Current Reviews in Clinical and Experimental Pharmacology - Volume 16, Issue 2, 2021

Background: Successful integration of in vitro into in vivo data on Drug-Drug Interaction (DDI) is dependent on the inhibitory concentration used. Obtaining plasma concentration of a drug is only readily available for a small number of drugs in clinical practice. We propose the use of a therapeutic range as a substitute for inhibitory concentration. Objective: Because of this, we aimed to construct a linear-regression model based on the areaunder- curve of the victim drugs and the therapeutic range for a set of known inhibitors of the CYP2D6 of interest. Methods: Correlation analysis of linear log-log regression of two main variables: The Area-Under- Curve ratio (AUCr) of the victim drugs and the therapeutic range-to-inhibition constant ratio, with data obtained from literature. Results: Data were fitted to linear log-log regression, between the average of AUCr values and mean value of therapeutic range-to-inhibition constant ratio (TRm-to-Ki), of the inhibitory drugs. Conclusion: According to our results, knowledge of the inhibition constant and therapeutic range (or its plasma levels if disponible) of the inhibitor would be sufficient to determine the intensity and clinical relevance of a CYP2D6-mediated DDI.

Background: Helicobacter pylori (H. pylori) infection is the most common cause of peptic ulcer disease and it can be associated with many complications, including malignancies. In clinical practice, some clinicians may use Clavulanic Acid (CA) in combination with amoxicillin or other beta-lactams as an addition to the standard treatment regimens. This practice may be done by habitual mistake, non-evidence based hypothetical assumptions, or by prescribing it as an alternative treatment. This review aims to expose the effect of CA against H. pylori infection and to review the possible mechanisms that may contribute to that effect. Methods: A PubMed and Google Scholar literature search was obtained on both pre-clinical and clinical studies related to CA and H. pylori infection. Results: Available clinical studies showed improvement in the eradication of H. pylori by about 10- 20% when CA was added to the treatment regimens. This effect for CA could be related to several mechanisms including inhibition of H. pylori growth by binding to Penicillin-Binding Proteins (PBPs), the transformation of H. pylori from the active filamentous form into coccoidal form, induction of the release of dopamine, modulation of immunological response towards H. pylori infection and its relationship with other microbiota. Randomized-controlled studies on patients with resistance to H. pylori are needed. Moreover, in vitro studies to evaluate the mechanisms by which CA may influence H. pylori are warranted. Conclusion: The presented literature suggests potential avenues for the use of CA in the management of peptic ulcer disease and H. pylori infection.

Background: Berberine (BBR), an isoquinoline alkaloid, acts as a multipotent active pharmaceutical ingredient to counteract several types of dementia based on its numerous pharmacological actions including antioxidant, anti-inflammatory, cholesterol-lowering effect, and inhibition of Aβ production and AChE. However, BBR suffers from poor absorption, bioavailability and brain drug uptake. The present study is directed for the formulation and characterization of Chitosan BBR-Nanoparticles (BBR-NPs) as well as the estimation of its neuroprotective effects against scopolamine induced cognitive impairments. Methods: BBR-NPs were formulated using the ionic gelation method, and tripolyphosphate was chosen as a crosslinker. Nanoparticles size, zeta potential, encapsulation efficiency and releasing profile were estimated. To investigate the neuroprotective effects, adult fifty-six Wistar male rats were randomly distributed into three control groups, received saline, polyethylene glycol or Chitosan- NPs, respectively; induced group, received scopolamine (2 mg/ kg, i.p.) and three treated groups were orally administrated BBR (50 mg/ kg), BBR- NP (7 mg/ kg) and donepezil (2.25 mg/ kg, as positive control) followed by scopolamine injection after 40 min, daily for 4 weeks. Morris water maze test, oxidative stress parameters, cholinergic and amyloid-β processing intermediates, as well as neuroplasticity markers and histopathological examination were assessed. Results: Our results showed that BBR- NPs were better than BBR and donepezil as BBR- NPs were powerful inhibitory ligands towards AChE and Aβ42 formation and significantly down-regulated Tau, iNOS and BACE gene expression in rats’ hippocampus. BBR-NPs administration, at 1/6 of BBR therapeutic recommended dose, significantly improved learning and memory function. This could be accredited to the diminution of oxidative stress and amyloid-β toxicity in addition to the improvement of the neuroplasticity markers. Conclusion: The enhancing effect of BBR- NPs could be related to the enhancing of its bioavailability, absorption and brain drug uptake, which need more investigation in future work.

Background: Hesperetin has antihyperuricemia activity, and the pharmacokinetic profiles of hesperetin may be altered by hyperuricemia. This study aimed to develop a highly sensitive and specific method for the determination of hesperetin in normal and hyperuricemia rats, and to compare pharmacokinetic profiles of hesperetin after oral administration between normal and hyperuricemia rats. Methods: Sprague-Dawley (SD) rats were randomly divided into one normal group (group A) and four hyperuricemia groups (group B, C, D, and E). Groups A, B, C, and D received a single dose (9–81 mg/kg) of hesperetin on Day 28, respectively, while group E received multiple doses (27 mg/kg) of hesperetin once daily for 28 days. Blood samples were collected at 10 different time points post-dose, and hesperetin was determined by Ultra-high Performance Liquid Chromatography- tandem Mass Spectrometric (UPLC-MS/MS). Results: Compared with normal condition of group A, hyperuricemia of group C induced 48.19% and 19.57% decreases in Cmax and CL/F, and resulted in 58.25% and 19.48% increases in Tmax and AUC0-t for hesperetin, respectively. After 28 days of hesperitin treatment, Cmax of group E was significantly elevated than that of group C (p < 0.05). Hesperetin exhibited nonlinear pharmacokinetic properties in the range of 9-81 mg/kg in hyperuricemia rats. Conclusion: The pharmacokinetic parameters of hesperetin in hyperuricemia rats were reported for the first time. Intestinal injury may be ameliorated by hesperetin in hyperuricemia rats after 28 days’ treatment. These findings could provide more beneficial information to the mechanism and clinical applications of hesperetin.

Background: It was previously thought that inflammation and an immune response were the only factors capable of causing IL-1β, IL-6 and other cytokine`s production. In recent years data have appeared that stressful effects can also occupy an important place, enhancing production of IL- 1β, IL-6 and other cytokines; the result will be a change in the functional activity of a particular cell element, for example immunocompetent cells with subsequent development of inflammation, or a change in the functional activity of neurons. This experiment is aimed at studying the effect of the Selank glyprolin neuropeptide drug on the level of cytokines in animals under conditions of “social” stress, the results of which indicate the presence of stress-protective activity. Methods: White nonlinear rats were used as experimental animals. A model of confrontations between males was chosen to create a “social” stress. The animals were in pairs in a cage which were separated by a septum preventing physical contact but having openings that provide sensory contact. Each day, the septum was removed for 10 minutes leading in an overwhelming majority to agonistic collisions (confrontations). Laboratory animals were divided into 3 groups: a group of intact males, a group of animals that were subjected to stress (sensory contact) for 20 days and a group that received intraperitoneally Selank at a dose of 100 mcg/kg/day under conditions of 20-day stress. The level of cytokines under study was determined by enzyme-linked immunosorbent assay. Results: As a result of the work performed to determine the concentration of pro-inflammatory and anti- inflammatory cytokines, it was found that in the serum of animals exposed to stress, there was a statistically significant increase in the level of IL-1β, IL-6 and TGF-β1 in individuals with both types of behavior. It should be noted that, under the conditions of this stressful impact, there was a tendency to decrease the concentration of IL-4 and increase the level of TNF-α but these indicators were not statistically significant. Evaluation of the effect of Semax on the level of the cytokines in a stress-induced state showed that this neuropeptide causes a decrease in the concentration of IL-1β and IL-6, restoration of the level of IL-4, as well as suppression of the production of TGF-β1 and TNF-α in these conditions. Conclusion: This peptide is able to reduce the concentration of IL-1β, IL-6 and TNF-α, as well as TGF-β1, practically reaching control values, when studying the effect of Selank on the level of cytokines under conditions of " social" stress. There is the need for a detailed study of the role of cytokines in the development of stress-induced changes in order to find optimal correction tools.

Background: Signal strength for any drug-event combination can be determined using disproportionality analysis. Vemurafenib is a BRAF inhibitor approved by the US Food and Drug Administration (FDA) in 2011 for the treatment of metastatic melanoma. This study aims to identify the signal strength of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) associated with vemurafenib using disproportionality analysis in FDA database of Adverse Event Reporting System (FAERS). Methods: Data were obtained from the public release of data in FAERS. The case/non-case method was adopted for the analysis of the association between vemurafenib use and DRESS. The data mining algorithm used for the analysis was the Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR). A value of ROR-1.96SE>1, PRR≥2 was considered as positive signal strength. Results: A total of 7,171 reports for DRESS have been reported in the FDA database. Amongst which, 125 reports were associated with vemurafenib. A cumulative ROR of 17.72 (95% CI 14.83; 21.18) and PRR of 17.46 (95% CI 14.65; 20.81) were observed. Combination treatment of vemurafenib with cobimetinib had a higher number of reports (100) with ROR of 103.42 (84.13- 127.14) and PRR of 94.52 (78.26- 114.15). Four deaths were reported and the non-death serious reports included hospitalization, life-threatening, disability, and other serious events with 61, 11, 2 and 39 reports, respectively. Conclusion: Positive signal strength was observed for vemurafenib associated DRESS. The signal strength was higher for vemurafenib in combination with cobimetinib than vemurafenib alone. Health care professionals should be cautious about encountering serious adverse events and should report such events to the regulatory authorities.

Background: Critically ill adults have Augmented Renal Clearance, (ARC) decreasing the systemic circulation of drugs with predominant renal elimination. The phenomenon of ARC is crucial for antimicrobial drugs as it hinders the therapeutic response and aids the development of antimicrobial resistance. The present study was conducted to assess the impact of ARC on an Intensive Care Unit (ICU) of a tertiary care hospital. Methods: This was a prospective observational study carried out in critically ill patients with normal serum creatinine without any history of renal disease. Details on their demographic characteristics, clinical diagnoses, laboratory parameters including trough levels of vancomycin and gentamicin, ICU length of stay, and clinical outcomes (discharged alive/death) were obtained. Creatinine clearance (Crcl) was estimated from 24-hour urine creatinine. Monte Carlo simulation test with 100000 iterations was used for predicting serum vancomycin trough levels with the observed Crcl. Results: Eighty patients were recruited in the study of which 52.5% had ARC. Patients in younger age and body weight were observed with a trend to have ARC. No significant differences were observed in any of the drug classes prescribed between patients with and without ARC, including the systemic antimicrobials. Although the observed serum trough levels of vancomycin in patients with ARC did not differ significantly from those without ARC, Monte Carlo simulation predicted that 90% of patients with ARC were likely to have trough levels between 5.63 and 7.85 mg/dl, while those without ARC may have it between 7.75 to 9.82 mg/dl. Conclusion: A significant proportion of critically ill adults exhibit ARC and such patients are more likely to achieve lower trough concentrations of vancomycin than recommended. All critically ill adults with normal serum creatinine have to be screened for ARC using urine creatinine as soon as possible for appropriate adjustment in the dosage regimen of antimicrobials with predominant renal elimination.

Background: Transvaginal Ultrasound-Guided Oocyte Retrieval (TUGOR) is a painful procedure, which often requires the application of anesthesia agents. There is a controversy in the literature about the effects of administrated anesthetics for TUGOR on patients & pregnancy outcomes. Objective: The current study aimed to compare the effects of remifentanil with or without propofol, administrated for TUGOR, on pregnancy and anesthesia outcomes. Method: In a double-blind randomized controlled trial, 180 candidates of TUGOR, aged 18-40 years old, were included in the study. All study women received midazolam 0.03 mg/kg and remifentanil 1 ug/kg as anesthesia induction; Later on, they were randomly assigned in two equalsize groups in terms of anesthesia maintenance, as the intervention group received remifentanil infusion 0.25 μg/kg/min and the control group received remifentanil infusion 1ug/kg/min with propofol 50-150 ug/kg/min. Hemodynamic symptoms, operation outcomes, including the side effects, and pregnancy outcomes, were compared between the study groups. The study is registered with the Iranian Clinical Trials Registry, number IRCT201611177013N15. Results: Although the hemodynamic symptoms showed significantly better ranges in the remifentanil group, however, the study groups were not significantly different in durations of operation, anesthesia, and recovery. However, the anesthesia side effects during and after the operation were not significantly different between the groups; they were more common in control one. The reproductive outcomes (numbers of collected oocytes, fertilized oocytes and transferred embryos, pregnancy rates) showed better but non-significant ranges in the remifentanil group. Conclusion: Using remifentanil alone in comparison to remifentanil & propofol in the TUGOR procedure can be achieved better pregnancy outcomes without imposing the side effects of propofol; therefore, it is not recommended to use propofol as an anesthesia agent for a TUGOR procedure.

Background: Anxiety disorders are the most universal psychiatric problems in the general population. Due to their chronic nature, these diseases are managed with a multi-drug regimen lasting for a long period of time. Medication discontinuation leads to 25% and 80% recurrence in the first month and the first year, respectively. Despite several treatment approaches, there is no specific and optimal method for patient management. Therefore, it is necessary to find some new therapeutic approaches with fewer side effects. Withania somnifera is a plant with GABAergic property responsible for its anxiolytic effect. The aim of this study was to investigate the effect of W. somnifera root extract as an alternative therapy to reduce standard Generalized Anxiety Disorder (GAD) symptoms. Methods: Forty patients who met the inclusion criteria (with a confirmed diagnosis of GAD as stated in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) took part in this randomized double-blind placebo-controlled trial and were randomly selected for participation in the treatment group (W. somnifera extract, 1g/day; n = 22) or the placebo group (n = 18). All patients were under treatment with Selective Serotonin Reuptake Inhibitors (SSRIs) and were prescribed one capsule of the extract or placebo per day for six weeks. The Hamilton anxiety rating scale (HAM-A) was used to assess the severity of GAD symptoms at baseline as well as the second and sixth weeks of the trial. Results: Comparison of the HAM-A scores during the course of the trial revealed a significant amelioration ofHAM-A score in the treatment group versus placebo (14 and 8 units reduction, respectively (P < 0.05)). Moreover, there was a significant difference in the reduction of GAD score between the second (P =0.04) and sixth week (P =0.02) in the treatment group. The extract was safe and no adverse effect was observed during the trial. Conclusion: W. somnifera extract offers some potential advantages as a safe and effective adjunctive therapy to SSRIs in GAD. The clinical trial protocol has been registered under the Iranian Registry of Clinical Trials (IRCT20180615040105N1).

Background: The cesarean section has shown an increasing trend within the past few years. The use of appropriate and effective anesthesia for the procedure is important, not only to reduce the incidence of maternal and fetal morbidities but also to reduce the incidence of intraoperative consciousness. The aim of this study is to evaluate the intraoperative and postoperative effects of adjuvant ketamine, when used in combination with general anesthesia. Methods: The study was conducted on the patients referred to Asali hospital for the cesarean section. 100 patients were assigned into two groups. Patients in Group A received thiopental (4 mg / kg) as an anesthetic agent for the surgery, whereas those in group B received thiopental along with 0.5 mg/kg of intravenous ketamine. The effects of ketamine, such as depth of anesthesia, intraoperative and postoperative awareness, vomiting and hallucination were recorded in the questionnaire and data were statistically analyzed using SPSS v25. Results: Of 100 patients in group A, 10 of them were not deeply unconscious. 40 patients in group A and 25 in group B had intraoperative awareness. Depth of anesthesia was significantly associated with the use of ketamine (p = 0.0017) 1 patient in group A and 3 in group B had vomiting and 1 patient in group B was presented with the hallucinations. These parameters were not significantly associated with the dose of ketamine (p = 0.5). Conclusion: Overall use of ketamine is associated with better sedation and no significant side effects, with low doses of ketamine, were seen in our study. Comparative studies using other analgesics, with larger sample size, are therefore recommended.

Rationale & Objective: Rodenticide poisoning, either accidental or intentional, is very common in rural India. The absence of a definite antidote made it a major concern with a high mortality rate. Therefore, this study aimed to assess the effectiveness of N-Acetyl Cysteine (NAC) in rodenticide poisoning as there are recent positive shreds of evidence on it. Methodology: A retrospective study was conducted in a tertiary care teaching hospital on patients admitted with rodenticide poisoning during a period of 2012-2017. The Fischer’s exact test and relative risk were measured to analyze the outcome of treatment and risk factors, respectively. Results: A total of 229 patients were enrolled in the study with a mean age of 30.04 ± 15.67 years. The suicidal attack was the major (86.0%) reason for poison consumption. The survival rate was significantly (p ≤ 0.03) higher in the NAC treatment group compared to the non-NAC group. Moreover, the majority (93.4%) of participants did not experience any adverse effects. The mean oral loading dose and maintenance dose was 7580.95 ± 2204.29 mg and 3694.53 ± 2322.58 mg, respectively. Yellow Phosphorus poisoning (Relative Risk [RR] 2.888 (1.179-7.079); p=0.020) and Time lag of ≥ 24 hours (RR 3.479 (1.137-10.645); p=0.029) were the significant risk factors for mortality. Conclusion: NAC is shown to have a significant survival benefit with a good safety profile among rodenticide poisoners. Further adequately powered prospective researches with more emphasis on dosing parameters are warranted for better quantification in different settings and for clinical implementation.