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Annals of the Rheumatic Diseases Jul 2022In the anifrolumab systemic lupus erythematosus (SLE) trial programme, there was one trial (TULIP-1) in which BILAG-based Composite Lupus Assessment (BICLA) responses...
OBJECTIVES
In the anifrolumab systemic lupus erythematosus (SLE) trial programme, there was one trial (TULIP-1) in which BILAG-based Composite Lupus Assessment (BICLA) responses favoured anifrolumab over placebo, but the SLE Responder Index (SRI(4)) treatment difference was not significant. We investigated the degree of concordance between BICLA and SRI(4) across anifrolumab trials in order to better understand drivers of discrepant SLE trial results.
METHODS
TULIP-1, TULIP-2 (both phase 3) and MUSE (phase 2b) were randomised, 52-week trials of intravenous anifrolumab (300 mg every 4 weeks, 48 weeks; TULIP-1/TULIP-2: n=180; MUSE: n=99) or placebo (TULIP-1: n=184, TULIP-2: n=182; MUSE: n=102). Week 52 BICLA and SRI(4) outcomes were assessed for each patient.
RESULTS
Most patients (78%-85%) had concordant BICLA and SRI(4) outcomes (Cohen's Kappa 0.6-0.7, nominal p<0.001). Dual BICLA/SRI(4) response rates favoured anifrolumab over placebo in TULIP-1, TULIP-2 and MUSE (all nominal p≤0.004). A discordant TULIP-1 BICLA non-responder/SRI(4) responder subgroup was identified (40/364, 11% of TULIP-1 population), comprising more patients receiving placebo (n=28) than anifrolumab (n=12). In this subgroup, placebo-treated patients had lower baseline disease activity, joint counts and glucocorticoid tapering rates, and more placebo-treated patients had arthritis response than anifrolumab-treated patients.
CONCLUSIONS
Across trials, most patients had concordant BICLA/SRI(4) outcomes and dual BICLA/SRI(4) responses favoured anifrolumab. A BICLA non-responder/SRI(4) responder subgroup was identified where imbalances of key factors driving the BICLA/SRI(4) discordance (disease activity, glucocorticoid taper) disproportionately favoured the TULIP-1 placebo group. Careful attention to baseline disease activity and monitoring glucocorticoid taper variation will be essential in future SLE trials.
TRIAL REGISTRATION NUMBERS
NCT02446912 and NCT02446899.
Topics: Alprostadil; Antibodies, Monoclonal, Humanized; Glucocorticoids; Humans; Lupus Erythematosus, Systemic; Severity of Illness Index; Treatment Outcome
PubMed: 35580976
DOI: 10.1136/annrheumdis-2021-221847 -
Current Urology Reports Jan 2021To highlight and review encouraging preliminary studies behind several alternative products and interventions for erectile dysfunction (ED). (Review)
Review
PURPOSE OF REVIEW
To highlight and review encouraging preliminary studies behind several alternative products and interventions for erectile dysfunction (ED).
RECENT FINDINGS
Alternative treatments for ED are becoming more prevalent with increased consumer interest. "Natural" products are sold online, and numerous clinics offer various off-label and investigational interventions. These alternative treatments have demonstrated varying degrees of efficacy in randomized trials and meta-analyses, but none of these interventions has robust enough evidence to be considered first-line therapy. These treatments may find a role in combination with guideline treatments or may be used in novel penile rehabilitation research protocols. With growing interest in alternative treatment for men's health, an awareness of the literature is imperative for patient counsel. Alternative treatments, like L-arginine, have a growing body of evidence for efficacy in combination with PDE5i, and low-intensity shock wave therapy and stem cell therapy continue to demonstrate encouraging outcomes in ED trials.
Topics: Alprostadil; Amino Acids; Complementary Therapies; Erectile Dysfunction; Extracorporeal Shockwave Therapy; Humans; Hyperbaric Oxygenation; Male; Men's Health; Penis; Phytotherapy; Platelet-Rich Plasma; Stem Cell Transplantation; Ultrasonic Waves; Urological Agents; Vibration
PubMed: 33420972
DOI: 10.1007/s11934-020-01023-9 -
Scientific Reports Sep 2023Multilineage-differentiating stress-enduring (Muse) cells are endogenous reparative pluripotent stem cells present in the bone marrow, peripheral blood, and organ...
Multilineage-differentiating stress-enduring (Muse) cells are endogenous reparative pluripotent stem cells present in the bone marrow, peripheral blood, and organ connective tissues. We assessed the homing and therapeutic effects of systemically administered nafimestrocel, a clinical-grade human Muse cell-based product, without immunosuppressants in a neonatal hypoxic-ischemic (HI) rat model. HI injury was induced on postnatal day 7 (P7) and was confirmed by T2-weighted magnetic resonance imaging on P10. HI rats received a single dose nafimestrocel (1 × 10 cells/body) or Hank's balanced salt solution (vehicle group) intravenously at either three days (on P10; M3 group) or seven days (on P14; M7 group) after HI insult. Radioisotope experiment demonstrated the homing of chromium-51-labeled nafimestrocel to the both cerebral hemispheres. The cylinder test (M3 and M7 groups) and open-field test (M7 group) showed significant amelioration of paralysis and hyperactivity at five weeks of age compared with those in the vehicle group. Nafimestrocel did not cause adverse events such as death or pathological changes in the lung at ten weeks in the both groups. Nafimestrocel attenuated the production of tumor necrosis factor-α and inducible nitric oxide synthase from activated cultured microglia in vitro. These results demonstrate the potential therapeutic benefits and safety of nafimestrocel.
Topics: Humans; Animals; Rats; Animals, Newborn; Alprostadil; Hypoxia-Ischemia, Brain; Hypoxia; Excipients; Brain Injuries
PubMed: 37696826
DOI: 10.1038/s41598-023-41026-3 -
Seminars in Thoracic and Cardiovascular... 2015The introduction of prostaglandin E1 in the late 1970s revolutionized the management of interrupted aortic arch. Complete resuscitation should proceed over several days... (Review)
Review
The introduction of prostaglandin E1 in the late 1970s revolutionized the management of interrupted aortic arch. Complete resuscitation should proceed over several days if necessary before surgery is undertaken. One-stage primary neonatal repair with direct arch anastomosis and ventricular septal defect closure is the preferred surgical approach. Selective cerebral perfusion with near-infrared monitoring is being used with increasing frequency. Although repair of interrupted arch is physiologically corrective, it should not be viewed as fully corrective because of the high incidence of important late left ventricular outflow tract obstruction. This may respond to a simple surgical reintervention such as subaortic resection, but in some cases, an extensive procedure to enlarge the left ventricular outflow tract is necessary. However, procedures directed against subaortic stenosis should rarely be used as part of the initial surgical management during the neonatal period. Careful developmental follow-up is needed for all patients because of the high incidence of DiGeorge syndrome, which frequently manifests as moderately severe developmental delay.
Topics: Alprostadil; Aorta, Thoracic; Humans; Reoperation; Treatment Outcome; Vascular Malformations; Vascular Surgical Procedures; Ventricular Outflow Obstruction
PubMed: 26686446
DOI: 10.1053/j.semtcvs.2015.04.003 -
Cell Transplantation 2023Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of motor neurons. Multilineage-differentiating stress-enduring (Muse) cells are unique... (Randomized Controlled Trial)
Randomized Controlled Trial
Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of motor neurons. Multilineage-differentiating stress-enduring (Muse) cells are unique endogenous stem cells that show therapeutic effects on motor function in ALS mouse models. We conducted a single-center open phase II clinical trial to evaluate the safety and clinical effects of repeated intravenous injections of an allogenic Muse cell-based product, CL2020, in patients with ALS. Five patients with ALS received CL2020 intravenously once a month for a total of six doses. The primary endpoints were safety and tolerability, and the secondary endpoint was the rate of change in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score. In addition, serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), sphingosine-1-phosphate (S1P), cerebrospinal fluid chitotriosidase-1 (CHIT-1), and neurofilament light chain (NfL) levels were evaluated. The CL2020 treatment was highly tolerated without serious side effects. The ALSFRS-R score change trended upward at 12 months post-CL2020 treatment compared with that at 3 months pre-administration, but the difference was not statistically significant. Among five patients diagnosed with ALS, three exhibited a decrease in the rate of ALSFRS-R score change, one demonstrated an increase, and another showed no change. In addition, the patients' serum IL-6 and TNF-α levels and cerebrospinal fluid CHIT-1 and NfL levels increased for up to 6 months post-treatment; however, their serum S1P levels continuously decreased over 12 months. These findings indicate a favorable safety profile of CL2020 therapy. In the near future, a double-blind study of a larger number of ALS patients should be conducted to confirm the efficacy of ALS treatment with CL2020.
Topics: Animals; Mice; Humans; Amyotrophic Lateral Sclerosis; Alprostadil; Interleukin-6; Tumor Necrosis Factor-alpha; Motor Neurons
PubMed: 38014622
DOI: 10.1177/09636897231214370 -
Cell Transplantation 2023Fat graft is widely used in plastic and reconstructive surgery. The size of the injectable product, the unpredictable fat resorption rates, and subsequent adverse...
Fat graft is widely used in plastic and reconstructive surgery. The size of the injectable product, the unpredictable fat resorption rates, and subsequent adverse effects make it tricky to inject untreated fat into the dermal layer. Mechanical emulsification of fat tissue, which Tonnard introduced, solves these problems, and the product obtained was called nanofat. Nanofat is widely used in clinical and aesthetic settings to treat facial compartments, hypertrophic and atrophic scars, wrinkle attenuation, skin rejuvenation, and alopecia. Several studies demonstrate that the tissue regeneration effects of nanofat are attributable to its rich content of adipose-derived stem cells. This study aimed to characterize product by investigating morphology, cellular yield, adipose-derived stem cell (ASC) proliferation rate and clonogenic capability, immunophenotyping, and differential potential. The percentage of SEEA3 and CD105 expression was also analyzed to establish the presence of multilineage-differentiating stress-enduring (MUSE) cell. Our results showed that the kit could isolate 3.74 × 10 ± 1.31 × 10 proliferative nucleated cells for milliliter of the treated fat. Nanofat-derived ASC can grow in colonies and show high differentiation capacity into adipocytes, osteocytes, and chondrocytes. Moreover, immunophenotyping analysis revealed the expression of MUSE cell antigen, making this nanofat enriched of pluripotent stem cell, increasing its potential in regenerative medicine. The unique characteristics of MUSE cells give a simple, feasible strategy for treating a variety of diseases.
Topics: Humans; Alprostadil; Cells, Cultured; Adipose Tissue; Mesenchymal Stem Cells; Obesity; Pluripotent Stem Cells; Stem Cell Transplantation
PubMed: 37243545
DOI: 10.1177/09636897231175968 -
Journal of the American College of... Mar 2021Phosphodiesterase 5 inhibitor (PDE5i) treatment is associated with reduced mortality compared with no treatment for erectile dysfunction after myocardial infarction (MI). (Comparative Study)
Comparative Study Observational Study
BACKGROUND
Phosphodiesterase 5 inhibitor (PDE5i) treatment is associated with reduced mortality compared with no treatment for erectile dysfunction after myocardial infarction (MI).
OBJECTIVES
This study sought to investigate the association between treatment with PDE5i or alprostadil and outcomes in men with stable coronary artery disease.
METHODS
All Swedish men with a prior MI or revascularization who received PDE5i or alprostadil during 2006 through 2013 at >6 months after the event were included, using the Swedish Patient Register and the Swedish Prescribed Drug Register. Cox regression was used to estimate adjusted hazard ratios with 95% confidence intervals for all-cause mortality, MI, heart failure, cardiovascular mortality, noncardiovascular mortality, cardiac revascularization, peripheral arterial disease, and stroke in men treated with PDE5i versus alprostadil.
RESULTS
This study included 16,548 men treated with PDE5i and 1,994 treated with alprostadil. The mean follow-up was 5.8 years, with 2,261 deaths (14%) in the PDE5i group and 521 (26%) in the alprostadil group. PDE5i compared with alprostadil treatment was associated with lower mortality (hazard ratio: 0.88; 95% confidence interval: 0.79 to 0.98) and with similar associations for MI, heart failure, cardiovascular mortality, and revascularization. When quintiles (q) of filled PDE5i prescriptions were compared using q1 as reference, patients in q3, q4, and q5 had lower all-cause mortality. Among alprostadil users, those in q5 had a lower all-cause mortality compared to q1.
CONCLUSIONS
In men with stable coronary artery disease, treatment with PDE5i is associated with lower risks of death, MI, heart failure, and revascularization compared with alprostadil treatment. Although the decrease in all-cause mortality was PDE5i dose dependent, the data do not permit the inference of causality or any clinical benefits of PDE5i because of the observational study design.
Topics: Aged; Alprostadil; Cohort Studies; Coronary Artery Disease; Erectile Dysfunction; Humans; Male; Middle Aged; Myocardial Infarction; Phosphodiesterase 5 Inhibitors; Survival Rate
PubMed: 33766260
DOI: 10.1016/j.jacc.2021.01.045 -
Cardiology in the Young Dec 2014Neonatal critical aortic stenosis is a rare form of CHD that often presents with cardiogenic shock. Although surgical and cardiac catheterisation-based interventions... (Review)
Review
Neonatal critical aortic stenosis is a rare form of CHD that often presents with cardiogenic shock. Although surgical and cardiac catheterisation-based interventions have been successful in alleviating left ventricular outflow tract obstruction, it remains associated with high morbidity and mortality. Critical aortic stenosis results in elevated left ventricular wall stress, which ultimately increases myocardial oxygen consumption and disrupts coronary artery perfusion during diastole, leading to ventricular dysfunction and cardiogenic shock. Critical care management before definitive intervention should be tailored to optimising oxygen delivery and reducing metabolic consumption of the myocardium and peripheral organ systems. This can be accomplished with prostaglandin infusion to maintain system perfusion through patency of the arterial duct, inotropic support, mechanical ventilation, and central nervous system abrogation. Management should also include a multi-specialty medical team including paediatric cardiothoracic surgeons and paediatric cardiologists with expertise in cardiac catheterisation, imaging, and transplantation.
Topics: Alprostadil; Aortic Valve Stenosis; Balloon Valvuloplasty; Cardiac Catheterization; Cardiac Surgical Procedures; Cardiotonic Agents; Critical Care; Heart Defects, Congenital; Humans; Infant, Newborn; Preoperative Care; Respiration, Artificial; Vasoconstrictor Agents; Vasodilator Agents
PubMed: 25647388
DOI: 10.1017/S1047951114002029 -
Archivio Italiano Di Urologia,... Sep 2022We describe an original minimally invasive penile plication technique with scrotal or infrapubic access, not requiring circumcision, for penile curvature of different...
OBJECTIVE
We describe an original minimally invasive penile plication technique with scrotal or infrapubic access, not requiring circumcision, for penile curvature of different severity and types. This technique can be used to correct both congenital and acquired curvatures, mono or bidirectional deformities.
MATERIALS AND METHODS
Between 2012 and 2018 we treated 134 patients suffering from congenital curvature (33) and acquired curvature from Peyronie's disease (101). The average curvature was 62.2° (± 30.4°). Preoperative evaluation included prostaglandin E1 injection with photographic documentation and measurement of penile angulation, administration of IIEF- 15, vasoactive penile Doppler ultrasound, analysis of thermal and vibratory sensitivity with Genito-Sensory-Analyzer (GSA) and assessment of nocturnal penile stiffness with Rigiscan, performed twice, for a detailed evaluation of patient's erectile function. Scrotal access was performed in patients with dorsal and/or lateral penile curvature; the infrapubic access was performed in patients with ventral curvature. After preparation and incision of Colles' fascia, penis was partially degloved and an original plication technique called "binary corporoplasty" was performed at the site or sites established at preoperative assessment, with non-resorbable synthetic multifilament (Premicron®) suture.
RESULTS
Complete correction of penile curvature was achieved in 96.8 % of patients. No major complications were reported, and no patients suffered worsening in erectile function or in penile sensitivity. The average shortening of convex side was 1.65 cm (± 0.7 cm) and all patients report easy intercourse after correction. The average time of surgery was 46 minutes (± 11 min) and all procedures were performed as a day-hospital or ambulatory settings, with local anesthesia and light sedation. Overall satisfaction rate is 96%.
CONCLUSIONS
This is a simple and rapid technique that perfectly corrects even the most severe and complex penile curvatures. In comparison to traditional techniques, such as Nesbit procedure, this technique is associated with low morbidity, a very low recurrence rate and a great aesthetic results. Aesthetic and functional patients' satisfaction was excellent.
Topics: Alprostadil; Circumcision, Male; Erectile Dysfunction; Humans; Male; Penile Induration; Penis
PubMed: 36165481
DOI: 10.4081/aiua.2022.3.334 -
Nutrition (Burbank, Los Angeles County,... Feb 2015Nutritional factors such as magnesium, folic acid, vitamins B12 and B6, L-arginine, and polyunsaturated fatty acids (PUFAs) appear to be significantly beneficial for... (Review)
Review
Nutritional factors such as magnesium, folic acid, vitamins B12 and B6, L-arginine, and polyunsaturated fatty acids (PUFAs) appear to be significantly beneficial for patients with coronary artery disease (CAD), and in the prevention and arresting the progression of HF and cardiac arrhythmias. Additionally, ingestion of adequate amounts of protein and maintaining normal concentrations of plasma albumin seem to be essential for these patients. These nutrients closely interact with the metabolism of L-arginine-nitric oxide (NO) system, essential fatty acids, and eicosanoids such that beneficial products such as NO, prostaglandin E1, prostacyclin, prostaglandin I3, lipoxins, resolvins, and protectins are generated and synthesis of proinflammatory cytokines is suppressed that results in platelet anti-aggregation, vasodilation, angiogenesis, and prevention of CAD, cardiac arrhythmias, and stabilization of HF. This implies that individuals at high risk for CAD, cardiac arrhythmias, and HF and those who have these diseases need to be screened for plasma levels of magnesium, folic acid, vitamins B12 and B6, L-arginine, NO, various PUFAs, lipoxin A4, resolvins, protectins, asymmetrical dimethylarginine (an endogenous inhibitor of NO), albumin, and various eicosanoids and cytokines and correct their abnormalities to restore normal physiology.
Topics: Alprostadil; Anti-Inflammatory Agents; Arginine; CD59 Antigens; Coronary Artery Disease; Diabetes Mellitus, Type 2; Epoprostenol; Fatty Acids, Essential; Fatty Acids, Unsaturated; Female; Folic Acid; Heart Failure; Humans; Hypertension; Lipoxins; Magnesium; Male; Middle Aged; Nitric Oxide; Nutritional Status; Serum Albumin; Vasodilation; Vitamin B 12; Vitamin B 6
PubMed: 25592005
DOI: 10.1016/j.nut.2014.08.011