. Clinical follow-up was over 6 months with an emphasis on possible stent-related complications. RESULTS: Fifty children underwent TIP urethroplasty for distal hypospadia repair. The mean age was 5.9 years (range 2-12). In 25 cases, a stent was removed within 1 week. In the other 25 cases, no postoperative stent was placed. The overall complication rate for the stented group was 48% (n = 12) and for the non-stented group 68% (n = 17), respectively. In the stented group, 1 patient (4%) developed a fistula, whilst there were 2 (8%) in the non-stented group. All fistulas were repaired after 6 months postoperatively. Neourethral stenosis and glans dehiscence occurred in each 1 case (4%) in both groups. Differences were not statistically significant. However, there were significantly more wound infections in the stented group. On the other hand, stents prevented temporary urinary retention which occurred in 2 patients in the non-stented group. CONCLUSION: Despite the limited number of cases, our study suggests that, all in all, there is no significant difference in severe complication rates regardless whether a postoperative stent is used or not.

Prevalence of schistosomiasis among patients attending Qena General Hospital over the years 2011 and 2012.

Schistosomiasis is a public health problem in Egypt. To detect the prevalence of schistosomiasis in Qena Governorate, 1601 urine and stool samples of patients attending Qena General Hospital were examined of whom 1601 patients had urinary symptoms and 893 patients had dysentery and bloody stool. Sheets were filled out on each patient. Also, a total of 7590 Bulinus truncatus and Biomphalaria alexandrina snails were collected from water bodies in Qena Governorate. The overall prevalence of S. haematobium was 13.9%; with maximum among 6-18 year-old age group and higher in males than in females. Risk factors for S. haematobium infection were this age group; particularly males. However, males swim and play in water bodies and women wash cloths and utensils there, and children swimming or playing in canals. The S. haematobium peak of infection was in winter correlated with the highest prevalence in Dandara City, Qena City, Awlad-Amr and El Hijarat. S. mansoni were negative in the examined individuals. The infective rate among snails was 1.82% in B. truncatus and 0.0% among B. alexandrina and M. tuberculata.

Relative bioavailability of griseofulvin lyophilized dry emulsion tablet vs. immediate release tablet: a single-dose, randomized, open-label, six-period, crossover study in healthy adult volunteers in the fasted and fed states.

The oral bioavailability of griseofulvin (GF) formulated as a fast disintegrating lyophilized dry emulsion (LDE) tablet was studied and compared to the commercially available immediate release (IR) tablet, as a reference, in both the fasted and fed states in nine healthy volunteers after a single oral dose (125 mg) in a crossover design. Furthermore the LDE tablets were ingested with and without water under both the fasted and fed states. In the fasted state, the rate of absorption was found to be significantly faster from LDE tablets, in the presence and absence of water, as shown by a higher C(max) (more than two times higher, p=0.0001) and a shorter t(max) (by more than 3h, p=0.0001) compared to IR tablets. The extent of absorption, expressed as AUC, from LDE tablets in the presence and absence of water was 65% and 77% larger and statistically significantly different relative to the mean AUC from IR tablets (p=0.006). In the fed state, C(max) from LDE tablets ingested with and without water was found to be about 30% and 50% higher, respectively, than the immediate release tablets. A shorter t(max) was also shown whether LDE tablets were ingested with or without water in the fed state as compared to immediate release tablets. The mean AUC from LDE tablets under fed conditions in the presence of water was about 21% larger and was not statistically significantly different from AUC from immediate release tablets (p=0.517). When ingested without water, AUC from LDE tablets was about 43% larger and statistically significantly different relative to AUC from IR tablets (p=0.033). The mean AUC from the LDE tablet ingested with water under fed conditions relative to AUC from LDE tablet ingested without water was not statistically significantly different (p=0.454). Results show that the food effect of the high fat meal is very pronounced in case of the immediate release tablets, Fulvin, than in case of LDE tablets whether given with or without water.

Administration of tobramycin in the beginning of the hemodialysis session: a novel intradialytic dosing regimen.

BACKGROUND: Aminoglycoside antibiotic efficacy is related to peak concentration (C(max)) and postantibiotic effect, whereas toxicity is directly related to body exposure as measured by area under the serum concentration versus time curve (AUC). On the basis of pharmacokinetic simulation models, tobramycin administration during the first 30 min of high-flux hemodialysis achieves similar C(max) but significantly lower AUC and prehemodialysis concentrations compared with conventional dosing in the last 30 min of hemodialysis. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: To test this hypothesis, a pilot study in which five adult chronic hemodialysis patients who were undergoing high-flux dialysis received one dose of tobramycin 1.5 mg/kg intravenously during the first or last 30 min of hemodialysis was conducted. After a 1-mo washout period, patients crossed over to the other treatment schedule. Tobramycin serum concentrations were measured to determine C(max), interdialytic and intradialytic elimination rate constants and half-lives, AUC, and clearance. RESULTS: Tobramycin administration during the first and last 30 min of hemodialysis resulted in similar C(max) of 5.63 +/- 0.49 and 5.83 +/- 0.67 mg/L (P > 0.05) but significantly lower prehemodialysis concentrations of 0.16 +/- 0.09 and 2.44 +/- 0.43 mg/L (P < 0.001) and AUC of 21.06 and 179.23 +/- 25.84 mg/h per L (P < 0.001), respectively. CONCLUSIONS: Tobramycin administration during the first 30 min of hemodialysis results in similar C(max) but lower AUC to conventional dosing, which may translate into comparable efficacy but lower toxicity.