Current Reviews in Clinical and Experimental Pharmacology - Volume 16, Issue 3, 2021

Inflammatory Bowel Diseases (IBDs) are chronic conditions characterized by unknown etiology and pathogenesis with deregulation of mucosal immunity. Among possible treatments, corticosteroids, already available from the ’50s, are still the mainstay of treatment for moderate to severe disease. Nonetheless, the use of steroids is still largely empirical and solid evidence about therapeutic schemes are lacking. Moreover, due to the important side-effects and for the unsatisfactory impact on the long-term natural history of the disease, the steroid-sparing has become an important therapeutic goal in IBD management. Besides conventional steroids, the so-called “low bioavailability” steroids, which are steroids with high affinity for peripheral receptors and elevated hepatic first-pass metabolism, have demonstrated efficacy and a more favorable safety profile. In the present review of the literature evidence of efficacy and safety of conventional and low bioavailability steroids in IBD patients are evaluated, and practical suggestions for a correct use in clinical practice are presented according to the current clinical guidelines.

Background: Interleukin-1 (IL-1) is a pro-inflammatory cytokine that is produced by endothelial cells, smooth muscle cells, and macrophages. It is an important regulator of a complex humoral and cellular inflammatory response. IL-1β is known to be implicated in the development of chronic inflammatory disorders such as rheumatoid arthritis. We aimed to review the effects of IL-1β antagonists in various cardiovascular disorders and to discuss their effectiveness in such diseases. Methods: Major biomedical databases, including PubMed and Scopus, were searched for clinical studies regarding the treatment of cardiovascular diseases (CVD) using IL-1β antagonists. Results: The drugs currently used in clinical trials are anakinra, the monoclonal antibodies canakinumab and gevokizumab, and the soluble decoy receptor rilonacept. There are clinical trials and case reports of patients with CVD in which anakinra administration, at the standard dose, has caused rapid clinical improvement and recovery in a few months. Our comprehensive search revealed that IL-1β antagonists have beneficial effects in the treatment of various cardiovascular disorders such as myocarditis, pericarditis, heart failure, acute coronary syndrome, myocardial infarction, atherosclerosis, and Kawasaki disease. Conclusion: The present review article shows that IL-1β has a major role in the pathophysiology of cardiovascular disorders, its antagonists have beneficial effects in these conditions, and their use should be considered in future studies.

Background: Monogenic Diabetes (MFD) represents close to 2% of all the cases of diabetes diagnosed in people younger than 45 years old. Maturity-Onset Diabetes of the Young (MODY), neonatal diabetes, and several syndromic forms of diabetes are included among the most accounts for about typical forms of MDF. MODY is the most frequent type of MFD, with MODY 1, 2, 3, and 5 being the most prevalent forms. The aim of this narrative review is to describe pregnancy associated changes in the pharmacological profile of the antidiabetic drugs used in women with the most frequent MODY subtypes. Methods: A comprehensive literature search was carried out to identify eligible studies from MEDLINE/ PubMed, EMBASE, and SCIELO databases from 1970 to 2019 first semester. Results: Pregnancy introduces changes in the pharmacodynamic and pharmacokinetic profile of some of the treatments used in MODY. MODY 3 (also known as HNF1-A MODY) is the most frequent MDF. MODY 3 patients are highly sensitive to Sulfonylureas (SU). This is also the case for MODY pregnant women. This high sensitivity to SU is also registered in patients with MODY 1 (HNF4-A MODY). Pharmacodynamic changes have been proposed to explain this behavior (Epac2 hyperactivity). However, changes in expression/activity of the metabolizing CYP2C9 cytochrome and/or alterations in the drug transporters oatp1 (Slc21a1), Lst-1 (Slc21a6), OATPD (SLC21A11), and oat2 may better explain, at least in part, this phenomenon by an increase in the concentration of the active drug. Conclusion: The impact of changes in the pharmacological behavior of drugs like SU and other metabolized/transported by mechanisms altered in a pregnancy complicated by MODY is unknown. However, switching-to-insulin recommendation formulated for MODY 1 and 3 seems to be justified. Further research in this field is needed for a better understanding of changes in drug activity associated with this particular subset of patients with MFD.

Background: Over the years, drug monitoring-such as Anti-Drug Antibodies (ADA) dosage- has witnessed major transformations. In fact, ADA are more and more used in rheumatology and gastro-enterology in monitoring chronic inflammatory disease therapeutic response. The main purpose of those researches is to produce less immunogenic drugs and, in consequences, to improve tolerance and efficiency since immunogenicity of those drugs still is the main constraint to their long-term use. The aim of this review was to highlight anti-drug-antibodies potential effects on the pharmacokinetics and bioavailability of biotherapies as well as their clinical implications. Methods: For this purpose, we collected and summarized published data on PubMed using keywords “Biologics, Rheumatoid Arthritis, Spondyloarthritis, Crohn disease, Anti-drug antibodies, residual rate, immunogenicity, efficacy, tolerance”. The time-period selected for this study was 2000-2019. Results: Anti-Drug-antibodies decrease the pharmaco-availability of drugs and, in consequences, its efficiency and high risk of refractory diseases and side effects. Conclusion: Recent literature is consistent with the fact that drug monitoring using ADA dosage coupled with residual drug concentration offers reliable options to comfort practitioner’ therapeutic management decisions. This is particularly interesting in failure of treatment or in side effects onset situations.

Background: Green tea has been extensively studied for its potential health benefits against diseases, such as cancers, cognitive degenerative diseases, and cardiovascular diseases. Methods: The authors undertook a structured search of peer-reviewed research articles from three databases including PubMed, Embase, and Ovid MEDLINE. Recent and up-to-date studies relevant to the topic were included. Results: Green tea extract exerts its functions by interacting with multiple signalling pathways in human cells. Protein tyrosine kinase is one of the examples. Abnormal activation of tyrosine kinase is observed in some tumour cells. Green tea extract inhibits phosphorylation, reduces expression, or attenuates downstream signalling of epidermal growth factor receptor, insulin-like growth factor receptor, vascular endothelial growth factor receptor, and non-receptor tyrosine kinase. Combination of green tea extract with tyrosine kinase inhibitors may provide synergistic effects by overcoming acquired resistance. Conclusion: Green tea extract can affect multiple receptor targets. In the current review, we discuss the pharmacological mechanisms of green tea on tyrosine kinases and their implications on common diseases.

Background: Iron-folic acid supplementation is a central preventive measure for maternal anemia, so considering the factors leading to or deterring from adherence is important. This review aims to establish if there is a correlation between increasing maternal education and adherence to iron-folic acid supplementation in Ethiopia. Methods: An electronic database search was conducted using PubMed, Google Scholar, Cochrane Library and African Journals Online. Joanna Briggs Institute Meta-Analysis of Statistical Assessment and Review Instrument was used for quality appraisal of the included studies. The extracted data were entered into Microsoft™ Excel sheet and exported to R-software version 3.6.1 for analysis. Maternal education on adherence of iron-folic acid supplementation was analyzed and subgroup analyses of difference between regions and time of study period were conducted. Results: The online search yielded a total of 936 articles, and based on inclusion/exclusion criteria nine were included in this study with a total of 3263 participants. Applying the random effect model, the analysis revealed that the odds of prenatal adherence of iron-folic acid supplementation were 2.89 times higher in mothers with secondary school education and above as compared to those who had not received formal education. Conclusion: This review identified that increased maternal education leads to improved adherence of iron-folic acid supplementation amongst women across Ethiopia. This information may inform efforts of government and non-government organizations to encourage maternal education in order to sustained adherence of iron-folic acid supplementation. Further research is required in this critical area at regional, national, and global levels.

Background: Knowledge of medication use during pregnancy presents a concern to pharmacists upon graduation since they will be responsible for drug-related inquiries and counselling pregnant women about their medications. The present study aimed to assess undergraduate senior pharmacy students’ knowledge about medication use during pregnancy in Jordan. Methods: A cross-sectional survey was conducted in Jordanian universities. A total of 409 senior pharmacy students participated in the study. Results: The results found that the majority of the students (60.6%) did not have enough instruction on medications during pregnancy through their undergraduate study. Overall, only 2.5% of the participating students were considered to have good knowledge about medicine use during pregnancy and accordingly, the majority (52.6%) were not confident to recommend medicines for pregnant women in the future. In view of that, participating students suggested the addition of an obligatory course to the current curriculum. Students in public universities, Pharm.D. students, and those in their sixth year of study were more knowledgeable than others (P > 0.05). Conclusion: It was concluded that pharmacy students have low knowledge regarding medication use in pregnancy. The results call for a reassessment of the current pharmacy curriculum.

Background: To address multidrug resistance, we developed engineered Cationic Antimicrobial Peptides (eCAPs). Lead eCAP WLBU2 displays potent activity against drug-resistant bacteria and effectively treats lethal bacterial infections in mice, reducing bacterial loads to undetectable levels in diverse organs. Objective: To support the development of WLBU2, we conducted a mass balance study. Methods: CD1 mice were administered 10, 15, 20 and 30 mg/kg of QDx5 WLBU2 or a single dose of [14C]-WLBU2 at 15 mg/kg IV. Tolerability, tissue distribution and excretion were evaluated with liquid scintillation and HPLC-radiochromatography. Results: The maximum tolerated dose of WLBU2 is 20 mg/kg IV. We could account for greater than >96% of the radioactivity distributed within mouse tissues at 5 and 15 min. By 24h, only ˜40-50% of radioactivity remained in the mice. The greatest % of the dose was present in liver, accounting for ˜35% of radioactivity at 5 and 15 min, and ˜ 8% of radioactivity remained at 24h. High radioactivity was also present in kidneys, plasma, red blood cells and lungs, while less than 0.2% of radioactivity was present in brain, fat, or skeletal muscle. Urinary and fecal excretion accounted for 12.5 and 2.2% of radioactivity at 24h. Conclusion: WLBU2 distributes widely to mouse tissues and is rapidly cleared with a terminal radioactivity half-life of 22 h, a clearance of 27.4 mL/h/kg, and a distribution volume of 0.94 L/kg. At 2-100 μg-eq/g, the concentrations of 14C-WLBU2 appear high enough in the tissues to account for the inhibition of microbial growth.

Background: The Area Under the Concentration-time curve (AUC) of Mycophenolic Acid (MPA), is a valid prognosticator of the risk of rejection and the gold standard in its Therapeutic Drug Monitoring (TDM), over time post-transplantation. Objective: This study aimed to investigate MPA pharmacokinetic parameters and develop a Limited Sampling Strategy (LSS) to estimate an abbreviated MPA AUC, in the stable phase post-renal transplantation. Methods: In this study, 19 patients with normal graft function (glomerular filtration rate >70 ml/min) who fulfilled the inclusion and exclusion criteria were involved. Blood samples at various times were taken in the stable phase after transplantation. MPA plasma concentration was measured by reverse-phase high-performance liquid chromatography. MPA AUC0–12h was calculated using the linear trapezoidal rule. Multiple stepwise regression analysis was used to determine the minimal time points of MPA levels that could be used to yield model equations best fitted to MPA AUC 0-12h. The findings of this study were compared with the results of our previous study, which was done similarly in the early phase post-renal transplantation. Results: The results demonstrated that the MPA-AUC and clearance were not affected over time, but MPA-tmax was significantly lower in the stable phase in comparison with the early phase (P=0.001). The best regression equation for AUC estimation in the stable phase was AUC=9.57*C6+27.238 (r²=0.907). The validation of the method was performed using the jackknife method. The mean prediction error of these models was not different from zero (P > 0.05) and had a high root mean square prediction error (7.91). Conclusion: In conclusion, the pharmacokinetics of MPA could be affected by time after transplantation, making it essential to develop a limited sampling strategy as an efficacious approach for therapeutic drug monitoring during the stable post-transplant period.

Background: The use of statins to lower high serum cholesterol levels may be associated with a number of adverse reactions, including severe myopathy. The solute carrier organic anion transporter 1B1 (SLCO1B1) gene, which encodes the organic anion-transporting polypeptide OATP1B1, is related to the intracellular transport of statins. The aim of this research was to study the association of rs2306283 and rs4149056 genetic polymorphism of the SLCO1B1 gene with the development of statin-induced myopathy in Jordanian diabetics receiving statins. Methods: We included 413 patients attending the Diabetes Clinics of the National Center for Diabetes, Endocrinology and Genetics, Amman, Jordan. The study was approved by the Institutional Review Board of NCDEG. Myopathy was defined as the elevation of creatine kinase more than 3 times the upper limit of normal. Every subject signed an informed consent form and donated 3-5 mL of venous blood. Genome DNA was extracted from lymphocytes of peripheral blood. Genotypes were identified using the Tetra Amplification Refractory Mutation System of SLCO1B1. Results: The minor allele frequencies of rs2306283 [G] and rs4149056 [C] were 0.38 and 0.23, respectively. The two SNPs followed the Hardy-Weinberg equilibrium. The development of SIM was significantly associated with the homozygous and heterozygous minor allele genotype of rs4149056 (CC and CT), and the homozygous wild type allele genotype of rs2306283 (AA). There was no linkage disequilibrium between the two SNPs in the studied subgroups. Conclusion: Genetic polymorphism in the SLCO1B1 Gene is a risk factor for the development of SIM in Jordanian patients.

Objective: Systemic administration of anti-Vascular Endothelial Growth Factors (anti- VEGFs) has been associated with severe cardiovascular adverse events in oncologic patients. The purpose of this pilot study is to evaluate the short-term effect of a single intravitreal injection of aflibercept on biomarkers related to increased risk of cardiovascular disease. Patients and Methods: Forty-seven treatment naïve patients with neovascular age-related macular degeneration in one eye were enrolled in the study. The patients underwent treatment with one intravitreal injection of aflibercept in the affected eye. Laboratory biomarkers of cardiovascular disease were evaluated before the first intravitreal injection of aflibercept and at 7 and 30 days after aflibercept administration. More precisely, we evaluated the levels of homocysteine, total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and Creactive protein. Results: There was not any statistically significant change in the levels of the evaluated parameters up to one month after the first intravitreal injection of aflibercept. Conclusion: According to our study, the administration of a single dose of aflibercept in eyes with neovascular age-related macular degeneration does not seem to affect the evaluated biomarkers that are related to cardiovascular disease.