Computational medicinal chemistry role in clinical pharmacy education: Ingavirin for coronavirus disease 2019 (COVID-19) discovery model

Objective: Given the major shift to patient-directed education, novel coronavirus (nCoV) provides a live example on how medicinal chemistry could be a key science to teach pharmacy students. In this paper, students and clinical pharmacy practitioners will find a stepwise primer on identifying new potential nCoV treatments mechanistically modulated through angiotensin-converting enzyme 2 (ACE2). Methods: First, we identified the maximum common pharmacophore between carnosine and melatonin as background ACE2 inhibitors. Second, we performed a similarity search to spot out structures containing the pharmacophore. Third, molinspiration bioactivity scoring enabled us to promote one of the newly identified molecules as the best next candidate for nCoV. Preliminary docking in SwissDock and visualization through University of California San Francisco (UCSF) chimera made it possible to qualify one of them for further detailed docking and experimental validation. Results: Ingavirin had the best docking results with full fitness of −3347.15 kcal/mol and estimated ΔG of −8.53 kcal/mol compared with melatonin (−6.57 kcal/mol) and carnosine (−6.29 kcal/mol). UCSF chimera showed viral spike protein elements binding to ACE2 retained in the best ingavirin pose in SwissDock at 1.75 Angstroms. Conclusion: Ingavirin has a promising inhibitory potential to host (ACE2 and nCoV spike protein) recognition, and hence could offer the next best mitigating effect against the current coronavirus disease (COVID-19) pandemic. (AU)

Computational medicinal chemistry role in clinical pharmacy education: Ingavirin for coronavirus disease 2019 (COVID-19) discovery model.

Objective: Given the major shift to patient-directed education, novel coronavirus (nCoV) provides a live example on how medicinal chemistry could be a key science to teach pharmacy students. In this paper, students and clinical pharmacy practitioners will find a stepwise primer on identifying new potential nCoV treatments mechanistically modulated through angiotensin-converting enzyme 2 (ACE2). Methods: First, we identified the maximum common pharmacophore between carnosine and melatonin as background ACE2 inhibitors. Second, we performed a similarity search to spot out structures containing the pharmacophore. Third, molinspiration bioactivity scoring enabled us to promote one of the newly identified molecules as the best next candidate for nCoV. Preliminary docking in SwissDock and visualization through University of California San Francisco (UCSF) chimera made it possible to qualify one of them for further detailed docking and experimental validation. Results: Ingavirin had the best docking results with full fitness of -3347.15 kcal/mol and estimated ΔG of -8.53 kcal/mol compared with melatonin (-6.57 kcal/mol) and carnosine (-6.29 kcal/mol). UCSF chimera showed viral spike protein elements binding to ACE2 retained in the best ingavirin pose in SwissDock at 1.75 Angstroms. Conclusion: Ingavirin has a promising inhibitory potential to host (ACE2 and nCoV spike protein) recognition, and hence could offer the next best mitigating effect against the current coronavirus disease (COVID-19) pandemic.

Maximizing acceptance of clinical pharmacy recommendations to reduce length of hospital stay in a private hospital from Amman, Jordan.

BACKGROUND: Clinical pharmacy interventions (CPI) usually require prior medical authorization. Physicians approve 80% of CPI and reject 20%. If pharmacists show that physicians should authorize all 100% CPI, the profession will step closer to a fully independent prescriber status. This study used an artificial neural network (ANN) model to determine whether clinical pharmacy (CP) may improve outcomes associated with rejected CPI. METHOD: This is a non-interventional, retrospective analysis of documented CPI in a 100-bed, acute-care private hospital in Amman, Jordan. Study consisted of 542 patients, 574 admissions, and 1694 CPI. Team collected demographic and clinical data using a standardized tool. Input consisted of 54 variables with some taking merely repetitive values for each CPI in each patient whereas others varying with every CPI. Therefore, CPI was consolidated to one rejected and/or one accepted per patient per admission. Groups of accepted and rejected CPI were compared in terms of matched and unmatched variables. ANN were, subsequently, trained and internally as well as cross validated for outcomes of interest. Outcomes were length of hospital and intensive care stay after the index CPI (LOSTA & LOSICUA, respectively), readmissions, mortality, and cost of hospitalization. Best models were finally used to compare the two scenarios of approving 80% versus 100% of CPI. Variable impacts (VI) automatically generated by the ANN were compared to evaluate the effect of rejecting CPI. Main outcome measure was Lengths of hospital stay after the index CPI (LOSTA). RESULTS: ANN configurations converged within 18 s and 300 trials. All models showed a significant reduction in LOSTA with 100% versus 80% accepted CPI of about 0.4 days (2.6 ± 3.4, median (range) of 2 (0-28) versus 3.0 ± 3.8, 2 (0-30), P-value = 0.022). Average savings with acceptance of those rejected CPI was 55 JD (~ 78 US dollars) and could help hire about 1.3 extra clinical pharmacist full-time equivalents. CONCLUSIONS: Maximizing acceptance of CPI reduced the length of hospital stay in this model. Practicing Clinical Pharmacists may qualify for further privileges including promotion to a fully independent prescriber status.

Carnosine to Combat Novel Coronavirus (nCoV): Molecular Docking and Modeling to Cocrystallized Host Angiotensin-Converting Enzyme 2 (ACE2) and Viral Spike Protein.

AIMS: Angiotensin-converting enzyme 2 (ACE2) plays an important role in the entry of coronaviruses into host cells. The current paper described how carnosine, a naturally occurring supplement, can be an effective drug candidate for coronavirus disease (COVID-19) on the basis of molecular docking and modeling to host ACE2 cocrystallized with nCoV spike protein. METHODS: First, the starting point was ACE2 inhibitors and their structure-activity relationship (SAR). Next, chemical similarity (or diversity) and PubMed searches made it possible to repurpose and assess approved or experimental drugs for COVID-19. Parallel, at all stages, the authors performed bioactivity scoring to assess potential repurposed inhibitors at ACE2. Finally, investigators performed molecular docking and modeling of the identified drug candidate to host ACE2 with nCoV spike protein. RESULTS: Carnosine emerged as the best-known drug candidate to match ACE2 inhibitor structure. Preliminary docking was more optimal to ACE2 than the known typical angiotensin-converting enzyme 1 (ACE1) inhibitor (enalapril) and quite comparable to known or presumed ACE2 inhibitors. Viral spike protein elements binding to ACE2 were retained in the best carnosine pose in SwissDock at 1.75 Angstroms. Out of the three main areas of attachment expected to the protein-protein structure, carnosine bound with higher affinity to two compared to the known ACE2 active site. LibDock score was 92.40 for site 3, 90.88 for site 1, and inside the active site 85.49. CONCLUSION: Carnosine has promising inhibitory interactions with host ACE2 and nCoV spike protein and hence could offer a potential mitigating effect against the current COVID-19 pandemic.

Effectiveness of Liraglutide in Type II Diabetes Mellitus Management: Experience in Emirati Patients.

OBJECTIVE: To measure effectiveness of liraglutide in reducing glycated hemoglobin (HbA1C), weight, and systolic blood pressure (SBP) in Emirati patients. DESIGN: A retrospective cohort study. SETTING: Endocrinology clinic in a 300-bed military hospital. PATIENTS: A total of 152 patients who qualified for liraglutide between September 21, 2012, (first patient visit) and May 5, 2014 (last patient visit). METHODS: Team collected demographic and clinical data using a standard form. Data keeper performed univariate analyses to measure the effect of liraglutide in reducing the three outcomes of interest; namely, HbA1C, weight, and SBP. RESULTS: One hundred patients had at least the first visit in the clinic and 98 patients came for a second follow-up visit while on the medication. Adherence of clinicians to the internal criteria for prescribing liraglutide was 92%. Patients' ages were 47.9 ± 11.7 years. Male-to-female ratio was almost 1:1. Overall, in the paired analyses, HbA1C decreased from first to second visits (8.7 ± 1.9 vs. 7.6 ± 1.8, P > 0.0001) and remained unchanged in subsequent visits (eg, in visit 3, HbA1C was 7.4 ± 1.8). Patients lost an average of 1.3 kg between the first and second visits (99.3 ± 19.3 vs. 98.0 ± 19.5, P = 0.0003). The reduction in SBP between visits 1 and 2 was less (130.9 ± 15.8 vs. 129.9 ± 16.5, P = 0.5896). ANOVA yielded a significant reduction in HbA1C at 4 months and 6 months (P values < 0.05). SBP dropped by about 3.6 mmHg and weight by about 2.3 kg (P values > 0.05). CONCLUSIONS: Liraglutide is effective in reducing HbA1C, weight, and to a lesser extent, SBP in Emirati patients.

Palivizumab prophylaxis during nosocomial outbreaks of respiratory syncytial virus in a neonatal intensive care unit: predicting effectiveness with an artificial neural network model.

STUDY OBJECTIVE: To identify subgroups of premature infants who may benefit from palivizumab prophylaxis during nosocomial outbreaks of respiratory syncytial virus (RSV) infection. DESIGN: Retrospective analysis using an artificial intelligence model. SETTING: Level IIIB, 35-bed, neonatal intensive care unit (NICU) at a tertiary care hospital in the United Arab Emirates. PATIENTS: One hundred seventy six premature infants, born at a gestational age of 22-34 weeks, and hospitalized during four RSV outbreaks that occurred between April 2005 and July 2007. MEASUREMENTS AND MAIN RESULTS: We collected demographic and clinical data for each patient by using a standardized form. Input data consisted of seven categoric and continuous variables each. We trained, tested, and validated artificial neural networks for three outcomes of interest: mortality, days of supplemental oxygen, and length of NICU stay after the index case was identified. We compared variable impacts and performed reassignments with live predictions to evaluate the effect of palivizumab. Of the 176 infants, 31 (17.6%) received palivizumab during the outbreaks. All neural network configurations converged within 4 seconds in less than 400 training cycles. Infants who received palivizumab required supplemental oxygen for a shorter duration compared with controls (105.2 ± 7.2 days vs 113.2 ± 10.4 days, p=0.003). This benefit was statistically significant in male infants whose birth weight was less than 0.7 kg and who had hemodynamically significant congenital heart disease. Length of NICU stay after identification of the index case and mortality were independent of palivizumab use. CONCLUSION: Palivizumab may be an effective intervention during nosocomial outbreaks of RSV in a subgroup of extremely low-birth-weight male infants with hemodynamically significant congenital heart disease.

Management options of chronic low back pain. A randomized blinded clinical trial.

OBJECTIVE: To compare efficacies of 2 active programs in the management of chronic low back pain (CLBP). METHODS: This prospective, stratified, randomized single-blinded controlled study was conducted in the Department of Rehabilitation Medicine, King Abdullah University Hospital, Irbid, Jordan, between February and December 2010. A total of 100 patients were randomized to either 6-weeks of multidisciplinary rehabilitation (group A) or therapist-assisted exercise (group B). At baseline and 6 weeks, the visual analogue scale (VAS) pain score was estimated, as a primary outcome measure. McGill pain score, Oswestry Disability Index (ODI), trunk forward flexion and extension, left and right lateral bending, were applied before and after treatment and were employed as secondary outcome measures. RESULTS: All outcome measures significantly improved in group A after treatment, compared with group B. The VAS, McGill, ODI scores, left and right lateral bending decreased significantly, whereas forward and backward bending increased. A significant number of patients returned to work in group A at the end of 6 weeks, compared with group B. These effects were maintained over 12 and 24 weeks of follow-up. CONCLUSION: Multidisciplinary rehabilitation improved functional indices and pain scale scores in group A compared with B. This would be an effective strategy in CLBP management.

Homocystinemia and stroke in vegetarians.

Homocysteine is a sulfurated amino acid with a central role in the metabolism of thiol compounds. Homocystinemia is a recognized independent potentially remediable risk factor for vascular disease. It is associated with both macro and micro vascular ischemic stroke. It can often be normalized by polyvitamin therapy. This inexpensive and well-tolerated treatment is considered effective in decreasing the incidence of stroke. We report 2 young strict vegetarians with no known vascular risk factors. The first suffered a left middle cerebral artery infarct, and the second multiple bilateral small cerebral infarctions. Extensive investigations showed moderately elevated homocysteine and low serum B12 levels, suggesting that these are most probably the underlying etiology. We believe that a high index of suspicion is needed, particularly in younger people with a potential underlying cause for B12 deficiency and no identifiable stroke risk factor.

Autonomy and rehabilitation.

In minority world countries, autonomy is central to client focused rehabilitation, as it represents a prerequisite for effective participation in the process of rehabilitation. The diverse and dynamic paradoxes within the "autonomy paradigm" will ensure its safe application and survival in such communities. However, the strong family relationships and different cultural backgrounds of majority world countries motivate us to conclude that a "patient-family interactive deliberative process" based on accommodation and negotiation is more acceptable, reliable and implementable in these communities. Our suggested model of decision making is more convenient, particularly in cases where competency is compromised by cognitive dysfunction, political or religious restrictions. The insistence on absolute autonomy beyond such borders could be counter productive for both patients and health care personnel. Clearly, the need for further research is paramount, as a deeper understanding of the various cultures and subcultures is essential for developing a more useful structural framework for rehabilitation.