Indicators of Critical Illness and Predictors of Mortality in COVID-19 Patients.

COVID-19 is an emerging disease all over the world and spreading at an unpredicted rate, resulting in significant influences on global economies and public health. Clinical, laboratory, and imaging characteristics have been partially described in some observational studies. Not enough systematic reviews on predictors of critical illness and mortality in COVID 19 have been published to date. In this review, we had illustrated the prognostic predictors of COVID-19 by gathering published information on the risk factors related to the outcomes of SARS-CoV-2 infections.

Stroke and renal artery stenosis from Takayasu's arteritis diagnosed in a 57-year-old male patient.

Takayasu arteritis (TA) is a rare chronic granulomatous inflammatory arterial disease of unknown etiology that affects the aorta, its main branches and pulmonary artery. The clinical presentation is nonspecific, with signs and symptoms that vary according to the affected arterial segment. The most commonly affected vessel is the subclavian artery, while renal artery stenosis is relatively uncommon. We report a case of a 57-year-old male patient with late diagnosis of TA and various related complications including stroke in the left middle cerebral artery territory, predominant left renal artery stenosis, and hypertension with discrepancy of blood pressure between two arms due to predominant left subclavian artery stenosis. Thus, physicians should keep in their mind this late presentation after the age of 40 years. The aim is to increase the awareness of this condition because of early diagnosis and the timely introduction of treatment can lead to improved outcomes in this poorly understood clinical enigma.

Stabilization benefits of single and multi-layer self-nanoemulsifying pellets: A poorly-water soluble model drug with hydrolytic susceptibility.

Solidified self-nanoemulsifying drug delivery systems (SNEDDS) offer strong option to enhance both drug aqueous solubility and stability. The current study was designed to evaluate the potential stabilization benefits of solidifying cinnarizine (CN) liquid SNEDDS into single and multi-layer self-nanoemulsifying pellets (SL-SNEP and ML-SNEP, respectively). The selected formulations were enrolled into accelerated, intermediate and long-term stability studies. The chemical stability was assessed based on the % of intact CN remaining in formulation. The physical stability was assessed by monitoring the in-vitro dissolution and physical appearance of the formulations. The degradation pathway of CN within lipid-based formulation was proposed to involve a hydroxylation reaction of CN molecule. The chemical stability study revealed significant CN degradation in liquid SNEDDS, SL-SNEP and ML-SNEP (lacking moisture-sealing) within all the storage conditions. In contrast, the moisture sealed ML-SNEP showed significant enhancement of CN chemical stability within the formulation. In particular, ML-SNEP coated with Kollicoat Smartseal 30D showed superior CN stabilization and no significant decrease in dissolution efficiency, at all the storage conditions. The observed stability enhancement is owing to the complete isolation between CN and SNEDDS layer as well as the effective moisture protection provided by Kollicoat Smartseal 30D. Hence, the degradation problem could be eradicated completely. The incorporation of silicon dioxide had an important role in the inhibition of pellet agglomeration upon storage. Accordingly, ML-SNEP coated with Kollicoat Smartseal 30D and/or silicon dioxide could be an excellent dosage form that combine dual enhancement of CN solubilization and stabilization.

Multi-Layer Self-Nanoemulsifying Pellets: an Innovative Drug Delivery System for the Poorly Water-Soluble Drug Cinnarizine.

Beside their solubility limitations, some poorly water-soluble drugs undergo extensive degradation in aqueous and/or lipid-based formulations. Multi-layer self-nanoemulsifying pellets (ML-SNEP) introduce an innovative delivery system based on isolating the drug from the self-nanoemulsifying layer to enhance drug aqueous solubility and minimize degradation. In the current study, various batches of cinnarizine (CN) ML-SNEP were prepared using fluid bed coating and involved a drug-free self-nanoemulsifying layer, protective layer, drug layer, moisture-sealing layer, and/or an anti-adherent layer. Each layer was optimized based on coating outcomes such as coating recovery and mono-pellets%. The optimized ML-SNEP were characterized using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray diffraction (XRD), in vitro dissolution, and stability studies. The optimized ML-SNEP were free-flowing, well separated with high coating recovery. SEM showed multiple well-defined coating layers. The acidic polyvinylpyrrolidone:CN (4:1) solution presented excellent drug-layering outcomes. DSC and XRD confirmed CN transformation into amorphous state within the drug layer. The isolation between CN and self-nanoemulsifying layer did not adversely affect drug dissolution. CN was able to spontaneously migrate into the micelles arising from the drug-free self-nanoemulsifying layer. ML-SNEP showed superior dissolution compared to Stugeron® tablets at pH 1.2 and 6.8. Particularly, on shifting to pH 6.8, ML-SNEP maintained > 84% CN in solution while Stugeron® tablets showed significant CN precipitation leaving only 7% CN in solution. Furthermore, ML-SNEP (comprising Kollicoat® Smartseal 30D) showed robust stability and maintained > 97% intact CN within the accelerated storage conditions. Accordingly, ML-SNEP offer a novel delivery system that combines both enhanced solubilization and stabilization of unstable poorly soluble drugs.

New gentle-wing high-shear granulator: impact of processing variables on granules and tablets characteristics of high-drug loading formulation using design of experiment approach.

The aim of this work was to study the application of design of experiment (DoE) approach in defining design space for granulation and tableting processes using a novel gentle-wing high-shear granulator. According to quality-by-design (QbD) prospective, critical attributes of granules, and tablets should be ensured by manufacturing process design. A face-centered central composite design has been employed in order to investigate the effect of water amount (X1), impeller speed (X2), wet massing time (X3), and water addition rate (X4) as independent process variables on granules and tablets characteristics. Acetaminophen was used as a model drug and granulation experiments were carried out using dry addition of povidone k30. The dried granules have been analyzed for their size distribution, density, and flow pattern. Additionally, the produced tablets have been investigated for; weight uniformity, breaking force, friability and percent capping, disintegration time, and drug dissolution. Results of regression analysis showed that water amount, impeller speed and wet massing time have significant (p < .05) effect on granules and tablets characteristics. However, the water amount had the most pronounced effect as indicated by its higher parameter estimate. On the other hand, water addition rate showed a minimal impact on granules and tablets properties. In conclusion, water amount, impeller speed, and wet massing time could be considered as critical process variables. Thus, understanding the relationship between these variables and quality attributes of granules and corresponding tablets provides the basis for adjusting granulation variables in order to optimize product performance.

HIGH SHEAR GRANULATION PROCESS: ASSESSING IMPACT OF FORMULATION VARIABLES ON GRANULES AND TABLETS CHARACTERISTICS OF HIGH DRUG LOADING FORMULATION USING DESIGN OF EXPERIMENT METHODOLOGY.

High shear wet granulation is a significant component procedure in the pharmaceutical industry. The objective of the study was to investigate the influence of two independent formulation variables; polyvinypyrrolidone (PVP) as a binder (X,) and croscarmellose sodium (CCS) as a disintegrant (X2) on the crit- ical quality attributes of acetaminophen granules and their corresponding tablets using design of experiment (DoE) approach. A two factor, three level (32) full factorial design has been applied; each variable was investi- gated at three levels to characterize their strength and interaction. The dried granules have been analyzed for their density, granule size and flowability. Additionally, the produced tablets have been investigated for: break- ing force, friability, disintegration time and t. of drug dissolution. The analysis of variance (ANOVA) showed that the two variables had a significant impact (p < 0.05) on granules and tablets characteristics, while only the binder concentration influenced the tablets friability. Furthermore, significant interactions (p < 0.05) between the two variables, for granules and tablets attributes, were also found. However, variables interaction showed minimal effect for granules flowability as well as tablets friability. Desirability function was carried out to opti- mize the variables under study to obtain product within the USP limit. It was found that the higher desirability (0.985) could be obtained at the medium level of PVP and low level of CCS. Ultimately, this study supplies the formulator with beneficial tools in selecting the proper level of binder and disintegrant to attain product with desired characteristics.

HIGH-SHEAR GRANULATION PROCESS: INFLUENCE OF PROCESSING PARAMETERS ON CRITICAL QUALITY ATTRIBUTES OF ACETAMINOPHEN GRANULES AND TABLETS USING DESIGN OF EXPERIMENT APPROACH.

Application of quality by design (QbD) in high shear granulation process is critical and need to recognize the correlation between the granulation process parameters and the properties of intermediate (granules) and corresponding final product (tablets). The present work examined the influence of water amount (X,) and wet massing time (X2) as independent process variables on the critical quality attributes of granules and corresponding tablets using design of experiment (DoE) technique. A two factor, three level (32) full factorial design was performed; each of these variables was investigated at three levels to characterize their strength and interaction. The dried granules have been analyzed for their size distribution, density and flow pattern. Additionally, the produced tablets have been investigated for weight uniformity, crushing strength, friability and percent capping, disintegration time and drug dissolution. Statistically significant impact (p < 0.05) of water amount was identified for granule growth, percent fines and distribution width and flow behavior. Granule density and compressibility were found to be significantly influenced (p < 0.05) by the two operating conditions. Also, water amount has significant effect (p < 0.05) on tablet weight unifornity, friability and percent capping. Moreover, tablet disintegration time and drug dissolution appears to be significantly influenced (p < 0.05) by the two process variables. On the other hand, the relationship of process parameters with critical quality attributes of granule and final product tablet was identified and correlated. Ultimately, a judicious selection of process parameters in high shear granulation process will allow providing product of desirable quality.

Optimization of self-nanoemulsifying formulations for weakly basic lipophilic drugs: role of acidification and experimental design

ABSTRACT Formulators face great challenges in adopting systematic approaches for designing self-nanoemulsifying formulations (SNEFs) for different drug categories. In this study, we aimed to build-up an advanced SNEF development framework for weakly basic lipophilic drugs, such as cinnarizine (CN). First, the influence of formulation acidification on CN solubility was investigated. Second, formulation self-emulsification in media with different pH was assessed. Experimentally designed phase diagrams were also utilized for advanced optimization of CN-SNEF. Finally, the optimized formulation was examined using cross polarizing light microscopy for the presence of liquid crystals. CN solubility was significantly enhanced upon external and internal acidification. Among the various fatty acids, oleic acid-based formulations showed superior self-emulsification in all the tested media. Surprisingly, formulation turbidity and droplet size significantly decreased upon equilibration with CN. The design was validated using oleic acid/Imwitor308/Cremophor El (25/25/50), which showed excellent self-nanoemulsification, 43-nm droplet size (for CN-equilibrated formulations), and 88 mg/g CN solubility. In contrast to CN-free formulations, CN-loaded SNEF presented lamellar liquid crystals upon 50% aqueous dilution. These findings confirmed that CN-SNEF efficiency was greatly enhanced upon drug incorporation. The adopted strategy offers fast and accurate development of SNEFs and could be extrapolated for other weakly basic lipophilic drugs.

Results of treatment of lymphoblastic lymphoma at the children cancer hospital Egypt - A single center experience.

Introduction Lymphoblastic lymphoma (LBL) and acute lymphoblastic leukemia (ALL) are neoplasms of immature B or T-cell precursors. They are considered as a unique biological entity in the 2008 World Health Organization Classification of Hematologic Neoplasm. Both entities are arbitrarily separated by a cut-off point of 20-25% of blast cells in the bone marrow. Treatment of LBL has evolved over time from conventional high-grade NHL schedules to ALL-derived protocols. The aim of this work is to report the clinical characteristics, overall survival (OS), event free survival (EFS), and common chemotherapy toxicities of lymphoblastic lymphoma (LBL) patients during a 5.5year period. Patients and methods A Retrospective review of patient's charts diagnosed and treated as LBL during the period between July 2007 and end of December 2012 was done. Patients were treated according to St. Jude Children Research Hospital ALL Total Therapy XV protocol, standard risk arm. Results This study included 77 patients. T-cell LBL patients were 67, while 10 were of B-cell origin. The median age at diagnosis was 9years (95% CI: 7-10). The majority were males 54/77. Stage III patients were 51, stage IV 13, stage II 11 and stage I 2 patients. Two patients were excluded from analysis as they died before receiving chemotherapy. Complete remission post induction chemotherapy was seen in 22 patients considered early responders, and partial remission in 55 considered late responders. With a median follow up duration of 47months (95% CI: 38-56), the 4year overall survival and event free survival were 86.45% (95% CI: 73.78-94.09) and 82.18% (95% CI: 69.25-90.61) respectively. Twelve patients died during the study period; 2 early deaths before starting chemotherapy from disease progression, 2 in CR due to chemotherapy related toxicity and 8 from disease progression. All the relapsed patients were T-cell, had advanced disease at presentation (6 with stage III; 2 with stage IV). Two patients (2.6%) had isolated local, BM, and CNS relapse each, while 1 (1.3%) had both local and CNS relapse. Disease recurrence was local in 3 patients (3.9%), and systemic in 5 (6.4%), while it was early in 6 (7.8%), and late in 2 (2.6%) patients. Median time to disease progression was 20months (range 5-39months). All relapsed patients did not survive salvage chemotherapy. The most common chemotherapy toxicities were cerebral venous thrombosis (20%), followed by bone infarcts (10.6%), and avascular necrosis (AVN) of head of femur (9.3%). One patient developed secondary acute myeloid leukemia after 3years of FU with unfavorable cytogenetic abnormalities. Conclusion Results of treatment of LBL on the St Jude's total therapy XV study are comparable to most of the similar reported studies. Outcome of relapsing patients is extremely poor, hence there is a need to identify biologic or clinical prognostic factors including minimal residual tumor to better evaluate chemotherapy response. Steroid induced AVN, and cerebral vascular thrombosis were the main chemotherapeutic adverse events.

Fulminant hepatic failure with virtually undetectable serum alkaline phosphatase.

Wilson's disease presenting as fulminant hepatic failure is a rare presentation that carries a high morbidity and mortality. We report a young patient who developed fulminant hepatic failure as the initial manifestation of Wilson's disease. Virtually undetectable serum alkaline phosphatase provided the first clue to the diagnosis. Our patient underwent a successful liver transplantation which is the only effective treatment in patients with Wilsonian fulminant hepatic failure. In this report, we discuss laboratory clues to the diagnosis of this form of Wilson's disease. Clinicians should have a high suspicion of Wilson's disease as any delay in diagnosis can be catastrophic.

Early use of hemodialysis for active rewarming in severe hypothermia: a case report and review of literature.

Deep accidental hypothermia (body temperature below 28°C) is rare. Even with modern supportive care of active external and internal rewarming techniques it is associated with a high mortality rate. We report the early and successful use of hemodialysis (HD) for active rewarming of a middle-aged alcoholic man with severe deep accidental hypothermia after failure of initial efforts of rewarming using conventional strategies. This case report and review of the literature highlights the advantages and the challenges of using HD in this setting and suggests a potential role for HD in the routine management of severe hypothermia in the absence of circulatory arrest.

Autonomic dysfunction as a delayed sequelae of acute ethylene glycol ingestion : a case report and review of the literature.

Ethylene glycol poisoning is a common form of poisoning worldwide. The clinical course of ethylene glycol poisoning usually follows a three-stage progression, although these stages may overlap. A fourth stage of delayed neurological dysfunction consisting of cranial neuropathies has been suggested in several case reports. We describe a patient with unique findings of postural hypotension and gastroparesis following ethylene glycol toxicity with the additional uncommon features of albuminocytologic dissociation and increased intracranial pressure with papilledema. In addition, we provide a review of the literature on delayed neurological manifestations in ethylene glycol toxicity and further elucidate a description of a fourth stage of delayed neurological dysfunction following ethylene glycol poisoning.

Preparation and comparative evaluation of sustained release metoclopramide hydrochloride matrix tablets.

Metoclopramide hydrochloride (MCP) is commonly used for the management of gastrointestinal disorders. Frequent administration and the undesired side effects (extra pyramidal symptoms) of the drug on the central nervous system due to the fluctuations of its plasma concentrations may lead to patient incompliance, and hence, improper therapy. Therefore, the present work will be devoted to formulate the drug in sustained release formulations. MCP was incorporated in 12 formulae containing different polymers and/or different polymer ratios. These polymers were hydroxypropylmethyl cellulose (HPMC), carboxymethylcellulose (CMC) and ethyl cellulose (EC). Sodium starch glycolate (SSG) was added to some formulae in different amounts in order to soften and/or disintegrate the tablets. Both direct compression and granulation techniques were used to prepare the tablets. The physical properties were found to be satisfactory for all the formulae. The dissolution profiles of the tablets were constructed using the change-over method. The drug release involved a combination of both diffusion and polymer-chain relaxation mechanisms. The time required to release 50% of MCP ranged from 1.2 to more than 8 h. Direct compression and dry granulation techniques produced sufficient sustaining of the drug release. However, the pellets made by wet granulation released MCP in about 2 h, i.e., pelletization spheronization technique was not effective in sustaining the drug.

Three-Dimensional Echocardiographic Assessment of Aortic Dissection.

In the present study, we report our experience of using three-dimensional reconstruction of transesophageal two-dimensional echocardiographic images in the assessment of aortic dissection (22 patients), aortic rupture (1 patient), aortic aneurysm without dissection (2 patients), and aortic tumor (1 patient).

Transesophageal Three-Dimensional Echocardiographic Assessment of Normal and Stenosed Coronary Arteries.

We describe our preliminary experience in assessing normal and stenosed coronary arteries using transesophageal three-dimensional echocardiography (3-D echo) in 27 adult patients. Multiplane transesophageal two-dimensional images of the coronary arteries (20 left, 3 right, 3 both left and right, and 1 posterior descending) were first acquired in the TomTec computer in 3 degrees sequential increments, from 0 degrees to 180 degrees, and then 3-D reconstruction was performed. The entire left main (LMC, measuring 0.5 to 1.7 cm, mean 1.0 cm) as well as variable lengths of proximal or both proximal and middle segments of the left anterior descending (LAD, measuring 0.2 to 2.5 cm, mean 0.8 cm) and circumflex (LCX, measuring 0.2 to 2.8 cm, mean 0.9 cm) coronary arteries together with some of their branches could be visualized in 3-D in 22 of 23 patients. In the remaining patient, the LMC was absent, and both LAD and LCX could be visualized in 3-D as having separate but adjacent origins from the left sinus of Valsalva (proven by angiography). In two patients, long segments of interventricular and great cardiac veins were also visualized accompanying the LAD and LCX, respectively. The right coronary artery (RCA, measuring 0.7 to 3.0 cm, mean 1.9 cm) was also successfully delineated in 3-D in all six patients in whom an attempt was made to visualize it during echo examination. Using the transgastric approach, a long (1.8 cm) segment of the posterior descending branch (PDA) of RCA was imaged in one patient. In addition, nine significantly stenotic lesions (>50% lumen diameter) were identified by 3-D in eight patients involving LMC (1), proximal LAD (1), mid LAD (1), proximal LCX (2), proximal RCA (3), and mid PDA (1). Eight of these 9 lesions were confirmed by coronary angiography. The remaining lesion (mid PDA) could not be confirmed since the patient did not undergo angiography. Our preliminary study demonstrates the usefulness of transesophageal 3-D echo not only in delineating normal coronary arteries but also diagnosing significant atherosclerotic stenosis in these vessels. (ECHOCARDIOGRAPHY, Volume 13, September 1996)