Current Clinical Pharmacology - Volume 14, Issue 3, 2019

Background: Current guidelines recommend the use of vancomycin for the initial treatment of moderate to severe Clostridioides difficile Infection (CDI). Surotomycin, a novel antibiotic, has been utilized for the management of CDI with variable results. Methods: A systematic literature search was performed using the following electronic databases [Medline, Embase, google scholar and Cochrane] for eligible studies. Randomized controlled trials comparing Surotomycin with Vancomycin for the CDI treatment were included. Demographic variables and outcomes (CDI resolution, CDI recurrence, B1/NAP1/027-specific strain treatment, B1/NAP1/027-strain recurrence, death not related to treatment) were analyzed. The primary outcome was clinical cure rate defined as the resolution of CDI at the end of the 10-day drug course. Results: Three RCTs met the inclusion criteria with a total of 1280 patients with CDI who received either surotomycin 250 mg twice daily (642 patients) or vancomycin 125 mg four times daily (638 patients). Clinical cure rates after 10 days of treatment with either surotomycin or vancomycin were not significantly different (pooled OR: 0.89, 95% CI 0.66-1.18, p=0.41). Sustained clinical response at clinical follow-up and the overall recurrence of CDI were also not significantly different between the two groups – pooled OR 1.15 (95% CI 0.89-1.50, p=0.29) and pooled OR 0.74 (95%CI 0.52- 1.04, p=0.08), respectively. With regards to the NAP1/BI/027 strain, patients in the surotomycin group had significantly lower rates of recurrence compared to vancomycin (pooled OR 0.35, 95% CI 0.19-0.63, p<0.01). Conclusion: Surotomycin is non-inferior to vancomycin and offers a promising alternative for the treatment and prevention of C. diff infection.

Background: Due to inappropriate diet, smoking, alcohol consumption, regular use of drugs like NSAIDs and sedentary lifestyle, one may feel upper abdominal pain which may be the predictor of the gastrointestinal disorder called Peptic Ulcer. When an imbalance occurs between the defensive factor and aggressive factor of the stomach, ulcer formation in the esophageal lining, stomach, or duodenum takes place. This leads to the formation of small sores that cause pain. Another condition that synergizes the abdominal pain is vomiting materials which look like coffee grounds, blood in the stool, black or tarry stools. This pain may increase after lunch or dinner. This problem persists, that often leads to the gastroenterologist's consultation. Objective: There are many antiulcer screening models present for the determination of antiulcer activity of the drug molecule. The main objective of this study is to find which model is best for the determination of antiulcer activity. Methods: A literature search was conducted on the databases namely Science direct and PubMed with the help of different keywords such as "Anti-ulcer", "In-vitro models" and "In-vivo models". 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. Result: There are different research and review papers based on the antiulcer screening models for the determination of antiulcer activity of new drug molecules. Conclusion: On the basis of our study, we found some useful models for the antiulcer activity of drugs and suggested that, if we use in-vitro and in-vivo methods together, then we may obtain the most relevant result in our research area.

Background: Exposure, safety and/or efficacy of drugs are subject to potential differences between human races or ethnicities, as acknowledged by regulatory guidance and by label texts of various, but not all approved drugs. Objective: The objective of the present review was to assess recent regulatory precedence on drug use and race or ethnicity, with the goal of identifying opportunities for increasing the informative value of clinical ethnic or racial bridging in drug development. Methods: Recently, (January 2014-July 2018) FDA approved drug product label texts and approval packages were reviewed for claims, comments and underlying data on use of the product in specific ethnic or racial groups. Results: Among the 266 FDA-approved products, no product with unambiguous race- or ethnicity specific dosing instructions was retrieved. A small majority (55%) was approved with a claim or comment on race or ethnicity, and of these, a large majority (87%) was based on population pharmacokinetic data analysis. Statements were often related to incidence of a genotype for drug metabolizing enzyme or for other risk factors, or were related to body weight. Absence of clinically relevant exposure differences were often justified in terms of exposure ratios that notably exceeded the typical 0.80-1.25 no-effect boundary. Conclusions: Recent precedence reflected a pragmatic, descriptive approach of racial or ethnic bridging, apparently meeting current regulatory expectations, whilst not resulting in strict guidance to prescribers. We recommend further work on defining the objectives of bridging studies, as well as criteria for their design and data analysis. Regarding the latter, we recommend investigating the value of prospectively defined tests for similarity with appropriate follow-up analysis in the case where the test has failed.

Background: Cesarean section is the most common midwifery operation. The aim of this study is to determine the mean minimum dose of bolus oxytocin for proper uterine contraction during cesarean section. Methods: Patients were divided into two groups: elective cesarean section (n=41) and cesarean section due to difficulty in labor (n=42 patients). Patients underwent spinal anesthesia and oxytocin infusion was begun at 30 drops per minute (20 units of oxytocin per 1000 cc serum), and was also administered as a half-dose in cc to achieve effective contraction of the uterus. Meanwhile, the information of patients including systolic and diastolic blood pressure (SBP and DBP), heart rate and amount of bleeding during the operation was recorded in a questionnaire. Results: In the elective cesarean section group, the average SBP was about 117.10mmHg, average DBP 70.50 mmHg, the amount of bleeding during surgery was 623.63mL, and heart rate was 88.88bpm. In the cesarean section group due to difficulty in labor progress, SBP was 113.5 mmHg, DBP 62.69 mmHg, and bleeding was 573.81mL. In addition, 9 patients in the elective group and 3 patients in the lack of progress group, did not require bolus oxytocin. In the lack of a progress group, 8 patients needed more than 5 doses of oxytocin. In addition, about 10 (12%) of all patients had no side effects, and hypotension. Conclusion: Given that, the minimum effective dose of oxytocin in the elective cesarean section was 1IU, and in those in labor progress was 1-1.5IU, less oxytocin administration represents lesser side effects. It is recommended that patients who are candidates of cesarean section should be administered 1.5IU of oxytocin in the form of bolus.

Background: Cotrimoxazole is the main antibiotic used in primary prophylaxis for opportunistic infections in advanced HIV infection. This drug can inhibit one of the metabolic pathways of atazanavir (ATV), such as the cytochromes P450 (CYP) 2C8/2C9 and could interfere with its safety and efficacy. Objective: We studied the drug-drug interaction (DDI) between cotrimoxazole and ATV by using therapeutic drug monitoring (TDM) and pharmacovigilance (PV) approaches. Methods: We compared a group of patients treated with cotrimoxazole and receiving an ATV-based regimen to controls. This historical cohort analysis used data from Dat’AIDS in HIV-infected patients who had at least two lowest plasma concentrations (C-trough) of ATV during their outpatient follow-up. Likewise, we used the international pharmacovigilance data from VigiBase to evaluate the notifications of hyperbilirubinemia reported with ATV. Results: In the TDM analysis, the two groups of patients (treated with cotrimoxazole and controls) were almost homogeneous concerning the main baseline features. After at least six months of ATVbased regimen, there was no significant difference in the safety threshold of the ATV C-trough [with an adjusted odds ratio (aOR) of 1.4 (95% CI: 0.5 - 4.4)] compared to controls. We observed similar results with the efficacy thresholds of ATV C-trough. Regarding the PV analysis, there was no difference in hyperbilirubinemia occurring with ATV when cotrimoxazole was concomitant, with an adjusted reporting odds ratio (aROR) of 0.9 (95% CI: 0.6 to 1.2). Conclusion: This study showed a relevant concomitant use between Cotrimoxazole and ATV based on TDM and PV approaches.

Background: Exposure to ionizing radiation may lead to chronic upregulation of inflammatory mediators and pro-oxidant enzymes, which give rise to continuous production of reactive oxygen species (ROS). NADPH oxidases are among the most important ROS producing enzymes. Their upregulation is associated with DNA damage and genomic instability. In the present study, we sought to determine the expressions of NADPH oxidases; NOX2 and NOX4, in rat’s lung following whole body or pelvis irradiation. In addition, we evaluated the protective effect of melatonin on the expressions of NOX2 and NOX4, as well as oxidative DNA injury. Methods: 35 male rats were divided into 7 groups, G1: control; G2: melatonin (100 mg/kg) treatment; G3: whole body irradiation (2 Gy); G4: melatonin plus whole body irradiation; G5: local irradiation to pelvis area; G6: melatonin treatment plus 2 Gy gamma rays to pelvis area; G7: scatter group. All the rats were sacrificed after 24 h. afterwards, the expressions of TGFβR1, Smad2, NF- ΚB, NOX2 and NOX4 were detected using real-time PCR. Also, the level of 8-OHdG was detected by ELISA, and NOX2 and NOX4 protein levels were detected by western blot. Results: Whole body irradiation led to the upregulation of all genes, while local pelvis irradiation caused upregulation of TGFβR1, NF-ΚB, NOX2 and NOX4, as well as protein levels of NOX2 and NOX4. Treatment with melatonin reduced the expressions of these genes and also alleviated oxidative injury in both targeted and non-targeted lung tissues. Results also showed no significant reduction for NOX2 and NOX4 in bystander tissues following melatonin treatment. Conclusion: It is possible that upregulation of NOX2 and NOX4 is involved in radiation-induced targeted and non-targeted lung injury. Melatonin may reduce oxidative stress following upregulation of these enzymes in directly irradiated lung tissues but not for bystander.

Background: Serotonin 5-HT3 receptor antagonists such as ondansetron have been investigated to attenuate opioid withdrawal signs in studies. Objective: Therefore, we designed a randomized double-blinded placebo-controlled trial to evaluate this effect on opioid-addicted patients who were admitted to the orthopedic department for surgery due to bone fractures. Methods: Male adults who were addicted to opioids, aged 18 to 79 years were enrolled (n=96) and randomized into intravenous doses (4 & 8 mg) of ondansetron (n=32) and placebo (n=32). The vital signs, withdrawal symptoms and the frequency requirement of fentanyl were recorded during anesthesia, and opioid (pethidine) analgesic was received during the recovery period. Outcome parameters were analyzed for reduction of withdrawal symptoms in addicted adults. Results: We indicated that ondansetron demonstrated significant differences with few vital outcomes including systolic blood pressure (SBP) 20 (SBP3) and 50 min (SBP4) after injection of ondansetron during the period of surgery. Ondansetron could also significantly reduce the frequency requirement of fentanyl at 20 min (dose 3) in general anesthesia. Furthermore, requirement for further administration of opioid analgesic drugs such as pethidine was significantly reduced in the ondansetron groups. Objective opioid withdrawal scale (OOWS) results indicated that few clinical parameters including tremor, hot and cold flushes and anxiety were significantly attenuated in addicted patients who received ondansetron. Conclusion: This study demonstrated supporting evidence for the beneficial treatment of ondansetron for the control of withdrawal symptoms and pain in addicted patients, and more clinical studies are suggested in this regard.

Background: Azithromycin is one of the most popular antibiotics in current clinical practice. This medication generally considered to be safe and well-tolerated in different demographic populations. Like any other drug, azithromycin use is not without risk and adverse effects. In recent years, cardiovascular accidents have been announced as its major and most important side effect. But azithromycin use can be accompanied with less recognized complications which are significantly discomforting. In this article, we presented a neglected adverse effect of azithromycin in medical literature which is aphthous stomatitis. Methods: We detected three cases with this complication in our center during a one-year period. All the accessible clinical data were recorded and PubMed database was explored to assess the relevant literature. Results: The patients had aphthous stomatitis within 24 hours of the first dose which was healed in about 2 to 3 weeks. Naranjo scoring system showed a probable stage for this adverse drug reaction. There was no such a report in our database search process. Conclusion: It could be stated that aphthous stomatitis is an important adverse effect of azithromycin that can affect the patient’s quality of life during therapy and in the majority of cases, it can be neglected by healthcare practitioners.