Current Clinical Pharmacology - Volume 12, Issue 4, 2017

Background: Pharmacogenetics is a promising area of medical research, providing methods to identify the appropriate pharmaceutical agent and dosing for each unique patient. Glucagon- like peptide-1 (GLP-1) agonists are a novel therapeutic choice used in the treatment of type 2 diabetes mellitus (T2DM), demonstrating efficacy regarding glycemic control and weight loss. Therapeutic response to GLP-1 agonist treatment is a complex biophenomenon, dependent on a plethora of modifiable (diet, exercise, adherence) and non-modifiable (genetic individual variants, ethnic characteristics) parameters. n this context, it has been hypothesized that genetic polymorphisms of GLP-1 related genes may be associated with the therapeutic response to GLP-1 agonist treatment. This review focuses on the most important polymorphisms of the GLP-1 biological network that could affect clinical response to GLP-1 agonist treatment. Methods: Biomedical databases were searched to identify key articles in the field and their results are critically presented in this review. Result: Recent pharmacological and clinical studies demonstrated a significant variation in GLP-1 agonist treatment, in cohorts with homogeneous adherence to diet, exercise and antidiabetic treatment. These studies identified several cases of non-responders to GLP-1 agonist therapy, in association with specific allelic patterns of GLP-1 receptor or other biomolecules implicated in glucose homeostasis. Conclusion: Although the exact DNA sequences that cause the molecular changes leading to a variable response to GLP-1 agonists have not been yet fully identified, these findings underline the importance of an individualized approach in anti-diabetic treatment.

Background: The most common acquired cause of Long QT syndrome (LQTS) is drug induced QT interval prolongation. It is an electrophysiological entity, which is characterized by an extended duration of the ventricular repolarization. Reflected as a prolonged QT interval in a surface ECG, this syndrome increases the risk for polymorphic ventricular tachycardia (Torsade de Pointes) and sudden death. Method: Bibliographic databases as MEDLINE and EMBASE, reports and drug alerts from several regulatory agencies (FDA, EMEA, ANMAT) and drug safety guides (ICH S7B, ICH E14) were consulted to prepare this article. The keywords used were: polymorphic ventricular tachycardia, adverse drug events, prolonged QT, arrhythmias, intensive care unit and Torsade de Pointes. Such research involved materials produced up to December 2017. Results: Because of their mechanism of action, antiarrhythmic drugs such as amiodarone, sotalol, quinidine, procainamide, verapamil and diltiazem are associated to the prolongation of the QTc interval. For this reason, they require constant monitoring when administered. Other noncardiovascular drugs that are widely used in the Intensive Care Unit (ICU), such as ondansetron, macrolide and fluoroquinolone antibiotics, typical and atypical antipsychotics agents such as haloperidol, thioridazine, and sertindole are also frequently associated with the prolongation of the QTc interval. As a consequence, critical patients should be closely followed and evaluated. Conclusion: ICU patients are particularly prone to experience a QTc interval prolongation mainly for two reasons. In the first place, they are exposed to certain drugs that can prolong the repolarization phase, either by their mechanism of action or through the interaction with other drugs. In the second place, the risk factors for TdP are prevalent clinical conditions among critically ill patients. As a consequence, the attending physician is expected to perform preventive monitoring and ECG checks to control the QTc interval.

Background: Polidocanol is approved for its competence in the treatment of varicose veins and spider veins; however, unfortunately, many of its off-label uses are still underappreciated. Objective: Lack of an appropriate comprehensive review for off-label uses of this medication troubles physicians about making evidence-based decisions on prescribing it for its various outstanding off-label uses. This article attempts to provide physicians with the latest information concerning successful and unsuccessful use of polidocanol as an alternative treatment for esophageal and gastric varices, tendinopathy and epicondylitis, vascular malformations, varicocele, hydrocele and spermatocele, aneurysmal bone cysts, itching, management of gastrointestinal bleeding, simple renal cysts, reducing the incidence and severity of radio-induced dermatitis and hemorrhoids. Method: The two databases of MEDLINE and Cochrane Library were searched for all human English studies, published in January 2006 to November 2017, which contained the keyword of “polidocanol” or its alternative MeSH terms. Results: Our search identified a total number of 597 articles. Those articles that were only discussing the approved uses of polidocanol were excluded and the remaining 116 articles were reviewed. Eleven major and 30 minor off-label uses were found within included studies. Conclusion: Numerous successful administrations of this drug in a variety of clinical conditions lead to promising perspectives toward it. Sclerotherapy with polidocanol as a minimal-invasive method (having similar outcomes like the prevalent surgeries) may reduce the rate of complications. Furthermore, for determining the most appropriate method and dosage, randomized clinical trials are needed, confirming and providing more clear instructions for different conditions.

Background: Essential oils (EOs) are natural volatile plant extracts that have different biological activities including antiproliferative potentials. Objective: The current study aims at evaluating the antiproliferative activities against some cancer cell lines of six EOs in their neat oily state and in water-based microemulsions where the EOs exist as nanoparticles. The EOs included marjoram (Origanum majorana), turmeric (Curcuma longa), sweet basil (Ocimum basillicum), clove buds (Syzygium aromaticum), geranium (plargonium graviolenis), and black cumin (Nigella sativa). Method: GC-MS chromatographic analysis was used to reveal the chemical composition of EOs. Self-microemulsification method and oil titration method were used for the fabrication of the different microemulsions. MTT assay and IC50 determinations were used for evaluating the extent of the antiproliferative activity. Results: Results indicated that geranium EO was the most active against the evaluated cancer cell lines followed by basil EO and marjoram EO. On the other hand, turmeric followed by black cumin EOs showed the least antiproliferative activity relative to the other EOs. Clove EO showed selective activity depending on the type of cancer cell lines. Formulation of these EOs in microemulsions led to the development of water-borne nanoparticles having an average particle size from 10.7nm to 18.0 nm depending on the type of EO. Re-evaluation of the antiproliferative activity of these EOs after microemulsification showed differential behavior ranging from activity enhancement to retardation relative to the original activity of each corresponding neat EO in its oily state. Potential factors that could justify the obtained results are discussed. Conclusion: Some EOs and their microemulsions may potentially be used as natural adjuvants to classical anti-cancer drugs.

Background: Pharmaceutical companies provide a broad range of different mandatory trainings to their medical representatives to keep the business running; however research related training has often been neglected by these companies. Thus, this study was developed to assess the amount of scientific research knowledge and interest among pharmacy medical representatives in Jordan. Method: A cross sectional study was conducted in Jordan in 2016. During the study period, a questionnaire was administered to 250 medical representatives working in pharmaceutical companies to evaluate their scientific research knowledge and attitudes. Results: The majority of medical representatives had positive attitudes towards clinical trials and research communication and believe that it will increase the value of their work, but a considerable number of medical representatives did not detail clinical trials on every visit and found difficulty in answering clinical trials and research related questions asked by health care professionals. Most of the medical representatives did not have a complete understanding of some basic research terminologies. Medical representatives working in multinational companies seemed to have a significantly better understanding of research and terminologies compared to local companies (P-value= 0.000). Also Medical representatives with higher educational degrees seemed to have significantly better understanding of basic research terminologies (P-value= 0.023). Conclusion: The majority of medical representatives had positive attitudes towards clinical trials and research communication and found that it will increase the value of their work, but still there is a gap in their frequency of detailing. Thus, local pharmaceutical companies need to invest more in research and clinical trials knowledge kind of training. Also, universities need to include research related courses and subject in their bachelors' program curriculum in order to make pharmacists equipped in terms of research knowledge, regardless of the career path they choose.

Objective: Curcumin is a naturally occurring polyphenol derived from tumeric that has been reported to have anti-inflammatory properties with effects on adipokine and ghrelin levels. Adiponectin, leptin and ghrelin modulate energy homeostasis but each has modulatory effects on inflammatory cytokines and the immune system. Therefore, this analysis was performed to investigate the effect of curcumin on adiponectin, leptin and ghrelin. Method: A double blind randomised control trial comparing curcumin 1000mg with 10mg of piperine daily to placebo over a 12 week period. 118 patients with type 2 diabetes were recruited out of which 50 control and 50 active subjects completed the trial. Adiponectin, leptin, ghrelin and tumor necrosis factor-α (TNF-α) were measured at baseline and 12 weeks. Results: Between group comparison of the magnitude of changes showed serum levels of leptin (p<0.001), TNF-α (p<0.001) and leptin:adiponectin ratio (p<0.001) to be significantly reduced while serum adiponectin levels were elevated in the curcuminoids versus placebo group (p=0.032). Changes in serum ghrelin levels did not differ between the study groups (p=0.135). Conclusion: Curcumin supplementation increased adiponectin, whilst the the leptin:adiponectin ratio (a measure of atherosclerosis) and leptin levels were decreased independent of weight change and reflected a decrease in the inflammatory TNF-α levels.

Background: Methadone toxicity is one of the major causes of death in opioiddependent individuals. Objective: We aimed to compare two different protocols of naloxone administration in terms of reversal of overdose signs and symptoms and frequency of complications in opioid-dependent methadone-intoxicated patients. Method: One-hundred opioid-dependent patients with signs/symptoms of methadone overdose were included. The patients were consecutively assigned into Tintinalli (group 1) or Goldfrank regimen protocol (group 2) of naloxone administration. Group 1 received naloxone with the dose 0.1 mg given every two to three minutes while group 2 received naloxone with the initial dose of 0.04 mg increasing to 0.4, 2, and 10 mg every two to three minutes to reverse respiratory depression. They were then compared regarding reversal of toxicity and risk of development of complications. Results: The time to reversal of the overdose signs/symptoms was significantly less in Goldfrank regimen protocol (P<0.001). Frequency of withdrawal syndrome and recurrence of respiratory depression were not significantly different between the two groups. Aspiration pneumonia and intubation were more frequent in group 2, as well. Conclusion: It seems that gradual titration of naloxone by Tintinalli protocol can reduce major complications compared to the Goldfrank regimen. However, this protocol was not perfect in opioid-dependent methadone-overdosed patients, either, since it could induce complications, as well. We may need new protocols in overdosed opioid-dependent patients.