BACKGROUND Low-volume preparations for colonoscopy have shown similar efficacy compared to high-volume ones in randomized controlled trials(RCT).However,most RCTs do not provide data about clinical outcomes including ...BACKGROUND Low-volume preparations for colonoscopy have shown similar efficacy compared to high-volume ones in randomized controlled trials(RCT).However,most RCTs do not provide data about clinical outcomes including lesions detection rate.Moreover,real-life comparisons are lacking.AIM To compare efficacy(both in terms of adequate bowel preparation and detection of colorectal lesions)and tolerability of a high-volume(HV:4 L polyethylene glycol,PEG)and a low-volume(LV:2 L PEG plus bisacodyl)bowel preparation in a real-life setting.METHODS Consecutive outpatients referred for colonoscopy were prospectively enrolled between 1 December 2014 and 31 December 2016.Patients could choose either LV or HV preparation,with a day-before schedule for morning colonoscopies and a split-dose for afternoon procedures.Adequate bowel preparation according to Boston Bowel Preparation Scale(BBPS),clinical outcomes including polyp detection rate(PDR),adenoma detection rate(ADR),advanced adenoma detection rate(AADR),sessile/serrated lesion detection rate(SDR)and cancer detection rate and self-reported tolerability of HV and LV were blindly assessed.RESULTS Total 2040 patients were enrolled and 1815(mean age 60.6 years,50.2%men)finally included.LV was chosen by 52%of patients(50.8%of men,54.9%of women).Split-dose schedule was more common with HV(44.7%vs 38.2%,P=0.005).High-definition scopes were used in 33.4%of patients,without difference in the two groups(P=0.605).HV and LV preparations showed similar adequate bowel preparation rates(89.2%vs 86.6%,P=0.098),also considering the two different schedules(HV split-dose 93.8%vs LV split-dose 93.6%,P=1;HV daybefore 85.5%vs LV day-before 82.3%,P=0.182).Mean global BBPS score was higher for HV preparations(7.1±1.7 vs 6.8±1.6,P<0.001).After adjustment for sex,age and indications for colonoscopy,HV preparation resulted higher in PDR[Odds ratio(OR)1.32,95%CI:1.07-1.63,P=0.011]and ADR(OR 1.29,95%CI 1.02–1.63,P=0.038)and comparable to LV in AADR(OR 1.51,95%CI 0.97-2.35,P=0.069),SDR and cancer detection rate.The use of standard-definition colonoscopes was associated to lower PDR(adjusted OR 1.59,95%CI:1.22-2.08,P<0.001),ADR(adjusted OR 1.71,95%CI:1.26–2.30,P<0.001)and AADR(adjusted OR 1.97,95%CI:1.09-3.56,P=0.025)in patients receiving LV preparation.Mean Visual Analogue Scale tolerability scored equally(7,P=0.627)but a≥75%dose intake was more frequent with LV(94.6%vs 92.1%,P=0.003).CONCLUSION In a real-life setting,PEG-based low-volume preparation with bisacodyl showed similar efficacy and tolerability compared to standard HV preparation.However,with higher PDR and ADR,HV should still be considered as the reference standard for clinical trials and the preferred option in screening colonoscopy,especially when colonoscopy is performed with standard resolution imaging.展开更多
The current study was designed to determine the safety, tolerability and pharmacokinetic parameters of recombinant human parathyroid hormone [rhPTH （1-84）] used for the treatment of osteoporosis. In the single-dose ...The current study was designed to determine the safety, tolerability and pharmacokinetic parameters of recombinant human parathyroid hormone [rhPTH （1-84）] used for the treatment of osteoporosis. In the single-dose format pharmacokinetic study, thirty-six healthy male volunteers received three dose levels of rhPTH （1-84） subcutaneously： 1, 2, and 4 μg/kg. The blood was timing drawn and the serum concentration of rhPTH （1-84） was determined by enzyme linked immunosorbent assay （ELISA）. Serum concentration-time curves of PTH （1-84） exhibited a double-peak pattern, the first peak appearing about 10 to 30 min after administration and the second peak occurring about 1.5 to2 h after administration. Serum terminal half-time of PTH （1-84） was approximately 2 h. The parameters indicated the serum levels were directly proportional to the administered dose, with the mean Cmax and AUC0_24 ranging from approximately 543.47 to 1845 pg/mL and 2358.6 to 9232.12 pg.h.mL^-1 over the dose range. The drug was well tolerated, the clinical symptoms were generally mild and of short duration.展开更多
BACKGROUND Colonoscopy remains the gold standard for detection of colonic disease.An optimal evaluation depends on adequate bowel cleansing.Patients with inflammatory bowel disease(IBD),require frequent endoscopic ass...BACKGROUND Colonoscopy remains the gold standard for detection of colonic disease.An optimal evaluation depends on adequate bowel cleansing.Patients with inflammatory bowel disease(IBD),require frequent endoscopic assessment for both activity and dysplasia assessment.Two commonly used bowel preparations in Australia are Prep Kit-C(Pc)and Moviprep(Mp).Little is known about tolerability,efficacy and safety of split protocols of Mp and Pc in both IBD and non-IBD patients.AIM To primary aim was to compare the tolerability,efficacy and safety of split protocols of Mp and Pc in patients having a colonoscopy.The secondary aim was to compare the efficacy,tolerability and safety of either preparation in patients with or without IBD.METHODS Patients were randomized to Pc or Mp bowel preparation.Patients completed a questionnaire to assess tolerability.Efficacy was assessed using the Ottawa Bowel Preparation Score.Serum electrolytes and renal function were collected one week prior to colonoscopy and on the day of colonoscopy.RESULTS Of 338 patients met the inclusion criteria.Of 168 patients randomized to Mp and 170 to Pc.The efficacy of bowel preparation(mean Ottawa Bowel Preparation Score)was similar between Mp(5.4±2.4)and Pc(5.1±2.1)(P=0.3).Mean tolerability scores were similar in Mp(11.84±5.4)and Pc(10.99±5.2;P=0.17).125 patients had IBD(73 had Crohn’s Disease and 52 had Ulcerative colitis).Sixtyfour IBD patients were allocated to Mp and 61 to Pc.In non-IBD patients,104 were allocated to Mp and 109 to Pc.The mean tolerability score in the IBD group was lower than the non-IBD group(mean tolerability scores:IBD:10.3±5.1 and non-IBD:12.0±5.3;P=0.01).IBD patients described more abdominal pain with Mp when compared with Pc;(Mp:5.7±4.4 vs Pc:3.6±2.6,P=0.046).Serum magnesium level increased with Pc compared with Mp in all patients(mean increase in mmol/L:Mp:0.03±0.117 and Pc:0.11±0.106;P<0.0001).CONCLUSION In this study,the efficacy,tolerability and safety of Mp and Pc were similar in all patients.However,patients with IBD reported lower tolerability with both preparations.Specifically,IBD patients had more abdominal pain with Mp.These results should be considered when recommending bowel preparation especially to IBD patients.展开更多
Huperzine A is a potent, reversible, and blood-brain barrier permeable acetylcholinesterase inhibitor. The aim of this study was to compare the pharmacokinetics, tolerability, and bioavailability of two formulations w...Huperzine A is a potent, reversible, and blood-brain barrier permeable acetylcholinesterase inhibitor. The aim of this study was to compare the pharmacokinetics, tolerability, and bioavailability of two formulations with the established reference formulation of huperzine A in a fasting, healthy Chinese male population. This was a randomized, single-dose, 3-period, 6-sequence crossover study. The plasma concentrations of huperzine A were determined by liquid chromatography tandem mass spectrometry. Tolerability was assessed based on subject interview, vital sign monitoring, physical examination, and routine blood and urine tests. The mean（SD） pharmacokinetic parameters of the reference drug were Cmax, 1.550（0.528） ng/m L; t1/2, 12.092（1.898） h; AUC0-72 h, 17.550（3.794） ng·h/m L. Those of the test formulation A and test formulation B were Cmax, 1.412（0.467）, 1.521（0.608） ng/m L; t1/2, 12.073（2.068）, 12.271（1.678） h; AUC0-72 h, 15.286（3.434） ng·h/mL, 15.673（3.586） ng·h/m L. The 90% confidence intervals for the AUC0-72 h and Cmax were between 0.80 and 1.25. No adverse events were reported by the subjects or found with results of clinical laboratory test. The test and reference products met the regulatory criteria for bioequivalence in these fasting, healthy Chinese male volunteers. All three formulations appeared to be well tolerated.展开更多
BACKGROUND Adjuvant chemotherapy using intraperitoneal(IP)treatment has demonstrated survival benefit over intravenous(IV)therapy alone in patients treated with upfront debulking surgery for advanced stage ovarian can...BACKGROUND Adjuvant chemotherapy using intraperitoneal(IP)treatment has demonstrated survival benefit over intravenous(IV)therapy alone in patients treated with upfront debulking surgery for advanced stage ovarian cancer.Neoadjuvant chemotherapy followed by interim surgery and adjuvant chemotherapy has similar outcome in survival as compared to upfront surgery followed by adjuvant IV chemotherapy.IP chemotherapy has not been widely adopted in clinical practice for a number of reasons.Whether IP chemotherapy delivered in the patients who received neoadjuvant chemotherapy can be well tolerated or confers any clinical benefit has not been well studied.AIM To evaluate the experience of adjuvant IP chemotherapy in the community cancer clinic setting,and the clinical benefit and tolerability of incorporating IP chemotherapy in patients who received neoadjuvant treatment.METHODS We retrospectively evaluated toxicities and outcomes of patients with stage III and IV ovarian cancer diagnosed at our institution between 07/2007 and 07/2015 who received intraperitoneal chemotherapy after cytoreductive surgery(group 1)or after neoadjuvant chemotherapy followed by interim surgery(group 2).RESULTS Thirty eight patients were treated with IP chemotherapy,median age was 54 years old(range 38.6 to 71 years).In group 1(n=25),12(48%)of the patients completed 4 or more cycle of IP treatment after upfront debulking surgery;while in group 2(n=13),8(61.5%)of the patients completed all 3 cycles of the assigned IP chemotherapy after receiving neoadjuvant IV chemotherapy followed by surgery,and 2(15.4%)more patients tolerated more than 3 cycles.In those patients who did not get planned IP chemotherapy,most of them were treated with substitutional IV chemotherapy,and the completion rate for 6 cycles of IV+IP was 92%.Abdominal pain,(64%in group 1 and 38%in group 2),vomiting,(36%in group 1 and 30.8%in group 2),dehydration(16%in group 1 and 15.4%in group 2),and hypomagnesemia(12%in group 1 and 15.4%in group 2)were the most common adverse effects in all patients,while patients who have received neoadjuvant chemotherapy were more likely to get hypokalemia,fatigue and renal insufficiency.Progression free survival(PFS)was 26.5 mo(95%CI 14.9,38.0)in group 1 and 27.6 mo(95%CI 13.1,42.1)in group 2.The overall survival was 100.2 mo(95%CI 67.9,132.5)for group 1 and 68.2 mo(95%CI 32.2,104.0)for group 2.For the entire cohort,PFS was 26.5 mo(95%CI 15.9,37.0)and OS was 78.8 mo(95%CI 52.3,105.4).CONCLUSION The use of IP/IV chemotherapy can be safely administrated in the community cancer clinic setting.The use of IP/IV chemotherapy in patients who have received neoadjuvant chemotherapy followed by surgery is feasible and tolerable.Despite various modification of the IP regimen,incorporation of IP chemotherapy in the adjuvant setting appears to be associated with improved PFS and overall survival.展开更多
Hypertension is one of the well-established risk factor for cardiovascular diseases. Calcium channel blockers（CCBs）, chemicals that could block voltage-gated calcium channels（VGCCs） in cardiac muscle and blood ves...Hypertension is one of the well-established risk factor for cardiovascular diseases. Calcium channel blockers（CCBs）, chemicals that could block voltage-gated calcium channels（VGCCs） in cardiac muscle and blood vessels, has been widely used for the treatment of hypertension. Isradipine, a second-generation CCB with high affinity for voltage-operated calcium channels, has not been marked in China. The purpose of this study was to investigate the efficacy, safety and tolerability of isradipine in a phase I clinical trial including 31 healthy Chinese subjects. All subjects received different doses of isradipine at 2.5, 5.0 and 10.0 mg in single-dose study. When the test is completed, subjects treated with 5.0 mg isradipine stayed at the research center for multiple-dose study（5.0 mg isradipine twice daily for 9 d）. Systolic blood pressure（SBP） and diastolic blood pressure（DBP） were measured pre-dose and post-dose（1, 2, 4, 6, 8, 12, 24, 36 and 48 h after isradipine treatment）. Electrocardiography（ECG） and peripheral edema were monitored pre-dose and 4, 8, 24 and 48 h after isradipine treatment. SBP and DBP in single-dose study decreased after isradipine treatment. SBP reached the lowest values 8 h after dosing with a decrease of（7.0±9.7） mmHg（5.4%, P = 0.111） in 2.5 mg group,（7.0±6.9） mmHg（6.0%, P = 0.008） in 5.0 mg group, and（14.0±10.5） mmHg（12.7%, P = 0.005） for 10.0 mg group respectively. Similarly, DBP also reached the lowest values 8 h after dosing with a decrease of（10.0±7.9） mmHg（12.8%, P = 0.004） in 2.5 mg group,（6.0±7.0） mmHg（8.6%, P = 0.003） in 5.0 mg group, and（11.0±4.1） mmHg（15.1%, P = 0.000） in 10.0 mg group respectively. No significant changes of SBP and DBP were observed in multiple-dose study. We detected mild adverse events（AEs）, such as increased transaminase and headache that resolved rapidly and spontaneously without intervention. No serious or potentially life-threatening AE was detected. Our results indicate that isradipin has a good safety and tolerability in Chinese healthy subjects. Long-term study with larger sample size is needed to confirm our conclusion.展开更多
AIM To investigate the efficacy and safety of mineralwater with a high content of hydrogen carbonate inpatients with heartburn.METHODS： This open, single-center, single-armclinical pilot study enrolled 50 patients, 1...AIM To investigate the efficacy and safety of mineralwater with a high content of hydrogen carbonate inpatients with heartburn.METHODS： This open, single-center, single-armclinical pilot study enrolled 50 patients, 18-64 yearsold, who had been suffering from heartburn at leasttwice a week for at least 3 mo before entering thestudy. Pharmacological treatment of heartburn was notpermitted, and patients with severe organic diseaseswere excluded. After a run-in period of one week, theparticipants received 1.5 L of the test water for thefollowing 6 wk; 300 mL with meals t.i.d., the remainderto be drunk throughout the day. During the trial, therewere five visits at the study center （screening, baseline,two interim visits and the final visit）. The efficacyendpoints included incidence and duration of heartburnepisodes per week by patient＇s self-assessment （heartburndiary） as well as changes in symptom severity asper symptom specific questionnaires [Reflux Disease Questionnaire （RDQ）; Quality of Life in Reflux andDyspepsia （QOLRAD）; Gastrointestinal Quality of LifeIndex] and overall health-related quality of life per SF-12（12-question short form） at each visit. At the end of thestudy, patients and investigators independently ratedthe overall efficacy of the test water on a 4-point Likertscale. Safety was assessed by evaluation of adverseevents （AEs）, vital signs （heart rate, blood pressure）and laboratory parameters. Changes from initial to finalexaminations were assessed by the non-parametricWilcoxon test; categorical variables were comparedusing the χ 2 test, and for more than 5 categories, by theU-test.RESULTS： Twenty-eight participants were men, 22women. The mean age of the patients in the fullanalysis set/intention-to treat population （FAS/ITT） was40.6 years. Forty-two participants completed the studyaccording to the study protocol and formed the perprotocolset （PP population）; 48 participants drank thewater at least once as requested and were analyzedas ITT population. The occurrence of heartburn wasstatistically significantly reduced at wk 6 in both the ITTand the PP populations. At wk 6, the mean number ofheartburn episodes/week decreased by 5.1 episodes（P 〈 0.001） and the mean duration of heartburnsymptoms by 19 min （ITT） （P = 0.002）. The frequencyof heartburn symptoms was reduced in 89.6% of thepatients （P 〈 0.001）, and the duration of symptoms in79.2% of patients （ITT） （P 〈 0.001）. All dimensions ofthe RDQ （heartburn, regurgitation, gastro-esophagealreflux disease symptoms, dyspepsia） showed asignificant improvement at 6 wk. Likewise, diseasespecificquality of life improved significantly （QOLRAD,GIQLI）. Overall, 89.4% of patients rated the efficacyof the test water as ＂good＂ or ＂very good＂, as did theinvestigators for 91.5% of the patients. There wereno serious AEs. After 6 wk, systolic and diastolic bloodpressure values decreased slightly but significantly [-3.5and -3.0 mmHg, respectively （P = 0.008 and P = 0,002）].Ninety-six percent of patients and investigators for thesame percentage of patients rated the tolerability of thewater as ＂good＂ or ＂very good＂.CONCLUSION： The data demonstrate effectiveness ofa hydrogen carbonate-rich mineral water in alleviatingheartburn frequency and severity, thereby improvingquality of life. The water has excellent tolerability.展开更多
In a placebo-controlled, double-blind, randomized clinical trial, the tolerability of a proprietary larch arabinogalactan preparation (ResistAidTM) was investigated. METHODS: 199 healthy participants were randomly ass...In a placebo-controlled, double-blind, randomized clinical trial, the tolerability of a proprietary larch arabinogalactan preparation (ResistAidTM) was investigated. METHODS: 199 healthy participants were randomly assigned to receive either placebo (n = 98) or an arabinogalactan preparation (n = 101) over a period of 12 weeks. As safety parameters the total number of adverse events, changes in various biochemical and laboratory parameters as well as the global evaluation of tolerability by investigator and subjects compared to placebo were evaluated. RESULTS: In total 16 adverse events were observed in 16 subjects, with no difference between the arabinogalactan and the placebo group (p = 0.935). There were no differences in the mean changes of the measured biochemical and laboratory parameters. The tolerability of the arabinogalactan extract was rated as “very good” or “good” by the investigators for 99% of the subjects and by 98% subjects in self-assessment with no statistical differences to placebo. CONCLUSION: The measured parameters as well as the evaluation of the tolerability by the investigators and the subjects demonstrate a very good tolerance profile of the proprietary arabinogalactan extract with no differences to placebo when taken for 12 weeks.展开更多
This 12-month open-label, but dose-blinded extension phase, evaluated the safety and tolerability of flexibly-dosed edivoxetine (6, 9, 12 or 18 mg once daily) in patients (N = 397) with major depressive disorder, who ...This 12-month open-label, but dose-blinded extension phase, evaluated the safety and tolerability of flexibly-dosed edivoxetine (6, 9, 12 or 18 mg once daily) in patients (N = 397) with major depressive disorder, who completed the 10-week randomized, double-blind, placebo-controlled acute phase of the study.All patients were treated with edivoxetine during the extension phase. The mean age of the patients was 45 years, and most were white females. Safety evaluations included assessment of treatment-emergent adverse events (TEAEs), laboratory and vital sign measures, and suicidality. Within-group t-tests based on a 2-sided significance level of 0.05 and 95% confidence levels were used to assess whether changes from baseline were statistically significant from zero. The overall completion rate was 54%. Adverse event was the most common (14.4%) reason for discontinuation, which included blood pressure increased (1.3%), heart rate increased (1.3%), anxiety (1.0%), and tachycardia (1.0%). At least 1 TEAE was reported by 72.3% of patients, of which headache (10.8%) and hyperhidrosis (10.1%) were the most common;2.8% of patients had ≥1 serious adverse events, and there were no completed suicides. No clinically relevant changes were observed in most laboratory measures. Potentially clinically significant changes in ALT values occurred in 1.8% of patients, and either normalized or had decreased by the last assessment. Mean increases in blood pressure and pulse were consistent with those observed in the acute phase and appeared to reach a plateau within 3 to 5 months of treatment. In conclusion, safety and tolerability findings during this long-term extension phase evaluation of edivoxetine were consistent with its norepinephrine reuptake inhibition profile.展开更多
Background: Parkinson’s disease (PD) is a progressive neurodegenerative disease that occurs as a result of loss of dopaminergic neurons from the substantia nigra. Rotigotine is a non-ergolinic dopamine agonist availa...Background: Parkinson’s disease (PD) is a progressive neurodegenerative disease that occurs as a result of loss of dopaminergic neurons from the substantia nigra. Rotigotine is a non-ergolinic dopamine agonist available as a silicone-based transdermal patch for the treatment of PD. In the European Union, rotigotine transdermal patch is indicated for use as monotherapy in early idiopathic PD, or in combination with levodopa through the disease course to the late stages where motor complications with levodopa become an issue. Objective: To investigate the safety and tolerability of transdermal rotigotine, in patients with PD being treated during routine clinical practice for 2 years. Results: 114 patients were enrolled, and evaluated for adverse events over a 24-month period. Adverse events occurred in 39 patients (34.21%). 23 patients (20.17%) reported application site reactions (dermatitis, erythema, itching), and 16 (14.03%) had systemic adverse events. Sleep disorders were the most common problem;the others were hallucinations, depression, dizziness, and syncope. No patient experienced dyskinesia. Adverse events necessitated the discontinuation of rotigotine for application site reactions in fourteen patients (12.28%) and 11 patients (9.64%);reasons for discontinuation were systemic adverse events. Conclusion: Rotigotine is safe and well tolerated when used to treat PD in routine clinical practice.展开更多
Background: “Diarra”, a traditional herbal remedy made from five (5) medicinal plants, might be endowed with anti-diarrhoeal properties according to its owner. However, scientific evidence of its safety, tolerabilit...Background: “Diarra”, a traditional herbal remedy made from five (5) medicinal plants, might be endowed with anti-diarrhoeal properties according to its owner. However, scientific evidence of its safety, tolerability and activity has not been established. Objective: This study aimed to assess the safety, tolerability and anti-diarrhoeal activity of “Diarra” in experimental rats. Materials and Methods: Safety was assessed by acute (OECD 423) and sub-acute (OECD 407) toxicity studies at doses of 5, 10 and 20 mg/kg. Clinical tolerability was assessed for 28 days. On day 29, a blood sample was taken to evaluate biological tolerability. The anti-diarrhoeal activity was investigated in a castor oil-induced diarrhoea model. Rats were given the remedy at doses of 5, 10 and 20 mg/kg and then castor oil 1 hour later. They were observed for 4 hours and diarrhoeal stools were collected. The Percentage of diarrhoeal inhibition was calculated. Results: A single dose of “Diarra” at a dose of 2000 mg/kg did not induce any lethality, behavioural or weight change in rats for 14 days. When administered once daily for 28 days, “Diarra” did not cause lethality or significant behavioural disorders or significant weight loss in rats. No biological disorders were observed. The treatment of rats with “Diarra” at doses of 5 mg/kg, 10 mg/kg and 20 mg/kg in a single administration inhibited the occurrence of diarrhoeal stools. The respective percentages of inhibition were 60%, 50% and 62%, similar to those of loperamide at a dose of 2 mg/kg (68%). Conclusion: “Diarra” has an anti-diarrheal activity in rats. It is also safe to use this remedy as such.展开更多
BACKGROUND Infants'nutrition significantly influences their growth,development,and overall well-being.With the increasing demand for organic infant formula driven by the perception of health benefits and growing a...BACKGROUND Infants'nutrition significantly influences their growth,development,and overall well-being.With the increasing demand for organic infant formula driven by the perception of health benefits and growing awareness of natural feeding options,it is crucial to conduct a comparative analysis of the gastrointestinal tolerability between organic and traditional infant formulas.AIM To provide a concise and precise analysis of the gastrointestinal tolerability of organic infant formula compared to traditional infant formula.Due to limited direct comparisons,the review synthesizes available literature on each formula type,presenting insights into their potential effects on infants'digestive health.METHODS An extensive literature search was conducted,compiling studies on organic and traditional infant formulas,their compositions,and reported effects on gastrointestinal tolerability.We searched academic databases such as PubMed and Google Scholar and specialized nutrition,paediatrics,and infant health journals using relevant keywords till October 1,2023.RESULTS Although specific comparative studies are scarce and formula heterogeneity is a significant limitation,this systematic review provides an in-depth understanding of organic infant formulas'composition and potential benefits.While scientific evidence directly comparing gastrointestinal tolerability is limited,organic formulas strive to use carefully selected organic ingredients to imitate breast milk composition.Potential benefits include improved lipid profiles,higher methionine content,and decreased antibiotic-resistant bacteria levels.Understanding the gastrointestinal tolerability of organic and traditional infant formulas is crucial for parents and healthcare providers to make informed decisions.CONCLUSION Despite limitations in direct comparisons,this systematic review provides insights into the composition and potential benefits of organic infant formulas.It emphasizes the need for further research to elucidate their gastrointestinal effects comprehensively.展开更多
AIM: To determine the tolerability and safety profile of a low-dose maintenance therapy with 6-TG in azathioprine (AZA) or 6-mercaptopurine (6-MP) intolerant inflammatory bowel disease (IBD) patients over a treatment ...AIM: To determine the tolerability and safety profile of a low-dose maintenance therapy with 6-TG in azathioprine (AZA) or 6-mercaptopurine (6-MP) intolerant inflammatory bowel disease (IBD) patients over a treatment period of at least 1 year.METHODS: Database analysis.RESULTS: Twenty out of ninety-five (21%) patients discontinued 6-TG (mean dose 24.6 mg; mean 6-TGN level 540 pmol/8×108 RBC) within 1 year. Reasons for discontinuation were GI complaints (31%), malaise (15%)and hepatotoxicity (15%). Hematological events occurred in three patients, one discontinued treatment. In the 6-TG-tolerant group, 9% (7/75) could be classified as hepatotoxicity. An abdominal ultrasound was performed in 54% of patients, one patient had splenomegaly.CONCLUSION: The majority of AZA or 6-MP-intolerant IBD patients (79%) is able to tolerate maintenance treatment with 6-TG (dosages between 0.3 and 0.4 mg/kg per d). 6-TG may still be considered as an escape maintenance immunosuppressant in this difficult to treat group of patients, taking into account potential toxicity and efficacy of other alternatives. The recently reported hepatotoxicity is worrisome and 6-TG should therefore be administered only in prospective trials.展开更多
Background:To review the available evidence from prospective studies on the safety and tolerability of the ketogenic diet (KD) for the treatment of refractory childhood epilepsy.Methods:A comprehensive bibliographic s...Background:To review the available evidence from prospective studies on the safety and tolerability of the ketogenic diet (KD) for the treatment of refractory childhood epilepsy.Methods:A comprehensive bibliographic search was performed with the aim of retrieving prospective studies that monitored adverse effects (AEs) in children after receiving the classic or medium-chain triglyceride KD therapy for refractory epilepsy.Results:A total of 45 studies were retrieved,including 7 randomized controlled trials.More than 40 categories of AEs were reported.The most common AEs included gastrointestinal disturbances (40.6%),hyperlipidemia (12.8%),hyperuricemia (4.4%),lethargy (4.1%),infectious diseases (3.8%) and hypoproteinemia (3.8%).Severe AEs,such as respiratory failure and pancreatitis,occurred in no more than 0.5% of children.Specifically,patients receiving KD therapy should be monitored for osteopenia,urological stones,right ventricular diastolic dysfunction,and growth disturbance.The total retention rates of the diet for 1 year and 2 years were 45.7% and 29.2%,respectively.Nearly half of the patients discontinued the diet because of lack of efficacy.AEs were not the main reason for the KD discontinuation.None of the 24 deaths reported after initiation of the diet was attributed to the KD.Conclusions:KD is a relatively safe dietary therapy.However,because the KD can cause various AEs,it should be implemented under careful medical supervision.Continuous follow-up is needed to address the long-term impact of the diet on the overall health of children.展开更多
Background The combination of cisplatin and vinorelbine is an evidence-supported regimen for adjuvant chemotherapy for treating non-small cell lung cancer （NSCLC）. But this doublet has considerable toxicity and unfa...Background The combination of cisplatin and vinorelbine is an evidence-supported regimen for adjuvant chemotherapy for treating non-small cell lung cancer （NSCLC）. But this doublet has considerable toxicity and unfavorable tolerability, and results in poor compliance. The cisplatin and gemcitabine regimen is one of the most active and well-tolerated regimens against advanced NSCLC, but its toxicity and tolerability has not been adequately evaluated in the adjuvant setting. Methods From a lung cancer database we retrospectively reviewed NSCLC patients receiving adjuvant chemotherapy of cisplatin （75 mg/m2） and gemcitabine （1250 mg/m2） between January 2005 and December 2011. Postoperative demographics, compliance to adjuvant therapy and toxicity were retrieved from medical records. Results A total of 132 patients met the criteria and were included in the study, 96 were male （72.7%） and 36 were female （27.3%）. Median age was 60.5 years old, range 29-75 years, and 41.7% of patients were 〉65 years old. Overall, 68.2% patients received all four planned cycles, and the cumulative dose delivered for gemcitabine was 8333 mg （83.3% of the planned dose） and cisplatin 248 mg （82.7% of the planned dose）. There were no treatment-related deaths. Grade 3/4 neutropenia developed in 47 patients （35.6%） and was the predominant hematologic toxicity. Common grade 3/4 non- hematologic toxicities were nausea/vomiting （22.0%）, infection （12.3%）, and febrile neutropenia （11.4%）. Conclusion Cisplatin and gemcitabine are feasible for use in the adjuvant setting with a favorable toxicity profile and superior tolerabilitv compared with Dublished data on cisDlatin and vinorelbine.展开更多
Post-translational modifications(PTMs)regulate the occurrence and development of cancer,and lactylation modification is a new form of PTMs.Recent studies have found that lactic acid modification can regulate the immun...Post-translational modifications(PTMs)regulate the occurrence and development of cancer,and lactylation modification is a new form of PTMs.Recent studies have found that lactic acid modification can regulate the immune tolerance of cancer cells.The classical theory holds that prostate apoptosis response-4(PAR-4)is a tumor suppressor protein.However,our recent research has found that PAR-4 has a biological function of promoting cancer in hepatocellular carcinoma(HCC),and our analysis shows that PAR-4 can be modified of lactic acid.These research evidences suggest that PAR-4 lactylation modification may drive immune tolerance in HCC.Therefore,inhibiting PAR-4 lactylation modification is very likely to increase the sensitivity of HCC to immunotherapy.展开更多
BACKGROUND Due to the dry and cold climate,the obvious temperature difference between day and night,and the low oxygen content of the air in the plateau area,people are prone to upper respiratory tract diseases,and of...BACKGROUND Due to the dry and cold climate,the obvious temperature difference between day and night,and the low oxygen content of the air in the plateau area,people are prone to upper respiratory tract diseases,and often the condition is prolonged,and the patients are prone to anxiety and uneasiness,which may be related to the harshness of the plateau environment,somatic discomfort due to the lack of oxygen,anxiety about the disease,and other factors.AIM To investigate the effects of cognitive behavioral therapy(CBT)on anxiety,sleep disorders,and hypoxia tolerance in patients with high-altitude respiratory diseases.METHODS A total of 2337 patients with high-altitude-related respiratory diseases treated at our hospital between November 2023 and January 2024 were selected as the study subjects.The subjects’pre-high-altitude residential altitude was approximately 1700 meters.They were divided into two groups.Both groups were given symptomatic treatment,and the control group implemented conventional nursing intervention,while the research group simultaneously conducted CBT intervention;assessed the degree of health knowledge of the two groups,and applied the Hamilton Anxiety Scale and the Pittsburgh Sleep Quality Index to assess the anxiety and sleep quality of the patients before and after the intervention,respectively.It also observed the length and efficiency of sleep,and detected the level of serum hypoxia inducible factor-1α,erythropoietin(EPO)and clinical intervention before and after intervention.EPO levels,and investigated satisfaction with the clinical intervention.RESULTS The rate of excellent health knowledge in the intervention group was 93.64%,which was higher than that in the control group(74.23%;P<0.05).Before the intervention,there was no significant difference in Hamilton Anxiety Scale and Pittsburgh Sleep Quality Index scores between the two groups(P>0.05),and after the intervention,the scores of the study group were significantly lower than those of the control group(P<0.05).There was no significant difference in sleep duration and sleep efficiency between the groups before the intervention(P>0.05),and after the intervention,the scores of the study group were significantly larger than those of the control group(P<0.05).There was no significant difference in serum hypoxia inducible factor-1αand EPO between the two groups before intervention(P>0.05),and both research groups were significantly lower than the control group after intervention(P<0.05).According to the questionnaire survey,the intervention satisfaction of the study group was 95.53%,which was higher than that of the control group(80.14%;P<0.05).CONCLUSION The CBT intervention in the treatment of patients with high-altitude-related respiratory diseases helps improve patients'health knowledge,relieve anxiety,improve sleep quality and hypoxia tolerance,and improve nursing satisfaction.展开更多
Regulatory T cells,a subset of CD4^(+)T cells,play a critical role in maintaining immune tolerance and tissue homeostasis due to their potent immunosuppressive properties.Recent advances in research have highlighted t...Regulatory T cells,a subset of CD4^(+)T cells,play a critical role in maintaining immune tolerance and tissue homeostasis due to their potent immunosuppressive properties.Recent advances in research have highlighted the important therapeutic potential of Tregs in neurological diseases and tissue repair,emphasizing their multifaceted roles in immune regulation.This review aims to summarize and analyze the mechanisms of action and therapeutic potential of Tregs in relation to neurological diseases and neural regeneration.Beyond their classical immune-regulatory functions,emerging evidence points to non-immune mechanisms of regulatory T cells,particularly their interactions with stem cells and other non-immune cells.These interactions contribute to optimizing the repair microenvironment and promoting tissue repair and nerve regeneration,positioning non-immune pathways as a promising direction for future research.By modulating immune and non-immune cells,including neurons and glia within neural tissues,Tregs have demonstrated remarkable efficacy in enhancing regeneration in the central and peripheral nervous systems.Preclinical studies have revealed that Treg cells interact with neurons,glial cells,and other neural components to mitigate inflammatory damage and support functional recovery.Current mechanistic studies show that Tregs can significantly promote neural repair and functional recovery by regulating inflammatory responses and the local immune microenvironment.However,research on the mechanistic roles of regulatory T cells in other diseases remains limited,highlighting substantial gaps and opportunities for exploration in this field.Laboratory and clinical studies have further advanced the application of regulatory T cells.Technical advances have enabled efficient isolation,ex vivo expansion and functionalization,and adoptive transfer of regulatory T cells,with efficacy validated in animal models.Innovative strategies,including gene editing,cell-free technologies,biomaterial-based recruitment,and in situ delivery have expanded the therapeutic potential of regulatory T cells.Gene editing enables precise functional optimization,while biomaterial and in situ delivery technologies enhance their accumulation and efficacy at target sites.These advancements not only improve the immune-regulatory capacity of regulatory T cells but also significantly enhance their role in tissue repair.By leveraging the pivotal and diverse functions of Tregs in immune modulation and tissue repair,regulatory T cells–based therapies may lead to transformative breakthroughs in the treatment of neurological diseases.展开更多
Background:The introductions of anti-human epidermal growth factor receptor-2(HER2)agents have significantly improved the treatment outcome of patients with HER2-positive breast cancer.BAT8001 is a novel antibodydrug ...Background:The introductions of anti-human epidermal growth factor receptor-2(HER2)agents have significantly improved the treatment outcome of patients with HER2-positive breast cancer.BAT8001 is a novel antibodydrug conjugate targeting human epidermal growth factor receptor-2(HER2)-expressing cells composed of a trastuzumab biosimilar linked to the drug-linker Batansine.This dose-escalation,phase I study was designed to assess the safety,tolerability,pharmacokinetics,and preliminary anti-tumor activity of BAT8001 in patients with HER2-positive locally advanced or metastatic breast cancer.Methods:This trial was conducted in subjects with histologically confirmed HER2-positive breast cancer(having evaluable lesions and an Eastern Cooperative Oncology Group performance status of 0 or 1)using a 3+3 design of escalating BAT8001 doses.Patients received BAT8001 intravenously in a 21-day cycle,with dose escalation in 5 cohorts:1.2,2.4,3.6,4.8,and 6.0 mg/kg.The primary objective was to evaluate the safety and tolerability of BAT8001.Preliminary activity of BAT8001 was also assessed as a secondary objective.Results:Between March 2017 to May 2018,29 HER2-positive breast cancer patients were enrolled.The observed dose-limiting toxicities were grade 4 thrombocytopenia and grade 3 elevated transaminase.The maximum tolerated dose was determined to be 3.6 mg/kg.Grade 3 or greater adverse events(AEs)occurred in 14(48.3%)of 29 patients,including thrombocytopenia in 12(41.4%)patients,aspartate aminotransferase increased in 4(13.8%)patients,γ-glutamyl transferase increased in 2(6.9%)patients,alanine aminotransferase increased in 2(6.9%)patients,diarrhea in 2(6.9%)patients.Objective response was observed in 12(41.4%,95%confidence interval[CI]=23.5%-61.1%)and disease control(including patients achieving objective response and stable disease)was observed in 24(82.8%,95%CI=64.2%-94.2%)patients.Conclusions:BAT8001 demonstrated favorable safety profiles,with promising anti-tumor activity in patients with HER2-positive locally advanced or metastatic breast cancer.BAT8001 has the potential to provide a new therapeutic option in patients with metastatic HER2-positive breast cancer.展开更多
Global warming impacts plant growth and development,which in turn threatens food security.Plants can clearly respond to warm-temperature(such as by thermomorphogenesis)and high-temperature stresses.At the molecular le...Global warming impacts plant growth and development,which in turn threatens food security.Plants can clearly respond to warm-temperature(such as by thermomorphogenesis)and high-temperature stresses.At the molecular level,many small molecules play crucial roles in balancing growth and defense,and stable high yields can be achieved by fine-tuning the responses to external stimuli.Therefore,it is essential to understand the molecular mechanisms underlying plant growth in response to heat stress and how plants can adjust their biological processes to survive heat stress conditions.In this review,we summarize the heat-responsive genetic networks in plants and crop plants based on recent studies.We focus on how plants sense the elevated temperatures and initiate the cellular and metabolic responses that allow them to adapt to the adverse growing conditions.We also describe the trade-off between plant growth and responses to heat stress.Specifically,we address the regulatory network of plant responses to heat stress,which will facilitate the discovery of novel thermotolerance genes and provide new opportunities for agricultural applications.展开更多
文摘BACKGROUND Low-volume preparations for colonoscopy have shown similar efficacy compared to high-volume ones in randomized controlled trials(RCT).However,most RCTs do not provide data about clinical outcomes including lesions detection rate.Moreover,real-life comparisons are lacking.AIM To compare efficacy(both in terms of adequate bowel preparation and detection of colorectal lesions)and tolerability of a high-volume(HV:4 L polyethylene glycol,PEG)and a low-volume(LV:2 L PEG plus bisacodyl)bowel preparation in a real-life setting.METHODS Consecutive outpatients referred for colonoscopy were prospectively enrolled between 1 December 2014 and 31 December 2016.Patients could choose either LV or HV preparation,with a day-before schedule for morning colonoscopies and a split-dose for afternoon procedures.Adequate bowel preparation according to Boston Bowel Preparation Scale(BBPS),clinical outcomes including polyp detection rate(PDR),adenoma detection rate(ADR),advanced adenoma detection rate(AADR),sessile/serrated lesion detection rate(SDR)and cancer detection rate and self-reported tolerability of HV and LV were blindly assessed.RESULTS Total 2040 patients were enrolled and 1815(mean age 60.6 years,50.2%men)finally included.LV was chosen by 52%of patients(50.8%of men,54.9%of women).Split-dose schedule was more common with HV(44.7%vs 38.2%,P=0.005).High-definition scopes were used in 33.4%of patients,without difference in the two groups(P=0.605).HV and LV preparations showed similar adequate bowel preparation rates(89.2%vs 86.6%,P=0.098),also considering the two different schedules(HV split-dose 93.8%vs LV split-dose 93.6%,P=1;HV daybefore 85.5%vs LV day-before 82.3%,P=0.182).Mean global BBPS score was higher for HV preparations(7.1±1.7 vs 6.8±1.6,P<0.001).After adjustment for sex,age and indications for colonoscopy,HV preparation resulted higher in PDR[Odds ratio(OR)1.32,95%CI:1.07-1.63,P=0.011]and ADR(OR 1.29,95%CI 1.02–1.63,P=0.038)and comparable to LV in AADR(OR 1.51,95%CI 0.97-2.35,P=0.069),SDR and cancer detection rate.The use of standard-definition colonoscopes was associated to lower PDR(adjusted OR 1.59,95%CI:1.22-2.08,P<0.001),ADR(adjusted OR 1.71,95%CI:1.26–2.30,P<0.001)and AADR(adjusted OR 1.97,95%CI:1.09-3.56,P=0.025)in patients receiving LV preparation.Mean Visual Analogue Scale tolerability scored equally(7,P=0.627)but a≥75%dose intake was more frequent with LV(94.6%vs 92.1%,P=0.003).CONCLUSION In a real-life setting,PEG-based low-volume preparation with bisacodyl showed similar efficacy and tolerability compared to standard HV preparation.However,with higher PDR and ADR,HV should still be considered as the reference standard for clinical trials and the preferred option in screening colonoscopy,especially when colonoscopy is performed with standard resolution imaging.
文摘The current study was designed to determine the safety, tolerability and pharmacokinetic parameters of recombinant human parathyroid hormone [rhPTH （1-84）] used for the treatment of osteoporosis. In the single-dose format pharmacokinetic study, thirty-six healthy male volunteers received three dose levels of rhPTH （1-84） subcutaneously： 1, 2, and 4 μg/kg. The blood was timing drawn and the serum concentration of rhPTH （1-84） was determined by enzyme linked immunosorbent assay （ELISA）. Serum concentration-time curves of PTH （1-84） exhibited a double-peak pattern, the first peak appearing about 10 to 30 min after administration and the second peak occurring about 1.5 to2 h after administration. Serum terminal half-time of PTH （1-84） was approximately 2 h. The parameters indicated the serum levels were directly proportional to the administered dose, with the mean Cmax and AUC0_24 ranging from approximately 543.47 to 1845 pg/mL and 2358.6 to 9232.12 pg.h.mL^-1 over the dose range. The drug was well tolerated, the clinical symptoms were generally mild and of short duration.
文摘BACKGROUND Colonoscopy remains the gold standard for detection of colonic disease.An optimal evaluation depends on adequate bowel cleansing.Patients with inflammatory bowel disease(IBD),require frequent endoscopic assessment for both activity and dysplasia assessment.Two commonly used bowel preparations in Australia are Prep Kit-C(Pc)and Moviprep(Mp).Little is known about tolerability,efficacy and safety of split protocols of Mp and Pc in both IBD and non-IBD patients.AIM To primary aim was to compare the tolerability,efficacy and safety of split protocols of Mp and Pc in patients having a colonoscopy.The secondary aim was to compare the efficacy,tolerability and safety of either preparation in patients with or without IBD.METHODS Patients were randomized to Pc or Mp bowel preparation.Patients completed a questionnaire to assess tolerability.Efficacy was assessed using the Ottawa Bowel Preparation Score.Serum electrolytes and renal function were collected one week prior to colonoscopy and on the day of colonoscopy.RESULTS Of 338 patients met the inclusion criteria.Of 168 patients randomized to Mp and 170 to Pc.The efficacy of bowel preparation(mean Ottawa Bowel Preparation Score)was similar between Mp(5.4±2.4)and Pc(5.1±2.1)(P=0.3).Mean tolerability scores were similar in Mp(11.84±5.4)and Pc(10.99±5.2;P=0.17).125 patients had IBD(73 had Crohn’s Disease and 52 had Ulcerative colitis).Sixtyfour IBD patients were allocated to Mp and 61 to Pc.In non-IBD patients,104 were allocated to Mp and 109 to Pc.The mean tolerability score in the IBD group was lower than the non-IBD group(mean tolerability scores:IBD:10.3±5.1 and non-IBD:12.0±5.3;P=0.01).IBD patients described more abdominal pain with Mp when compared with Pc;(Mp:5.7±4.4 vs Pc:3.6±2.6,P=0.046).Serum magnesium level increased with Pc compared with Mp in all patients(mean increase in mmol/L:Mp:0.03±0.117 and Pc:0.11±0.106;P<0.0001).CONCLUSION In this study,the efficacy,tolerability and safety of Mp and Pc were similar in all patients.However,patients with IBD reported lower tolerability with both preparations.Specifically,IBD patients had more abdominal pain with Mp.These results should be considered when recommending bowel preparation especially to IBD patients.
文摘Huperzine A is a potent, reversible, and blood-brain barrier permeable acetylcholinesterase inhibitor. The aim of this study was to compare the pharmacokinetics, tolerability, and bioavailability of two formulations with the established reference formulation of huperzine A in a fasting, healthy Chinese male population. This was a randomized, single-dose, 3-period, 6-sequence crossover study. The plasma concentrations of huperzine A were determined by liquid chromatography tandem mass spectrometry. Tolerability was assessed based on subject interview, vital sign monitoring, physical examination, and routine blood and urine tests. The mean（SD） pharmacokinetic parameters of the reference drug were Cmax, 1.550（0.528） ng/m L; t1/2, 12.092（1.898） h; AUC0-72 h, 17.550（3.794） ng·h/m L. Those of the test formulation A and test formulation B were Cmax, 1.412（0.467）, 1.521（0.608） ng/m L; t1/2, 12.073（2.068）, 12.271（1.678） h; AUC0-72 h, 15.286（3.434） ng·h/mL, 15.673（3.586） ng·h/m L. The 90% confidence intervals for the AUC0-72 h and Cmax were between 0.80 and 1.25. No adverse events were reported by the subjects or found with results of clinical laboratory test. The test and reference products met the regulatory criteria for bioequivalence in these fasting, healthy Chinese male volunteers. All three formulations appeared to be well tolerated.
文摘BACKGROUND Adjuvant chemotherapy using intraperitoneal(IP)treatment has demonstrated survival benefit over intravenous(IV)therapy alone in patients treated with upfront debulking surgery for advanced stage ovarian cancer.Neoadjuvant chemotherapy followed by interim surgery and adjuvant chemotherapy has similar outcome in survival as compared to upfront surgery followed by adjuvant IV chemotherapy.IP chemotherapy has not been widely adopted in clinical practice for a number of reasons.Whether IP chemotherapy delivered in the patients who received neoadjuvant chemotherapy can be well tolerated or confers any clinical benefit has not been well studied.AIM To evaluate the experience of adjuvant IP chemotherapy in the community cancer clinic setting,and the clinical benefit and tolerability of incorporating IP chemotherapy in patients who received neoadjuvant treatment.METHODS We retrospectively evaluated toxicities and outcomes of patients with stage III and IV ovarian cancer diagnosed at our institution between 07/2007 and 07/2015 who received intraperitoneal chemotherapy after cytoreductive surgery(group 1)or after neoadjuvant chemotherapy followed by interim surgery(group 2).RESULTS Thirty eight patients were treated with IP chemotherapy,median age was 54 years old(range 38.6 to 71 years).In group 1(n=25),12(48%)of the patients completed 4 or more cycle of IP treatment after upfront debulking surgery;while in group 2(n=13),8(61.5%)of the patients completed all 3 cycles of the assigned IP chemotherapy after receiving neoadjuvant IV chemotherapy followed by surgery,and 2(15.4%)more patients tolerated more than 3 cycles.In those patients who did not get planned IP chemotherapy,most of them were treated with substitutional IV chemotherapy,and the completion rate for 6 cycles of IV+IP was 92%.Abdominal pain,(64%in group 1 and 38%in group 2),vomiting,(36%in group 1 and 30.8%in group 2),dehydration(16%in group 1 and 15.4%in group 2),and hypomagnesemia(12%in group 1 and 15.4%in group 2)were the most common adverse effects in all patients,while patients who have received neoadjuvant chemotherapy were more likely to get hypokalemia,fatigue and renal insufficiency.Progression free survival(PFS)was 26.5 mo(95%CI 14.9,38.0)in group 1 and 27.6 mo(95%CI 13.1,42.1)in group 2.The overall survival was 100.2 mo(95%CI 67.9,132.5)for group 1 and 68.2 mo(95%CI 32.2,104.0)for group 2.For the entire cohort,PFS was 26.5 mo(95%CI 15.9,37.0)and OS was 78.8 mo(95%CI 52.3,105.4).CONCLUSION The use of IP/IV chemotherapy can be safely administrated in the community cancer clinic setting.The use of IP/IV chemotherapy in patients who have received neoadjuvant chemotherapy followed by surgery is feasible and tolerable.Despite various modification of the IP regimen,incorporation of IP chemotherapy in the adjuvant setting appears to be associated with improved PFS and overall survival.
文摘Hypertension is one of the well-established risk factor for cardiovascular diseases. Calcium channel blockers（CCBs）, chemicals that could block voltage-gated calcium channels（VGCCs） in cardiac muscle and blood vessels, has been widely used for the treatment of hypertension. Isradipine, a second-generation CCB with high affinity for voltage-operated calcium channels, has not been marked in China. The purpose of this study was to investigate the efficacy, safety and tolerability of isradipine in a phase I clinical trial including 31 healthy Chinese subjects. All subjects received different doses of isradipine at 2.5, 5.0 and 10.0 mg in single-dose study. When the test is completed, subjects treated with 5.0 mg isradipine stayed at the research center for multiple-dose study（5.0 mg isradipine twice daily for 9 d）. Systolic blood pressure（SBP） and diastolic blood pressure（DBP） were measured pre-dose and post-dose（1, 2, 4, 6, 8, 12, 24, 36 and 48 h after isradipine treatment）. Electrocardiography（ECG） and peripheral edema were monitored pre-dose and 4, 8, 24 and 48 h after isradipine treatment. SBP and DBP in single-dose study decreased after isradipine treatment. SBP reached the lowest values 8 h after dosing with a decrease of（7.0±9.7） mmHg（5.4%, P = 0.111） in 2.5 mg group,（7.0±6.9） mmHg（6.0%, P = 0.008） in 5.0 mg group, and（14.0±10.5） mmHg（12.7%, P = 0.005） for 10.0 mg group respectively. Similarly, DBP also reached the lowest values 8 h after dosing with a decrease of（10.0±7.9） mmHg（12.8%, P = 0.004） in 2.5 mg group,（6.0±7.0） mmHg（8.6%, P = 0.003） in 5.0 mg group, and（11.0±4.1） mmHg（15.1%, P = 0.000） in 10.0 mg group respectively. No significant changes of SBP and DBP were observed in multiple-dose study. We detected mild adverse events（AEs）, such as increased transaminase and headache that resolved rapidly and spontaneously without intervention. No serious or potentially life-threatening AE was detected. Our results indicate that isradipin has a good safety and tolerability in Chinese healthy subjects. Long-term study with larger sample size is needed to confirm our conclusion.
基金Supported by Deutsche Heilbrunnen im Verband Deutscher Mineralbrunnen e.V.,Kennedyallee 28,53175 Bonn,Germany,www.vdm-bonn.de
文摘AIM To investigate the efficacy and safety of mineralwater with a high content of hydrogen carbonate inpatients with heartburn.METHODS： This open, single-center, single-armclinical pilot study enrolled 50 patients, 18-64 yearsold, who had been suffering from heartburn at leasttwice a week for at least 3 mo before entering thestudy. Pharmacological treatment of heartburn was notpermitted, and patients with severe organic diseaseswere excluded. After a run-in period of one week, theparticipants received 1.5 L of the test water for thefollowing 6 wk; 300 mL with meals t.i.d., the remainderto be drunk throughout the day. During the trial, therewere five visits at the study center （screening, baseline,two interim visits and the final visit）. The efficacyendpoints included incidence and duration of heartburnepisodes per week by patient＇s self-assessment （heartburndiary） as well as changes in symptom severity asper symptom specific questionnaires [Reflux Disease Questionnaire （RDQ）; Quality of Life in Reflux andDyspepsia （QOLRAD）; Gastrointestinal Quality of LifeIndex] and overall health-related quality of life per SF-12（12-question short form） at each visit. At the end of thestudy, patients and investigators independently ratedthe overall efficacy of the test water on a 4-point Likertscale. Safety was assessed by evaluation of adverseevents （AEs）, vital signs （heart rate, blood pressure）and laboratory parameters. Changes from initial to finalexaminations were assessed by the non-parametricWilcoxon test; categorical variables were comparedusing the χ 2 test, and for more than 5 categories, by theU-test.RESULTS： Twenty-eight participants were men, 22women. The mean age of the patients in the fullanalysis set/intention-to treat population （FAS/ITT） was40.6 years. Forty-two participants completed the studyaccording to the study protocol and formed the perprotocolset （PP population）; 48 participants drank thewater at least once as requested and were analyzedas ITT population. The occurrence of heartburn wasstatistically significantly reduced at wk 6 in both the ITTand the PP populations. At wk 6, the mean number ofheartburn episodes/week decreased by 5.1 episodes（P 〈 0.001） and the mean duration of heartburnsymptoms by 19 min （ITT） （P = 0.002）. The frequencyof heartburn symptoms was reduced in 89.6% of thepatients （P 〈 0.001）, and the duration of symptoms in79.2% of patients （ITT） （P 〈 0.001）. All dimensions ofthe RDQ （heartburn, regurgitation, gastro-esophagealreflux disease symptoms, dyspepsia） showed asignificant improvement at 6 wk. Likewise, diseasespecificquality of life improved significantly （QOLRAD,GIQLI）. Overall, 89.4% of patients rated the efficacyof the test water as ＂good＂ or ＂very good＂, as did theinvestigators for 91.5% of the patients. There wereno serious AEs. After 6 wk, systolic and diastolic bloodpressure values decreased slightly but significantly [-3.5and -3.0 mmHg, respectively （P = 0.008 and P = 0,002）].Ninety-six percent of patients and investigators for thesame percentage of patients rated the tolerability of thewater as ＂good＂ or ＂very good＂.CONCLUSION： The data demonstrate effectiveness ofa hydrogen carbonate-rich mineral water in alleviatingheartburn frequency and severity, thereby improvingquality of life. The water has excellent tolerability.
文摘In a placebo-controlled, double-blind, randomized clinical trial, the tolerability of a proprietary larch arabinogalactan preparation (ResistAidTM) was investigated. METHODS: 199 healthy participants were randomly assigned to receive either placebo (n = 98) or an arabinogalactan preparation (n = 101) over a period of 12 weeks. As safety parameters the total number of adverse events, changes in various biochemical and laboratory parameters as well as the global evaluation of tolerability by investigator and subjects compared to placebo were evaluated. RESULTS: In total 16 adverse events were observed in 16 subjects, with no difference between the arabinogalactan and the placebo group (p = 0.935). There were no differences in the mean changes of the measured biochemical and laboratory parameters. The tolerability of the arabinogalactan extract was rated as “very good” or “good” by the investigators for 99% of the subjects and by 98% subjects in self-assessment with no statistical differences to placebo. CONCLUSION: The measured parameters as well as the evaluation of the tolerability by the investigators and the subjects demonstrate a very good tolerance profile of the proprietary arabinogalactan extract with no differences to placebo when taken for 12 weeks.
文摘This 12-month open-label, but dose-blinded extension phase, evaluated the safety and tolerability of flexibly-dosed edivoxetine (6, 9, 12 or 18 mg once daily) in patients (N = 397) with major depressive disorder, who completed the 10-week randomized, double-blind, placebo-controlled acute phase of the study.All patients were treated with edivoxetine during the extension phase. The mean age of the patients was 45 years, and most were white females. Safety evaluations included assessment of treatment-emergent adverse events (TEAEs), laboratory and vital sign measures, and suicidality. Within-group t-tests based on a 2-sided significance level of 0.05 and 95% confidence levels were used to assess whether changes from baseline were statistically significant from zero. The overall completion rate was 54%. Adverse event was the most common (14.4%) reason for discontinuation, which included blood pressure increased (1.3%), heart rate increased (1.3%), anxiety (1.0%), and tachycardia (1.0%). At least 1 TEAE was reported by 72.3% of patients, of which headache (10.8%) and hyperhidrosis (10.1%) were the most common;2.8% of patients had ≥1 serious adverse events, and there were no completed suicides. No clinically relevant changes were observed in most laboratory measures. Potentially clinically significant changes in ALT values occurred in 1.8% of patients, and either normalized or had decreased by the last assessment. Mean increases in blood pressure and pulse were consistent with those observed in the acute phase and appeared to reach a plateau within 3 to 5 months of treatment. In conclusion, safety and tolerability findings during this long-term extension phase evaluation of edivoxetine were consistent with its norepinephrine reuptake inhibition profile.
文摘Background: Parkinson’s disease (PD) is a progressive neurodegenerative disease that occurs as a result of loss of dopaminergic neurons from the substantia nigra. Rotigotine is a non-ergolinic dopamine agonist available as a silicone-based transdermal patch for the treatment of PD. In the European Union, rotigotine transdermal patch is indicated for use as monotherapy in early idiopathic PD, or in combination with levodopa through the disease course to the late stages where motor complications with levodopa become an issue. Objective: To investigate the safety and tolerability of transdermal rotigotine, in patients with PD being treated during routine clinical practice for 2 years. Results: 114 patients were enrolled, and evaluated for adverse events over a 24-month period. Adverse events occurred in 39 patients (34.21%). 23 patients (20.17%) reported application site reactions (dermatitis, erythema, itching), and 16 (14.03%) had systemic adverse events. Sleep disorders were the most common problem;the others were hallucinations, depression, dizziness, and syncope. No patient experienced dyskinesia. Adverse events necessitated the discontinuation of rotigotine for application site reactions in fourteen patients (12.28%) and 11 patients (9.64%);reasons for discontinuation were systemic adverse events. Conclusion: Rotigotine is safe and well tolerated when used to treat PD in routine clinical practice.
文摘Background: “Diarra”, a traditional herbal remedy made from five (5) medicinal plants, might be endowed with anti-diarrhoeal properties according to its owner. However, scientific evidence of its safety, tolerability and activity has not been established. Objective: This study aimed to assess the safety, tolerability and anti-diarrhoeal activity of “Diarra” in experimental rats. Materials and Methods: Safety was assessed by acute (OECD 423) and sub-acute (OECD 407) toxicity studies at doses of 5, 10 and 20 mg/kg. Clinical tolerability was assessed for 28 days. On day 29, a blood sample was taken to evaluate biological tolerability. The anti-diarrhoeal activity was investigated in a castor oil-induced diarrhoea model. Rats were given the remedy at doses of 5, 10 and 20 mg/kg and then castor oil 1 hour later. They were observed for 4 hours and diarrhoeal stools were collected. The Percentage of diarrhoeal inhibition was calculated. Results: A single dose of “Diarra” at a dose of 2000 mg/kg did not induce any lethality, behavioural or weight change in rats for 14 days. When administered once daily for 28 days, “Diarra” did not cause lethality or significant behavioural disorders or significant weight loss in rats. No biological disorders were observed. The treatment of rats with “Diarra” at doses of 5 mg/kg, 10 mg/kg and 20 mg/kg in a single administration inhibited the occurrence of diarrhoeal stools. The respective percentages of inhibition were 60%, 50% and 62%, similar to those of loperamide at a dose of 2 mg/kg (68%). Conclusion: “Diarra” has an anti-diarrheal activity in rats. It is also safe to use this remedy as such.
文摘BACKGROUND Infants'nutrition significantly influences their growth,development,and overall well-being.With the increasing demand for organic infant formula driven by the perception of health benefits and growing awareness of natural feeding options,it is crucial to conduct a comparative analysis of the gastrointestinal tolerability between organic and traditional infant formulas.AIM To provide a concise and precise analysis of the gastrointestinal tolerability of organic infant formula compared to traditional infant formula.Due to limited direct comparisons,the review synthesizes available literature on each formula type,presenting insights into their potential effects on infants'digestive health.METHODS An extensive literature search was conducted,compiling studies on organic and traditional infant formulas,their compositions,and reported effects on gastrointestinal tolerability.We searched academic databases such as PubMed and Google Scholar and specialized nutrition,paediatrics,and infant health journals using relevant keywords till October 1,2023.RESULTS Although specific comparative studies are scarce and formula heterogeneity is a significant limitation,this systematic review provides an in-depth understanding of organic infant formulas'composition and potential benefits.While scientific evidence directly comparing gastrointestinal tolerability is limited,organic formulas strive to use carefully selected organic ingredients to imitate breast milk composition.Potential benefits include improved lipid profiles,higher methionine content,and decreased antibiotic-resistant bacteria levels.Understanding the gastrointestinal tolerability of organic and traditional infant formulas is crucial for parents and healthcare providers to make informed decisions.CONCLUSION Despite limitations in direct comparisons,this systematic review provides insights into the composition and potential benefits of organic infant formulas.It emphasizes the need for further research to elucidate their gastrointestinal effects comprehensively.
文摘AIM: To determine the tolerability and safety profile of a low-dose maintenance therapy with 6-TG in azathioprine (AZA) or 6-mercaptopurine (6-MP) intolerant inflammatory bowel disease (IBD) patients over a treatment period of at least 1 year.METHODS: Database analysis.RESULTS: Twenty out of ninety-five (21%) patients discontinued 6-TG (mean dose 24.6 mg; mean 6-TGN level 540 pmol/8×108 RBC) within 1 year. Reasons for discontinuation were GI complaints (31%), malaise (15%)and hepatotoxicity (15%). Hematological events occurred in three patients, one discontinued treatment. In the 6-TG-tolerant group, 9% (7/75) could be classified as hepatotoxicity. An abdominal ultrasound was performed in 54% of patients, one patient had splenomegaly.CONCLUSION: The majority of AZA or 6-MP-intolerant IBD patients (79%) is able to tolerate maintenance treatment with 6-TG (dosages between 0.3 and 0.4 mg/kg per d). 6-TG may still be considered as an escape maintenance immunosuppressant in this difficult to treat group of patients, taking into account potential toxicity and efficacy of other alternatives. The recently reported hepatotoxicity is worrisome and 6-TG should therefore be administered only in prospective trials.
基金This study is supported by National Natural Science Foundation of China(81501066 and 81501301)the Grants from Science and Technology Bureau of Chengdu,China(2015-HM01-00010-SF).
文摘Background:To review the available evidence from prospective studies on the safety and tolerability of the ketogenic diet (KD) for the treatment of refractory childhood epilepsy.Methods:A comprehensive bibliographic search was performed with the aim of retrieving prospective studies that monitored adverse effects (AEs) in children after receiving the classic or medium-chain triglyceride KD therapy for refractory epilepsy.Results:A total of 45 studies were retrieved,including 7 randomized controlled trials.More than 40 categories of AEs were reported.The most common AEs included gastrointestinal disturbances (40.6%),hyperlipidemia (12.8%),hyperuricemia (4.4%),lethargy (4.1%),infectious diseases (3.8%) and hypoproteinemia (3.8%).Severe AEs,such as respiratory failure and pancreatitis,occurred in no more than 0.5% of children.Specifically,patients receiving KD therapy should be monitored for osteopenia,urological stones,right ventricular diastolic dysfunction,and growth disturbance.The total retention rates of the diet for 1 year and 2 years were 45.7% and 29.2%,respectively.Nearly half of the patients discontinued the diet because of lack of efficacy.AEs were not the main reason for the KD discontinuation.None of the 24 deaths reported after initiation of the diet was attributed to the KD.Conclusions:KD is a relatively safe dietary therapy.However,because the KD can cause various AEs,it should be implemented under careful medical supervision.Continuous follow-up is needed to address the long-term impact of the diet on the overall health of children.
文摘Background The combination of cisplatin and vinorelbine is an evidence-supported regimen for adjuvant chemotherapy for treating non-small cell lung cancer （NSCLC）. But this doublet has considerable toxicity and unfavorable tolerability, and results in poor compliance. The cisplatin and gemcitabine regimen is one of the most active and well-tolerated regimens against advanced NSCLC, but its toxicity and tolerability has not been adequately evaluated in the adjuvant setting. Methods From a lung cancer database we retrospectively reviewed NSCLC patients receiving adjuvant chemotherapy of cisplatin （75 mg/m2） and gemcitabine （1250 mg/m2） between January 2005 and December 2011. Postoperative demographics, compliance to adjuvant therapy and toxicity were retrieved from medical records. Results A total of 132 patients met the criteria and were included in the study, 96 were male （72.7%） and 36 were female （27.3%）. Median age was 60.5 years old, range 29-75 years, and 41.7% of patients were 〉65 years old. Overall, 68.2% patients received all four planned cycles, and the cumulative dose delivered for gemcitabine was 8333 mg （83.3% of the planned dose） and cisplatin 248 mg （82.7% of the planned dose）. There were no treatment-related deaths. Grade 3/4 neutropenia developed in 47 patients （35.6%） and was the predominant hematologic toxicity. Common grade 3/4 non- hematologic toxicities were nausea/vomiting （22.0%）, infection （12.3%）, and febrile neutropenia （11.4%）. Conclusion Cisplatin and gemcitabine are feasible for use in the adjuvant setting with a favorable toxicity profile and superior tolerabilitv compared with Dublished data on cisDlatin and vinorelbine.
基金supported by the National Natural Science Foundation of China(Nos.82573045,82460602,82560459)the Hainan Provincial Graduate Student Innovative Research Project(No.Qhys2024-440).
文摘Post-translational modifications(PTMs)regulate the occurrence and development of cancer,and lactylation modification is a new form of PTMs.Recent studies have found that lactic acid modification can regulate the immune tolerance of cancer cells.The classical theory holds that prostate apoptosis response-4(PAR-4)is a tumor suppressor protein.However,our recent research has found that PAR-4 has a biological function of promoting cancer in hepatocellular carcinoma(HCC),and our analysis shows that PAR-4 can be modified of lactic acid.These research evidences suggest that PAR-4 lactylation modification may drive immune tolerance in HCC.Therefore,inhibiting PAR-4 lactylation modification is very likely to increase the sensitivity of HCC to immunotherapy.
基金Supported by Army Logistics Department Health Bureau Project,No.QJGYXYJZX-012.
文摘BACKGROUND Due to the dry and cold climate,the obvious temperature difference between day and night,and the low oxygen content of the air in the plateau area,people are prone to upper respiratory tract diseases,and often the condition is prolonged,and the patients are prone to anxiety and uneasiness,which may be related to the harshness of the plateau environment,somatic discomfort due to the lack of oxygen,anxiety about the disease,and other factors.AIM To investigate the effects of cognitive behavioral therapy(CBT)on anxiety,sleep disorders,and hypoxia tolerance in patients with high-altitude respiratory diseases.METHODS A total of 2337 patients with high-altitude-related respiratory diseases treated at our hospital between November 2023 and January 2024 were selected as the study subjects.The subjects’pre-high-altitude residential altitude was approximately 1700 meters.They were divided into two groups.Both groups were given symptomatic treatment,and the control group implemented conventional nursing intervention,while the research group simultaneously conducted CBT intervention;assessed the degree of health knowledge of the two groups,and applied the Hamilton Anxiety Scale and the Pittsburgh Sleep Quality Index to assess the anxiety and sleep quality of the patients before and after the intervention,respectively.It also observed the length and efficiency of sleep,and detected the level of serum hypoxia inducible factor-1α,erythropoietin(EPO)and clinical intervention before and after intervention.EPO levels,and investigated satisfaction with the clinical intervention.RESULTS The rate of excellent health knowledge in the intervention group was 93.64%,which was higher than that in the control group(74.23%;P<0.05).Before the intervention,there was no significant difference in Hamilton Anxiety Scale and Pittsburgh Sleep Quality Index scores between the two groups(P>0.05),and after the intervention,the scores of the study group were significantly lower than those of the control group(P<0.05).There was no significant difference in sleep duration and sleep efficiency between the groups before the intervention(P>0.05),and after the intervention,the scores of the study group were significantly larger than those of the control group(P<0.05).There was no significant difference in serum hypoxia inducible factor-1αand EPO between the two groups before intervention(P>0.05),and both research groups were significantly lower than the control group after intervention(P<0.05).According to the questionnaire survey,the intervention satisfaction of the study group was 95.53%,which was higher than that of the control group(80.14%;P<0.05).CONCLUSION The CBT intervention in the treatment of patients with high-altitude-related respiratory diseases helps improve patients'health knowledge,relieve anxiety,improve sleep quality and hypoxia tolerance,and improve nursing satisfaction.
基金supported by the National Natural Science Foundation of China,Nos.32271389,31900987(both to PY)the Natural Science Foundation of Jiangsu Province,No.BK20230608(to JJ)。
文摘Regulatory T cells,a subset of CD4^(+)T cells,play a critical role in maintaining immune tolerance and tissue homeostasis due to their potent immunosuppressive properties.Recent advances in research have highlighted the important therapeutic potential of Tregs in neurological diseases and tissue repair,emphasizing their multifaceted roles in immune regulation.This review aims to summarize and analyze the mechanisms of action and therapeutic potential of Tregs in relation to neurological diseases and neural regeneration.Beyond their classical immune-regulatory functions,emerging evidence points to non-immune mechanisms of regulatory T cells,particularly their interactions with stem cells and other non-immune cells.These interactions contribute to optimizing the repair microenvironment and promoting tissue repair and nerve regeneration,positioning non-immune pathways as a promising direction for future research.By modulating immune and non-immune cells,including neurons and glia within neural tissues,Tregs have demonstrated remarkable efficacy in enhancing regeneration in the central and peripheral nervous systems.Preclinical studies have revealed that Treg cells interact with neurons,glial cells,and other neural components to mitigate inflammatory damage and support functional recovery.Current mechanistic studies show that Tregs can significantly promote neural repair and functional recovery by regulating inflammatory responses and the local immune microenvironment.However,research on the mechanistic roles of regulatory T cells in other diseases remains limited,highlighting substantial gaps and opportunities for exploration in this field.Laboratory and clinical studies have further advanced the application of regulatory T cells.Technical advances have enabled efficient isolation,ex vivo expansion and functionalization,and adoptive transfer of regulatory T cells,with efficacy validated in animal models.Innovative strategies,including gene editing,cell-free technologies,biomaterial-based recruitment,and in situ delivery have expanded the therapeutic potential of regulatory T cells.Gene editing enables precise functional optimization,while biomaterial and in situ delivery technologies enhance their accumulation and efficacy at target sites.These advancements not only improve the immune-regulatory capacity of regulatory T cells but also significantly enhance their role in tissue repair.By leveraging the pivotal and diverse functions of Tregs in immune modulation and tissue repair,regulatory T cells–based therapies may lead to transformative breakthroughs in the treatment of neurological diseases.
基金This study was supported by the Natural Science Foundation of Guangdong Province(2020A1515010105)Joint Fund of the National Natural Science Foundation of China and Natural Science Foundation of Guangdong Province(U1601224).
文摘Background:The introductions of anti-human epidermal growth factor receptor-2(HER2)agents have significantly improved the treatment outcome of patients with HER2-positive breast cancer.BAT8001 is a novel antibodydrug conjugate targeting human epidermal growth factor receptor-2(HER2)-expressing cells composed of a trastuzumab biosimilar linked to the drug-linker Batansine.This dose-escalation,phase I study was designed to assess the safety,tolerability,pharmacokinetics,and preliminary anti-tumor activity of BAT8001 in patients with HER2-positive locally advanced or metastatic breast cancer.Methods:This trial was conducted in subjects with histologically confirmed HER2-positive breast cancer(having evaluable lesions and an Eastern Cooperative Oncology Group performance status of 0 or 1)using a 3+3 design of escalating BAT8001 doses.Patients received BAT8001 intravenously in a 21-day cycle,with dose escalation in 5 cohorts:1.2,2.4,3.6,4.8,and 6.0 mg/kg.The primary objective was to evaluate the safety and tolerability of BAT8001.Preliminary activity of BAT8001 was also assessed as a secondary objective.Results:Between March 2017 to May 2018,29 HER2-positive breast cancer patients were enrolled.The observed dose-limiting toxicities were grade 4 thrombocytopenia and grade 3 elevated transaminase.The maximum tolerated dose was determined to be 3.6 mg/kg.Grade 3 or greater adverse events(AEs)occurred in 14(48.3%)of 29 patients,including thrombocytopenia in 12(41.4%)patients,aspartate aminotransferase increased in 4(13.8%)patients,γ-glutamyl transferase increased in 2(6.9%)patients,alanine aminotransferase increased in 2(6.9%)patients,diarrhea in 2(6.9%)patients.Objective response was observed in 12(41.4%,95%confidence interval[CI]=23.5%-61.1%)and disease control(including patients achieving objective response and stable disease)was observed in 24(82.8%,95%CI=64.2%-94.2%)patients.Conclusions:BAT8001 demonstrated favorable safety profiles,with promising anti-tumor activity in patients with HER2-positive locally advanced or metastatic breast cancer.BAT8001 has the potential to provide a new therapeutic option in patients with metastatic HER2-positive breast cancer.
基金supported by the National Natural Science Foundation of China(32171945,32301760)the Program for Innovative Research Team(in Science and Technology)in University of Henan Province,China(22IRTSTHN023)+2 种基金the Scientific and Technological Research Project of Henan Province,China(242102111116)the National Science Foundation for Postdoctoral Scientists of China(2023M731003)the Postdoctoral Research Subsidize Fund of Henan Province,China(HN2022139)。
文摘Global warming impacts plant growth and development,which in turn threatens food security.Plants can clearly respond to warm-temperature(such as by thermomorphogenesis)and high-temperature stresses.At the molecular level,many small molecules play crucial roles in balancing growth and defense,and stable high yields can be achieved by fine-tuning the responses to external stimuli.Therefore,it is essential to understand the molecular mechanisms underlying plant growth in response to heat stress and how plants can adjust their biological processes to survive heat stress conditions.In this review,we summarize the heat-responsive genetic networks in plants and crop plants based on recent studies.We focus on how plants sense the elevated temperatures and initiate the cellular and metabolic responses that allow them to adapt to the adverse growing conditions.We also describe the trade-off between plant growth and responses to heat stress.Specifically,we address the regulatory network of plant responses to heat stress,which will facilitate the discovery of novel thermotolerance genes and provide new opportunities for agricultural applications.
