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.

Analysis and Enlightenment of Big Data Platform for Adverse Drug Reaction Supervision in China and the United States

Objective To introduce the relevant big data platforms of FDA regulatory sciences and to provide reference for the construction of big data platform for China’s regulatory science under the“14th five-year plan”to deepen the reform of medical and health system.Methods A comparative analysis was made on China’s big data for regulatory science after studying the development process,operation mode,practical significance and characteristics of the big data platform for FDA regulatory science,which would help China to establish a perfect big database.Results and Conclusion The construction of big data platform for China’s regulatory science is not comprehensive compared with that in the United States.It is necessary to build data platforms in line with China’s national conditions through efforts in law,talents,standards,and other aspects.

A Personalized Adverse Drug Reaction Early Warning Method Based on Contextual Ontology and Rules Learning

Background: The fatality of adverse drug reactions (ADR) has become one of the major causes of the non-natural disease deaths globally, with the issue of drug safety emerging as a common topic of concern. Objective: The personalized ADR early warning method, based on contextual ontology and rule learning, proposed in this study aims to provide a reference method for personalized health and medical information services. Methods: First, the patient data is formalized, and the user contextual ontology is constructed, reflecting the characteristics of the patient population. The concept of ontology rule learning is then proposed, which is to mine the rules contained in the data set through machine learning to improve the efficiency and scientificity of ontology rule generation. Based on the contextual ontology of ADR, the high-level context information is identified and predicted by means of reasoning, so the occurrence of the specific adverse reaction in patients from different populations is extracted. Results: Finally, using diabetes drugs as an example, contextual information is identified and predicted through reasoning, to mine the occurrence of specific adverse reactions in different patient populations, and realize personalized medication decision-making and early warning of ADR.

Analysis of Adverse Reactions in the Treatment of COVID-19 with Three Chinese Patent Medicines and Three Herbal Formulas

Objective To explore the rules and characteristics of the adverse drug reactions(ADRs)of three Chinese patent medicines and three herbal formulas for the treatment of COVID-19,and to provide a reference for clinical safe medication.Methods The cases and ADR reports of the three Chinese patent medicines and three herbal formulas in PubMed,Web of Science,Springer Link,CNKI,Wanfang and VIP database were retrieved from December 2019 to May 2021.Then we extracted and analyzed the effective information included in the literature.Results and Conclusion According to the pre-developed retrieval plan,a total of 136 documents were obtained,and a total of 6 documents met the inclusion criteria finally.553 patients used three Chinese patent medicines and three herbal formulas,and there were 133 cases of adverse reactions.The adverse reactions of patients taking the three Chinese patent medicines and three herbal formulas can all be explained under the theory of traditional Chinese medicine,and the adverse reactions can be eliminated by adding or subtracting the flavor of the medicine or stopping the medicine.

The dopaminergic system and Alzheimer's disease

Alzheimer's disease is a common neurodegenerative disorder in older adults.Despite its prevalence,its pathogenesis remains unclea r.In addition to the most widely accepted causes,which in clude excessive amyloid-beta aggregation,tau hyperphosphorylation,and deficiency of the neurotransmitter acetylcholine,numerous studies have shown that the dopaminergic system is also closely associated with the occurrence and development of this condition.Dopamine is a crucial catecholaminergic neurotransmitter in the human body.Dopamine-associated treatments,such as drugs that target dopamine receptor D and dopamine analogs,can improve cognitive function and alleviate psychiatric symptoms as well as ameliorate other clinical manifestations.Howeve r,therapeutics targeting the dopaminergic system are associated with various adverse reactions,such as addiction and exacerbation of cognitive impairment.This review summarizes the role of the dopaminergic system in the pathology of Alzheimer's disease,focusing on currently available dopamine-based therapies for this disorder and the common side effects associated with dopamine-related drugs.The aim of this review is to provide insights into the potential connections between the dopaminergic system and Alzheimer's disease,thus helping to clarify the mechanisms underlying the condition and exploring more effective therapeutic options.

Evidence-based expert consensus on clinical management of safety of Bruton’s tyrosine kinase inhibitors(2024)

Bruton’s tyrosine kinase inhibitors(BTKis)have revolutionized the treatment of B-cell lymphomas.However,safety issues related to the use of BTKis may hinder treatment continuity and further affect clinical efficacy.A comprehensive and systematic expert consensus from a pharmacological perspective is lacking for safety issues associated with BTKi treatment.A multidisciplinary consensus working group was established,comprising 35 members from the fields of hematology,cardiovascular disease,cardio-oncology,clinical pharmacy,and evidencebased medicine.This evidence-based expert consensus was formulated using an evidence-based approach and the Delphi method.The Joanna Briggs Institute Critical Appraisal(JBI)tool and Grading of Recommendations Assessment,Development,and Evaluation(GRADE)approach were used to rate the quality of evidence and grade the strength of recommendations,respectively.This consensus provides practical recommendations for BTKis medication based on nine aspects within three domains,including the management of common adverse drug events such as bleeding,cardiovascular events,and hematological toxicity,as well as the management of drug-drug interactions and guidance for special populations.This multidisciplinary expert consensus could contribute to promoting a multi-dimensional,comprehensive and standardized management of BTKis.

Application and Effect Evaluation of the Integrated“5A and 3+3”Management Model in the Safe Medication Use for Chemotherapy Patients

Objective:To explore the application and effect evaluation of the integrated“5A and 3+3”management model in ensuring safe medication use for chemotherapy patients.Methods:A total of 100 intravenous chemotherapy patients admitted to the oncology department of Shaanxi Provincial People’s Hospital were randomly divided into two groups using a random number list method.Both groups received conventional nursing management during chemotherapy,while the study group additionally received the integrated“5A and 3+3”safety management model.The nursing intervention effects between the two groups were compared.Results:After the intervention,the study group showed higher levels of self-management ability,compliance,and nursing satisfaction compared to the control group.The overall incidence of adverse events during hospitalization was lower in the study group,with statistically significant differences(P<0.05).The knowledge scores of medical staff in the study group,related to the prevention and treatment of chemotherapy drug side effects,daily symptom management,and daily life management,were higher than those in the control group,with statistically significant differences(P<0.05).Conclusion:Implementing the integrated“5A and 3+3”model in the safe medication management of intravenous chemotherapy patients can effectively enhance patients’self-management abilities and compliance,improve medical staff’s ability to safely administer chemotherapy drugs,reduce adverse events caused by chemotherapy,and increase patient satisfaction.

Research and Enlightenment of Text Mining Applications in ADR from Social Media

Objective To discuss how to use social media data for post-marketing drug safety monitoring in China as soon as possible by systematically combing the text mining applications,and to provide new ideas and methods for pharmacovigilance.Methods Relevant domestic and foreign literature was used to explore text classification based on machine learning,text mining based on deep learning(neural networks)and adverse drug reaction(ADR)terminology.Results and Conclusion Text classification based on traditional machine learning mainly include support vector machine(SVM)algorithm,naive Bayesian(NB)classifier,decision tree,hidden Markov model(HMM)and bidirectional en-coder representations from transformers(BERT).The main neural network text mining based on deep learning are convolution neural network(CNN),recurrent neural network(RNN)and long short-term memory(LSTM).ADR terminology standardization tools mainly include“Medical Dictionary for Regulatory Activities”(MedDRA),“WHODrug”and“Systematized Nomenclature of Medicine-Clinical Terms”(SNOMED CT).

Clinical features of adverse reactions associated with telbivudine

AIM: To analyze the clinical features and risk factors of adverse reactions associated with telbivudine. METHODS: Clinical data were collected from cases that presented with serious adverse reactions to telbivudine. We analyzed general information and medicine status, clinical features, results of examination, and misdiagnosis. RESULTS: Out of 105 patients who were treated with telbivudine for hepatitis B in an outpatient department from January, 2007 to January, 2008, five presented with serious adverse drug reactions. Most of these five patients had used other nucleoside analogues in the past. Four were treated with a combination of telbivudine and interferon or another nucleoside analogue, while the other received an increased dose of telbivudine. The main adverse reactions were myalgia and general weakness. This was accompanied by cardiac arrhythmia in one patient, and nervous symptoms in three. Serum creatine kinase was elevated. The rate of misdiagnosis was high. CONCLUSION: The adverse reactions were related to telbivudine, but the biological mechanism of the reactions is not yet clear. Combination therapy with interferon or another nucleoside analogue and a high dose may increase the risk of adverse reactions.

Prevalence and Risk Factors Associated with Adverse Drug Reactions among Previously Treated Tuberculosis Patients in China

We assessed the incidence of adverse drug reactions （ADRs） with anti-TB medications and evaluated the risk factors for developing ADRs in previously treated tuberculosis patients in China. All patients received the first-line anti-TB regimen （2HREZS/6HRE） as recommended by the national guidelines.

Research on the Opening of Adverse Drug Reaction Data in the EU

Systematically analyze the composition of post-marketing adverse drug reaction data and the open mode in the EU, and summarize its characteristics. EU post-marketing ADR data is open to six categories of stakeholders: EMA, EC, medicines regulatory authorities in EEA member states, healthcare professionals and the public, Marketing Authorization Holders, academia, WHO and medicines regulatory authorities in third countries. The EU has implemented hierarchical opening for ADRs, with different levels containing different data and facing different stakeholders. Openness is divided into active and passive openness. In opening up data, the EU complies with relevant personal data protection laws to protect the privacy of individuals. The EU’s post-marketing adverse drug reaction data openness is characterized by a combination of data openness and privacy protection, active and passive openness, and a hierarchy of data openness. It is hoped that this can provide a reference for the opening up of post-marketing adverse drug reaction data in China.

Sex-dimorphic adverse drug reactions to immune suppressive agents in inflammatory bowel disease

AIM:To analyze sex differences in adverse drug reactions(ADR) to the immune suppressive medication in inflammatory bowel disease(IBD) patients.METHODS:All IBD patients attending the IBD outpatient clinic of a referral hospital were identified through the electronic diagnosis registration system.The electronic medical records of IBD patients were reviewed and the files of those patients who have used immune suppressive therapy for IBD,i.e.,thiopurines,methotrexate,cyclosporine,tacrolimus and anti-tumor necrosis factor agents(anti-TNF);infliximab(IFX),adalimumab(ADA) and/or certolizumab,were further analyzed.The reported ADR to immune suppressive drugs were noted.The general definition of ADR used in clinical practice comprised the occurrence of the ADR in the temporal relationship with its disappearance upon discontinuation of the medication.Patients for whom the required information on drug use and ADR was not available in the electronic medical record and patients with only one registered contact and no further followup at the outpatient clinic were excluded.The difference in the incidence and type of ADR between male and female IBD patients were analyzed statistically by χ 2 test.RESULTS:In total,1009 IBD patients were identified in the electronic diagnosis registration system.Out of these 1009 patients,843 patients were eligible for further analysis.There were 386 males(46%),mean age 42 years(range:16-87 years) with a mean duration of the disease of 14 years(range:0-54 years);578 patients with Crohn's disease,244 with ulcerative colitis and 21 with unclassified colitis.Seventy percent(586 pts) of patients used any kind of immune suppressive agents at a certain point of the disease course,the majority of the patients(546 pts,65%) used thiopurines,176 pts(21%) methotrexate,46 pts(5%) cyclosporine and one patient tacrolimus.One third(240 pts,28%) of patients were treated with anti-TNF,the majority of patients(227 pts,27%) used IFX,99(12%) used ADA and five patients certolizumab.There were no differences between male and female patients in the use of immune suppressive agents.With regards to ADR,no differences between males and females were observed in the incidence of ADR to thiopurines,methotrexate and cyclosporine.Among 77 pts who developed ADR to one or more anti-TNF agents,significantly more females(54 pts,39% of all anti-TNF treated women) than males(23 pts,23% of all antiTNF treated men) experienced ADR to an anti-TNF agent [P = 0.011;odds ratio(OR) 2.2,95%CI 1.2-3.8].The most frequent ADR to both anti-TNF agents,IFX and ADA,were allergic reactions(15% of all IFX users and 7% of all patients treated with ADA) and for both agents a significantly higher rate of allergic reactions in females compared with males was observed.As a result of ADR,36 patients(15% of all patients using anti-TNF) stopped the treatment,with significantly higher stopping rate among females(27 females,19% vs 9 males,9%,P = 0.024).CONCLUSION:Treatment with anti-TNF antibodies is accompanied by sexual dimorphic profile of ADR with female patients being more at risk for allergic reactions and subsequent discontinuation of the treatment.

Patterns of adverse drug reaction reporting in Ethiopia:A database analysis of spontaneous reports from 2013 to 2018

Objective:To examine the frequency and profile of spontaneous reports of adverse drug reactions(ADRs)sent to Ethiopia's pharmacovigilance(PV)database system.Methods:The descriptive and retrospective study analysed spontaneous ADR complaints reported to the PV database by healthcare professionals between 2013 and 2018.Spontaneous ADR reports that reached the PV center and met the minimum reporting criteria were identified and assessed in terms of reporting rate,patient characteristics,type of ADRs,suspected drugs,report sources,and reporters’profession.Results:A total of 657 spontaneous ADR reports were filed to the PV center between 2013 and 2018.During the study period,the reporting pattern of ADRs changed dramatically.The number of reports increased from 2013(n=12)and peaked in 2015(n=205),and then declined from 2016 to 2018(n=144,142 and 65 in 2016,2017 and 2018,respectively).Females had a higher percentage of reported cases(56.3%)than males(43.7%).The highest number of ADRs was reported in the age categories of 15-64 years(475,72.3%),followed by 0-14 years(154,23.4%),and 65 years and above(21,3.2%).Pharmacists reported the majority of ADRs(81.7%),followed by health officers(7.2%),nurses(5.8%),and physicians(5.2%).Skin and subcutaneous tissue abnormalities were the most commonly reported ADRs.The anatomical therapeutic chemicals code class"anti-infective for systemic use"was the most usually suspected medication.Trimethoprim with sulfamethoxazole as a combination ADRs was the most commonly reported drug that cause ADRs(14.2%).Conclusions:The number of ADRs reported in Ethiopia was small and unpredictable compared to developed countries,indicating the performance of PV system and level of awareness of health care professionals towards ADR reporting was not satisfactory.In order to increase the frequency of spontaneous reports,more efficient PV methods and public policies must be implemented.

Analysis of Adverse Drug Reactions Caused by Chinese Patent Medicine Treatment Based on Kidney Damp-heat Syndrome and Damp-turbidity Syndrome

[Objectives]To determine relationship of the adverse drug reaction(ADR)occurrence of the single use and combined use of Huangkui Capsule and Haikun Shenxi Capsule.[Methods]To determine relationship of the ADR occurrence of the single use and combined use of Huangkui Capsule and Haikun Shenxi Capsule.[Results]The main adverse drug reactions of the single use of Huangkui Capsule or Haikun Shenxi Capsule was severe diarrhea(n=7,n=9),however the combined use of the two resulted in more occurrence of adverse drug reactions(n=23)with significant difference in contrast to the single use group(P=0.0015,P=0.0069).[Conclusions]When traditional Chinese patent medicines are used in combination to treat kidney damp-heat syndrome and damp-turbid syndrome,it is necessary to pay close attention to the occurrence of adverse drug reactions,especially the digestive system.

Systematic review on the adverse reactions of oral administration of Indigo Naturalis and its preparations

Objective:This article systematically analyses the effects of adverse drug events/adverse drug reactions(ADEs/ADRs)of oral Indigo Naturalis(Qingdai)preparations in order to provide references for its rational clinical application.Methods:All clinical studies reporting ADE/ADR related to the oral administration of Qingdai preparations were searched through electronic databases,including PubMed,the Cochrane Library,Embase,China National Knowledge Infrastructure(CNKI),China Biology Medicine disc(CBM),VIP Information Chinese Journal Service Platform(VIP),and Wanfang database,from inception to September 27,2020.Information were extracted from these literatures,including primary disease,type of adverse reactions,dose,treatment,outcomes and so on.Incidence of ADE/ADR was estimated,as well as distribution of primary diseases and victim organs and systems were analyzed.Results:A total of 682 articles were included,with 651 clinical population studies and 31 case reports.Among them,604 detailed ADR/AE involving 33459 patients using oral Qingdai preparations,and a total of 5061 cases were found to present adverse events,including 2827 cases of digestive system(abdominal pain,diarrhea,etc.),469 cases of blood system damage(thrombocytopenia,leukopenia,anemia,etc.),313 cases of liver damage(abnormal liver function,liver toxicity,elevated liver enzymes,etc.),327 cases of nervous system reactions(headache,dizziness,poor sleep,etc.)and 1186 cases of other systems and organs.Severe adverse events(SAEs)mainly were liver damage,and could be relived after symptomatic treatment.Conclusion:From the systematic information retrieval and analysis,it is found that oral Qingdai preparations application may clinically cause ADEs/ADRs in terms of gastrointestinal tract and liver damage.Therefore,when using oral Qingdai preparations,liver and stomach protection should be done.At the same time,pay close attention to various biochemical indicators and the patient's drug response during the treatment process,and,if necessary,deal with it in time so as not to deteriorate the condition.Moreover,active surveillance system should be conducted to monitor ADE/ADR,so as to establish a clearer causal relationship between the drug and the adverse event.

A review on the Pharmacology and Adverse Drug Reaction of Chaihu Herbal Injection

The Chaihu herbal injection was the first herbal injection to be developed and used in China,which has been used in clinic for more than 70 years.This injection is widely used to treat fever caused by influenza or common cold and malaria.However,there is an ongoing debate about the safety of the clinical use of Chaihu herbal injection in view of the large number of adverse drug reaction reports and literature in China.On May 29,2018,the China Food and Drug Administration issued a notice requiring to revise the instruction manual of Chaihu herbal injection,list"prohibit for children"under the taboo item,and add the warning"adverse reactions of this product include anaphylactic shock".The purpose of this review is to provide updated,comprehensive information on the pharmacology and adverse drug reaction of Chaihu herbal injection based on scientific literatures in the past few decades.

Random Forest Analysis the Influencing Factors on Adverse Drug Reactions of Qingkailing Injection

Objective:To investigate the influencing factors of adverse drug reaction(ADR)in Qingkailing injection.Methods:Based on the hospitals centralized monitoring data of multicenter and prospective,the patients who used Qingkailing injection from January 2013 to March 2016 were monitored in 48 medical institutions in China.The nesting case-control study was used and the random forest was used for analysis.The main contents of the analysis are as follows:past history,past allergy history and ADR history,clinical diagnosis,dosage,interval drug,solvent type,combined drug use,etc.Results:A total of 30842 cases with Qingkailing injection were included,with 92 cases of adverse reactions and the incidence of adverse reactions was 3‰.According to the nested case-control study design,the influencing factors of 92 patients with ADR and 276 non-drug-related adverse reactions were displayed on the basis of statistical description(significance level P≤0.2 and clinical information)using Random forest analysis shows that the factors affecting the ADR of the Qingkailing injection according to the MeandecaseGini are from high to low in the first 15 positions:Vitamin supplements,tumors,gastrointestinal diseases,traditional Chinese medicine,previous allergic history,cerebral insufficiency,rash,urinary tract infection,vascular and lymphovascular diseases,pioglitazone,metabolic and endocrine system drugs,past ADR history,respiratory and mediastinal diseases,dioxpromazide,pneumonia.Conclusion:The incidence of adverse reactions in Qingkailing injection hospital is 3%.The factors closely related to the occurrence of ADR are previous tumors,gastrointestinal diseases,history of adverse reactions of rash,urinary tract infection,insufficient cerebral blood supply,respiratory system and other diseases,pioglitazone and other combined drugs.

Analysis of the adverse reactions of atezolizumab: A real-world study based on FAERS database

Objective In this study,we aimed to determine the incidence of adverse drug reactions(ADRs)of atezolizumab,identify ADR signals that are significantly related to atezolizumab,and provide a reference for the rational use of atezolizumab in the clinic through the statistical analysis of its adverse drug events(ADEs)reported in the American Food and Drug Administration(FDA)Adverse Event Reporting System(FAERS)database.Methods In total,4796 cases of atezolizumab ADEs reported in the American FAERS database from 2017 to 2019 were retrospectively analyzed.Results The top three ADEs were febrile neutropenia(3.7%),anemia(2.9%),and acute renal failure(2.3%).In addition,the incidence rates of some ADEs were significantly different according to sex and age.The systematic organ classification of atezolizumab ADEs involved 32 systems,among which the top three were blood and lymphatic system disorders(585 cases,12.2%),gastrointestinal disorders(433 cases,9.0%),and infections and infestations(401 cases,8.4%).The reporting odds ratio(ROR)method was used to detect the ADR signals of atezolizumab.The ROR(95%confidence interval)of the top ADE,febrile neutropenia,was 39.236(33.757–45.604).In addition,we found 121 cases of complications associated with immune-related ADEs.Conclusion The ADRs of atezolizumab reported in the FAERS database were consistent with those mentioned in the instructions for atezolizumab use,suggesting that atezolizumab has an acceptable and controllable drug effect.

The Construction and Thinking of the National Sentinel Alliance for Adverse Drug Reaction Monitoring

Objective To briefly introduce the construction and operation of the National Sentinel Alliance for Adverse Drug Reaction(ADR)Monitoring,and provide reference for strengthening the safety monitoring of drugs after listing in China.Methods The literature research method was used to analyze the establishment and promotion measures of the National Sentinel Alliance for ADR Monitoring,and then some countermeasures and suggestions were put forward to enhance the construction of the alliance.Results and Conclusion The alliance based on Chinese hospital pharmacovigilance system(CHPS)has played an important role in ADR monitoring and reporting.Promoting the construction of the alliance can provide a new method for improving the scientific evaluation system and active supervision system of drug safety after listing.Therefore,the construction of alliances at the national and provincial levels should be strengthened.Besides,relevant laws and regulations must be improved to accelerate the research and development of information systems,which will deepen the active monitoring of the alliance continuously.

Safety profile of 0.0015%tafluprost eye drops in China:a post-marketing observational study

AIM:To investigate the treatment pattern and safety of tafluprost for glaucoma and ocular hypertension(OH)in clinical practice in China.METHODS:This post-marketing observational study included patients who received tafluprost to lower intraocular pressure(IOP)within 30d between September 2017 and March 2020 in 20 hospitals in China.Adverse drug reactions(ADRs)during tafluprost treatment and within 30d after the treatment were collected.RESULTS:A total of 2544 patients were included in this study,of them 58.5%(1488/2544)had primary open angle glaucoma(POAG),21.9%(556/2544)had OH and 19.7%(500/2544)used tafluprost for other reasons.Of 359 ADRs occurred in 10.1%(258/2544)patients,and no serious adverse event occurred.The most common ADR was conjunctival hyperemia(128 ADRs in 124 patients,4.9%).Totally 1670 participants(65.6%)combined tafluprost with carbonic anhydrase inhibitors(CAIs;37.1%,620/1670),sympathomimetics(33.5%,559/1670),β-blockers(33.2%,555/1670),other prostaglandin analogs(PGAs;15.6%,260/1670)and other eye drops(15.1%,253/1670).The highest incidence of conjunctival hyperemia was noted in patients who received tafluprost in combination with other PGAs(23 ADRs in 23 patients,8.8%,23/260)and the lowest was in combination with CAIs(16 ADRs in 16 patients,2.6%,16/620).Tafluprost was applied in primary angle-closure glaucoma(41.6%,208/500),after glaucoma surgery(17.8%,89/500)and after non-glaucoma surgery(15.8%,79/500).CONCLUSION:Tafluprost is safe for POAG and OH,and tolerable when combined with other eye drops and under various clinical circumstances.