In vivo recovery and survival of apheresis and whole blood-derived platelets: a paired comparison in healthy volunteers

BACKGROUND: Methods of platelet preparation may alter the recovery and survival characteristics of platelets following transfusion. As suggested by a recent clinical trial, platelet recovery may be better preserved with apheresis platelet preparations than with platelets prepared from whole blood by the platelet-rich plasma (PRP) method. STUDY DESIGN AND METHODS: In vivo platelet recovery and survival of autologous leukoreduced (LR) apheresis platelets and autologous filter-LR PRP platelets were compared in 22 healthy volunteers using a paired crossover design. On the same day, each participant gave one apheresis platelet donation and one whole blood donation from which platelets were recovered from the PRP. The sequence of donations was randomly assigned for each participant. Following 5 days of storage and bacterial screening, a sample from each platelet product was labeled with either (51)chromium or (111)indium (randomly assigned) and both samples were simultaneously re-infused into the original donor. Recovery and gamma-function platelet survival were calculated for each platelet product using the multiple hit mathematical model. RESULTS: Five day stored LR-apheresis platelets had 18.8 percent better recovery, and 32.9 percent longer gamma-survival than filter-LR PRP platelets. Stored apheresis platelets had lower p-selectin expression and higher morphology scores than stored PRP platelets. CONCLUSIONS: Filter-LR PRP platelet preparation appears to adversely affect platelet recovery and survival characteristics. The reasons for this effect are not clear. These results may not apply to all apheresis and PRP methods of platelet preparation.     

A randomized controlled clinical trial evaluating the performance and safety of platelets treated with MIRASOL pathogen reduction technology

BACKGROUND: Pathogen reduction of platelets (PRT‐PLTs) using riboflavin and ultraviolet light treatment has undergone Phase 1 and 2 studies examining efficacy and safety. This randomized controlled clinical trial (RCT) assessed the efficacy and safety of PRT‐PLTs using the 1‐hour corrected count increment (CCI_1hour) as the primary outcome. STUDY DESIGN AND METHODS: A noninferiority RCT was performed where patients with chemotherapy‐induced thrombocytopenia (six centers) were randomly allocated to receive PRT‐PLTs (Mirasol PRT, CaridianBCT Biotechnologies) or reference platelet (PLT) products. The treatment period was 28 days followed by a 28‐day follow‐up (safety) period. The primary outcome was the CCI_1hour determined using up to the first eight on‐protocol PLT transfusions given during the treatment period. RESULTS: A total of 118 patients were randomly assigned (60 to PRT‐PLTs; 58 to reference). Four patients per group did not require PLT transfusions leaving 110 patients in the analysis (56 PRT‐PLTs; 54 reference). A total of 541 on‐protocol PLT transfusions were given (303 PRT‐PLTs; 238 reference). The least square mean CCI was 11,725 (standard error [SE], 1.140) for PRT‐PLTs and 16,939 (SE, 1.149) for the reference group (difference, ?5214; 95% confidence interval, ?7542 to ?2887; p < 0.0001 for a test of the null hypothesis of no difference between the two groups). CONCLUSION: The study failed to show noninferiority of PRT‐PLTs based on predefined CCI criteria. PLT and red blood cell utilization in the two groups was not significantly different suggesting that the slightly lower CCIs (PRT‐PLTs) did not increase blood product utilization. Safety data showed similar findings in the two groups. Further studies are required to determine if the lower CCI observed with PRT‐PLTs translates into an increased risk of bleeding.     

A randomized controlled trial comparing the frequency of acute reactions to plasma-removed platelets and prestorage WBC-reduced platelets

BACKGROUND: Removal of the plasma supernatant from platelets before transfusion is effective in preventing acute reactions to platelets caused by cytokines. Prestorage WBC reduction of platelets may be even more effective at preventing reactions as the WBCs are removed and WBC-derived cytokines do not accumulate in this component. This study evaluates the effectiveness of plasma removal and two methods of prestorage WBC reduction for preventing acute reactions to platelets. STUDY DESIGN AND METHODS: Platelets given to adults with hematologic malignancies were randomly allocated to one of three types: plasma supernatant removed and a platelet storage solution added, whole blood-derived platelets that are prestorage WBC reduced by filtration before storage, and prestorage WBC-reduced apheresis platelets. Patients were monitored before, during, and after transfusion, and the severity of reactions was graded on a Likert scale. RESULTS: A total of 129 patients from four centers were given 1190 platelet transfusions. The overall frequency of reactions was 13.6 percent (162 of 1190), 21.3 percent (36 of 169) for the plasma-removed platelets, 11.4 percent (59 of 517) for random donor WBC-reduced platelets, and 13.3 percent (67 of 504) for apheresis WBC-reduced platelets (p=0.384). The overall frequency of severe reactions was 4.1 percent with plasma-removed platelets, 1.7 percent for whole blood-derived, prestorage WBC-reduced platelets, and 1.4 percent for prestorage WBC-reduced apheresis platelets. CONCLUSION: The frequency of reactions to plasma-removed platelets and prestorage WBC-reduced platelets was not significantly different; however, the power of the study for this comparison was low. There was no difference in the frequency of reactions to the two types of prestorage WBC-reduced platelets. The frequency of severe reactions to prestorage WBC-reduced platelets is low, occurring in only 1 to 2 percent of transfusions.     

Seven-day storage of single-donor platelets: recovery and survival in an autologous transfusion study

BACKGROUND: Bacterial screening may effectively reduce the morbidity and mortality risk associated with extended storage of platelets. Platelet viability then becomes the primary determinant of acceptable storage time. This study evaluates the effectiveness of platelets stored in plasma for 7 days. STUDY DESIGN AND METHODS: WBC-reduced, single-donor platelets (n = 24) were collected and stored by standard methods at two sites. Standard in vitro platelet biochemical and functional parameters were monitored over the storage period. On Days 5 and 7 of storage, platelets were alternately labeled with 51Cr and (111)In and returned to the subject, and recovery and survival were determined. RESULTS: Component pH(22 degrees C) was maintained in the range 6.2 to 7.61 through 7 days and did not detrimentally affect either in vitro or in vivo outcomes. In vitro platelet characteristics were adequately maintained over 7 days. Day 5 platelets had better recovery (63.0 +/- 4.36 vs. 53.9 +/- 4.36%, p < 0.0001) and survival (161 +/- 8.1 vs. 133 +/- 8.1 hr, p = 0.006) than Day 7 platelets adjusting for radioisotope, center, and donor effects. CONCLUSION: Although declines in recovery and survival were noted, these are less than used previously to gain licensure of 7-day storage and are unlikely to be clinically significant. Extension of storage to 7 days could be implemented with bacterial screening methods to select out contaminated components without a significant effect on the platelet efficacy compared to 5-day components.     

The effect of a combination of gabapentin and donepezil in an experimental pain model in healthy volunteers: Results of a randomized controlled trial

This double-blind, placebo-controlled, 3-period cross-over, 4-treatment option, incomplete block study (ClinicalTrials.gov number NCT01485185), with an adaptive design for sample size re-estimation, was designed to evaluate gabapentin plus donepezil in an established experimental model of electrical hyperalgesia. Thirty healthy male subjects aged 18–55 years were randomized to receive gabapentin 900 mg or gabapentin 900 mg + donepezil 5 mg for 2 of the 3 treatment periods, with 50% of subjects randomized to receive placebo (negative control) and 50% to gabapentin 1800 mg (positive control) for the remaining period. Each treatment period was 14 days. Gabapentin or corresponding placebo was administered on Day 13 and the morning of Day 14. Donepezil or corresponding placebo was administered nocturnally from Day 1–13 and the morning of Day 14. Co-primary endpoints were the area of pinprick hyperalgesia (260 mN von Frey filament) and allodynia (stroking by cotton bud) evoked by electrical hyperalgesia on Day 14. Gabapentin 1800 mg (n = 14) significantly reduced the area of allodynia vs placebo (n = 14; −12.83 cm²; 95% confidence interval [CI] −23.14 to −2.53; P = 0.015) with supportive results for hyperalgesia (−14.04 cm²; 95% CI −28.49–0.41; P = 0.057), validating the electrical hyperalgesia model. Gabapentin + donepezil (n = 30) significantly reduced the area of hyperalgesia vs gabapentin 900 mg (n = 30; −11.73 cm²; 95% CI −21.04 to −2.42; P = 0.014), with supportive results for allodynia (−6.62 cm²; 95% CI −13.29–0.04; P = 0.052). The adverse event profile for gabapentin + donepezil was similar to the same dose of gabapentin. Data are supportive of further clinical investigation of a gabapentin-and-donepezil combination in patients with an inadequate response to gabapentin.     

A double-blind, randomized, incomplete crossover trial to assess the dose proportionality of rosuvastatin in healthy volunteers

BACKGROUND: Rosuvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has been developed for the treatment of patients with dyslipidemia. OBJECTIVE: This study assessed the dose proportionality and pharmacokinetics of single oral doses of rosuvastatin in healthy volunteers. METHODS: This was a double-blind, randomized, incomplete crossover trial consisting of 3 trial days separated by >/=7-day washout periods. Healthy men were allocated to 1 of 2 treatment regimens: rosuvastatin 10, 20, and 80 mg, or rosuvastatin 10, 40, and 80 mg, administered as single doses on separate trial days in random order. Pharmacokinetic and tolerability assessments were made up to 96 hours after administration. Dose proportionality was tested using the power-law approach. RESULTS: Eighteen healthy white men participated in the trial (mean age, 41.2 years; mean height, 178.4 cm; mean body weight, 81.6 kg). Geometric mean rosuvastatin maximum plasma concentration (C(max)) values of 3.75, 6.79, 10.3, and 30.1 ng/mL were achieved at a median time to C(max) of 5.0 hours after doses of 10, 20, 40, and 80 mg, respectively. The corresponding geometric mean values for rosuvastatin area under the plasma concentration-time curve from time 0 to time of the last measurable concentration (AUC(0-t)) were 31.6, 56.8, 98.2, and 268 ng.h/mL. C(max) and AUC(0-t) were both linearly related to dose. The estimates of the proportionality coefficient (90% CI) for CmaX and AUC(o-t) were 0.999 (0.898-1.099) and 1.024 (0.941-1.107), respectively; all values fell within the prespecified range of 0.847 to 1.153. Rosuvastatin was well tolerated in this group of healthy men when administered orally at doses of 10 to 80 mg. CONCLUSION: Rosuvastatin systemic exposure was dose proportional over the dose range of 10 to 80 mg.     

Alterations in coagulation and fibrinolysis after levothyroxine exposure in healthy volunteers: a controlled randomized crossover study

Summary. Background: Several hemostatic abnormalities have been reported in hyperthyroidism, but the overall effect of thyroid hormone excess on coagulation and fibrinolysis is unclear. Objective: Our aim was to assess whether the use of supraphysiological doses of levothyroxine leads to coagulation activation and inhibition of fibrinolysis. Patients and methods: Healthy volunteers were randomized to receive levothyroxine or no medication for 14 days with a washout period of at least 28 days in a crossover design. To study the effects of different degrees of thyroid hormone excess, 16 participants received levothyroxine in a dose of 0.3 mg per day, and 12 received levothyroxine 0.45 or 0.6 mg per day depending on body weight. Several variables of coagulation and fibrinolysis were measured. Results: Levels of von Willebrand factor activity (VWF:RiCo) and antigen (VWF:Ag), factor (F) VIII, plasminogen activator inhibitor‐1 (PAI‐1) and clot‐lysis time were slightly higher after levothyroxine 0.3 mg per day than after the control situation, but only levels of VWF showed a significant increase from baseline. After levothyroxine 0.45 or 0.6 mg per day, levels of fibrinogen increased by 17%, VWF activity by 24%, VWF antigen by 26%, FVIII by 19%, FIX by 14%, FX by 7%, PAI‐1 by 116% and clot‐lysis time by 14%, and activated partial thromboplastin time decreased by 3%; all were significant changes compared with the control situation. We did not observe clear evidence of coagulation activation. Conclusions: Our data suggest that thyroid hormone excess increases coagulation factor levels and inhibits fibrinolysis in a dose‐dependent fashion. This implies an increased risk of venous thrombosis during hyperthyroidism.     

Randomized dose-ranging controlled trial of AQ-13, a candidate antimalarial, and chloroquine in healthy volunteers

Objectives:     

精神分裂症恢复期综合式家庭心理干预的前瞻、随机、对照研究

目的以精神分裂症恢复期患者为主要研究对象,采用前瞻性随机对照研究,探讨综合式家庭心理干预对患者的近期效果。方法80例患者抽答法被随机分配到干预组40例和对照组40例,干预组除药物治疗外接受系统的综合式家庭心理干预,对照组只有药物维持治疗。结果在1年末,干预组患者的简明精神病量表(BPRS)、社会功能缺陷量表(SDSS)、症状自评量表(SCL-90)、与对照组比较均有显著性差异(t=3.62～3.68,P<0.001),服药依从率、年复发率(u=3.48,3.52,P<0.001),说明干预组患者的精神症状、社会功能、心理状况明显改善,服药依从率明显提高,年复发率明显降低。结论综合式家庭心理干预对精神分裂症恢复期具有良好的效果。