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The severe coronavirus disease 2019 (COVID-19) is associated with increased levels of blood interleukin (IL)-6. Therefore, it is hypothesized that modulating the levels or effects of IL-6 could diminish airway inflammation and alter the course of COVID-19. We conducted a controlled, randomized, double-blind clinical trial on hospitalized patients with severe COVID-19 in Iran. The patients were randomly distributed by block randomization to take either standard-of-care (SOC) plus 1 or 2 doses of tocilizumab 8 mg/kg or SOC alone. The endpoint was defined by clinical improvement and discharge. We enrolled 40 patients (20 patients in each group) from 10 July to 10 December 2020. After randomization, 1 patient in the SOC arm and 3 patients in the tocilizumab arm refused to participate and were eliminated from the study. The mean age of participants was 59.62±15.80 in the tocilizumab group (8 women and 9 men) and 63.52±12.83 years old in the SOC group (9 women and 10 men) groups. The number of patients who recovered did not differ significantly between the tocilizumab and SOC groups (12 [70.6%][70.6%] vs. 15 [78.9%]), respectively). Hospitalization rates were also similar between the groups (Log-rank test, p=0.615; hazard ratio, 0.83; 95% CI [0.39–1.78]). The results show that tocilizumab could not be a beneficial agent for treating severe cases of COVID-19 patients and would not significantly improve clinical outcomes. [ABSTRACT FROM AUTHOR]

Objective: Data about the contribution of drugs to the development of acute kidney injury are scarce in hematological cancer patients. The current study evaluated the relationship between the use of different medications and acute kidney injury development in hematological cancer patients. Methods: This study was designed as a prospective observational cross-sectional study. All patients admitted to hematology wards of Shariati Hospital of Tehran University of Medical Sciences were evaluated, and patients younger than 18 years of age, those who were not able to consent to participate and those who presented with acute kidney injury were excluded. Acute kidney injury was diagnosed per KDIGO criteria. Results: Overall, 450 patients were evaluated in this study and 138 cases of acute kidney injury were detected; this translates into 30.6% incidence rate in hematology wards of the study center. The median age of the patients with acute kidney injury was 49 years and 84 (60.9%) of them were men. Length of hospital stay and mortality rate was significantly higher in patients with acute kidney injury than those without (P < .001 and < .001, respectively). Results of the multivariate analysis showed that treatment with vancomycin (odds ratio 1.77), the combination of vancomycin and amphotericin B deoxycholate (odds ratio 3.10), and idarubicin (odds ratio 2.10) could significantly increase the odds of acute kidney injury development in patients with hematological malignancy, but treatment with hydrocortisone (odds ratio 0.26) could have significant nephroprotective effects. Conclusion: This study showed that treatment with vancomycin, the combination of vancomycin and amphotericin B deoxycholate, and idarubicin could significantly increase the odds of acute kidney injury development. Hydrocortisone treatment showed significant nephroprotective effects. Mortality and duration of hospital stay were significantly higher in patients with acute kidney injury. [ABSTRACT FROM AUTHOR]

Introduction: Patients undergoing hematopoietic stem cell transplantation (HSCT) are suspected to develop febrile neutropenia (FN) and severe infections. Therefore, appropriate prescription of antibiotics in these patients is crucial to reduce the rates of morbidity, mortality, and antimicrobial resistance. The present study aimed to evaluate the physicians' prescription and adherence to the FN clinical guidelines among patients undergoing HSCT. Methods: This prospective observational single-center study was conducted during a 15-month period in a tertiary referral hospital in Iran. The patients with at least one episode of FN following HSCT were included in the current study. The physicians' adherence to the Infectious Diseases Society of America (IDSA) and National Comprehensive Cancer Network (NCCN) clinical guidelines for the management of FN was evaluated using prescription data and medical record reviews. Results: Two hundred and fifteen patients with 297 FN episodes were evaluated. The timing of antibiotics and the selection of the initial regimen were considered guideline-based therapy. However, antibiotic dosing and initial regimen modification were not followed in terms of the guideline recommendations in 58.1% of the patients. In particular, vancomycin was inappropriately given in 83.1% of patients. The overall adherence of physicians to the guidelines was 35.8%. Conclusion: Non-adherence to clinical guidelines is high particularly in initial regimen modification and administration of vancomycin, which affects hospital stay and patient's outcome. Implementation of guideline-review sessions to raise the awareness of the physicians and to improve the rational use of antimicrobial agents may be crucial. [ABSTRACT FROM AUTHOR]

Introduction: Current guidelines on vancomycin dosing lack specific recommendations about its dosing in hematopoietic stem cell transplant (HSCT) patients, the objective of the current study was to compare vancomycin pharmacokinetic variables in this population with those of general population. Methods: A prospective study was designed and the calculated parameters of vancomycin pharmacokinetic were compared with individualized parameters. Two trough levels before 4th and 5th doses and a peak level after the 4th dose, were taken. All patients received a dose of 15 mg/kg of vancomycin two or three times a day. Pharmacokinetic parameters were calculated using a one compartmental model. The association between different variables and of acute kidney injury (AKI) development and achievement of target levels were also evaluated. Results: A significant difference was observed between population Volume of distribution (Vd) and individualized Vd (mean 57.33 L vs 162.86 L, p value 0.019) and trough and peak levels (p values 0.0001 and 0.001; for mean trough and peak levels respectively). The achievement of the recommended trough levels and area under the concentration time curve per minimum inhibitory concentration (AUC24/MIC) was very low (5/71 and 24/71 patients respectively). No significant differences were observed between population and individualized clearance and rate of elimination of vancomycin (p values of 0.092 and 0.55 respectively). Concomitant receipt of cyclosporine was significantly related with development of AKI (p value 0.046). Conclusion: The dosing methods which use population-based pharmacokinetic variables does not result in desired therapeutic levels in HSCT patients, mainly because of larger vancomycin volume of distribution. [ABSTRACT FROM AUTHOR]

Reperfusion therapies are recommended for patients with hemodynamic instability or high-risk acute pulmonary embolism (PE). Lower doses of tissue plasminogen activator (rt-PA) could be considered to improve bleeding complications. The aim of this study was to evaluate the efficacy and safety of a reduced dose of rt-PA for the treatment of acute PE, compared with anticoagulation and standard dose. PubMed Central, Scopus, Web of Science and Embase were searched for all relevant randomized studies and prospective observational studies that compared reduced dose of rt-PA with anticoagulation alone or standard dose of rt-PA in patients with acute PE. The risk ratios (RR, with 95% CI) were calculated according to the value of I2. Outcomes were described as bleeding events, all-cause death, and recurrence of PE. Thirteen articles, including four observational studies (4223 patients) and nine RCTs (780 patients), were included. In comparing reduced dose of rt-PA with anticoagulant, a greater incidence of total bleeding events in low dose was showed (RR, 5.08 (95% CI, (1.39-18.6), I2 = 0.0%). In the standard dose rt-PA vs. reduced dose, there was a greater incidence of total bleeding events in the standard dose of rt-PA, RR 1.48 (95% CI, (1.00-2.19), I2 = 0.0%) was shown. There were no statistical differences in recurrent PE or all-cause mortality. It concluded that in the absence of the benefit of a standard dose of rt-PA in comparison with dose reduction, a reduced dose of rt-PA showed a lower rate of total bleeding events and similar efficacy regarding mortality and PE recurrence rate. [ABSTRACT FROM AUTHOR]

Purpose: Although the current widespread use of amikacin is in intra-abdominal sepsis treatment, its pharmacokinetic changes in the present setting are not yet well known. This study was aimed to evaluate the amikacin pharmacokinetic profile in critically ill patients with intra-abdominal sepsis compared to pneumosepsis. Methods: Adult septic patients received amikacin therapy were studied. Patients with intra-abdominal sepsis were enrolled in group 1 (n=16), and patients with pneumosepsis were enrolled in group 2 (n=13). The amikacin serum concentrations were evaluated in the first, second, fourth and sixth hours after initiating 30-minute infusion. The pharmacokinetic parameters were calculated for each patient. Results: There was no significant difference in the volume of distribution between the two groups (0.33±0.08 vs. 0.28±0.10 L/kg, P = 0.193). The amikacin clearance was significantly lower in group 1 compared to group 2 (58.5±21.7 vs. 83.9±37.0 mL/min, P = 0.029). There was no significant correlation between amikacin clearance and creatinine clearance estimated by Cockcroft-Gault formula in all patients (P = 0.206). The half-life was significantly longer in group 1 compared to group 2 (5.3±2.8 vs. 3.4±3.2 hours, P = 0.015). Conclusion: Pathophysiologic changes following intra-abdominal sepsis can affect amikacin pharmacokinetics behavior. The clearance and half-life may change, but the alteration of the volume of distribution is not significantly different in comparison with pneumosepsis. Further studies are required to evaluate the pharmacokinetic variables of amikacin in critically ill patients with intra-abdominal sepsis. [ABSTRACT FROM AUTHOR]

BACKGROUND: Fluid and antimicrobial therapy are the essential parts of sepsis management. The type of fluid to resuscitate with is an unsettled issue in the treatment of severe sepsis and septic shock. The objective of this study was to evaluate the cost-effectiveness of albumin-based resuscitation over crystalloids. METHODS: A cost-effectiveness analysis was conducted by extracting data from a database of Sina Hospital, Islamic Republic of Iran. A decision tree was constructed by using Tree Age Pro 2011. The patients were grouped based on the types of fluids used for resuscitation into crystalloid alone or crystalloid + albumin groups at the initial decision node. The patients were followed from the onset of severe sepsis and septic shock upto 28 days. The healthcare payers’ perspective was considered in constructing the model. The cost was measured in US dollars and the effectiveness was measured by life years gained. RESULTS: The addition of albumin during resuscitation of patients with severe sepsis and septic shock has an effectiveness gain of 0.09 life years and cost increment of 495.00 USD. The estimated ICER for this analysis was 5500.00 USD per life year gained. The probability that albumin is cost-effective at one GDP per capita is 49.5%. CONCLUSION: Albumin-based resuscitation is not cost-effective in Iran when a GDP per capita was considered for a life year gain. The cost-effectiveness was insensitive to the cost of standard care. We recomend the caustious use albumin as per the Surviving Sepsis Campaign guideline. [ABSTRACT FROM AUTHOR]

Introduction: Calcineurin inhibitors are widely used for the prevention and treatment of graft versus host disease in patients undergoing allogeneic hematopoietic stem cell transplantation, and successful treatment with calcineurin inhibitors is very important for the management of these cases. Case report: A 19-year-old man with thalassemia major experienced hypersensitivity reaction to parenteral vitamin K, cyclosporine, and tacrolimus before hematopoietic stem cell transplantation. All three episodes of reaction appeared a few minutes after administration of offended drugs and cause systemic signs and symptoms of anaphylaxis, i.e. itching, flushing, difficulty in breathing, and hypotension. Management and outcome: Hypersensitivity reaction was fully controlled by immediately discontinuing the drug and administering hydrocortisone, chlorpheniramine, epinephrine, and intravenous fluids. During hospitalization, the patient tolerated oral tacrolimus without any complication. Discussion: It appears that Cremophor EL (polyoxyethylated castor oil) which acts as a carrier, solubilizer, and emulsifier in intravenous calcineurin inhibitors is responsible for the occurrence of anaphylactic reaction (anaphylaxis); therefore, it is suggested that the administration of cremophor-containing drug should be avoided in patients with a previous history of hypersensitivity reaction to one of these drugs. [ABSTRACT FROM AUTHOR]

Abdominal aortic aneurysm (AAA) is widely considered as the disease of elderly white men. Inflammation is one of the most well-known mechanisms involved in the pathogenesis of AAA. Magnesium is one of the most important minerals in the body with established antiinflammatory effects. In this study, we aimed to investigate the impact of Mg loading following AAA surgery on two inflammation markers, IL-6 and CRP, as well as patient's outcome. This study was conducted as a randomized clinical trial on 18 patients (divided into two groups) after surgical correction of Acute Aortic Aneurysm (AAA). All the patients admitted in ICU ward of Sina Hospital. In intervention group, 10 g of MgSO4 has been infused through 12 h. The control group has not received the intervention. IL-6 and CRP were measured and compared at times 0, 12, 24 and 36 h. The patients were monitored for 36 h. After intervention, the differences of heart rate and APACHE II score were not statistically significant between intervention and control groups (P = 0.097 and P = 0.472, respectively). IL-6 levels decreased consistently in both groups after inclusion in the study. However, IL-6 level was significantly less in intervention group early after the end of MgSO4 infusion comparing with control group (P = 0.01). Likewise, the CRP level decreased significantly after inclusion in the study (P = 0.005). However, these changes were not significant between intervention and control groups (P = 0.297). According to the results of this study, continuous infusion of MgSO4 after AAA surgery may provide IL-6 suppression. [ABSTRACT FROM AUTHOR]

Detection of adverse drug reactions (ADRs) in hospitals provides an important measure of the burden of drug related morbidity on the healthcare system. Spontaneous reporting of ADRs is scare and several obstacles to such reporting have been identified formerly. This study aimed to determine the role of clinical pharmacy residents in ADR reporting within a hospital setting. Clinical pharmacy residents were trained to report all suspected ADRs through ADR-reporting yellow cards. The incidence, pattern, seriousness, and preventability of the reported ADRs were analyzed. During the period of 12 months, for 8559 patients, 202 ADR reports were received. The most frequently reported reactions were due to anti-infective agents (38.38%). Rifampin accounted for the highest number of the reported ADRs among anti-infective agents. The gastro-intestinal system was the most frequently affected system (21.56%) of all reactions. Fifty four of the ADRs were reported as serious reactions. Eighteen of the ADRs were classified as preventable. Clinical pharmacy residents involvement in the ADR reporting program could improve the ADR reporting system. [ABSTRACT FROM AUTHOR]

Wilson disease (WD) is an autosomal recessive disorder well recognized by the copper progressive accumulation. Copper accumulation in various organs and tissues causes toxic effects in various tissues including liver, brain, kidneys and eyes. Chelation therapy is the mainstay of treatment for patients with Wilson's disease. Chelators are naturally occurring or chemically designed molecules that bind to specific toxins in the body and promote excretion of them. Diethylenetriamine penta-acetic acid (DTPA) is one of the well-known Chelators which is used in WD treatment but it's main defect is that it cannot enter into the intracellular space. When an amine such as D-glucosamine (DG) was conjugated to DTPA, the resulting compound obtains the ability to enter cells and may be used to treat the intracellular metal overload. Based on the hypothesis, A new compound consisting of D-glucose (1.1 nm) conjugated DTPA, was synthesized and evaluated on HepG2 WD cell model in vitro. Our results revealed that that the copper accumulation significantly P<0.05 decreased in the HepG2 WD cells by DTPA-DG as compared with D-penicillamine (as gold standard treatment) compared with the D-penicillamine (gold standard). Interestingly, no toxicological findings were seen in HepG2 WD cell. Based on our findings, administration of DTPA-DG could be significantly decrease the copper accumulation in HepG2 WD cell model without any toxicity and seems to have a very good prognosis for treatment of WD in the future. [ABSTRACT FROM AUTHOR]

Patients with hematologic malignancies often receive multiple medications, leading to potential drug-drug interactions (DDIs). Identifying and managing these DDIs is crucial for ensuring patient safety and effective care. This study aimed to identify and describe DDIs and associated factors in hematologic malignancy patients.This prospective interventional study was conducted at a referral center and included hospitalized patients with hematologic malignancies who were receiving at least four concurrent medications. A pharmacist initially compiled a comprehensive list of all medications through patient interviews and medication reviews, and subsequently, identified and categorized potential DDIs using the Lexi-interact® and Micromedex® databases. The clinical pharmacist then evaluated the clinical impact of the identified DDIs in every individual patient and provided appropriate interventions to resolve them.A total of 200 patients met the inclusion criteria for the study, with 1281 DDIs identified across 337 distinct types. The majority of identified DDIs exhibited major severity (52.1%) and pharmacokinetic mechanisms (50.3%), with an unspecified onset (79.4%) and fair evidence (67%). Of the identified DDIs, 81.1% were considered clinically significant, prompting 1059 pharmacotherapy interventions by the clinical pharmacist. Additionally, a significant relationship was observed between the number of drugs used during hospitalization and the occurrence of DDIs (P < 0.001, r = 0.633).DDIs are highly prevalent among hospitalized patients with hematologic malignancies, with their occurrence increasing alongside the number of medications administrated. The intervention of a clinical pharmacist is crucial to evaluate the clinical impact of these DDIs and implement effective interventions for their management. [ABSTRACT FROM AUTHOR]

High-dose extended-interval dosage (HDED) regimen of aminoglycosides is now considered as the standard dosage strategy in sepsis. Although safety and efficacy of this dosing regimen is well studied, but new experiments show increased the risk of resistance development associated with %T>MIC less than 60% of the dosing interval following extended interval dosing. Moreover, limited information is available about safety of more frequent administration of high dose aminoglycosides. Authors studied nephrotoxicity following seven days' exposure to more frequent administration of higher doses of amikacin comparing with HDED regimen. In addition to Serum Creatinine (SrCr) and estimated glomerular filtration rate (eGFR), nephrotoxicity was studied with Neutrophil gelatinase-associated lipocalin (NGAL), a direct marker of tubular injury. A total of 40 patients with sepsis were quasi-randomized in two groups. Seven days' course of treatment with a moderate dose of amikacin (12.5 mg/Kg) was administered every 12 hours, known as the moderate-dose non-liberal-interval dosage (MDNLD) regimen compared with the high-dose extended-interval dosage (HDED) regimen (25 mg/Kg every 24 hours). The pharmacokinetic/pharmacodynamic (PK/PD) goal of the MDNLD regimen was the Cmax>40 and the %T>MIC more than 60% during the PK/PD goal for the HDED regimen was the Cmax>60. The eGFR change from the baseline was the primary outcome of the study with a minimum clinical significance of 20 ml/min (estimated SD of 20, Power>90%, P<0.05). No difference was observed between groups for the values of eGFR change and the SrCr percent change from the baseline (P=0.359 and P=0.114, respectively). Frequency of acute kidney injury also did not differ between groups (P=0.342). Serum NGAL level values' change from the baseline was more in the HDED regimen in comparison with the MDNLD regimen at third day and fifth day of the treatment (P=0.001 and P =0.002, respectively). This indicates a safer pattern of moderate doses with more frequent administration of amikacin at the tubular injury level. Higher doses of amikacin could be safely administered to achieve PK/PD goal of Cmax>40 and %T>MIC more than 60% of the dosing interval. This dosing regimen would be considered as an alternative to minimize the resistance development associated with the extended-interval dosing in septic patients with multi-drug resistant gram-negative organisms.

Objective: Phenytoin is an antiepileptic drug used widely for prophylaxis and treatment of seizure after neurotrauma. Phenytoin has a complex pharmacokinetics and monitoring of its serum concentrations is recommended during treatment. Total phenytoin concentration is routinely measured for monitoring of therapy. In this study, we evaluated the correlation between phenytoin total and free concentrations in neurotrauma critically-ill patients to determine whether the phenytoin total concentration is a reliable predictor of free drug, which is responsible for the therapeutic effects., Methods: A total of 40 adult head trauma patients evaluated for free (unbound) and total serum phenytoin concentrations. Patients were divided into two groups. Group A consists of 20 unconscious patients with severe head injury under mechanical ventilation and Group B consists of 20 conscious self-ventilated patients. Correlation and agreement between total and free phenytoin plasma concentrations were analyzed., Findings: Pearson correlation analysis and Bland-Altman test showed weak to moderate correlation (r = 0.528) and poor agreement between free and total phenytoin concentrations in patients with severe trauma and higher Acute Physiology And Chronic Health Evaluation II (APACHE II) scores (Group A) and good correlation (r = 0.817) and moderate agreement in patients with mild to moderate trauma and lower APACHE II scores (Group B)., Conclusion: Our results indicated that total phenytoin serum concentration is not a reliable therapeutic goal for drug monitoring in severely-ill head trauma patients even in the absence of hypoalbuminemia, renal and hepatic failure. It seems justifiable to measure free phenytoin concentration in all severely ill neurotrauma patients.