Current Reviews in Clinical and Experimental Pharmacology - Volume 16, Issue 4, 2021

Background: Our study aims at assessing the pre-clinical impact of the synergistic mechanism of Daptomycin (DAP) and Ceftaroline (CFT) on patients with Methicillin-Resistant Staphylococcus aureus Bacteremia infections (MRSAB). Methods: A systematic overview was conducted by searching PubMed, Oxford academic, and Cochrane library up to June 2020. Study selection and data extraction: All English- language clinical trials, in vitro studies, and case reports related to the synergistic drug therapy for MRSAB. Results: In the case of MRSAB infections, we examined two different in vitro studies that showed effective synergism with DAP and CFT. The Minimum Inhibitory Concentration (MIC) range observed for each is as follow: DAP 0.125-1 mg/L, CFT 0.38-1 mg/L, DAP + CFT 0.094-0.5 mg/L, vancomycin (VAN) 0.75-2 mg/L, VAN + CFT 0.25-2 mg/L. DAP + CFT combination displayed the most efficacy with the lowest MIC. The statistical analysis performed showed that DAP + CFT obtained significantly lower fractional inhibitory concentration (FIC) values (0.941 ± 0.328) compared with VAN + CFT. In vitro activities of regimens tested on DAP non-susceptibility and VAN intermediate after 96 hours showed DAP 8.29 ± 0.03^a log10 CFU/mL, VAN 6.82 ± 0.04^a log10 Colony Forming Unit (CFU)/mL, CFT 4.63 ± 0.19^a log10 CFU/mL, DAP + CFT 1.15 ± 0.20^b log10 CFU/mL, VAN + CFT 3.18 ± 0.49^a log10 CFU/mL. (^a meaning significantly different than DAP plus CFT, P< equal to 0.001^b meaning therapeutic enhancement combination was defined as ≥ 2 log10 CFU/ml reduction over the most active single agent). Based on these results, although DAP was not susceptible, the Colony Forming Unit (CFU) for DAP and CFT had the best therapeutic results. Conclusion: In vitro studies have shown that a combination DAP and CFT is more efficacious than the combination of VAN and CFT in MRSA bacteremia infections. The synergic effects of DAP (bactericidal) and CFT (bactericidal) is statistically significant, in recent trials, warranting promising evidence for its use in complicated bacteremia infection.

Background: The prevalence of cholelithiasis in developed countries is high and its cause is multifactorial, with a negligible proportion of drug-induced cholelithiasis. Methods: Relevant studies were identified by PubMed, Google Scholar and Science Direct. Reference lists of retrieved articles were also reviewed. The most relevant and up-to-date information was incorporated. Results: There is a wide range of drugs that can induce lithiasis. While the risk of developing lithiasis is high with some drugs (ceftriaxone, atazanavir, somatostatin analogues), it is lower or even questionable with others. Some drugs precipitate in the bile and may account for up to 100% of the weight of the stone. Conclusion: Cholelithiasis can be induced by a wide range of drugs with different mechanisms of action. The aim of the article is to draw attention to this lesser known fact and the need to take into account the risk of developing lithiasis prior to therapy initiation.

While facing potentially high morbidity from COVID-19 without known effective therapies, the off-label use of several non-specific drugs has been advocated, including re-purposed anti- viral (e.g., remdesivir or the lopinavir/ritonavir combination), biologic agents (e.g., tocilizumab), and antimalarial drugs such as chloroquine and hydroxychloroquine, in association with or without azithromycin. Data regarding the effectiveness of these drugs in treating COVID-19 has been shown in some trials and clinical settings, but further randomised controlled trials are still being carried out. One of the main concerns regarding their widespread use, however, is their possible effects on the QT interval and arrhythmogenic potential. Some of these drugs have been associated with QT prolongation and Torsades de Point, a potentially lethal ventricular arrhythmia. The review aims to highlight the magnitude of this problem, to quickly refresh clinically impacting cornerstones of QT interval and TdP pathophysiology, to summarize the available evidence regarding the QT and arrhythmia impact of drugs used in different clinical settings in COVID-19 patients, and to help the physicians dealing with the knowledge needed in the everyday clinical duties in case of doubts regarding QT-induced arrhythmias in this time of emergency.

Background: Poisoning is one of the leading causes of childhood morbidity and mortality worldwide. Despite the advancement of poison detection by modern investigation methods, the clinical skill of toxidrome recognition by combining the findings from a detailed history, thorough physical examination, and the results of basic investigations is still indispensable for the management of children with suspected poisoning. Objective: The aim was to review pediatric toxidromes and poisoning management. Methods: A literature search was conducted on PubMed (between February 1 and 15, 2020) with keywords "toxidrome" "poisoning" "intoxication” “children” and "pediatric". The search was customized by applying the appropriate filters so as to get the most relevant articles to meet the objective of this review article. Results: Toxidrome recognition may offer a quick guide to possible toxicology diagnosis so that specific antidote can be administered in a timely manner. This article discusses a few commonly encountered toxidromes in pediatric poisoning, with an emphasis on the symptomatology and source of exposure. The antidote and specific management for each toxidrome are also discussed. Although most patients with intoxication can be managed with close observation, supportive measures and antidote treatment, it is unfortunate that antidotes are only available for a limited number of poisons responsible for intoxication. Extracorporeal toxin removal is being increasingly recognized as a mode of treatment for patients with rapid deterioration who are unresponsive to conventional management. The decision to apply such technique and the choice of modality are frequently individualized due to the paucity of high-level evidence. The various patient and toxin/medication factors involved in the decision- making process are discussed. Conclusion: Poisoning is a common cause of pediatric accidents and injuries. Physicians should be familiar with common toxidromes and poisoning management.

Background: Coronary artery disease is a major cause of morbidity and mortality worldwide. A major health concern in the developing countries is opioid addiction, which has controversial cardiovascular side effects. We aimed to investigate whether Myocardial Infarction (MI) and its risk factors are associated with morphine dependency in the Iranian population. Methods: Electronic databases, including PubMed, Medline, Scopus, SID, Element, and Magiran were searched to find published articles including the keywords morphine, coronary artery disease, hypertension, hyperlipidemia, and diabetes mellitus. Results: Twelve studies involving 25,800 people were included in this systematic review and metaanalysis. Morphine dependency was significantly associated with MI with an adjusted odds ratio (AOR) of 2.28 (95%CI=1.26-4.11). It neither has significant associations with hypertension (AOR=0.952; 95%CI=0.696-1.301) nor diabetes (AOR=0.895; 95%CI=0.644-1.246). Morphine dependency also had no significant association with hyperlipidemia with a Crude Odds Ratio (COR) of 0.906 (95%CI=0.786-1.045). Conclusion: Morphine dependency was significantly related to MI, but its risk factors were not significantly associated with morphine dependency. The increasing prevalence of opioid abuse in developing countries may be a reason for the growing incidence of MI in younger ages and individuals with no risk factors. Besides, physicians should consider the presence of impurities in morphine-based opioids and their possible effects on health.

Background: Ceftriaxone is recommended for empiric antimicrobial therapy in patients with sepsis. Therapeutic Drug Monitoring (TDM) guided dose optimisation could elucidate pharmacokinetic variabilities, improving treatment efficacy. However, detailed data on Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS) for unbound ceftriaxone quantification in serum are scarce. Objective: The authors aimed to develop a reliable UPLC-MS/MS method for serum ceftriaxone quantification and exhibit its application potential in routine hospital settings. Methods: In this observational, single centre study, UPLC-MS/MS method validation included specificity, carry-over, linearity, repeatability, intermediate precision, accuracy, the limit of quantification, and plasma protein binding. Unbound and total ceftriaxone were quantified in the serum of 5 critically ill patients. Pharmacokinetic/Pharmacodynamic (PK/PD) target attainment calculations were performed for both unbound and total ceftriaxone. The PK/PD target for unbound ceftriaxone in serum was set at 4 times the non-species related minimum inhibitory concentration breakpoint of 1 mg/L for at least 60% of the dosing interval. Results: The UPLC-MS/MS method revealed acceptable limits for clinical samples, with coefficients of variation < 15.0% for concentrations between 0.2 – 400.0 mg/L. Ceftriaxone eluted at 1.94 min and ceftazidime, as internal standard, eluted at 1.42 min. Patients demonstrated a median unbound ceftriaxone fraction of 29.1% (IQR: 15.2 – 52.2). Day 1 of ceftriaxone treatment presented a median PK/PD target attainment of 100.0% (IQR: 81.1 – 100.0) for unbound ceftriaxone in serum, while for calculations based on total concentrations, this figure was 23.9% (IQR: 10.5 – 80.6). Conclusion: The described UPLC-MS/MS method enables reliable and rapid ceftriaxone quantification in the serum of critically ill patients. Method feasibility was exhibited for TDM purposes in routine clinical practice.

Objective: The study was conducted to determine whether synthetic Disease-Modifying Anti Rheumatic Drugs (DMARDs) suppress the latency of Tuberculosis (TB) infection in Rheumatoid Arthritis (RA) patients along with other variables. Methods: This was done through Tuberculin Skin Test (TST) using purified protein derivative (PPD) in a cohort of RA patients. The TST was taken positive when induration post-PPD injection was ≥ 5mm and negative or anergic when it was < 5mm. We included 100 patients (N = 100). Results: The prevalence of positive TST was 36%, while 64% presented a negative result. Negative TST was significantly associated with steroid usage (39.4%, 95% CI: 28.4%-51.4%). Anergic (TST negative) and non-anergic (TST positive) patients were separated into groups, and a new analysis was conducted with elaboration on DMARDs used. Conclusion: The use of steroids was associated with TST negativity, The same is not true with use of methotrexate or other DMARDs. Thus TST should be interpreted with caution, especially before starting biologicals.

Background/Objective: Tacrolimus HEXAL®/Crilomus® is an approved generic immunosuppressant for the prevention and treatment of rejection following renal transplantation. For safe and socioeconomically efficient conversion of the innovator into a generic formulation, high- -quality data are necessary, in view of the different and country-specific comorbidities and pharmacokinetics in kidney transplant recipients. Patients and Methods: From 2014 to 2017, we enrolled 32 kidney transplant recipients, receiving newly prescribed Tacrolimus HEXAL®/Crilomus® in 5 German centers. Efficacy and safety data were collected over 6-8 months and retrospectively compared to the period prior to conversion. Results: The mean tacrolimus trough level was 4.91 ng/mL Standard Deviation (SD) (SD ±1.7) before and 5.06 ng/mL (SD ±1.97) after conversion. Mean tacrolimus trough concentration-dose-ratio (+/- SD) was 187.1 ng/mL/mg/kg/day (SD 99.2) for the reference and 205.1 ng/mL/mg/kg/day (SD 133) for the generic product, resulting in a non-significant difference of 18.0 ng/mL/mg/kg/day (SD 71.8) (p=0.84, Wilcoxon V=180). Overall, dosing had to be changed in 4 (14.8%) patients. Graft function remained stable and no rejections occurred. Conclusion: In conclusion, conversion to the generic tacrolimus formulation can be considered safe and feasible in long-term kidney transplant recipients in Germany. As suggested by guidelines, vigilant therapeutic drug monitoring is recommended to account for possible tacrolimus concentration variability on the individual patient level.

Background: Pain after cesarean section can turn the pleasant event of childbirth into an unpleasant experience for the mother. Pain relief through non-pharmaceutical methods, such as aromatherapy, could potentially be a useful intervention. In this study, the analgesic effect of chamomile oil was studied. Purpose: The current research was conducted to study the effect of chamomile oil on cesarean section pain in primiparous women. Materials and Methods: This was a randomized, double-blind clinical trial wherein 128 primiparous pregnant women (who willingly selected cesarean section) took part. In the aromatherapy group, the subjects inhaled one drop of 5% chamomile oil, and in the control group, the subjects inhaled one placebo drop. In both groups, the subjects inhaled for 15-20 minutes at a distance of 5 cm from the nose at 4, 8, and 12 hours after surgery, and pain intensity was measured half an hour before and after inhalation using the Visual Analog Scale (VAS). For data analysis, the software SPSS (version 25) and descriptive statistics (frequency, frequency percentage, mean, and standard deviation) were used. In order to determine the significance, inferential statistics (Mann-Whitney, Wilcoxon, independent t-test, and Chi-square) were used. Findings: Data indicated that the intervention and placebo groups were homogeneous in terms of demographic variables. The average weights and heights of women in the intervention group were 86/5± 5/9 and 163/7 ±5/1, respectively. Corresponding values for women in the control group were 84/5± 5/7 kg and 163/4± 5/8 cm. The finding of the current research indicates that the intervention and placebo groups showed no significant statistical difference in terms of baseline pain before intervention (p=0.08), while the difference between the two groups was significant in terms of pain, 4, 8, and 12 hours after the intervention (p<0.01). Therefore, inhalation of chamomile oil reduced pain intensity significantly compared to post-intervention. Conclusion: According to the results of the present study, inhalation of chamomile oil following the cesarean sectionin primiparous women reduced pain and also the need for analgesics. Therefore, the use of aromatherapy with chamomile oil as a simple way without any side effects for the reduction of pain in mothers after the cesarean section is recommended.