Effectiveness and adverse effects of hormonal therapy for prostate cancer： Japanese experience and perspective

Recently, novel anti-androgens and inhibitors of androgen biosynthesis have been developed through the elucidation of mechanisms of castration resistance of prostate cancer. We believe that these new developments will improve hormonal therapy. On the other hand, there has been an increase in criticism of hormonal therapy, because hormonal therapy is supposed to induce adverse effects such as cardiovascular disease. In this review, we have introduced the Japanese experience of hormonal therapy, because we believe that there may be ethnic differences between Caucasians and Asian people in the efficacy and adverse effects of hormonal therapy. First, we showed that primary hormonal therapy can achieve long-term control of localized prostate cancer in some cases and that quality of life of patients receiving hormonal therapy is rather better than previously thought. Neoadjuvant and adjuvant hormonal therapy in cases undergoing radical prostatectomy or radiotherapy are very useful for high-risk or locally advanced prostate cancer. Further clinical trials are required to confirm the efficacy of neoadjuvant or adjuvant hormonal therapy. We showed that the death from cardiovascular dis- eases in Japanese patients receiving hormonal therapy was not higher than that in the general population. However; efforts should be made to decrease the adverse effects of hormonal therapy, because life-style change may increase the susceptibility to adverse effects by hormonal therapy even in Japan. Managements of endocrine and metabolic dysfunction, such as diabetes mellitus, are essential. New hormonal compounds such as selective androgen receptor modulators capable of specifically targeting prostate cancer are expected to be developed.

Does Low-Dose Intravenous Methylprednisolone Pulse Therapy Produce Unacceptable Adverse Effects in Children?

Background: Intravenous methylprednisolone pulse therapy has been used since the late 1960s for acute transplant rejection or severe renal involvement in systemic lupus erythematosus and primary glomerulonephritis. However, reports of serious adverse effects such as life-threatening cardiac arrhythmias and sudden death raise questions about its safety. Objective: To investigate the incidence of significant adverse effects associated with low-dose methylprednisolone pulse therapy (LDMPT) in pediatric patients. Methods: We retrospectively analyzed adverse effects during and after LDMPT in 68 patients (median age: 11.4 years;43% male) with various glomerular diseases who were admitted to Saitama Children’s Medical Center between April 2007 and December 2010. LDMPT consisted of pulse methylprednisolone (15-20 mg/kg;maximum 600 mg/d) for 3 consecutive days weekly for 2-3 weeks. Results: Although adverse effects occurred in 54 of 68 patients (79%), most were mild and transient. Transient glycosuria was noted in 46 patients (68%), hypertension in 6 (9%), elevated intraocular pressure in 6 (9%), hypokalemia in 5 (7%), and liver damage in 2 (3%). No late-onset adverse effects such as osteoporotic fractures, steroid diabetes mellitus, or short stature were observed. Conclusion: LDMPT appears to be relatively safe and well tolerated in children with various glomerular diseases.

Why Don’t We Adequately Identify and Manage Adverse Drug Reactions despite Having the Needed Information?

Importance/Objective: Adverse Drug Reactions (ADRs) are unavoidable, but recognizing and addressing ADRs early can improve wellness and prevent permanent injury. We suggest that available medical information and digital/electronic methods could be used to manage this major healthcare problem for individual patients in real time. Methods: We searched the available digital applications and three literature databases using the medical subject heading terms, adverse drug reaction reporting systems or management, filtered by clinical trial or systemic reviews, to detect publications with data about ADR identification and management approaches. We reviewed the reports that had abstract or summary data or proposed or implemented methods or systems with potential to identify or manage ADRs in clinical settings. Results: The vast majority of the 481 reports used retrospectively collected data for groups of patients or were limited to surveying one population group or class of medication. The reports showed potential and definite associations of ADRs for specific drugs and problems, mostly, but not exclusively, for patients in hospitals and nursing homes. No reports described complete methods to collect comprehensive data on ADRs for individual patients in a healthcare system. The digital applications have ADR information, but all are too cumbersome or incomplete for use in active clinical settings. Several studies suggested that providing information about potential ADRs to clinicians can reduce these problems. Conclusion and Relevance: Although investigators and government agencies agree with the need, there is no comprehensive ADR management program in current use. Informing the patient’s healthcare practitioners of potential ADRs at the point of service has the potential for reduction of these complications, which should improve healthcare and reduce unneeded costs.

Intravesical bacillus Calmette-Guerin(BCG)in treating non-muscle invasive bladder cancer—analysis of adverse effects and effectiveness of two strains of BCG(Danish 1331 and Moscow-I)

Objective:To compare the differences in adverse effects and efficacy profile between bacillus Calmette-Guerin(BCG)Danish 1331 and BCG Moscow-I strain in management of non-muscle invasive bladder cancer.Methods:Clinical data of 188 cases of non-muscle invasive bladder cancer treated with BCG between January 2008 and December 2018 in our institute were collected prospectively and analysed retrospectively,and 114 patients who completed a minimum of 12 months of follow-up were analysed.Patient and tumor characteristics,strain of BCG,adverse effects,and tumor progression were included for analysis.Intravesical BCG was instilled in intermediate-and high-risk patients.Six weeks of induction BCG,followed by three weekly maintenance BCG at 3,6,12,18,and 24 months was advised in high-risk patients.Results:Overall 68 patients received BCG Danish 1331 strain and 46 patients received Moscow-I strain.Patient and tumor characteristics were well balanced between the two groups.The median follow-up period was 42.5 months and 34.5 months in Danish 1331 and Moscow-I groups,respectively.Adverse events like dropout rate,antitubercular treatment requirement,and need of cystectomy were higher in Moscow-I group(n=31,67.4%)when compared to Danish 1331 strain(n=33,48.5%)(p=0.046).On direct comparison between Danish 1331 and Moscow-I strain,there was similar 3-year recurrence-free survival(80.0%vs.72.9%)and 3-year progression-free survival(96.5%vs.97.8%).Conclusion:Study results suggest no significant differences between Danish 1331 and Moscow-I strain in recurrence-free survival and progression-free survival,but a significantly higher incidence of moderate to severe adverse events in BCG Moscow-I strain.

Excellent effects and possible mechanisms of action of a new antibody–drug conjugate against EGFR-positive triple-negative breast cancer

Background:Triple-negative breast cancer(TNBC)is the most aggressive subtype and occurs in approximately 15%–20%of diagnosed breast cancers.TNBC is characterized by its highly metastatic and recurrent features,as well as a lack of specific targets and targeted therapeutics.Epidermal growth factor receptor(EGFR)is highly expressed in a variety of tumors,especially in TNBC.LR004-VC-MMAE is a new EGFR-targeting antibody–drug conjugate produced by our laboratory.This study aimed to evaluate its antitumor activities against EGFR-positive TNBC and further studied its possible mechanism of antitumor action.Methods:LR004-VC-MMAE was prepared by coupling a cytotoxic payload(MMAE)to an anti-EGFR antibody(LR004)via a linker,and the drug-to-antibody ratio(DAR)was analyzed by HIC-HPLC.The gene expression of EGFR in a series of breast cancer cell lines was assessed using a publicly available microarray dataset(GSE41313)and Western blotting.MDA-MB-468 and MDA-MB-231 cells were treated with LR004-VC-MMAE(0,0.0066,0.066,0.66,6.6 nmol/L),and the inhibitory effects of LR004-VC-MMAE on cell proliferation were examined by CCK-8 and colony formation.The migration and invasion capacity of MDA-MB-468 and MDA-MB-231 cells were tested at different LR004-VCMMAE concentrations(2.5 and 5 nmol/L)with wound healing and Transwell invasion assays.Flow cytometric analysis and tumorsphere-forming assays were used to detect the killing effects of LR004-VC-MMAE on cancer stem cells(MDA-MB-468 and MDA-MB-231 cells).The mouse xenograft models were also used to evaluate the antitumor efficacy of LR004-VC-MMAE in vivo.Briefly,BALB/c nude mice were subcutaneously inoculated with MDA-MB-468 or MDAMB-231 cells.Then they were randomly divided into 4 groups(n=6 per group)and treated with PBS,naked LR004(10 mg/kg),LR004-VC-MMAE(10 mg/kg),or doxorubicin,respectively.Tumor sizes and the body weights of mice were measured every 4 d.The effects of LR004-VC-MMAE on apoptosis and cell cycle distribution were analyzed by flow cytometry.Western blotting was used to detect the effects of LR004-VC-MMAE on EGFR,ERK,MEK phosphorylation and tumor stemness marker gene expression.Results:LR004-VC-MMAE with a DAR of 4.02 were obtained.The expression of EGFR was found to be significantly higher in TNBC cells compared with non-TNBC cells(P<0.01).LR004-VC-MMAE inhibited the proliferation of EGFRpositive TNBC cells,and the ICvalues of MDA-MB-468 and MDA-MB-231 cells treated with LR004-VC-MMAE for 72 h were(0.13±0.02)nmol/L and(0.66±0.06)nmol/L,respectively,which were significantly lower than that of cells treated with MMAE[(3.20±0.60)nmol/L,P<0.01,and(6.60±0.50)nmol/L,P<0.001].LR004-VC-MMAE effectively inhibited migration and invasion of MDA-MB-468 and MDA-MB-231 cells.Moreover,LR004-VC-MMAE also killed tumor stem cells in EGFR-positive TNBC cells and impaired their tumorsphere-forming ability.In TNBC xenograft models,LR004-VC-MMAE at 10 mg/kg significantly suppressed tumor growth and achieved complete tumor regression on day 36.Surprisingly,tumor recurrence was not observed until the end of the experiment on day 52.In a mechanistic study,we found that LR004-VC-MMAE significantly induced cell apoptosis and cell cycle arrest at G/M phase in MDAMB-468[(34±5)%vs.(12±2)%,P<0.001]and MDA-MB-231[(27±4)%vs.(18±3)%,P<0.01]cells.LR004-VC-MMAE also inhibited the activation of EGFR signaling and the expression of cancer stemness marker genes such as Oct4,Sox2,KLF4 and EpCAM.Conclusions:LR004-VC-MMAE showed effective antitumor activity by inhibiting the activation of EGFR signaling and the expression of cancer stemness marker genes.It might be a promising therapeutic candidate and provides a potential therapeutic avenue for the treatment of EGFR-positive TNBC.

Active surveillance of adverse drug reactions in children in five Italian paediatric wards

Adverse drug reactions (ADRs) are an important clinical problem and contribute significantly to mortality and morbidity. Scant data on the safety of drug use in children are usually available at the time of marketing authorization, due to the limited number of trials performed in the paediatric population. Few studies monitored the incidence of ADRs in Italian hospitalized children, that cannot be compared for methodological reasons. A 6-month prospective observational study was, therefore, conducted on the paediatric wards of five hospitals in the Campania Region, Italy. Data were collected on all patients admitted to the wards during the study period through a structured questionnaire administered to the mothers and through a hospital chart review. Of the 752 patients enrolled, 86.2% were exposed to one or more drugs during hospitalization. The therapeutic class most prescribed was systemic antibacterial agents (47%). Six ADRs occurred during hospitalization (incidence 0.9%;95% CI 0.2% - 1.7%). In addition, one child was admitted to a hospital for an ADR. Five out of seven ADRs occurred in girls. The skin was the most affected organ. The medications implicated were amoxicillin, acyclovir, ibuprofen, ceftriaxone, paracetamol, and ranitidine. According to the Naranjo probability criteria, six ADRs were probably, and one possibly, related to the suspected drug. In conclusion, this study reveals that ADRs may be under-reported in children hospitalized in the Campania Region. Consequently, healthcare personnel should be alert to the possibility of ADRs. More accurate reporting of ADRs in children would result in safer use of drugs in such patients.

Intensive care drug therapy and its potential adverse effects on blood pressure and heart rate in critically ill children

Background Owing to complex treatment,critically ill children may experience alterations in their vital parameters.We investigated whether such hemodynamic alterations were temporally and causally related to drug therapy.Methods In a university pediatric intensive care unit,we retrospectively analyzed hemodynamic alterations defined as values exceeding the limits set for heart rate(HR)and blood pressure(BP).For causality assessment,we used the World Health Organization–Uppsala Monitoring Center(WHO–UMC)system,which categorizes the probability of causality as“certain,”“probable,”“possible,”and“unlikely.”Results Of 315 analyzed patients with 43,200 drug prescriptions,59.7%experienced at least one hemodynamic alteration;39.0%were affected by increased HR,19.0%by decreased HR,18.1%by increased BP,and 16.2%by decreased BP.According to drug information databases,83.9%of administered drugs potentially lead to hemodynamic alterations.Overall,88.3%of the observed hemodynamic alterations had a temporal relation to the administration of drugs;in 80.2%,more than one drug was involved.Based on the WHO–UMC system,a drug was rated as a“probable”causing factor for only 1.4%of hemodynamic alterations.For the remaining alterations,the probability ratings were lower because of multiple potential causes,e.g.,several drugs.Conclusions Critically ill children were frequently affected by hemodynamic alterations.The administration of drugs with potentially adverse effects on hemodynamic parameters is often temporally related to hemodynamic alterations.Hemodynamic alterations are often multifactorial,e.g.,due to administering multiple drugs in rapid succession;thus,the influence of individual drugs cannot easily be captured with the WHO–UMC system.

The Adverse Event Profile in Patients Treated with Transferon^TM(Dialyzable Leukocyte Extracts): A Preliminary Report

Background: Dialyzable leukocyte extracts (DLE) are heterogeneous mixtures of peptides less than 10 kDa in size that are used as immunomodulatory adjuvants in immune-mediated diseases. TransferonTM is DLE manufactured by National Polytechnic Institute (IPN), and is registered by Mexican health-regulatory authorities as an immunomodulatory drug and commercialized nationally. The proposed mechanism of action of TransferonTM is induction of a Th1 immunoregulatory response. Despite that it is widely used, to date there are no reports of adverse events related to the clinical safety of human DLE or TransferonTM. Objective: To assess the safety of TransferonTM in a large group of patients exposed to DLE as adjuvant treatment. Methods: We included in this study 3844 patients from our Clinical Immunology Service at the Unit of External Services and Clinical Research (USEIC), IPN. Analysis was performed from January 2014 to November 2014, searching for clinical adverse events in patients with immune-mediated diseases and treated with TransferonTM as an adjuvant. Results: In this work we observed clinical nonserious adverse events (AE) in 1.9% of patients treated with TransferonTM (MD 1.9, IQR 1.7 - 2.0). AE were 2.8 times more frequently observed in female than in male patients. The most common AE were headache in 15.7%, followed by rash in 11.4%, increased disease-related symptomatology in 10%, rhinorrhea in 7.1%, cough in 5.7%, and fatigue in 5.7% of patients with AE. 63% of adverse event presentation occurred from day 1 to day 4 of treatment with TransferonTM, and mean time resolution of adverse events was 14 days. In 23 cases, the therapy was stopped because of adverse events and no serious adverse events were observed in this study. Conclusion: TransferonTM induced low frequency of nonserious adverse events during adjuvant treatment. Further monitoring is advisable for different age and disease groups of patients.

Observation of therapeutic effects of point application at Shenque(CV 8)plus moxa-salt hot compress for prevention of gastrointestinal adverse reactions after chemotherapy for non-Hodgkin Iymphoma

Objective:To observe the clinical efficacy of point application with De Huang(Rhizome Rhei Crude)powder at Shenque(CV 8)plus moxa-salt hot compress on the umbilicus for preventing gastrointestinal adverse reactions after chemotherapy for non-Hodgkin lymphoma(NHL).Methods:A total of 60 cases with NHL under chemotherapy were divided into two groups by hospitalization order,with 30 cases in each group.The control group was treated with routine nursing and the observation group was additionally given point application with Da Hueng(Rhizome Rhei Crude)powder plus moxa-salt hot compress on the umbilicus,to compare the effect in preventing gastrointestinal adverse reactions after chemotherapy between the two groups.Results:The occurrence rates of constipation,nausea,vomiting and poor appetite on the second day and fifth day after chemotherapy were obviously lower in the observation group than those in the control group,with statistically significant differences between the two groups(all P〈0.05).Conclusion;The point application with De Hueng(Rhizome Rhei Crude)powder at Shenque(CV 8)plus maxa-salt hot compress on the umbilicus can produce more significant efficacy in preventing the gastrointestinal adverse reactions after chemotherapy for NHL than routine nursing.Moreover,it is simple and easy to be used and popularized.

抗菌压电材料:对细菌无选择性杀伤和不产生细菌耐药性

背景:压电材料可通过催化作用产生活性氧,通过多种途径来破坏细菌,而且不会导致细菌产生耐药性。这种不依赖抗生素的抗菌方式具有明显的优势,可以对细菌进行无差别的杀伤,为今后的抗菌策略提供了一种新思路。目的:文章主要总结了有关压电材料特性与抗菌机制,并讨论了部分压电材料在抗菌领域的研究现状。方法:在Pub Med、Web of Science、中国知网和万方数据库中,以“压电材料,压电催化,活性氧,抗菌,细菌感染,抗感染,耐药性”为中文检索词,以“piezoelectric materials,piezoelectricity,piezoelectric catalysis,piezocatalysis,reactive oxygen species,ROS,bacterial infection,antibacterial strategies,anti-infection,drug resistance,drug-resistant bacteria”为英文检索词。检索时间范围重点为2013年1月至2023年12月,通过阅读文题和摘要进行初步筛选;排除中英文重复性研究及内容不相关的文献,经文献质量评价后,最后纳入68篇文献进行综述。结果与结论:(1)压电材料是一类性质稳定的环境友好型材料,其大多数具有良好的生物相容性。(2)压电材料在压电效应过程中可催化产生大量活性氧,活性氧可通过细胞外氧化和细胞内氧化,破坏细菌的细胞膜、胞内蛋白质、酶以及核酸等物质,影响细菌的结构和功能,甚至导致细菌死亡从而实现抗菌。抗菌性能与催化生成活性氧速率相关,而催化速率与材料体系、形貌及外界条件等多种因素相关。(3)压电催化产生的活性氧对细菌不具备选择性,因此表现出广谱抗菌性,且这种抗菌方式不需要依赖抗菌药物,故不会引起细菌耐药性问题。(4)结合超声波无创、可控性与穿透性强等优点,未来压电材料作为耐药菌感染的辅助或替代治疗等具有重要价值和巨大潜力。(5)目前压电材料催化效率低下的难题限制了其在抗菌领域的应用,如何提高压电催化效率成为了学者们关注的焦点。

Standard triple therapy for Helicobacter pylori infection in China: A meta-analysis

AIM: To assess the efficacy and safety of standard triple therapy compared with other pre-existing and new therapies in China.

Biochemical mechanisms in drug-induced liver injury:Certainties and doubts

Drug-induced liver injury is a significant and still unresolved clinical problem. Limitations to knowledge about the mechanisms of toxicity render incomplete the detection of hepatotoxic potential during preclinical development. Several xenobiotics are lipophilic substances and their transformation into hydrophilic compounds by the cytochrome P-450 system results in production of toxic metabolites. Aging, preexisting liver disease, enzyme induction or inhibition, genetic variances, local 02 supply and, above all, the intrinsic molecular properties of the drug may affect this process. Necrotic death follows antioxidant consumption and oxidation of intracellular proteins, which determine increased permeability of mitochondrial membranes, loss of potential, decreased ATP synthesis, inhibition of Ca^2＋-dependent ATPase, reduced capability to sequester Ca^2＋ within mitochondria, and membrane bleb formation. Conversely, activation of nucleases and energetic participation of mitochondria are the main intracellular mechanisms that lead to apoptosis. Non-parenchymal hepatic cells are inducers of hepatocellular injury and targets for damage. Activation of the immune system promotes idiosyncratic reactions that result in hepatic necrosis or cholestasis, in which different HLA genotypes might play a major role. This review focuses on current knowledge of the mechanisms of drug-induced liver injury and recent advances on newly discovered mechanisms of liver damage. Future perspectives including new frontiers for research are discussed.

Can acupuncture enhance therapeutic effectiveness of antidepressants and reduce adverse drug reactions in patients with depression? A systematic review and meta-analysis

Background: Some depressed patients receive acupuncture as an adjunct to their conventional medications.Objective: This review aims to provide evidence on whether acupuncture can enhance the therapeutic effectiveness of antidepressants for treating depression, and explore whether acupuncture can reduce the adverse reactions associated with antidepressants.Search strategy: English and Chinese databases were searched for randomized controlled trials(RCTs)published until December 1, 2021.Inclusion criteria: RCTs with a modified Jadad scale score ≥ 4 were included if they compared a group of participants with depression that received acupuncture combined with antidepressants with a control group that received antidepressants alone.Data extraction and analysis: Meta-analysis was performed, and statistical heterogeneity was assessed based on Cochran’s Q statistic and its related P-value. Primary outcomes were the reduction in the severity of depression and adverse reactions associated with antidepressants, while secondary outcomes included remission rate, treatment response, social functioning, and change in antidepressant dose.The Grading of Recommendations Assessment, Development and Evaluation(GRADE) framework was used to evaluate the overall quality of evidence in the included studies.Results: This review included 16 studies(with a total of 1958 participants). Most studies were at high risk of performance bias and at low or unclear risk of selection bias, detection bias, attrition bias, reporting bias, and other bias. Analysis of the 16 RCTs showed that, compared with antidepressants alone, acupuncture along with antidepressants reduced the Hamilton Depression Rating Scale-17(HAMD-17) scores(standard mean difference [SMD]-0.44, 95% confidence interval [CI]-0.55 to-0.33, P < 0.01;I^(2)= 14%), Self-rating Depression Scale(SDS) scores(SMD-0.53, 95% CI-0.84 to-0.23, P < 0.01;I^(2)= 79%), and the Side Effect Rating Scale(SERS) scores(SMD-1.11, 95% CI-1.56 to-0.66, P < 0.01;I^(2)= 89%). Compared with antidepressants alone, acupuncture along with antidepressants improved World Health Organization Quality of Life-BREF scores(SMD 0.31, 95% CI 0.18 to 0.44, P < 0.01;I^(2)= 15%), decreased the number of participants who increased their antidepressant dosages(relative risk[RR] 0.32, 95% CI 0.22 to 0.48, P < 0.01;I^(2)= 0%), and resulted in significantly higher remission rates(RR1.52, 95% CI 1.26 to 1.83, P < 0.01;I^(2)= 0%) and treatment responses(RR 1.35, 95% CI 1.24 to 1.47, P < 0.01;I^(2)= 19%) in terms of HAMD-17 scores. The HAMD-17, SDS and SERS scores were assessed as low quality by GRADE and the other indices as being of moderate quality.Conclusion: Acupuncture as an adjunct to antidepressants may enhance the therapeutic effectiveness and reduce the adverse drug reactions in patients receiving antidepressants. These findings must be interpreted with caution, as the evidence was of low or moderate quality and there was a lack of comparative data with a placebo control.Systematic review registration: INPLASY202150008.

Azithromycin-containing versus standard triple therapy for Helicobacter pylori eradication:A meta-analysis

AIM： To evaluate whether adding azithromycin to firstline Helicobacter pylori （H pylorl） eradication improved eradication and reduced side effects. METHODS： Eligible articles were identified by searches of electronic databases. We included all randomized trials that compared azithromycin-containing with standard triple-therapy regimens for first-line treatment of H pylori infection. Statistical analysis was performed with Review Manager 5.0.10. Sub-analyses were also performed. RESULTS： We identified 14 randomized trials （1431 patients）. Pooled Hpylori eradication rates were 72.01% （95% CI： 58.09%-85.93%） and 69.78% （95% CI： 66.47%-73.09%） for patients with or without azithromycin by intention-to-treat analysis, and the odds ratio （OR） was 1.17 （95% CI： 0.64-2.14）. The occurrence of side effects differed significantly and was 15.81% （95% CI： 12.50%-19.12%） and 25.20% （95% CI： 21.44%-28.96%） for treatment with or without azithromycin, respectively, and the summary OR was 0.58 （95% CI： 0.41-0.82）. Furthermore, the azithromycin-containing group had a lower occurrence of diarrhea, nausea and taste disturbance. CONCLUSION： Our review suggests that azithromycincontaining triple-therapy regimens could be equally effective in eradication of Hpylori compared with standard first-line triple-therapy regimens.

Pharmacological therapy of feed intolerance in the critically ills

Feed intolerance in the setting of critical illness is associated with higher morbidity and mortality,and thusrequires promptly and effective treatment. Prokineticagents are currently considered as the first-line therapygiven issues relating to parenteral nutrition and post-pyloric placement. Currently,the agents of choice areerythromycin and metoclopramide,either alone or incombination,which are highly effective with relativelylow incidence of cardiac,hemodynamic or neurologicaladverse effects. Diarrhea,however,can occur in up to 49% of patients who are treated with the dual prokinetic therapy,which is not associated with Clostridiumdifficile infection and settled soon after the cessation ofthe drugs. Hence,the use of prokinetic therapy over along period or for prophylactic purpose must be avoided,and the indication for ongoing use of the drug(s)must be reviewed frequently. Second line therapy,suchas total parenteral nutrition and post-pyloric feeding,must be considered once adverse effects relating theprokinetic therapy develop.

Current cancer therapies and their influence on glucose control

This review focuses on the development of hyperglycemia arising from widely used cancer therapies spanning four drug classes.These groups of medications were selected due to their significant association with new onset hyperglycemia,or of potentially severe clinical consequences when present.These classes include glucocorticoids that are frequently used in addition to chemotherapy treatments,and the antimetabolite class of 5-fluorouracil-related drugs.Both of these classes have been in use in cancer therapy since the 1950s.Also considered are the phosphatidyl inositol-3-kinase(PI3K)/AKT/mammalian target of rapamycin(mTOR)-inhibitors that provide cancer response advantages by disrupting cell growth,proliferation and survival signaling pathways,and have been in clinical use as early as 2007.The final class to be reviewed are the monoclonal antibodies selected to function as immune checkpoint inhibitors(ICIs).These were first used in 2011 for advanced melanoma and are rapidly becoming widely utilized in many solid tumors.For each drug class,the literature has been reviewed to answer relevant questions about these medications related specifically to the characteristics of the hyperglycemia that develops with use.The incidence of new glucose elevations in euglycemic individuals,as well as glycemic changes in those with established diabetes has been considered,as has the expected onset of hyperglycemia from their first use.This comparison emphasizes that some classes exhibit very immediate impacts on glucose levels,whereas other classes can have lengthy delays of up to 1 year.A comparison of the spectrum of severity of hyperglycemic consequences stresses that the appearance of diabetic ketoacidosis is rare for all classes except for the ICIs.There are distinct differences in the reversibility of glucose elevations after treatment is stopped,as the mTOR inhibitors and ICI classes have persistent hyperglycemia long term.These four highlighted drug categories differ in their underlying mechanisms driving hyperglycemia,with clinical presentations ranging from potent yet transient insulin resistant states[type 2 diabetes mellitus(T2DM)-like]to rare permanent insulin-deficient causes of hyperglycemia.Knowledge of the relative incidence of new onset hyperglycemia and the underlying causes are critical to appreciate how and when to best screen and treat patients taking any of these cancer drug therapies.

Clinical decision support for drug related events: Moving towards better prevention

Clinical decision support(CDS) systems with automated alerts integrated into electronic medical records demonstrate efficacy for detecting medication errors(ME) and adverse drug events(ADEs). Critically ill patients are at increased risk for ME, ADEs and serious negative outcomes related to these events. Capitalizing on CDS to detect ME and prevent adverse drug related events has the potential to improve patient outcomes. The key to an effective medication safety surveillance system incorporating CDS is advancing the signals for alerts by using trajectory analyses to predict clinical events, instead of waiting for these events to occur. Additionally, incorporating cutting-edge biomarkers into alert knowledge in an effort to identify the need to adjust medication therapy portending harm will advance the current state of CDS. CDS can be taken a step further to identify drug related physiological events, which are less commonly included in surveillance systems. Predictive models for adverse events that combine patient factors with laboratory values and biomarkers are being established and these models can be the foundation for individualized CDS alerts to prevent impending ADEs.

Liver injury associated with drug intake during pregnancy

Drug use during pregnancy is not common.Drug-induced liver injury(DILI)is a potential complication that is rare but can adversely affect both the mother and the fetus.Although many drugs can directly cause hepatotoxicity,idiosyncratic liver injury is common in pregnancy.Underreporting of adverse drug reactions,lack of adequate literature regarding drug safety in pregnancy,and the inherent difficulty in diagnosing DILI during pregnancy make the management of this condition challenging.This review attempts to describe the existing literature regarding DILI in pregnancy,which is mainly in the form of case reports;several studies have looked at the safety of antithyroid drugs,antiretroviral drugs,and paracetamol,which have an indication for use in pregnancy;the relevant data from these studies with regard to DILI has been presented.In addition,the review describes the diagnosis of DILI,grading the disease severity,assessment of causality linking the drug to the adverse event,regulatory guidelines for evaluating the potential of drugs to cause liver injury,efforts to ensure better participation of women in clinical trials and studies in pregnant women population in particular,and the challenges involved in generating adequate research evidence.The establishment of DILI registries in various countries is an encouraging development;however,there is a need for promoting active,spontaneous reporting of adverse events during pregnancy to ensure rapid generation of evidence regarding the safety of a drug in pregnant women.

Can antiretroviral therapy be tailored to each human immunodeficiency virus-infected individual? Role of pharmacogenomics

Pharmacogenetics refers to the effect of single nucleotide polymorphisms(SNPs) within human genes on drug therapy outcome. Its study might help clinicians to increase the efficacy of antiretroviral drugs by improving their pharmacokinetics and pharmacodynamics and by decreasing their side effects. HLAB*5701 genotyping to avoid the abacavir-associated hypersensitivity reaction(HSR) is a cost-effective diagnostic tool, with a 100% of negative predictive value, and, therefore, it has been included in the guidelines for treatment of human immunodeficiency virus(HIV) infection. HALDRB*0101 associates with nevirapine-induced HSR. CYP2B6 SNPs modify efavirenz plasma levels and their genotyping help decreasing its central nervous system, hepatic and HSR toxicities. Cytokines SNPs might influence the development of drug-associated lipodystrophy. APOA5, APOB, APOC3 and APOE SNPs modify lipids plasma levels and might influence the coronary artery disease risk of HIV-infected individuals receiving antiretroviral therapy. UGT1A1*28 and ABCB1(MDR1) 3435 C > T SNPs modify atazanavir plasma levels and enhance hyperbilirubinemia. Much more effort needs to be still devoted to complete large prospective studies with multiple SNPs genotyping in order to reveal more clues about the role played by host genetics in antiretroviral drug efficacy and toxicity.

Aged Patients and Use of Nonprescription Drugs

Elderly patients over 65, especially those over 75 years are more vulnerable to being prescribed inappropriate medications because of the high incidence of co-medication in this population resulting from the presence of multiple chronic diseases and also age-related changes in pharmacokinetics and pharmacodynamics. The aim at this study was to explore the habits of taking medications without recommendation fracture among older patients, to determine which medications are most often used without prescription, and if there is difference in this habits considering gender and age of respondents. Methods： A cross-sectional study was conducted by interviewing all patients 〉 65 years that have arrived from 01.10. to 15.12.2015 in one ambulance of the Health Center of Mostar using the adapted questionnaire made out for the research. 90 questionnaires were properly filled for analysis, 60.0% were women and 40.0% of them were men. There was 45.6% respondents between 65 and 75 years, and 54.4% 76 years and above. Resaults： 15.6% of respondents said that they don＇t take their therapy regularly. Women compared to men, significantly more often use non-prescription drugs （P = 0.007）. Analgesics and sedatives are more often used as non-prescription drugs, compare to supplements （P = 0.002）. Conclusion： This study, although conducted on a small sample should be an alarm for general practitioners. They should think more about adverse effects of drugs on the aged, and use Beers criteria in every day practice. In addition, pharmacists should respect the legislation and not sell drugs without doctor＇s prescription to which it applies.