Current Clinical Pharmacology - Volume 15, Issue 1, 2020

Background: Current guidelines recommend the use of vancomycin for the initial treatment of Clostridioides difficile Infection (CDI). Cadazolid, an experimental drug, has been utilized and compared in several studies with varying results. Methods: A systematic literature search was performed using electronic databases [Medline, Google Scholar and Cochrane] for eligible studies. Randomized Controlled Trials (RCTs) comparing cadazolid with vancomycin for CDI treatment were included. Demographic variables and outcomes (CDI resolution, CDI recurrence, and adverse events) were collected. The primary outcome was clinical cure rate defined as the resolution of CDI at the end of a 10-day course. Results: Two studies with three RCTs met the inclusion criteria with a total of 1283 patients with CDI who received either cadazolid 250 mg twice daily (624 patients) or vancomycin 125 mg four times daily (659 patients). Clinical cure rate at the end of the treatment was not statistically significant (pooled OR= 0.82; 95% CI = 0.61 to 1.11; p=0.20; I2= 0%). Sustained clinical response at clinical follow-up was also not significantly different (pooled OR = 1.14; 95% CI = 0.91 to 1.43; p=0.27; I2 = 0 %). Cadazolid had a lower recurrence rate than vancomycin (pooled OR = 0.71; 95% CI = 0.52 to 0.98; p=0.04; I2 = 13 %). Conclusion: Cadazolid is non-inferior to vancomycin and offers a promising alternative for the treatment of CDI. More studies including RCTs and longitudinal studies with large and diverse patient population are needed to further confirm this. Furthermore, cadazolid should also be compared with fidaxomicin in a head-to-head trial to evaluate their efficacy for CDI.

Background: In the recent years, immunotherapeutics and specifically immunecheckpoints inhibitors have marked a significant shift in the diagnostic and therapeutic algorithm of Non-Small Cell Lung Cancer (NSCLC), allowing us to use immunotherapeutics alone or combined with chemotherapy for a great subset of patients. However, new interesting approaches are being presently investigated, markedly immunotherapy combinations, that is, the use of two or more immunotherapeutics combined. Methods: In particular, the combination of anti-PD-1 nivolumab and anti-CTLA-4 ipilimumab has already provided groundbreaking positive results in the advanced NSCLC and other combinations are currently under investigation. Results: Therefore, this paper aims to provide a comprehensive state-of-the-art review about immunotherapy combination, along with suggestions about future directions. A comprehensive literature search was carried out to identify eligible studies from MEDLINE/PubMed and ClinicalTrials.gov. Conclusion: Nivolumab plus ipilimumab represent the most promising immunotherapy combination for the treatment of advanced NSCLC patients; safety, tolerability and efficacy of new immunotherapeutics (in monotherapy and in immunotherapy combinations) must be further assessed in future studies.

Background: Over the past few decades, nanotechnology has dramatically advanced; from the precise strategies of synthesizing modern nanostructures to methods of entry into the body. Using nanotechnology in diagnosis, drug delivery, determining signaling pathways, and tissue engineering is great hope for the treatment of stroke. The drug-carrying nanoparticles are a way to increase drug absorption through the mouth or nose in treating the stroke. Objective: In this article, in addition to explaining pros and cons of oral and intra-nasal administration of nanoparticles in the brain ischemia treatment of animal models, the researchers introduce some articles in this field and briefly mentioned their work outcomes. Methods: A number of relevant published articles 183 were initially collected from three popular databases including PubMed, Google Scholar, and Scopus. The articles not closely related to the main purpose of the present work were removed from the study process. The present data set finally included 125 published articles. Results: Direct delivery of the drug to the animal brain through the mouth and nose has more therapeutic effects than systemic delivery of drugs. The strategy of adding drugs to the nanoparticles complex can potentially improve the direct delivery of drugs to the CNS. Conclusion: Despite the limitations of oral and intra-nasal routes, the therapeutic potential of oral and intra-nasal administration of nano-medicines is high in cerebral ischemia treatment.

Background: Heart failure is a common medical problem in the world, which has a high prevalence in both developed and developing countries. Today, among the medications used for the heart failure treatment, there are many medications with a positive cardiac contraction effect (positive inotropic such as digital glycosides, adrenergic receptor stimulants, and phosphodiesterase inhibitors), a large number of cardiac diluents (such as Angiotensin-Converting Enzyme (ACE) inhibitor group), and a few other types of drugs whose final effects are still under review. Statins are valuable drugs that are broadly prescribed in hyperlipidemia and cardiovascular patients due to their multiple properties, such as cholesterol reduction, endothelial function improvement, antioxidative, anti-inflammatory, neovascularization, and immunomodulatory activities. Methods: There is evidence that the therapeutic role of statins in HF, due to myocardial hypertrophy, show reduction in cardiomyocyte loss in the apoptosis process, oxidative stress, inflammation, and also the return of neurohormonal imbalance. However, the fact that these drugs have no sideeffects has not been confirmed in all studies, as statins prevent the production of particular beneficial and protective factors, such as coenzyme Q10 (CoQ10), while inhibiting the production of specific proteins involved in pathologic mechanisms. Results: Recently, it has been hypothesized that, despite the positive effects reported, high doses of statins in patients with long-term heart failure lead to progress in heart failure by inhibiting CoQ10 synthesis and intensifying hypertrophy. Conclusion: Thus, it can be stated that the advantage of using statins depends on factors, such as stroke fraction, and the existence of other standard indications such as atherosclerotic diseases or high Low-Density Lipoprotein-C (LDL-C).

Background: Peripheral neuropathy is a painful condition deriving from many and varied etiologies. Certain medications have been implicated in the iatrogenic development of Drug Induced Peripheral Neuropathy (DIPN) and include chemotherapeutic agents, antimicrobials, cardiovascular drugs, psychotropic, anticonvulsants, among others. This review synthesizes current clinical concepts regarding the mechanism, common inciting medications, and treatment options for drug-induced peripheral neuropathy. Methods: The authors undertook a structured search of bibliographic databases for peer-reviewed research literature using a focused review question and inclusion/exclusion criteria. The most relevant and up to date research was included. Results: Drug-induced peripheral neuropathy is a common and painful condition caused by many different and frequently prescribed medications. Most often, DIPN is seen in chemotherapeutic agents, antimicrobials, cardiovascular drugs, psychotropic, and anticonvulsant drugs. Certain drugs exhibit more consistent neuropathic side effects, such as the chemotherapeutic compounds, but others are more commonly prescribed by a larger proportion of providers, such as the statins. DIPN is more likely to occur in patients with concomitant risk factors such as preexisting neuropathy, diabetes, and associated genetically predisposing diseases. DIPN is often difficult to treat, however medications including duloxetine, and gabapentin are shown to reduce neuropathic pain. Advanced techniques of neuromodulation offer promise though further randomized and controlled studies are needed to confirm efficacy. Conclusion: Awareness of the drugs covered in this review and their potential for adverse neuropathic effect is important for providers caring for patients who report new onset symptoms of pain, paresthesia, or weakness. Prevention of DIPN is especially important because treatment often proves challenging. While many pharmacologic therapies have demonstrated analgesic potential in the pain caused by DIPN, many patients remain refractive to treatment. More studies are needed to elucidate the effectiveness of interventional, neuromodulating therapies.

Objective: We aimed to determine the therapeutic drug monitoring (TDM) features and the relation to Brain-Derived Neurotrophic Factor (BDNF) of frequently used new antiepileptic drugs (NADs) including lamotrigine (LTG), oxcarbazepine (OXC), zonisamide (ZNS) and lacosamide (LCM). Moreover, we investigated their effect on the quality of life (QoL). Methods: Eighty epileptic patients who had been using the NADs, and thirteen healthy participants were included in this cross-sectional study. The participants were randomized into groups. The QOLIE-31 test was used for the assessment of QoL. We also prepared and applied "Safety Test". HPLC method for TDM, and ELISA method for BDNF measurements were used consecutively. Results: In comparison to healthy participants, epileptic participants had lower marriage rate (p=0.049), education level (p<0.001), alcohol use (p=0.002). BDNF levels were higher in patients with focal epilepsy (p=0.013) and in those with higher education level (p=0.016). There were negative correlations between serum BDNF levels and serum ZNS levels (p=0.042) with LTGpolytherapy, serum MHD levels (a 10-monohydroxy derivative of OXC, p=0.041) with OXCmonotherapy. There was no difference in BDNF according to monotherapy-polytherapy, drugresistant groups, regarding seizure frequency. There was a positive correlation between total health status and QoL (p<0.001). QOLIE-31 overall score (OS) was higher in those with OXC-monotherapy (76.5±14.5). OS (p<0.001), seizure worry (SW, p=0.004), cognition (C, p<0.001), social function (SF, p<0.001) were different in the main groups. Forgetfulness was the most common unwanted effect. Conclusion: While TDM helps the clinician to use more effective and safe NADs, BDNF may assist in TDM for reaching the therapeutic target in epilepsy.

Background: The present work aimed to evaluate the chemical composition of Curcuma zadoaria essential oil and to investigate its efficacy and safety against hydatid cyst protoscoleces. Methods: Collected protoscoleces from liver fertile hydatid cysts of infected sheep were exposed to different concentrations of the essential oil (75, 150, 300 μl/mL) for 5-30 min in vitro and ex vivo. Then, by using the eosin exclusion assay, the viability of protoscoleces was studied. In the next step, 24 male NMRI mice were examined to assess the toxicity of C. zadoaria essential oil by measuring the biochemical and hematological parameters. Results: Based on the obtained results, the LD50 value of intraperitoneal injection of the C. zadoaria essential oil was 1.76 mL/kg of body weight and the maximum non-fatal dose was 0.96 mL/kg of body weight. C. zadoaria essential oil had a strong proto scolicidal activity in vitro so that at the 300 and 150 μl/ml entirely eliminates the parasite after 5 and 10 minutes; whereas, weak proto scolicidal activity was observed at lower doses. Ex vivo assay, no similar effect with in vitro was observed, therefore, more time is required to show a potent proto scolicidal activity. C. zadoaria essential oil at the concentrations of 300 and 150 μl/mL after an exposure time of 7 and 12 min, killed 100% of protoscoleces within the hydatid cyst, respectively. After intraperitoneal injection of the C. zadoaria essential oil for 2 weeks, no significant difference (p > 0.05) was observed in the clinical chemistry and hematologic parameters at the doses of 0.15, 0.3, 0.6 mL/kg. Conclusion: The obtained results in vitro and ex vivo exhibited that C. zadoaria essential oil had a favorable proto scolicidal activity on hydatid cyst protoscoleces. However, more supplementary works are required to verify these findings by assessing clinical subjects.

Background and Objective: Despite the established importance of thromboprophylaxis in patients with Venous Thromboembolism (VTE), a limited number of studies have assessed the awareness of VTE and thromboprophylaxis therapy among the affected patients. The aim of the current study was to assess awareness and to explore variables associated with awareness about VTE and its thromboprophylaxis. Methods: A cross-sectional study was conducted on hospitalized patients who received thromboprophylaxis (5000 units of heparin subcutaneously (SC) q8-12h, or 30-40 mg of enoxaparin SC once daily). In addition to the sociodemographic variables, awareness and perception of VTE and its thromboprophylaxis were assessed using a validated questionnaire. Multiple logistic regressions were conducted to build a model of variables significantly associated with VTE awareness. Results: A total of 225 patients participated in the study, with only 38.2% and 22.2% of the participants being aware of Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) respectively. Logistic regression showed that the participants with low educational level had 3.046 value, with the odds being not aware of DVT or PE compared with participants with high educational level. Participants without a personal history of VTE had 7.374 value, with the odds being not aware of DVT or PE compared with those who had a personal history of VTE. Participants who had a negative perception of VTE had 2.582 value, with the odds being not aware of DVT or PE compared with participants who had a positive perception and those who did not have any information about DVT or PE had 13.727 value, with the odds being not aware of DVT or PE. Conclusion: The findings reveal that there is a lack of awareness about VTE and its thromboprophylaxis among the study participants. Patients with lower educational level and those with no history of previous VTE need awareness improvement about VTE and its thromboprophylaxis. Clinical Pharmacists need to focus on providing information about VTE and improving patients’ perception about VTE and its thromboprophylaxis with the aim of improving the awareness about VTE, and hence the better health outcome.

Background: Benzodiazepine is one of the most important causes of substance abuse and intoxication throughout the world and Iran. Objective: The aim of our study is to determine the role of stimulants in reversing CNS level in acute Benzodiazepine poisoning patients who were hospitalized at referral poison center. Method: This was a randomized double-blind placebo-controlled trial study on 32 cases with pure acute Benzodiazepine poisoning from March 2016 to February 2017. Diagnosis of pure acute poisoning was based on history, and laboratory confirmation. We gathered the demographics, clinical data, laboratory data, hospitalization and outcome. Participants were randomized into two groups: Methylphenidate Group (MPH) and Placebo Group (PBO). Results: The randomized sample consisted of 32 participants who were predominately female (83%). The majority of the PBO group and the MPH group reported improvement in their consciousness with a significant difference between the two groups (p = .005). Paired sample t-test analyses on Reed Scale data revealed an increase in the probability of improvement during the trial for the MPH group compared to the PBO group. Furthermore, the HCo3 (bicarbonate) level has a significant p-value with respect to age groups (p = .02). None of our cases required either the ICU facility or intubation. Conclusion: Our study provided the MPH superiority over PBO in reversing CNS symptoms in loss of consciousness in acute BZD poisoned patients. Thus, this trial provides concrete evidence that improvement in consciousness levels (Reed Scale rated) among those patients receiving MPH was associated with a methylphenidate use.