METHODS: The following treatments were repeatedly administered to seven female common marmosets: Treatment A, alfaxalone (12 mg kg-1 ) alone; treatment AK, alfaxalone (1 mg animal-1 ) plus ketamine (2.5 mg animal-1 ); treatment AMB, alfaxalone (4 mg kg-1 ), medetomidine (50 µg kg-1 ) plus butorphanol (0.3 mg kg-1 ); and treatment AMB-Ati, AMB with atipamezole at 45 minutes.
RESULTS AND CONCLUSIONS: Marmosets became laterally recumbent and unresponsive for approximately 30 minutes in A and AK and for approximately 60 minutes in AMB. The animals showed rapid recovery following atipamezole injection in AMB-Ati. The decrease in heart rate and SpO2 was significantly greater in AMB compared to A and AK. Oxygen supplementation, anaesthetic monitors and atipamezole should be available especially when AMB is administered.
Objective: To investigate the acceptability and pharmacokinetics (PK) of SC injection of TU.
Design: Randomized sequence, crossover clinical study of SC vs IM TU injections.
Setting: Ambulatory clinic of an academic andrology center.
Participants: Twenty men (11 hypogonadal, 9 transgender men) who were long-term users of TU. injections. Intervention: Injection of 1000 mg TU (in 4 mL castor oil vehicle) by SC or IM route. Main Outcome Measures: Patient-reported pain, acceptability, and preference scales. PK by measurement of serum testosterone, dihydrotestosterone (DHT), and estradiol (E2) concentrations with application of population PK methods and dried blood spot (DBS) sampling.
Results: Pain was greater after SC compared with IM injection 24 hours (but not immediately) after injection but both routes were equally acceptable. Ultimately 11 preferred IM, 6 preferred SC, and 3 had no preference. The DBS-based PK analysis of serum testosterone revealed a later time of peak testosterone concentration after SC vs IM injection (8.0 vs 3.3 days) but no significant route differences in model-predicted peak testosterone concentration (8.4 vs 9.6 ng/mL) or mean resident time (183 vs 110 days). The PK of venous serum testosterone, DHT, and E2 did not differ according to route of injection.
Conclusions: We conclude that SC TU injection is acceptable but produces greater pain 24 hours after injection that may contribute to the overall majority preference for the IM injection. The PK of testosterone, DHT, or E2 did not differ substantially between SC and IM routes. Hence whereas further studies are required, the SC route represents an alternative to IM injections without a need to change dose for men for whom IM injection is not desired or recommended.
Objective: To assess the efficacy and adverse event profile of the recombinant zoster vaccine in immunocompromised autologous HSCT recipients.
Design, Setting, and Participants: Phase 3, randomized, observer-blinded study conducted in 167 centers in 28 countries between July 13, 2012, and February 1, 2017, among 1846 patients aged 18 years or older who had undergone recent autologous HSCT.
Interventions: Participants were randomized to receive 2 doses of either recombinant zoster vaccine (n = 922) or placebo (n = 924) administered into the deltoid muscle; the first dose was given 50 to 70 days after transplantation and the second dose 1 to 2 months thereafter.
Main Outcomes and Measures: The primary end point was occurrence of confirmed herpes zoster cases.
Results: Among 1846 autologous HSCT recipients (mean age, 55 years; 688 [37%] women) who received 1 vaccine or placebo dose, 1735 (94%) received a second dose and 1366 (74%) completed the study. During the 21-month median follow-up, at least 1 herpes zoster episode was confirmed in 49 vaccine and 135 placebo recipients (incidence, 30 and 94 per 1000 person-years, respectively), an incidence rate ratio (IRR) of 0.32 (95% CI, 0.22-0.44; P
OBJECTIVES: To compare the efficacy and safety of autologous cells derived from different sources, prepared using different protocols, administered at different doses, and delivered via different routes for the treatment of 'no-option' CLI patients.
SEARCH METHODS: The Cochrane Vascular Information Specialist (CIS) searched the Cochrane Vascular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE Ovid, Embase Ovid, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Allied and Complementary Medicine Database (AMED), and trials registries (16 May 2018). Review authors searched PubMed until February 2017.
SELECTION CRITERIA: We included randomised controlled trials (RCTs) involving 'no-option' CLI patients comparing a particular source or regimen of autologous cell-based therapy against another source or regimen of autologous cell-based therapy.
DATA COLLECTION AND ANALYSIS: Three review authors independently assessed the eligibility and methodological quality of the trials. We extracted outcome data from each trial and pooled them for meta-analysis. We calculated effect estimates using a risk ratio (RR) with 95% confidence interval (CI), or a mean difference (MD) with 95% CI.
MAIN RESULTS: We included seven RCTs with a total of 359 participants. These studies compared bone marrow-mononuclear cells (BM-MNCs) versus mobilised peripheral blood stem cells (mPBSCs), BM-MNCs versus bone marrow-mesenchymal stem cells (BM-MSCs), high cell dose versus low cell dose, and intramuscular (IM) versus intra-arterial (IA) routes of cell implantation. We identified no other comparisons in these studies. We considered most studies to be at low risk of bias in random sequence generation, incomplete outcome data, and selective outcome reporting; at high risk of bias in blinding of patients and personnel; and at unclear risk of bias in allocation concealment and blinding of outcome assessors. The quality of evidence was most often low to very low, with risk of bias, imprecision, and indirectness of outcomes the major downgrading factors.Three RCTs (100 participants) reported a total of nine deaths during the study follow-up period. These studies did not report deaths according to treatment group.Results show no clear difference in amputation rates between IM and IA routes (RR 0.80, 95% CI 0.54 to 1.18; three RCTs, 95 participants; low-quality evidence). Single-study data show no clear difference in amputation rates between BM-MNC- and mPBSC-treated groups (RR 1.54, 95% CI 0.45 to 5.24; 150 participants; low-quality evidence) and between high and low cell dose (RR 3.21, 95% CI 0.87 to 11.90; 16 participants; very low-quality evidence). The study comparing BM-MNCs versus BM-MSCs reported no amputations.Single-study data with low-quality evidence show similar numbers of participants with healing ulcers between BM-MNCs and mPBSCs (RR 0.89, 95% CI 0.44 to 1.83; 49 participants) and between IM and IA routes (RR 1.13, 95% CI 0.73 to 1.76; 41 participants). In contrast, more participants appeared to have healing ulcers in the BM-MSC group than in the BM-MNC group (RR 2.00, 95% CI 1.02 to 3.92; one RCT, 22 participants; moderate-quality evidence). Researchers comparing high versus low cell doses did not report ulcer healing.Single-study data show similar numbers of participants with reduction in rest pain between BM-MNCs and mPBSCs (RR 0.99, 95% CI 0.93 to 1.06; 104 participants; moderate-quality evidence) and between IM and IA routes (RR 1.22, 95% CI 0.91 to 1.64; 32 participants; low-quality evidence). One study reported no clear difference in rest pain scores between BM-MNC and BM-MSC (MD 0.00, 95% CI -0.61 to 0.61; 37 participants; moderate-quality evidence). Trials comparing high versus low cell doses did not report rest pain.Single-study data show no clear difference in the number of participants with increased ankle-brachial index (ABI; increase of > 0.1 from pretreatment), between BM-MNCs and mPBSCs (RR 1.00, 95% CI 0.71 to 1.40; 104 participants; moderate-quality evidence), and between IM and IA routes (RR 0.93, 95% CI 0.43 to 2.00; 35 participants; very low-quality evidence). In contrast, ABI scores appeared higher in BM-MSC versus BM-MNC groups (MD 0.05, 95% CI 0.01 to 0.09; one RCT, 37 participants; low-quality evidence). ABI was not reported in the high versus low cell dose comparison.Similar numbers of participants had improved transcutaneous oxygen tension (TcO₂) with IM versus IA routes (RR 1.22, 95% CI 0.86 to 1.72; two RCTs, 62 participants; very low-quality evidence). Single-study data with low-quality evidence show a higher TcO₂ reading in BM-MSC versus BM-MNC groups (MD 8.00, 95% CI 3.46 to 12.54; 37 participants) and in mPBSC- versus BM-MNC-treated groups (MD 1.70, 95% CI 0.41 to 2.99; 150 participants). TcO₂ was not reported in the high versus low cell dose comparison.Study authors reported no significant short-term adverse effects attributed to autologous cell implantation.
AUTHORS' CONCLUSIONS: Mostly low- and very low-quality evidence suggests no clear differences between different stem cell sources and different treatment regimens of autologous cell implantation for outcomes such as all-cause mortality, amputation rate, ulcer healing, and rest pain for 'no-option' CLI patients. Pooled analyses did not show a clear difference in clinical outcomes whether cells were administered via IM or IA routes. High-quality evidence is lacking; therefore the efficacy and long-term safety of autologous cells derived from different sources, prepared using different protocols, administered at different doses, and delivered via different routes for the treatment of 'no-option' CLI patients, remain to be confirmed.Future RCTs with larger numbers of participants are needed to determine the efficacy of cell-based therapy for CLI patients, along with the optimal cell source, phenotype, dose, and route of implantation. Longer follow-up is needed to confirm the durability of angiogenic potential and the long-term safety of cell-based therapy.
DESIGN: A 4-site, prospective randomized double-blind, placebo-controlled trial was conducted among prison and jail inmates with HIV and OUD transitioning to the community from September 2010 through March 2016.
METHODS: Eligible participants (N = 93) were randomized 2:1 to receive 6 monthly injections of XR-NTX (n = 66) or placebo (n = 27) starting at release and observed for 6 months. The primary outcome was the proportion that maintained or improved VS (<50 copies/mL) from baseline to 6 months.
RESULTS: Participants allocated to XR-NTX significantly improved to VS (<50 copies/mL) from baseline (37.9%) to 6 months (60.6%) (P = 0.002), whereas the placebo group did not (55.6% at baseline to 40.7% at 6 months P = 0.294). There was, however, no statistical significant difference in VS levels at 6 months between XR-NTX (60.6%) vs. placebo (40.7%) (P = 0.087). After controlling for other factors, only allocation to XR-NTX (adjusted odds ratio = 2.90; 95% confidence interval = 1.04 to 8.14, P = 0.043) was associated with the primary outcome. Trajectories in VS from baseline to 6 months differed significantly (P = 0.017) between treatment groups, and the differences in the discordant values were significantly different as well (P = 0.041): the XR-NTX group was more likely than the placebo group to improve VS (30.3% vs. 18.5%), maintain VS (30.3% vs. 27.3), and less likely to lose VS (7.6% vs. 33.3%) by 6 months.
CONCLUSIONS: XR-NTX improves or maintains VS after release to the community for incarcerated people living with HIV with OUD.
PRINCIPAL FINDINGS: The serum antigen concentration-time profile of the N. sumatrana venom and its major toxins injected intravenously fitted a two-compartment model of pharmacokinetics. The systemic clearance (91.3 ml/h), terminal phase half-life (13.6 h) and systemic bioavailability (41.9%) of N. sumatrana venom injected intramuscularly were similar to those of N. sputatrix venom determined in an earlier study. The venom neurotoxin and cardiotoxin reached their peak concentrations within 30 min following intramuscular injection, relatively faster than the phospholipase A2 and whole venom (Tmax=2 h and 1 h, respectively). Rapid absorption of the neurotoxin and cardiotoxin from the injection site into systemic circulation indicates fast onsets of action of these principal toxins that are responsible for the early systemic manifestation of envenoming. The more prominent role of the neurotoxin in N. sumatrana systemic envenoming is further supported by its significantly higher intramuscular bioavailability (Fi.m.=81.5%) compared to that of the phospholipase A2 (Fi.m.=68.6%) or cardiotoxin (Fi.m.=45.6%). The incomplete absorption of the phospholipase A2 and cardiotoxin may infer the toxins' affinities for tissues at the injection site and their pathological roles in local tissue damages through synergistic interactions.
CONCLUSION/SIGNIFICANCE: Our results suggest that the venom neurotoxin is absorbed very rapidly and has the highest bioavailability following intramuscular injection, supporting its role as the principal toxin in systemic envenoming.