First-in-human clinical trial of transplantation of iPSC-derived NS/PCs in subacute complete spinal cord injury: Study protocol
Keiko SugaiMiho SumidaTomoko ShofudaRyo YamaguchiTakashi TamuraTsuneo KohzukiTakayuki AbeReo ShibataYasuhiro KamataShuhei ItoToshiki OkuboOsahiko TsujiSatoshi NoriNarihito NagoshiShinya YamanakaShin KawamataYonehiro KanemuraMasaya NakamuraHideyuki Okano
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Our group has conducted extensive basic and preclinical studies of the use of human induced pluripotent cell (iPSC)-derived neural stem/progenitor cell (hiPSC-NS/PC) grafts in models of spinal cord injury (SCI). Evidence from animal experiments suggests this approach is safe and effective. We are preparing to initiate a first-in-human clinical study of hiPSC-NS/PC transplantation in subacute SCI.NS/PCs were prepared at a Good Manufacturing Practice-grade cell processing facility at Osaka National Hospital using a clinical-grade integration-free hiPSC line established by the iPSC Stock Project organized by the Kyoto University Center for iPS Cell Research and Application. After performing all quality checks, the long-term safety and efficacy of cells were confirmed using immunodeficient mouse models.The forthcoming clinical study uses an open-label, single-arm design. The initial follow-up period is 1 year. The primary objective is to assess the safety of hiPSC-NS/PC transplantation in patients with subacute SCI. The secondary objective is to obtain preliminary evidence of its impact on neurological function and quality-of-life outcomes. Four patients with C3/4-Th10 level, complete subacute (within 24 days post-injury) SCI will be recruited. After obtaining consent, cryopreserved cells will be thawed and prepared following a multi-step process including treatment with a γ-secretase inhibitor to promote cell differentiation. A total of 2 × 106 cells will be transplanted into the injured spinal cord parenchyma 14-28 days post-injury. Patients will also receive transient immunosuppression. This study protocol has been reviewed and approved by the Certified Committee for Regenerative Medicine and the Japanese Ministry of Health, Labor and Welfare (University Hospital Medical Information Network Clinical Trials Registry [UMIN-CTR] number, UMIN000035074; Japan Registry of Clinical Trials [jRCT] number, jRCTa031190228).We plan to start recruiting a patient as soon as the COVID-19 epidemic subsides. The primary focus of this clinical study is safety, and the number of transplanted cells may be too low to confirm efficacy. After confirming safety, a dose-escalation study is planned.Keywords:
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Fourteen cases of depression resistant to multiple treatments were treated by lithium augmentation of fluoxetine. Tolerability of the treatment was poor. Lithium and fluoxetine may be a possible treatment for resistant depression but there is caution regarding tolerability and toxicity with the relatively high doses of lithium used in this series.
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Onabotulinumtoxin A (onabotA) has shown efficacy in chronic migraine (CM), with good tolerability and a low rate of adverse effects, most of them not severe. The aim of this study is to evaluate tolerability and adverse effects of onabotA in clinical practice and to analyze if there is a relationship between tolerability to treatment administration, adverse effects' (AEs) occurrence and clinical response. We included patients with CM that received treatment with onabotA for the first time. Tolerability to treatment was evaluated by a 0-10 numeric rating scale (0: worst possible, 10: optimal tolerability). We assessed the presence of AEs by using a standardized questionnaire. Treatment response was based on the 50 and 75% responder rate between weeks 20 and 24, compared with the baseline, according to headache diaries. We analyzed whether the tolerability was associated with a higher frequency of AEs or a higher probability of clinical response. We included 105 patients, 87.7% female, with an age of 43.9 ± 10.7 years. Mean tolerability was 7.8/10 and 7.2/10 in the first and second onabotA administration, respectively. AEs were reported by (first-second) 71.4-68.6% patients. The percentage of patients with a 50% response was 56.3%. There was no association between tolerability and AEs' occurrence or clinical response.
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For children with liver transplants (LT), achieving an "ideal outcome" is a balancing act: too little immunosuppression begets graft injury; too much begets systemic complications. We aimed to delineate the parental perspective on this tightrope.Parents of children with LT completed an internet-based survey about their child's immunosuppression.Children of respondents (n = 82) were a median 4 years from primary LT (range 0-22); 73% were on immunosuppression monotherapy. Parents' top concerns were related to immunosuppression complications; 46% were more concerned about immunosuppression complications than rejection; only 17% were more concerned about rejection than immunosuppression complications. Among parents of children on immunosuppression monotherapy, 29% still worried more about immunosuppression complications than rejection, 48% expressed equal concern for both. Time since LT (0-4 vs. >4 years) was not associated with concern level for rejection or immunosuppression complications. Caregivers were significantly more certain that their child's immunosuppression regimen was correct to prevent rejection than to mitigate complications (p < .005).Caregivers of children with LTs reported higher levels of concern and uncertainty about immunosuppression complications than rejection risk. Understanding parent and patient perspectives on IS, and incorporating them into immunosuppression counseling and decision-making, is critical to achieving truly "ideal" long-term outcomes.
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Skin lesions, increased transepidermal water loss, changes in pH in patients with allergodermathosis lead to a decrease in the protective mechanisms of the skin that makes individuals more susceptible to infections. The development of complications predefined the interest in improving topical therapy. The article presents a brief review of the literature data on high therapeutic activity and good tolerability of the topical drug Triderm. When compared with the original drug, the generics revealed differences in the structural and mechanical properties, which affects bioavailability. A comparison of therapeutic efficacy and tolerability has shown that Triderm is more effective, and comparable to Akriderm GK in terms of tolerability.
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Summary: Purpose: To evaluate the tolerability and safety of gabapentin (GBP) as add‐on therapy for seizure control. Methods: Conducted in an outpatient setting and reflecting usual practice, this study compared tolerability of GBP dosages ≤1,800 versus >1,800 mg/day, when these doses were required to achieve the most effective seizure control. Two analyses of adverse events are presented: tolerability and safety. In the tolerability analysis, each patient served as his or her own control to compare the occurrence of adverse events at GBP ≤1,800 versus >1,800 mg/day. The safety analysis required patients to receive at least one dose of GBP and have a follow‐up contact. Results: A total of 2,216 patients enrolled in this open‐label, 16‐week study and were evaluable for safety. Of these, 74.0% completed the 16‐week study, and 281 met the tolerability criteria. Within these 281 patients, two mutually exclusive groups were compared (a) those reporting adverse events at only ≤1,800 mg/day (low dose); and (b) those reporting adverse events at only >1,800 mg/day (high dose). Three adverse events (asthenia, headache, and dizziness) were observed in a statistically significantly larger number of patients at only the low dose than in the group reporting these same adverse events at only the high dose, suggesting that patients who tolerated GBP at ≤1,800 mg/day did not experience a significant increase in adverse events with dosages >1,800 mg/day. Overall, 10.6% of the 2,216 patients in the safety population prematurely withdrew because of adverse events, and 3.5% discontinued because of lack of efficacy. Safety and tolerability of GBP was rated as excellent or good for 78.5% of all patients. Conclusions: Gabapentin doses >1,800 mg/day were as well tolerated as doses ≤1,800 mg/day and were not associated with more adverse events.
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Objective:Investigate the mechanism of blood spinal cord barrier disruption after spinal cord injury.Method:Thirty five male adult Wistar rats(300～350g) were randomly assigned to this study,there were one control group and six spinal cord injury groups(acording to the time of post injury,4h,6h,12h,24h,48h and 72h).Each group contained 5 rats and New York University (NYU) Spinal Cord Injury Model was utilized to create the spinal cord injury.The immunoexpressior changes of immunglobularprotein G(IgG),c fragment of complement3 (C3c) in different time after spinal cord injury were evaluated utilizing immunohistochemistry method.Result:After spinal cord injury, there was a marked chang in the immunoexpressior of IgG and C3c in the impact site, near the impact site and spinal cord microvascular.Conclusion:After spinal cord injury,IgG and C3c may be important factors of barrier disruption and related to neuron secondary injury.
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Drug tolerability refers to the degree to which drugs' overt adverse effects can be tolerated by patients. The tolerability profile is of comparative importance to its efficacy and safety, as it largely determines adherence to treatment and ultimately treatment success or failure. However, the term is frequently used imprecisely, and it is unclear if tolerability is limited to subjective patient-reported symptoms or also covers certain objective signs and findings. The aim of this systematic review was to assess how clinical studies define, evaluate and present drug tolerability.The study consisted of a systematic review of clinical studies in PubMed® reporting the term "tolerability".Eighty clinical studies were screened and 56 studies reporting drug tolerability were retained. None of the retained studies defined events encompassed by the term tolerability by making a distinction between safety and tolerability. Twenty-five studies claimed to evaluate tolerability, but none of them described how to evaluate tolerability from the patient perspective. Most studies (54 out of 56) concluded that the treatment was well tolerated, apparently implying favourable safety. However, none of them actually presented tolerability in terms of a contrast between safety and tolerability.Tolerability is used frequently, albeit incorrectly, to refer to a drug's favourable safety profile. Focused evaluation of drug tolerability (i.e., the patient perspective of adverse drug reactions) should become routine. Presentation in regulatory documents, such as risk management plan summaries, product information and patient leaflets should be a continuation of the process of patient-centred healthcare.
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Objective To investigate the expression changes of CD44 in spinal cord in 3d,7d and 14d following hemisection of spinal cord injury(hSCI).Furthermore,to explore the relationships of CD44 and spinal cord injury.Besides,to offer the morphological datum for the research concerning the spinal cord repair.Methods 20 adult healthy Sprague-Dawley rats were randomly divided into sham-operated control group and day3,day7,day14 spinal cord injury groups.The spinal cords were hemisected between T9 and T10.The spinal cord of every rat was taken out from the rostral and caudal segments of lesioned areas.Then the tissue blocks were made into 25μm frozen sections and the immunohistochemistry ABC method was performed on these sections.We respectively observe and count the number of CD44 positive cells in spinal cord for all groups,and the average OD(optical density) value of immunoreactant were detected with computer image analysis technique.Results CD44 positive products were mainly distributed in extacellular matrix and neurons and neuroglial cells in spinal cord for the control group.The number of CD44 positive cells and its OD value of rostral or caudal part of injury site for the three spinal cord injury groups were all increased(P0.05).Conclusion The increased-expression CD44 may mutually play inhibitory effect on axon regeneration following SCI.
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Thirty to 40% of patients using topical treatments do not comply with their treatment regimen.To examine how tolerability is assessed, tolerability ratings, and clinical significance of tolerability ratings of topical antimicrobials for acne.A literature search was performed using the terms "tolerability AND acne AND (benzoyl peroxide OR antimicrobial OR clindamycin OR erythromycin OR dapsone OR sulfur OR sulfacetamide)." Inclusion criteria were: 1) evaluation of tolerability, 2) use of an identified topical antimicrobial for acne treatment without combination retinoid use, 3) an original study, in English.Thirty-four of 132 articles met the inclusion criteria. Tolerability was measured through subject and investigator assessment of specific tolerability parameters and by reporting of adverse events. Nearly all of the acne treatments were well tolerated. Treatment related study discontinuation rates were low and had little to no relation to the degree of tolerability measures.Patients may be more adherent in clinical trials than in clinical practice. Differences in the measure used to assess tolerability make comparisons difficult.Topical antimicrobial acne therapy is generally well tolerated. Discontinuation rates are low under study conditions. Tolerability of topical antimicrobial therapy for acne may not have great clinical significance.
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