Current clinical pharmacology最新文献

Diabetic nephropathy is defined as a decline in the renal function and an increase in the amount of albuminuria (>300 mg/day). The interruption of the renin-angiotensin-aldosterone system (RAAS) by well-established therapies such as angiotensin-converting enzyme inhibitor, angiotensin receptor blockers, calcium channel blockers or diuretics has been beneficial in reducing the progression of renal diseases; however, there is an increase in the levels of aldosterone due to the aldosterone escape phenomenon. Newer and novel approaches to counteract this aldosterone breakthrough while accentuating the anti-hypertensive and anti-proteinuric effects of these agents would be ideal and mineralocorticoid receptor antagonists fit in this slot perfectly. This review attempted to evaluate the safety and efficacy of and mineralocorticoid receptor antagonists for diabetic nephropathy. Presently mineralocorticoid receptor antagonists such as spironolactone, eplerenone and finerenone are being investigated as both monotherapies and as additional therapies. Clinical studies have shown that these drugs have been effective in the reduction of blood pressure, urinaryalbumin- excretion and estimated glomerular filtration rate. The commonly observed adverse effects are hyperkalemia, gynaecomastia and vaginal bleeding, that are bothersome with spironolactone seems to be avoidable if these patients are switched to non-steroidal and mineralocorticoid receptor antagonists such as finerenone and eplerenone. Most of the studies have only evaluated the shortterm effects of mineralocorticoid receptor antagonists on diabetic nephropathy. Hard outcomes such as cardiovascular events, creatinine doubling, progression to end-stage renal disease, mortality and the need for temporary or permanent dialysis need to be studied with these molecules.

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: 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.

Developing new biologics has led to regulations and norms aimed at guaranteeing their safety, quality and effectiveness, in terms of marketing, prescription, use, interchangeability and switching. Biologics are of great importance in treating patients suffering from rheumatic, autoimmune, inflammatory and neoplastic diseases. The expiry/lapse of reference biologics or originators' patents has meant that developing biosimilars involves accompanying legal requirements for their approval in countries worldwide. This paper has thus approached the situation of biosimilar regulation worldwide, the pertinent technical concepts and regulatory differences in some countries of interest.

Background: Nowadays, ionizing radiation is used for several applications in medicine, industry, agriculture, and nuclear power generation. Besides the beneficial roles of ionizing radiation, there are some concerns about accidental exposure to radioactive sources. The threat posed by its use in terrorism is of global concern. Furthermore, there are several side effects to normal organs for patients who had undergone radiation treatment for cancer. Hence, the modulation of radiation response in normal tissues was one of the most important aims of radiobiology. Although, so far, several agents have been investigated for protection and mitigation of radiation injury. Agents such as amifostine may lead to severe toxicity, while others may interfere with radiation therapy outcomes as a result of tumor protection. Metformin is a natural agent that is well known as an antidiabetic drug. It has shown some antioxidant effects and enhances DNA repair capacity, thereby ameliorating cell death following exposure to radiation. Moreover, through targeting endogenous ROS production within cells, it can mitigate radiation injury. This could potentially make it an effective radiation countermeasure. In contrast to other radioprotectors, metformin has shown modulatory effects through induction of several genes such as AMPK, which suppresses reduction/ oxidation (redox) reactions, protects cells from accumulation of unrepaired DNA, and attenuates initiation of inflammation as well as fibrotic pathways. Interestingly, these properties of metformin can sensitize cancer cells to radiotherapy.

Conclusion: In this article, we aimed to review the interesting properties of metformin such as radioprotection, radiomitigation and radiosensitization, which could make it an interesting adjuvant for clinical radiotherapy, as well as an interesting candidate for mitigation of radiation injury after a radiation disaster.

Background: Epilepsy is one of the most common and severe brain disorders in the world, characterized by recurrent spontaneous seizures due to an imbalance between cerebral excitability and inhibition. Oxidative stress is a biochemical state in which reactive oxygen species are generated and associated with various diseases including epilepsy. Pycnogenol, a polyphenol obtained from the pine tree and has antioxidant & anti-inflammatory activity. So, the aim of the study was to evaluate the effect of Pycnogenol on pentylenetetrazole (PTZ)-induced seizures in mice.

Methods: The mice of swiss strain each weighing 18-30g were used. Pycnogenol (50&100mg/kg) was suspended in carboxymethyl cellulose in saline and administered orally. Diazepam (1mg/kg, i.p) was used as a standard drug. The anticonvulsant effects of the drugs were measured using PTZ and cognitive behaviour was also assessed. The biochemical estimation was done by measuring Thiobarbituric acid, Superoxide dismutase, Catalase, and reduced glutathione followed by the histopathological study.

Result: Pycnogenol 50 & 100mg/kg showed a significant increase in latency to PTZ-induced seizures, decrease in duration and frequency of convulsions compared to control animals; however, the effects were dose-dependent and were more significant at a higher dose. No impairment in cognitive functions like memory and muscle relaxant was observed following pycnogenol 50 & 100 mg/kg. The effect of Pycnogenol on biochemical parameter was found to be significant. It significantly (p<0.01) decreases the level of TBARS and increases the levels of SOD, catalase, and GSH in the brain tissue. The histopathological evaluation showed less neuronal degeneration in the brain due to PTZ-induced seizures in comparison to control group.

Conclusion: Thus pycnogenol has a protective approach towards convulsion and can be included as an adjuvant therapy with antiepileptic drugs.

Background: Opioid analgesics are commonly used along with propofol during general anesthesia. Due to the dearth of data on the quality of anesthesia achieved with this combination, the present meta-analysis was carried out.

Methods: Electronic databases were searched for appropriate studies using a suitable search strategy. Randomized clinical trials comparing the combination of remifentanil/sufentanil/alfentanil with propofol with fentanyl and propofol, were included. The outcome measures were as follows: total propofol dose to achieve the desired general anesthesia; time of onset and duration of general anesthesia; depth of general anesthesia; and recovery time (time for eye-opening and time taken for extubation). Risk of bias was assessed and Forest plots were generated for eligible outcomes. The weighted mean difference [95% confidence intervals] was used as the effect estimate.

Results: Fourteen studies were included in the systematic review and 13 were included in the metaanalysis. Statistically significant differences were observed for remifentanil in comparison to fentanyl when combined with propofol: Propofol dose (in mg) -76.18 [-94.72, -57.64]; time of onset of anesthesia (min) -0.44 [-0.74, -0.15]; time taken for eye-opening (min) -3.95 [-4.8, -3.1]; and time for extubation (min) -3.53 [-4.37, -2.7]. No significant differences were observed for either sufentanil or alfentanil about the dose of propofol required and due to scanty data, pooling of the data could not be attempted for other outcome measures for either sufentanil or alfentanil.

Conclusion: To conclude, we found that remifentanil has a statistically significant anesthetic profile than fentanyl when combined with propofol. Scanty evidence for both alfentanil and sufentanil precludes any such confirmation.

Background: In this study, we aimed to detect the changes in the level of interleukin (IL)-4 and IL-13 cytokines and their downstream genes including interleukin-13 receptor subunit alpha-2 (IL13Ra2), interleukin-4 receptor subunit alpha-1 (IL4Ra1), dual oxidase 1 (DUOX1) and dual oxidase 2 (DUOX2). The protective effects of Selenium-L-methionine on radiation-induced histopathological damages and changes in the level of these cytokines and genes were detected.

Methods: Four groups of 20 rats (5 rats in each) namely, control; Selenium-L-methionine, radiation and radiation plus Selenium-L-methionine were used in this study. 4 mg/kg of Selenium-Lmethionine was administered 1 day before irradiation and five consecutive days after irradiation. Irradiation was done using a dose of 15 Gy 60Co gamma rays at 109 cGy/min. All rats were sacrificed 10 weeks after irradiation for detecting changes in IL-4 and IL-13 cytokines, the expressions of IL13Ra2, IL4Ra1, Duox1 and Duox2 and histopathological changes.

Results: The level of IL-4 but not IL-13 increased after irradiation. This was associated with increased expression of IL4Ra1, Duox1 and Duox2, in addition to changes in morphological properties. Selenium-L-methionine could attenuate all injury markers following lung irradiation.

Conclusion: Selenium-L-methionine can protect lung tissues against toxic effects of ionizing radiation. It is possible that the modulation of immune responses and redox interactions are involved in the radioprotective effect of this agent.

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.