Ilimaquinone (marine sponge metabolite) as a novel inhibitor of SARS-CoV-2 key target proteins in comparison with suggested COVID-19 drugs: designing,docking and molecular dynamics simulation study

The outbreak of novel coronavirus, SARS-CoV-2, has infected more than 36 million people and caused approximately 1 million deaths around the globe as of 9 October 2020. The escalating outspread of the virus and rapid rise in the number of cases require the instantaneous development of effectual drugs and vaccines. Presently, there are no approved drugs or vaccine available to treat the infection. In such scenario, one of the propitious therapeutic approaches against viral infection is to explore enzyme inhibitors amidst natural compounds, utilizing computational approaches aiming to get products with negligible side effects. In the present study, the inhibitory prospects of ilimaquinone (marine sponge metabolite) were assessed in comparison with hydroxychloroquine, azithromycin, favipiravir, ivermectin and remdesivir at the active binding pockets of nine different vital SARS-CoV-2 target proteins (spike receptor binding domain, RNA-dependent RNA polymerase, Nsp10, Nsp13, Nsp14, Nsp15, Nsp16, main protease, and papain-like-protease), employing an in silico molecular interaction based approach. In addition, molecular dynamics (MD) simulations of the SARS-CoV-2 papain-like protease (PLpro)–ilimaquinone complex were also carried out to calculate various structural parameters including root mean square fluctuation (RMSF), root mean square deviation (RMSD), radius of gyration (R_g) and hydrogen bond interactions. PLpro is a promising drug target, due to its imperative role in viral replication and additional function of stripping ubiquitin and interferon-stimulated gene 15 (ISG15) from host-cell proteins. In light of the possible inhibition of all vital SARS-CoV-2 target proteins, our study has emphasized the importance to study in depth ilimaquinone actions in vivo.

Inhibitory potential of ilimaquinone (marine sponge metabolite) against nine essential SARS-CoV-2 target proteins, employing a molecular interaction and dynamics simulation approach.     

Design and formulation of polymeric nanosponge tablets with enhanced solubility for combination therapy

Three drugs namely caffeine, paracetamol, and aceclofenac are commonly used for treating various acute and chronic pain related ailments. These 3 drugs have varied solubility profiles, and formulating them into a single tablet did not have the desired dissolution profile for drug absorption. The objective of the present research was to tailor the drug release profile by altering drug solubility. This was achieved by loading the drug into nanosponges. Here, three-dimensional colloidal nanosponges were prepared using β-cyclodextrin with dimethyl carbonate as a cross-linker using the hot-melt compression method. The prepared nanosponges were characterized by FTIR, ¹H NMR spectroscopy, DSC, XRPD studies and SEM. The FTIR and DSC results obtained indicated polymer-drug compatibility. The ¹H NMR spectroscopy results obtained indicated the drug entrapment within nanosponges with the formation of the inclusion complex. XRPD studies showed that the loaded drug had changed crystalline properties altering drug solubility. SEM photographs revealed the porous and spongy texture on the surface of the nanosponge. Box–Behnken experimental design was adopted for the optimization of nanosponge synthesis. Among the synthesized nanosponges containing paracetamol, aceclofenac and caffeine, batch F3–P31, F3–A31 and F3–C31 were considered optimized. Their particle size was 185, 181 and 199 nm with an entrapment efficiency of 81.53, 84.96, and 89.28% respectively. These optimized nanosponges were directly compressed into tablets and were studied for both pre and post-compression properties including in vitro drug release. The prepared tablet showed desired drug dissolution properties compared to the pure drug. The above outcomes indicated the applicability of nanosponges in modulating the drug release with varied solubility for combination therapy.

Polymeric nanosponges as potential carriers for successful combination therapy of poorly soluble drugs (paracetamol, aceclofenac, caffeine).     

Accuracy of conventional digital palpation and ultrasound of the cricothyroid membrane in obese women in labour

Success of cricothyroidotomy depends on accurate identification of anatomical neck landmarks. Anaesthetists palpated the cricothyroid membrane of 28 obese and 28 non‐obese women in labour (cut‐off BMI 30 kg.m^?2) and marked the entry point for device insertion with an ultraviolet invisible pen. Ultrasonography was used to mark the midpoint of the cricothyroid membrane and the distance between the two marks was measured. The median (IQR [range]) distance between the two marks was significantly greater in the obese than the non‐obese patients (5 (2–9.5 [0–34]) mm vs 1.8 (0.1–6 [0–15]) mm, respectively; p = 0.02). The cricothyroid membrane was accurately identified with digital palpation in only 39% (11/28) of obese compared with 71% (20/28) of non‐obese patients (p = 0.03). Increased neck circumference in obese patients was significantly associated with inaccuracy in locating the cricothyroid membrane. Percutaneous identification of the cricothyroid membrane in obese women in labour was poor. Pre‐procedural ultrasound may help improved the identification of neck landmarks for cricothyroidotomy.     

End of life in the intensive care unit: knowledge and practice of clinicians from Karachi, Pakistan

Background:  With improvements in the care of critically ill, physicians are faced with obligations to provide quality end-of-life care. Barriers to this include inadequate understanding of the dying patient and withdrawal or limitation of care. The objectives of this study were to document the comprehensions of physicians and nurses regarding the recognition and practice of end-of-life care for critically ill patients placed on life support in the intensive care unit.
Methods:  This was a cross-sectional study carried out at three hospitals in Karachi. Chi-squared analysis and one-way anova were used to compare differences in response between the groups.
Results:  One hundred and thirty-seven physicians and critical care nurses completed the survey. 'Brain death' was defined as an ' irreversible cessation of brainstem function' by 85% respondents, with 50% relying on specialty consultation. Withdrawal of life support is practised by 83.2%; physicians are more likely (Chi square test P -value < 0.001) to withdraw mechanical ventilation, compared with nurses who would withdraw vasopressors ( P -value 0.006). In a do not resuscitate patient, 72.3% use vasopressors, 83% initiate haemodialysis and 17.5% use non-invasive ventilation; 72.6% consult Hospital Ethics Committees; 16% respondents never withdraw life support; 28.3% considered it their responsibility to 'sustain life at all costs' and only 8% gave religious beliefs as a reason.
Conclusions:  There are confusions in the definition of brain death, end-of-life recognition and indications and processes of withdrawal of life support. There are discrepancies between physicians' and nurses' perceptions and attitudes. Clearly, teaching programmes will need to incorporate cultural and religious differences in their ethics curricula.     

Inferior glenohumeral joint dislocation with greater tuberosity avulsion

Inferior glenohumeral dislocation is the least common type of glenohumeral dislocations. It may be associated with fractures of the adjacent bones and neurovascular compromise. It should be treated immediately by close reduction. The associated neuropraxia usually recovers with time. Traction-counter traction method is commonly used for reduction followed by immobilization of the shoulder for three weeks. Here, we report a case of inferior glenohumeral joint dislocation with greater tuberosity fracture with transient neurovascular compromise and present a brief review of the literature.     

Photochemotherapeutic Strategy against Acanthamoeba Infections

Acanthamoeba is a protist pathogen that can cause serious human infections, including blinding keratitis and a granulomatous amoebic encephalitis that almost always results in death. The current treatment for these infections includes a mixture of drugs, and even then, a recurrence can occur. Photochemotherapy has shown promise in the treatment of Acanthamoeba infections; however, the selective targeting of pathogenic Acanthamoeba has remained a major concern. The mannose-binding protein is an important adhesin expressed on the surface membranes of pathogenic Acanthamoeba organisms. To specifically target Acanthamoeba, the overall aim of this study was to synthesize a photosensitizing compound (porphyrin) conjugated with mannose and test its efficacy in vitro. The synthesis of mannose-conjugated porphyrin was achieved by mixing benzaldehyde and pyrrole, yielding tetraphenylporphyrin. Tetraphenylporphyrin was then converted into mono-nitrophenylporphyrin by selectively nitrating the para position of the phenyl rings, as confirmed by nuclear magnetic resonance (NMR) spectroscopy. The mono-nitrophenylporphyrin was reduced to mono-aminophenylporphyrin in the presence of tin dichloride and confirmed by a peak at m/z 629. Finally, mono-aminoporphyrin was conjugated with mannose, resulting in the formation of an imine bond. Mannose-conjugated porphyrin was confirmed through spectroscopic analysis and showed that it absorbed light of wavelengths ranging from 425 to 475 nm. To determine the antiacanthamoebic effects of the derived product, amoebae were incubated with mannose-conjugated porphyrin for 1 h and washed 3 times to remove extracellular compound. Next, the amoebae were exposed to light of the appropriate wavelength for 1 h. The results revealed that mannose-conjugated porphyrin produced potent trophicidal effects and blocked excystation. In contrast, Acanthamoeba castellanii incubated with mannose alone and porphyrin alone did not exhibit an antiamoebic effect. Consistently, pretreatment with mannose-conjugated porphyrin reduced the A. castellanii-mediated host cell cytotoxicity from 97% to 4.9%. In contrast, treatment with porphyrin, mannose, or solvent alone had no protective effects on the host cells. These data suggest that mannose-conjugated porphyrin has application for the targeted photodynamic therapy of Acanthamoeba infections and may serve as a model in the development of therapeutic interventions against other eukaryotic infections.