Novel Drug Design for Treatment of COVID-19: A Systematic Review of Preclinical Studies.

Background: Since the beginning of the novel coronavirus (SARS-CoV-2) disease outbreak, there has been an increasing interest in discovering potential therapeutic agents for this disease. In this regard, we conducted a systematic review through an overview of drug development (in silico, in vitro, and in vivo) for treating COVID-19. Methods: A systematic search was carried out in major databases including PubMed, Web of Science, Scopus, EMBASE, and Google Scholar from December 2019 to March 2021. A combination of the following terms was used: coronavirus, COVID-19, SARS-CoV-2, drug design, drug development, In silico, In vitro, and In vivo. A narrative synthesis was performed as a qualitative method for the data synthesis of each outcome measure. Results: A total of 2168 articles were identified through searching databases. Finally, 315 studies (266 in silico, 34 in vitro, and 15 in vivo) were included. In studies with in silico approach, 98 article study repurposed drug and 91 studies evaluated herbal medicine on COVID-19. Among 260 drugs repurposed by the computational method, the best results were observed with saquinavir (n = 9), ritonavir (n = 8), and lopinavir (n = 6). Main protease (n = 154) following spike glycoprotein (n = 62) and other nonstructural protein of virus (n = 45) was among the most studied targets. Doxycycline, chlorpromazine, azithromycin, heparin, bepridil, and glycyrrhizic acid showed both in silico and in vitro inhibitory effects against SARS-CoV-2. Conclusion: The preclinical studies of novel drug design for COVID-19 focused on main protease and spike glycoprotein as targets for antiviral development. From evaluated structures, saquinavir, ritonavir, eucalyptus, Tinospora cordifolia, aloe, green tea, curcumin, pyrazole, and triazole derivatives in in silico studies and doxycycline, chlorpromazine, and heparin from in vitro and human monoclonal antibodies from in vivo studies showed promised results regarding efficacy. It seems that due to the nature of COVID-19 disease, finding some drugs with multitarget antiviral actions and anti-inflammatory potential is valuable and some herbal medicines have this potential.

Addition of Valerian and Lemon Balm Extract to Quetiapine Reduces Agitation in Critically Ill Patients with Delirium: A Pilot Randomized Clinical Trial.

BACKGROUND: This study was pointed to evaluate the efficacy and safety of valerian and lemon balm additional to the quetiapine in critically ill patients with delirium and agitation. METHODS: We conducted a randomized, double-blind, placebo-controlled study. Fifty-three adult intensive care unit (ICU) patients (according to ICU Confusion Assessment Method scores) who were treated for delirium received quetiapine and Neurogol syrup (a combination of valerian and lemon balm) or placebo 5 mL every 12 hours for five consecutive days. Improvement in agitation according to the Richmond Sedation and Restlessness Scale was considered the main outcome. RESULTS: The trial was completed for 53 patients (27 in the treatment group and 26 in the placebo group). The baseline characteristics between the groups were similar. In the treatment group, the number of agitated patients was significantly reduced and the difference was statistically significant (p = 0.000). Compared with the placebo group, the length of ICU stay in the treatment group was significantly reduced (p = 0.001). The Glasgow Coma Scale improved significantly at the end of day 5 (p = 0.04). There was no statistical difference in the improvement of delirium between the study groups (p = 0.14). Neurogol syrup was well tolerated. CONCLUSION: The addition of Neurogol to quetiapine (a combination of valerian and lemon balm) can reduce agitation and shorten the length of stay in the ICU without adverse effects. Clearly, more research is still needed to investigate the role of herbal medicines in ICUs and their efficacy and safety. HOW TO CITE THIS ARTICLE: Alikiaie B, Shahmoradi E, Yekdaneh A, Mousavi S. Addition of Valerian and Lemon Balm Extract to Quetiapine Reduces Agitation in Critically Ill Patients with Delirium: A Pilot Randomized Clinical Trial. Indian J Crit Care Med 2021;25(7):785-790.

Vasopressin in Septic Shock; Assessment of Sepsis Biomarkers: A Randomized, Controlled Trial.

BACKGROUND AND AIMS: Vasopressin (VP) in sepsis apart from vasoconstrictive effect may have some immunomodulatory effects. The aim of this study was to evaluate the effect of VP on different aspect of sepsis by measuring of sepsis biomarkers. MATERIALS AND METHODS: In this trial, a total number of 42 septic shock patients were included. The first group received norepinephrine (NE) infusion to reach the target mean arterial pressure (MAP) of ≥ 65 mm Hg and the second group received arginine vasopressin (AVP) infusion in addition to NE. Serum lactate, C-reactive protein (CRP), interleukin-6 (IL-6), IL-10, pentraxin 3 (PTX3), angiopoietin 1 and 2 (Ang 1 and 2) levels were assessed. RESULTS: Level of IL-6 and IL-10 decreased, but there was no significant difference between the two groups after 48 h. CRP and PTX3 levels were not also significantly different between groups. Although Angs were not statistically different, there was a trend toward higher Ang-1 in and lower Ang 2 in AVP group after 24 and 48 h. In addition, lactate level did not differ between NE and AVP groups. There was no interaction between VP and hydrocortisone use on IL-6, IL-10, and PTX3, but a significant statistical interaction on Ang 1 and Ang 2 were observed. CONCLUSIONS: Although analysis of sepsis biomarkers showed no significant difference between two groups, no immunomodulatory effect for VP alone, subgroup analysis of hydrocortisone used in this study showed that the combination of glucocorticoids and AVP had a significant effect on Angs level which eventually causes less endothelial permeability and higher MAP in this group of patients.

A Pilot Study of Nebulized Heparin for Prevention of Ventilator Induced Lung Injury: Comparative Effects with an Inhaled Corticosteroid.

BACKGROUND: Ventilator-induced lung injury (VILI) is a side effect of mechanical ventilation. Lung inflammation and pulmonary activation of coagulation are induced by mechanical stress. Clinical and preclinical studies show that heparin possesses anti-inflammatory properties. Therefore, we assessed the effects of nebulized heparin in VILI. METHODS: Sixty critically ill adult patients who require mechanical ventilation for more than 48 h were included in this prospective, nonrandomized controlled study. Patients received nebulized heparin (10,000 U every 6 h) for 5 days. The matched control group received nebulized budesonide as routine practice in our center. This study assessed changes in partial pressure of oxygen to inspired fraction of oxygen ratio (PaO2/FiO2) and rapid shallow breathing index (RSBI) during the study as primary endpoints. RESULTS: The average daily PaO2/FiO2 ratio was not statistically significant between both groups (187 ± 11.6 vs. 171 ± 11.6, P = 0.35). The RSBI also did not differ between groups (P = 0.58). Heparin administration was associated with a higher number of ventilator-free days among survivors but not significantly (7.7 ± 10.6 vs. 5.1 ± 8, 95% confidence interval - 2.2-7.5, P = 0.28). Successful weaning from mechanical ventilation was higher in the heparin group (P = 0.42). We did not observe any serious or increased adverse effects from nebulized heparin. CONCLUSION: The results of this study show that the overall effectiveness of nebulized heparin is at least as comparable with a potent corticosteroid (budesonide). Heparin could be a safe and effective modality for patients who at risk of VILI.

Pro-inflammatory cytokine profile of critically ill septic patients following therapeutic plasma exchange.

UNLABELLED: Severe sepsis involves a generalized inflammatory response, mediated by a number of various cytokines and factors. Plasma exchange (PE) has been proposed as a therapeutic approach to improve survival of patients with severe sepsis and septic shock. The theory is that removing harmful excessive endogenous inflammatory mediators is beneficial. Upon establishment of a diagnosis of severe sepsis, twelve patients received PE plus conventional sepsis treatment. Interleukin (IL)-6, IL-1ß and tumor necrosis factor (TNF)-α were assayed before and after each session of PE. RESULTS: There were no significant changes in cytokine plasma levels after each PE session compared to pre-procedure levels. Among measured pro-inflammatory cytokines, only the plasma levels of IL-6 before the 2nd and 3rd PE sessions were lower than baseline levels (p=0.011 and p=0.012, respectively). All patients tolerated PE therapy well without any adverse effects or homodynamic instability. The results of this study showed that PE does not have a direct and rapid effect on plasma level of TNF-α, IL-1ß and IL-6.

Comparison of silver nylon wound dressing and silver sulfadiazine in partial burn wound therapy.

The study aims to perform a comparative assessment of two types of burn wound treatment. To do the assessment, patients with partial thickness burn wounds with total body surface area <40% were simple randomised to treat with nanocrystalline silver nylon wound dressing or silver sulfadiazine cream. Efficacy of treatment, use of analgesics, number of wound dressing change, wound infection and final hospitalisation cost were evaluated. The study showed silver nylon wound dressing significantly reduced length of hospital stay, analgesic use, wound infection and inflammation compared with silver sulfadiazine.

Evaluation of outpatient prescription patterns of COVID-19 drugs in Iran: comparison of real practice with local therapeutic recommendations.

BACKGROUND: A comprehensive guideline named "Diagnostic Therapeutic Flow Chart for Covid-19″ (DTFC) was released by the Scientific Committee of Covid-19 of Iran's Ministry of Health and Medical Education and regularly was updated. The aim of this study was to compare the prescription pattern of drug treatment in outpatient Covid-19 patients with the DTFC. METHODS: A cross-sectional study was conducted on the prescription pattern of drugs given to outpatients with a diagnosis of Covid-19, in Isfahan City from June to September 2021 (concurrent with the fifth peak of Covid-19 in Iran) taking into account the recommendations of the 9th version of DTFC (December 2020). A total of 8250 prescriptions were retrieved from the Public Health Department of Isfahan City. RESULTS: Famotidine 20, 40 mg tablets (N = 936 patients) was the most prescribed drug followed by dexamethasone ampule (N = 588), prednisolone 5, 50 mg tablets (N = 478), azithromycin 250, 500 mg capsules (N = 452), diphenhydramine syrup (N = 362), vitamin D3 soft gel 50,000 Iu (N = 526), naproxen 250, 500 mg tablets (N = 266) and favipiravir 200 mg tablet (N = 191). The following drugs were administered against the recommendation of the DTFC-9: azithromycin, favipiravir, remdesivir, cetirizine, corticosteroids, vitamin C, vitamin B12, multivitamins, proton pump inhibitors (e.g., omperazole, anticoagulants (rivaroxaban,….), aspirin and ivermectin. Administration of analgesics, famotidine, hydroxychloroquine, vitamin D3, diphenhydramine and statins were in concordance with the DTFC-9. CONCLUSION: In this study, we showed frequent use of drugs with unproven efficacy in outpatient cases of Covid-19 mostly attributed to corticosteroids and antibiotics use. Our research highlights the discrepancy between recommendations for care and clinical practice and the need for strategy to bridge gaps in evidence-based informed decision-making.

Efficacy of Licorice as Adjunctive Therapy in Critically Ill Patients with COVID-19: A Randomized, Placebo-Controlled, Double-Blind Clinical Trial.

Objective: There is no definitive pharmacological strategy for COVID-19; thus, medicinal herbs can be an appropriate option for COVID-19 management. We investigated the efficacy of a D-reglis® tablet (root extract of licorice) as adjuvant therapy in critically ill patients with COVID-19 at intensive care units (ICUs) of Alzahra Teaching Hospital affiliated with Isfahan University of Medical Sciences, Isfahan, Iran. Methods: In the present double-blind, randomized, placebo-controlled clinical trial, critically ill cases with COVID-19 (n = 52) received a D-reglis® tablet (760 mg) or a placebo tablet for 5 days. The ICU stay length was the primary outcome. The secondary outcome included the changes in oxygen saturation, duration of mechanical ventilation, mortality rate, and Sequential Organ Failure Assessment (SOFA) Score during the study period. Findings: The ICU stay was significantly lower in the licorice group than in the placebo group (P = 0.015). No significant difference was detected between the groups regarding oxygen saturation, SOFA score, duration of mechanical ventilation, and mortality rate. Conclusion: The licorice tablet (D-reglis®) as an adjuvant treatment showed promising results regarding the ICU stay length in critically ill COVID-19 patients. However, further clinical trials with larger sample sizes, further duration of intervention, measurement of inflammatory markers, and further study about the molecular mechanism of the effect of licorice on COVID-19 should be done to obtain more conclusive findings.

Randomized trial of the effect of intravenous paracetamol on inflammatory biomarkers and outcome in febrile critically ill adults.

BACKGROUND AND THE PURPOSE OF THE STUDY: The febrile reaction is a complex response involving immunologic and other physiologic systems. Antipyretics are commonly used in critically ill patients with fever. We investigated the inflammatory responses following application of antipyretic therapy in febrile critically ill patients with Systemic Inflammatory Response Syndrome (SIRS). PATIENTS AND METHODS: In a prospective, randomized controlled study, critically ill patients with fever (T ≥ 38.3°C), SIRS diagnosed within 24 hours of Intensive Care Unit (ICU) admission and Acute Physiology and Chronic Health Evaluation II (APACHE II) score ≥10 were randomized into two groups. Upon appearance of fever, one group received intravenous paracetamol 650 mg every 6 hours for 10 days and other group received no treatment unless temperature reached 40°C. Body temperature, Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sepsis-related Organ Failure Assessment (SOFA) scores, length of ICU stay, ICU mortality and infectious complications were recorded. Levels of Interleukin-1 alpha (IL-1α), IL-6, IL-10, Tumour Necrosis Factor alpha (TNFα) and High-Sensitive C-Reactive Protein (HS-CRP) were assessed at baseline and 2, 6 and 24 hours after intervention. RESULTS AND DISCUSSION: During a period of 15-month screening, 20 patients met the criteria and randomized to the control or paracetamol group. Body temperature decreased significantly in the paracetamol group (p = 0.004) and control group (p = 0.001) after 24 hours, but there was no significant difference between two groups at this time point (p = 0.649). Levels of IL-6 and IL-10 decreased significantly (p = 0.025 and p = 0.047, respectively) in the paracetamol group at 24 hours but this was not of statistical significance in control group. No patterns over time in each group or differences across two groups were found for HS-CRP, TNFα, and IL-1α (p > 0.05). There were no differences regarding ICU length of stay, mortality and infectious complications between both groups. CONCLUSION: These results suggest that antipyretic therapy may not be indicated in all ICU patients. Allowing fever to take its natural course does not appear to have detrimental effects on critically ill patients with SIRS and may avoid unnecessary expenses.

Positive effect of septimeb™ on mortality rate in severe sepsis: a novel non antibiotic strategy.

BACKGROUND: Septimeb is a new herbal-derived remedy, recently approved for its potential immunomodulatory effects. Regarding the key role of immune system in the pathogenesis of severe sepsis and lack of any standard treatment for improving survival of these patients; we evaluated the effect of Septimeb -as an adjutant to standard treatment-on inflammatory biomarkers and mortality rates in patients with severe sepsis. METHODS: In this multicenter, randomized, single-blind trial, we assigned patients with severe sepsis and Acute Physiology and Chronic Health Evaluation (APACHE II) score of more than 20 to receive standard treatment of severe sepsis (control group) or standard treatment plus Septimeb. This group was treated with Septimeb for 14 days then followed up for another14 days. APACHE score, Sequential Organ Failure Assessment (SOFA) and Simplified Acute Physiology Score (SAPS) were calculated daily. Blood samples were analyzed for interleukin 2 tumor necrosis factor-α, total antioxidant power, platelet growth factor and matrix metalloproteinase 2. RESULTS: A total of 29 patients underwent randomization (13 in control group and 16 in Septimeb group). There was significant difference between the Septimeb and control group in the 14 days mortality rate (18.8% vs. 53.85 respectively, P=0.048). Compared to control group, Septimeb was significantly effective in improving SAPS (P= 0.029), SOFA (P=0.003) and APACHE II (P=0.008) scores. Inflammatory biomarkers didn't change significantly between the two groups (P>0.05). CONCLUSION: Septimeb reduces mortality rates among patients with severe sepsis and it could be added as a safe adjutant to standard treatment of sepsis.

Targeting Mitochondrial and Brain Injury Markers in Acquired Brain Injuries: A Randomized, Double-Blind, Placebo-Controlled Study with Melatonin.

Purpose: Oxidative stress-induced mitochondrial damage is the main event in acquired brain injuries (ABI). This study aimed to evaluate the effects of melatonin, a mitochondria-targeted antioxidant, on mitochondrial and brain injury markers, and the clinical outcomes of patients with ABI. Methods: In this randomized controlled trial, intensive care unit (ICU) or neurology patients with ABI (n=60) received melatonin (21 mg/day) or placebo tablets, within the first 72 hours of injury onset for five days. As a primary endpoint, serum levels of malondialdehyde (MDA), S100B and C-reactive protein (CRP) were compared at baseline, and after five days' intervention. Secondary endpoints included assessment of Glasgow Coma Scale and Sequential Organ Failure Assessment (at the end of day 5), Rancho Los Amigos Revised Scale and modified Rankin Scale (at the end of month 3), the duration of mechanical ventilation, the lengths of ICU and hospital stays, and in-hospital and three-month mortality. Results: There were no significant effects of melatonin on the primary and secondary outcomes. However, the subgroup analysis showed a significant reduction in S100B in patients with non-traumatic brain injuries, receiving melatonin versus placebo (p: 0.016). Conclusion: This study showed that melatonin supplementation in the early phase of brain injury had no significant effects on the injury markers and clinical outcomes of patients with ABI. However, it reduced the level of S100B in the non-traumatic subgroup. Further larger-scale studies are needed to determine the effects of melatonin on the ABI and its subgroups.

Oxidative stress and mitochondrial dysfunction following traumatic brain injury: From mechanistic view to targeted therapeutic opportunities.

Traumatic brain injury (TBI) is one of the most prevalent causes of permanent physical and cognitive disabilities. TBI pathology results from primary insults and a multi-mechanistic biochemical process, termed as secondary brain injury. Currently, there are no pharmacological agents for definitive treatment of patients with TBI. This article is presented with the purpose of reviewing molecular mechanisms of TBI pathology, as well as potential strategies and agents against pathological pathways. In this review article, materials were obtained by searching PubMed, Scopus, Elsevier, Web of Science, and Google Scholar. This search was considered without time limitation. Evidence indicates that oxidative stress and mitochondrial dysfunction are two key mediators of the secondary injury cascade in TBI pathology. TBI-induced oxidative damage results in the structural and functional impairments of cellular and subcellular components, such as mitochondria. Impairments of mitochondrial electron transfer chain and mitochondrial membrane potential result in a vicious cycle of free radical formation and cell apoptosis. The results of some preclinical and clinical studies, evaluating mitochondria-targeted therapies, such as mitochondria-targeted antioxidants and compounds with pleiotropic effects after TBI, are promising. As a proposed strategy in recent years, mitochondria-targeted multipotential therapy is a new hope, waiting to be confirmed. Moreover, based on the available findings, biologics, such as stem cell-based therapy and transplantation of mitochondria are novel potential strategies for the treatment of TBI; however, more studies are needed to clearly confirm the safety and efficacy of these strategies.

Inhibitory effects of curcumin on aldose reductase and cyclooxygenase-2 enzymes.

Diabetes is very much known as a wide-spread disorder all around the world with serious complications for the diabetic patient. In order to reduce these complications, inhibition the activity of aldose reductase (AR) and cyclooxygenase-2 (COX-2) enzymes is a proposed pathway. Within this work potency of curcumin (CUR) for the proposed enzymatic inhibition has been performed by the in silico methodologies. The main purposes of this work; evaluating first, the effect of original CUR on each of AR and COX-2 enzymes; second, the best CUR derivative for the individual action; third, the best CUR derivative with common effect on both enzymes, the results have been analyzed. The results based on the scoring factors of 66 derivatives indicated that C60 could be seen specific for AR and C62 could be seen specific for COX-2 enzyme. Further analysis indicated that C19 could be considered as a ligand with common Rank for interactions with both enzymes. The quantitative EB results indicated that the strength of interacting ligand…target complexes of C19, C60 and C62 are stronger than original inhibitors of AR and COX-2 whereas this trend has not been seen for the complexes of original CUR. The qualitative representations of interacting counterparts revealed that he proposed ligands could interact with those important parts of enzymes, especially NADPH of AR besides proper amino acids of active site for both of AR and COX-2 enzymes. The in silico methodologies have been performed based on Density Functional Theory calculations and Molecular Docking simulations.Communicated by Ramaswamy H. Sarma.

Topical Lidocaine plus Diclofenac as a Local Anesthetic Agent in Central Venous Catheterization; a Randomized Controlled Clinical Trial.

INTRODUCTION: Various methods of analgesia can be used to reduce or prevent procedural pain in emergency department (ED). This study aimed to evaluate the effectiveness of topical lidocaine-diclofenac combination compared to lidocaine-prilocaine combination (Xyla-P) in reduction of the pain during central venous catheter (CVC) insertion. METHODS: In this randomized clinical trial, 100 adult patients requiring CVC insertion in the ED were enrolled. These patients were randomly divided into two groups. The site of CVC insertion was covered with 2 g of topical Xyla-P cream in the first group, and 2 g of topical lidocaine-diclofenac cream in the second group. The primary outcome was the pain during CVC implantation. The secondary outcomes were physician satisfaction and the incidence of side effects. RESULTS:  On the visual analog scale (VAS), the pain score during CVC insertion was significantly lower in the second group (p = 0.027). However, there was no difference in pain scores during lidocaine injection between the two groups (p = 0.386). Also, there was no significant difference in the rate of side effects between the two groups (p = 1.0). The physician's satisfaction with the first group was significantly lower than the second group (p = 0.042). CONCLUSION: Although the CVC insertion pain was significantly lower in patients who received the topical combination of Lidocaine plus Diclofenac, there was no clinically important difference between the two groups and both topical anesthetics were effective and safe in reducing pain intensity. Also, lidocaine-diclofenac combination cream was more cost-effective than Xyla-P cream.

The cost-effectiveness and cost-utility analysis of the use of enoxaparin compared with heparin for venous thromboembolism prophylaxis in medical inpatients in Iran.

BACKGROUND: Moderate to high risk medical inpatients are at increased risk of Venous Thromboembolism (VTE). The present study aims to investigate the cost-effectiveness and cost-utility of using Enoxaparin compared to Heparin in VTE prophylaxis in medical inpatients, from Iranian payer's perspective. METHODS: Decision tree modeling technique was used to evaluate cost-effectiveness and cost-utility of the compared interventions. The main considered outcomes were Life Years Gained (LYG) for Cost-Effectiveness Analysis (CEA) and Quality-Adjusted Life Years (QALY) for Cost-Utility Analysis (CUA). Costs and consequences of the interventions were evaluated for a three-month period and reported as Incremental Cost-Effectiveness Ratios (ICERs). One-way and Probabilistic Sensitivity Analysis (PSA) were conducted to evaluate the robustness of the model due to uncertainty in the input data. RESULTS: In base case scenario (i.e. public tariff), incremental cost was $10.32, and incremental QALY and incremental LYG were 0.0001 and 0.0002 per patients respectively. Base case ICERs were 60,376 USD/QALY and 71,077 USD/LYG per patient. The results of the sensitivity analysis showed the robustness of the model. CONCLUSION: As the estimated ICER per QALY is more than three times the reported Gross Domestic Product (GDP) per capita by world bank for Iran in 2017 ($5415), the use of Enoxaparin for VTE prophylaxis in medical in patients doesn't seem to be a cost-effective intervention compared to the use of Heparin in Iran.

Evaluation of Pain Assessment and Management in Critically Ill Intubated Patients in a Referral University Hospital in Iran.

OBJECTIVE: This study aims to evaluate current pain assessment and management in critically ill patients and to describe (1) pain management episode, according to the behavioral pain scale (BPS), and (2) the effectiveness of analgesics, according to the recommendation of guidelines. METHODS: In this cross-sectional study, a sample of 60 intubated critically ill patients was selected from the intensive care units (ICUs). A researcher evaluated the patient' pain severity using the BPS tool in patients receiving analgesics according to nurses' note. At each time of analgesic administration, the BPS score was recorded, and this process was repeated 72 h later. The appropriateness of pharmacological interventions was assessed according to the American College of Critical Care Medicine guideline. FINDINGS: The most prescribed analgesic was morphine sulfate (48.3%) followed by fentanyl (23.3%). 55% of analgesics on day 1 and 25% on day 3 were prescribed appropriately according to the guideline recommendation and BPS score. Morphine was the most effective drug (17 patients out of 29). Even though a BPS score was <5, 26 patients received analgesics. CONCLUSION: Quality of pain assessment and management in our setting is inappropriate and inadequate, which leads to over- or under-use of analgesics. The lack of an established pain protocol may contribute to this situation.

Potential Role of Bupropion Sustained Release for Cancer-Related Fatigue: a Double-Blind, Placebo-Controlled Study

Background: Cancer-related fatigue (CRF) is very common and can be experienced at all stages of disease and in survivors. CRF causes patients more distress than pain or nausea and vomiting. Different pharmacologic interventions have been evaluated for the management of CRF. The purpose of this study was to determine the efficacy of bupropion sustained release (SR) as a treatment for fatigue in patients with cancer. Methods: In this randomized, double-blind, placebo-controlled trial, patients with fatigue due to cancer were randomly assigned to either 150mg daily of bupropion SR or matching placebo. The primary endpoint was the changes in average daily fatigue from baseline to week 4 using the Functional Assessment of Chronic Illness-therapy- Fatigue (FACIT-F) questionnaire. Results: 40 patients were randomly assigned to treatment with bupropion SR or placebo (20 in each group). Analysis of covariance (ANCOVA) showed a significant improvement in fatigue and quality of life in the bupropion group compared to baseline (P=0.000). Secondary outcome, including depression, severity of fatigue and performance status didn't show significant difference between groups. Generally, bupropion SR was tolerated well. Conclusion: Four weeks of 150 mg bupropion SR improve fatigue significantly in cancer patients. Bupropion has potential as an effective and safe pharmaceutical agent for treating CRF.

Serum Cystatin C for Evaluation of Acute Kidney Injury in Adults Treated with Colistin.

OBJECTIVE: Recent studies have shown that serum cystatin C (Cys C) is a better marker for measuring the glomerular filtration rate and may rise more quickly with acute kidney injury (AKI). The purpose of this study was to evaluate the clinical application of serum Cys C to predict colistin-induced nephrotoxicity in comparison with serum creatinine (SCr). METHODS: Thirty-two adult patients with no history of acute or chronic kidney injury having been planned to receive intravenous colistin for an anticipated duration of at least 1 week for any indication were recruited. At baseline and 5 days after colistin treatment, serum Cys C as well as creatinine levels were measured. The incidence of colistin-induced acute renal failure was defined according to the AKIN criteria for SCr. Rise in concentration of Cys C by more than 10% from baseline considered as AKI. FINDINGS: Colistin-induced nephrotoxicity (defined as SCr ≥0.3 mg/dl) occurred in 6 patients (18.8%). A Cys C increase concentration ≥10% after 5 days of colistin treatment was detected in 15 patients (46.9%). There was a poor agreement between the presence and absence of any SCr-AKI and Cys C-AKI (κ = 0.28, P = 0.04). CONCLUSION: Serum Cys C is a better marker of renal function in early stages of AKI and predictive of persistent AKI on colistin treatment.

Potential drug-drug interactions among hospitalized patients in a developing country.

BACKGROUND: Drug-drug interactions (DDIs) may often lead to preventable adverse drug events and health damage. Particularly in hospitals, this might be an important factor as multiple drug therapies are common. The objective of this study was to identify the frequency and levels of potential DDIs in internal medicine wards in an Iranian university hospital. METHODS: A cross-sectional study was conducted by reviewing charts of 448 hospitalized patients in internal medicine wards of a teaching hospital, from November 2014 to May 2015. "Lexicomp drug interaction software" and Micromedex Drug-Reax system were used for screening the potential DDIs. The identified DDIs were categorized by level of severity. Logistic regression was applied to determine the odds ratio for specific risk factors of potential DDIs e.g., age, gender, hospital stay and number of medications. RESULTS: The mean age of patients was 61 years, the length of hospital stay for patients was 9 days and the number of drugs per patient was 9. Potential interactions were detected in 386 patients. The most common types of interactions were type C (78.6%), moderate (60.9%) and delayed onset (56.5%). There was a significant association of the occurrence of potential DDIs with seven or more numbers of prescribed medications (OR: 0.048, 95% CI:0.02-0.12, p<0.0001). CONCLUSION: The present study has recorded a high prevalence of potential DDIs in internal medicine wards. Patients with polypharmacy were at high risk for DDIs. Education, computerized prescribing systems, drug information, and pharmaceutical care are important measures that were recommended to minimize harm associated with DDIs.

An Audit of Perioperative Antimicrobial Prophylaxis: Compliance with the International Guidelines.

OBJECTIVE: Antimicrobial prophylaxis has been demonstrated to lower the incidence of postoperative infection in nearly all types of surgery. The American Society of Health-System Pharmacists (ASHP) guideline summarizes current data on the appropriate use of antibiotic for surgical prophylaxis. The objective of this study was to assess and audit the use of antibiotics in a tertiary care center according to the recommendation of ASHP guideline. METHODS: This cross-sectional study was performed using prospective data gathered from April to September 2015 in the surgical wards of Al Zahra Hospital, Isfahan, Iran. Antibiotic indication and choice, dose, dosing interval, route of administration, and timing of first administration and duration of prophylaxis were compared with the ASHP guideline recommendations. FINDINGS: A total of 100 patients with the mean age of 49.8 ± 18.2 years were recruited for this study. About 22% of procedures had full compliance with all guideline recommendations. The most frequently encounter noncompliance type were the duration of prophylaxis (14%) and appropriate agent choice (35%). Timing of the initial dose was appropriate in most of the procedures (42%). CONCLUSION: This study revealed that most of the prescribed antibiotics for surgical prophylaxis are not in accordance with standard treatment guideline. The density of antimicrobial use for preoperative antimicrobial prophylaxis is very high. Furthermore, the hospital should develop a formal strategy, including a local guideline for antimicrobial prophylaxis in surgical procedures.