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Objective:To explore safe dosage of single intravitreal injection of ganciclovir (IVG) in healthy rabit eyes, and to explore retinal toxicity of different dosage of ganciclovir after continues intravitreal injection into the vitreous cavity of healthy albino rabbit eyes.Methods:Ten healthy New Zealand albino rabbits were divided into 5 groups with 2 rabbits in each group. Each group was injected with 1 mg/0.025 ml,2 mg/0.025 ml, 5 mg/0.025 ml, 10 mg/0.025 ml ganciclovir or 0.025 ml saline (control group). After 1 week of intervention, rabbits were examined by ultra-wide-angle fundus photography, optical coherence tomography (OCT) and full field electroretinogram (ERG). The maximum mixed response of rod and cone cells (Max-R) was measured under dark adaption conditions, cone response (Cone-R) and 30 Hz flicker response (30 Hz-R) were measured under light adaption conditions. Twenty-four healthy New Zealand albino rabbits were randomly divided into a low-dose experimental group, a low-dose control group, a high-dose experimental group, and a high-dose control group, with 6 rabbits in each group, with the right eye as the experimental eye. The rabbits in the high-dose experimental group were continuously injected with ganciclovir 2 mg/0.025 ml, once a week, for a total of 4 times. The rabbits in the low-dose experimental group were injected with 1 mg/0.025 ml ganciclovir, the induction period was 2 times/week, a total of 4 times; the maintenance period was 1 time/week, a total of 2 times. The rabbits in the high-dose control group and the low-dose control group were injected with 0.025 ml normal saline into the vitreous cavity respectively. Full-field ERG examination was performed 1 day before each injection and 1 week after the last injection. Max-R was measured under dark-adapted conditions, and Cone-R and 30 Hz-R were measured under light-adapted conditions. OCT was recorded before the first injection and one week after the last injection. One week after the last injection, the experimental rabbits in each group were sacrificed for hematoxylin-eosin staining, and the retinal structure was observed under a light microscope. The comparison of a-wave and b-wave amplitude of Max-R, Cone-R and 30 Hz-R amplitude at different time was performed by two independent sample nonparametric test.Results:There were no abnormal results of fundus photography, OCT and ERG after single intravitral injection of 1 mg or 2 mg ganciclovir. One week after single 5 mg IVG, fundus photography of rabbits showed vascular occlusion and preretinal hemorrhage and ERG showed slight decrease of amplitude of Max-R, Cone-R and 30 Hz-R. One week after single 10 mg IVG, retinal necrosis and exudative changes were also observed. OCT showed edema and unclear retinal structure in the necrotic area. ERG showed significant decrease of amplitude of Max-R, Cone-R and 30 Hz-R. After continuous IVG in high dose and low-dose experimental group, the amplitude of Max-R a wave ( Z=-0.160, 0.000) and b wave ( Z=-0.321, 0.000), Cone-R a wave ( Z=-0.641,-0.641) and b wave ( Z=-0.321, -0.160), and 30 Hz-R ( Z=-0.321,-0.160) showed no difference compared to control group. No histologic evidences of retinal microstructure abnormalities were found in both groups. OCT and fundus photography before and after the intervention did not show any difference, either. Conclusion:There was no retinal toxicity of continuous 1 mg or 2 mg IVG recorded in albino rabbits.
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AIM: To introduce a novel and flexible model-assisted design for Phase I clinical trials: Bayesian optimal interval (BOIN) design, including the process of implementation, practical implementation, and evaluation of its performance. METHODS: BOIN design decides dose escalation/de-escalation by comparing the observed toxicity rate at the current dose with an escalation boundary and a de-escalation boundary that are optimized to minimize the probability of making incorrect decision of dose assignment. The application of the BOIN design is illustrated using a trial example. RESULTS: BOIN combines the advantages of the algorithm-based methods and model-based methods. It enjoys desirable statistical properties -it is optimal, safe, robust and easy to implement. Simulation study shows that the BOIN substantially outperforms the existing designs with higher accuracy to identify the maximum tolerated dose (MTD). CONCLUSION: BOIN design possesses the similar statistical performance to the much more complicated model-based designs. It is simple to implement, and easy to calibrate to meet the safety requirement mandated by regulatory agents. The BOIN design has been widely used in different types of cancers. It is a novel design that holds great potential to substantially improve phase I trials in China.
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Objective To define the maximum-tolerated dose (MTD) of lobaplatin (LBP) in a weekly regimen combined with concurrent radiotherapy in the treatment of locally advanced nasopharyngeal carcinoma (NPC).Methods A total of 18 cases with stage Ⅲ/Ⅳ A NPC were enrolled.Concurrent chemoradiotherapy was given to all the patients with a dose escalation of LBP.The initial dose of LBP was 15 mg/m2 with an escalating dose of 5 mg/m2.At least 3 patients were assigned into each group.Patients were proceeded into the next dose group if no dose-limiting toxicity (DLT) occurred until the MTD was achieved.Efficacy and toxicity were evaluated regularly.Results Three patients were assigned into the 10 mg/m2,3 into the 15 mg/m2,and 6 into the 20 mg/m2 and 25 mg/m2 groups,respectively.Two patients experienced DLT in the 25 mg/m2 group.Hence,the MTD was determined as 20 mg/m2.At 3 months after corresponding treatment,the remission rate of nasopharyngeal tumors and neck-positive lymph nodes of the patients was 100％.The most common toxicity was reversible bone marrow suppression.Conclusions The MTD of weekly lobaplatin plus concurrent IMRT is 20 mg/m2 for locally advanced NPC.This regimen is reliable and safe,which is worthy of further clinical study.
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OBJECTIVE:To establish the quality standard of Hirudo nipponica freeze-dried powder(called"freeze-dried powder"for short),and to provide reference for controlling its quality. METHODS:A total of 3 batches of freeze-dried powder were collected,identified and tested according to the requirements of H. nipponica stated in 2015 edition of Chinese Pharmacopoeia(part Ⅰ)(shorted for pharmacopoeia);the antithrombin activity was also analyzed. The maximum tolerated dose (MTD)was used to investigate the toxicity. The stability was determined by designing temperature,humidity and strong light exposure tests. RESULTS:In the TLC of test sample,the same red spots were found in the corresponding location of the control drug chromatogram,and the same orange-red fluorescence spots were shown under the UV light(365 nm). Average content of moisture in 3 batches of samples was 2.61%,and the levels of total ash,acid-insoluble ash,pH aflatoxin and antithrombin activity were 2.83%,0.38%,6.92,0.28 μg/kg and 257.0 U/g,respectively. The content of Pb,Cd,As and Cu were in line with the requirements of pharmacopoeia except that the content of Hg was slightly higher than lower limit of H. nipponica in pharmacopoeia. Results of MTD showed that no death and ADR was found in mice after giving 26.4 g/kg freeze-dried powder by the amount of crude drug,which was 58 times as large as the maximum dosage that the pharmacopoeia described. Under the condition of 20, 40 ℃ and strong light exposure [(4 500±500)Lx],the anticoagulase activity of freeze-dried powder decreased significantly over time,while the anticoagulase activity of freeze-dried powder stored at 40 ℃ for 6 months was in line with the requirements of pharmacopoeia. Under the condition of high humidity(relative humidity were 90%,75%),freeze-dried powder showed a strong hygroscopicity. CONCLUSIONS:Established quality evaluation standard for freeze-dried powder according to pharmacopoeia standard could be used to control its quality.
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OBJECTIVE: This phase I study aimed to determine the maximum tolerated dose (MTD) of Genexol-PM, when combined with carboplatin, as a first-line treatment in patients with advanced ovarian cancer. METHODS: This open-label, multicenter, phase I, dose-escalation study included 18 patients (median age: 59.0 years, range: 40–75 years) diagnosed with advanced epithelial ovarian cancer. All patients had measurable residual disease after debulking surgery. Patients were assigned to groups (n=6 each group) that received different doses of Genexol-PM (220, 260, and 300 mg/m², once every 3 weeks) and 5 area under the curve (AUC) carboplatin. Safety and efficacy were analyzed for each dose group. RESULTS: In this intention-to-treat population, 3 out of 18 patients dropped out of the study: 1 due to dose-limiting toxicity (DLT), 1 due to hypersensitivity, and 1 was lost during follow-up. DLTs were not reported at 220 mg/m² or 260 mg/m², but at 300 mg/m², 1 patient experienced DLT (grade 3 general pain). The MTD of Genexol-PM was not determined, but a dose of 300 mg/m² or less could be recommended for the phase II study. Most patients (73.9%) with adverse events recovered without sequelae, and no death occurred that was related to the disease or treatment. The best overall response rate was 94.1%. CONCLUSION: Genexol-PM combined with carboplatin was well tolerated as a first-line treatment, and good responses were observed in patients with advanced ovarian cancer. Based on these results, we recommended a dose of 300 mg/m² or less for a phase II study.
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Humans , Carboplatin , Follow-Up Studies , Hypersensitivity , Maximum Tolerated Dose , Ovarian Neoplasms , Paclitaxel , Polymers , Toxicity TestsABSTRACT
Objective To discuss the maximum tolerated dose of oxaliplatin based on 5-fluorouracil derivative in patients with locally advanced rectal cancer who underwent neoadjuvant chemoradiotherapy.Methods From Mar 2015 to Oct 2015,15 locally advanced rectal cancer patients (T3,T4/N +) who received intensity modulated radiotherapy and concurrent chemotherapy with capecitabine and oxaliplatin were enrolled in this study.The prescription dose was 50.6 Gy for gross tumor volume(GTV) and 41.8 Gy for clinical tumor volume(CTV) in 22 fractions within 30 d with concomitant boost.There were four dose-level groups of oxaliplatin as 100,110,120 and 130 mg/m2 tri-weekly and fixed capecitabine dose (825 mg/m2 bid d1-5 per week).The first 12 patients were randomly assigned into 4 groups.For the 130 mg/m3 group,another 3 patients were enrolled because of dose-limiting toxicity (DLT).Treatment related toxicities and response rates were evaluated.Results The most common adverse events(AE) were radiation enteritis,skin reactions,nausea,fatigue,urinary system AE and bone marrow suppression.There was a trend of increase by the dose level of oxaliplatin for toxicities.Groups 100,110 and 120 mg/m2 had none DLT,while group 130 mg/m2 had 1 patient for grade 3 thrombopenia and 1 patient for grade 3 nausea.Postoperative pathology showed that all patients achieved tumor downstaging,among which 0,1,2,3 cases achieved complete remission of the four groups,respectively.Conclusions The combination regimen of capecitabine and oxaliplatin is safe and effective according to the preliminary results.The maximum tolerated dose of oxaliplatin was 130 mg/m2 tri-weekly.
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OBJECTIVE: To discuss early exploratory bridging studies between early screening phase and pivotal general toxicology studies and their application during new drug development. METHODS: The opinions on acute toxicity study from international counterparts and current application in domestic and overseas were briefly reviewed. At the same time, the study design and the strengths of an alternative maximum tolerated dose /dose range finding (MTD/DRF) study widely used abroad were fully discussed. Furthermore, considerations were also highlighted based on the authors' experience, which may aid in the design and the conduct of such bridging studies. RESULTS AND CONCLUSION: MTD/DRF study could provide more valuable information for subsequent non-clinical regulatory toxicity studies. It is a rational and practical general toxicological study with bridging character.
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Methods The maximum tolerated dose( MTD)of water and ethanol extracts of Radix millettiae speciosae were measured for the safety evaluation. Results Maximal tolerated dose( MTD)of water extract was higher than 1 000 g·kg-1 ,which equaled to 110 times the dose for human adults(60 kg). MTD of ethanol extract was higher than 1 700 g·kg-1 ,which equaled to 186 times the dose for human adults(60 kg). Conclusion Radix millettiae speciosae does not have obvious toxicity,thus its routine clinical dose is safe and feasible.
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OBJECTIVE: To prepare the paclitaxel liposomes and evaluate its physicochemical property, toxicity and pharmacodynamics. METHODS: SPC, mPEG2000-DSPE and paclitaxel were dissolved in chloroform in a mole ratio of 100:0.5:5. Oil phase and water phase were mixed and skived. The emulsion was homogenized to form liposomes. The mean diameter of liposomes was determined by dynamic light scattering (DLS) techniques. Low-speed centrifugation was employed to determine encapsulation efficiency (EE). The maximum tolerated doses (MTD) was determined in normal KM mice, and antitumor effect was evaluated in H22/KM mice xenograft tumor model. RESULTS: The mean diameter of paclitaxel liposomes was (140±10) nm. The EE was over 95% when the molar ratio of paclitaxel to SPC ranged from 3% to 6%. The MTDs of Pac-lipo and Pac-free in male KM mice were 64.8 and 29.4 mg · kg-1, respectively. Pac-lipo inhibited H22tumor weight dose-dependently. CONCLUSION: Pac-lipo had a high EE, and could increase the therapeutic index significantly, compared with Pac-free.
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Objective: To research the toxicity variation principle of "pinellia, trichosanthes, fritillaria, ampelopsis, bletilla attack aconitum" through studying on the acute toxicity for "pinellia, trichosanthes, fritillaria, ampelopsis, bletilla attack aconitum" in the single herb and anti-drug combination. Methods: Using the median lethal dose (LD50) or maximum tolerate dose (MTD) to evaluate the acute toxicity of single herb, then fix the raw aconitum dose of the compatibility group at LD50, another drug dose increased with the compatibility proportion changed gradually in order to examine the toxicity variation of anti-drug combination with death rate as the index. Results: The LD50 of raw Aconiti Radix (AR) was 4.4 g/kg, the MTD of raw Pinelliae Rhizoma (PR), Trichosanthis Fructus (TF), Fritillariae Thunbergii Bulbus (FTB), Ampelopsis Radix (AR), and Bletillae Rhizoma (BR) was respective 300, 37.8, 272, 167, and 180 g/kg; raw AR and raw PR showed no antagonism phenomenon; raw AR showed the antagonism effect against TF in 4:1 to 8:1 while without antagonism in 2:1-1:6; the compatibility of raw AR and FTB objected in 6:1-16:1 while without antagonism in 1:1-1:13; the compatibility of raw AR and AR objected in 3.5:1-16:1 while without antagonism in 1:1-1:13; the compatibility of raw AR and BR showed no obvious toxicity variation. Conclusion: The ethanol extract of raw AR has obvious acute toxicity; the ethanol extract of raw PR, TF, FTB, AR, and BR has no obvious acute toxicity; under the experimental conditions, the proportion of anti-drug compatibility affects the compatibility of the results.
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ObjectiveTo define the maximum tolerated dose (MTD) of weekly cisplatin in concurrent chemoradiotherapy for Chinese cervical carcinoma.MethodsCervical carcinoma of stage ⅠB2- ⅣA were eligible for the study.PhaseⅠstudy was dose-escalation trial with 15 patients.All patients received whole pelvic radiotherapy with three dimentional conformal radiotherapy technique. Concurrent cisplatin started from the dose of 20 mg/m2 to 25 mg/m2,30 mg/m2,35 mg/m2,40 mg/m2 for the weekly schedule ( ≥3 patients per dose group) and the doses were steadily escalated to 40 mg/.m2.If the dose was increased to 40 mg/m2 without dose-limiting toxicity ( DLT),40 mg/m2 would be the maximum tolerated dose (MTD).According to the MTD dose from Phase Ⅰ study,we conducted phase Ⅱ clinical trial with 36 patients.ResultsIn Phase Ⅰ study,cisplatin dose was escalated to 40 mg/m2 and DLT had not been reached.Thirty-six patients in Phase Ⅱ study included 9 inpatients and 27 outpatients.All 9 inpatients completed 6 cycles of chemotherapy. In 27 outpatients,18 patients (66％) completed 6 cycles of chemotherapy,19 patients (70％) completed 5 cycles and 25 patients (92％) completed 4 cycles of chemotherapy.All patients completed radiotherapy.Major adverse effects were grade 1 and 2 gastrointestinal toxicities and neutropenia.ConclusionsWeekly 40 mg/m2 cisplatin concurrent with radiotherapy is well tolerated when given to Chinese patients with cervical carcinoma. For outpatients with poor performance status,the cisplatin dose needs to be reduced.
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Objective Inaccurate dosing is an important cause of medical malpractice, how to adjust the medication dose to overcome the excessive deviation will be discussed in this paper. Methods Gold zone method was proposed on the basis of the probability theory and mathematical statistics for handling inaccurate dosing problems. Investigation and study in large sample size was carried out on adverse reactions of Cefamandole Nafate for Injection by adopting the method. Results The conclusions from the super large sample size test indicate that there is highly significant difference of total adverse reaction rates between taking values within and outside golden zone of dosage, and the adverse reaction rate of taking values within golden zone is significantly lower than that of outside golden zone. It is noteworthy that when dosage was lower than golden zone,the adverse reaction rate was significantly increased,which is more than 4 times of that within golden zone. Conclusion It is effective measures and simply and easy to apply that taking values within golden zone of dosage reduce adverse drug reactions,probability within golden zone less than 1/4 range of experience that contains the actual demand of the body up to 70%.
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Objective To investigate the acute toxicity of intravenous isoflurane in Beagles.Methods Six healthy adult Beagles of both sexes aged 6-8 months weighing 6-8 kg were used in this study.Isoflurane injectio (120 mg/ml) in 30% hpid emulsion was injected intravenously. Femoral artery was cannulated for direct BP monitoring.ECG was continuously monitored.The maximal tolerance dose (MTD) and approximate lethal dose (ALD) were determined by up-and-down technique. The initial dose was 3.0 ml/kg. The dose was decreased/increased by 0.3 ml/kg if the previous animal died/survived.The survived dogs were observed for 2 weeks.Autopsy and histopathological examination were performed on all dead Beagles.Results The ALD and MTD of intravenous isoflurane were 252 and 216 mg/kg. Autopsy and histopathological examination did not show any abnormality.Conclusion Cardiopulmonary depression is the main manifestation of the acute toxicity of intravenous isoflurane in Beagles.
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Objectives To determine maximal tolerated dose(MTD)and dose-limiting toxicity (DLT) of oxaliplatin(L-OHP)when combined with constant dosing of 5-Fu、Lv and concurrent radiotherapy in postoperative patients with rectal cancer.Methods A total of 21 patients with stage Ⅱ or Ⅲ rectal adenocarcinoma after curative surgery were treated with radiotherapy to a total dose of 50 Gy in 5 weeks.L-OHP was administered at a dosge of 45 mg/m2(n=3),55 mg/m2(n=3),65 mg/m2(n=3),75 mg/m2(n=6),and 85 mg/m2(n=6)once a week for 2 weeks(first cycle)followed by a second cycle after a 14-day break.5-Fu and LV at a fixed dose of 5-Fu 300 mg/m2 ivdrip for 2 h,then 500 mg/m2 ivdrip within 22 h,d1,d2.LV 200 mg/m2 ivdrip 2 h d1,d2.DLT was defined as grade Ⅲ or Ⅳ hematologic and nonhenmologic toxicity. Results Grade Ⅰ-Ⅲ leukopenia,diarrhea,and nausea/vomiting were the most common toxic side effects.and most were of grade 1-2.DLT was first observed in 2 of 3 patients at 75 mg/m2(1 of grade Ⅲ diarrhea and 1 of grade Ⅲ leukopenia).L-OHP at dosage of 85 mg/m2 caused DLT in 4 of 6 patients(2 of grade Ⅲ leukopenia and 1 of grade Ⅲ diarrhea and 1 of grade Ⅲ diarrhea).Conclusions Diarrhea was the most common dose-limiting toxicity(DLT).Tlle maximal tolerated dose(MTD)of L-OHP in this setting was 75 mg/m2 which was comparable to the maximal tolerated dose of L-OHP seen in the neoadjuvant setting.
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OBJECTIVE:To observe the clinical efficacy,safety,the maximal tolerated dose(MTD) and dose-limiting toxicity(DLT) of docetaxel(TXT) in the treatment advanced breast cancer.METHODS:Docetaxel was given by drip infusion in escalating doses from the initial dose of 65 mg?m-2 to 75 mg?m-2 and 85 mg?m-2 until the appearance of DLT.RESULTS:Among the 15 cases,1 case with CR,5 PR,4 SD,and 5 PD.The DLT of TXT was neutropenia,and its MTD was 85 mg?m-2.CONCLUSION:Docetaxel(at a dose of 75 mg?m-2) showed remarkable efficacy and good tolerance in patietns with advanced breast cancer.
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PURPOSE: Patients with advanced ovarian carcinoma and refractory to platinum based chemotherapy have a very poor prognosis and effective salvage regimens are needed. This study was conducted in order to determine the maximum tolerated dose (MTD) and dose limiting toxicity of combination with paclitaxel and ifosfamide. MATERIALS AND METHODS: After premedication, patients received paclitaxel (110~225 mg/m2) as a 24 hour IV infusion on day 1. Ifosfamide (1,000~1,500 mg/m2) was given as a 12 hour IV infusion with standard dose of mesna on day 2~6. All patients received G-CSF (granulocyte colony stimulating factor) on day 6~15. RESULTS: 12 patients with advanced ovarian cancer entered this trial. Toxicity included bone marrow suppression, neuromuscular toxicity, urothelial toxicity, gastrointestinal toxicity, which occurred in 84.6%, 65.3%, 30.7%, 88.4% of cycles. CONCLUSION: Neuromuscular toxicity was dose limiting toxicity. Maximum tolerated dose in com bination with paclitaxel and ifosfamide was 175 mg/m2 of paclitaxel and 1,500 mg/m2 of ifosfamide.