Peripheral Swelling Research Articles

A real-world pharmacovigilance study of FDA adverse event reporting system events for Capmatinib

Capmatinib is a potent selective mesenchymal-epithelial transition inhibitor approved in 2020 for the treatment of metastatic non-small cell lung cancer. As real-world evidence is very limited, this study evaluated capmatinib-induced adverse events through data mining of the FDA Adverse Event Reporting System database. Four disproportionality analysis methods were employed to quantify the signals of capmatinib-related adverse events. The difference in capmatinib-associated adverse event signals was further investigated with respect to sex, age, weight, dose, onset time, continent, and concomitant drug. A total of 1518 reports and 4278 adverse events induced by capmatinib were identified. New significant adverse event signals emerged, such as dysphagia, dehydration, deafness, vocal cord paralysis, muscle disorder, and oesophageal stenosis. Notably, higher risk of alanine aminotransferase and aspartate aminotransferase increases were observed in females, especially when capmatinib was combined with immune checkpoint inhibitors. Compared with Europeans and Asians, Americans were more likely to experience peripheral swelling, especially in people > 65 years of age. Renal impairment and increased blood creatinine were more likely to occur with single doses above 400 mg and in Asians. This study improves the understanding of safety profile of capmatinib.

PATTERN OF CHRONIC LIVER DISEASE IN CHILDREN IN A TERTIARY CARE HOSPITAL

The study aimed to identify the different signs, symptoms, and causes of chronic liver disease in children. The study involved patients between the ages of 1 and 12 years who were suspected of having chronic liver disease, excluding those with acute liver disease, congenital anomalies, and liver transplant recipients. The study was conducted in the Department of Pediatrics at Pak Emirates Military Hospital in Rawalpindi from September 2023 to December 2023. The results of the study showed that the most common causes of chronic liver disease in the patients were progressive familial intrahepatic cholestasis, followed by glycogen storage diseases, Hepatitis C, Wilson's disease, and Hepatitis B. Jaundice, abdominal distension, peripheral swelling, ascites, hepatomegaly, and splenomegaly were the most common symptoms of chronic liver disease. Some patients also suffered from variceal bleeding and hepatic encephalopathy. In conclusion, the study found that chronic liver disease in children from Pakistan has a diverse range of causes and symptoms.

A real-world disproportionality analysis of sacubitril/valsartan: data mining of the FDA adverse event reporting system.

Sacubitril/valsartan is extensively used in heart failure; however, there are few long-term safety studies of it in a wide range of populations. The aim of this study was to evaluate sacubitril/valsartan-induced adverse events (AEs) through data mining of the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). Reports in the FAERS from the third quarter of 2015 (FDA approval of sacubitril/valsartan) to the fourth quarter of 2023 were collected and analyzed. Disproportionality analyses, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and empirical Bayesian geometric mean (EBGM) algorithms were adopted in data mining to quantify signals of sacubitril/valsartan-associated AEs. A total of 12,001,275 reports of sacubitril/valsartan as the "primary suspected (PS)" and 99,651 AEs induced by sacubitril/valsartan were identified. More males than females reported AEs (59.95% vs. 33.31%), with the highest number of reports in the 60-70years age group (8.11%), and most AEs occurred < 7days (14.13%) and ≥ 60days (10.69%) after dosing. Sacubitril/valsartan-induced AE occurrence targeted 24 system organ classes (SOCs) and 294 preferred terms (PTs). Of these, 4 SOCs were strongly positive for all four algorithms, including cardiac disorders, vascular disorders, ear and labyrinth disorders, and respiratory, thoracic and mediastinal disorders. Among all PTs, consistent with the specification, hypotension (n = 10,078) had the highest number of reports, and dizziness, cough, peripheral swelling, blood potassium increased, and renal impairment were also reported in high numbers. Notably, this study also discovered a high frequency of side effects such as death, dyspnea, weight change, feeling abnormal, hearing loss, memory impairment, throat clearing, and diabetes mellitus. This study identified potential new AE signals and gained a more general understanding of the safety of sacubitril/valsartan, promoting its rational adoption in the cardiovascular system.

High risks adverse events associated with usage of aspirin in chronic obstructive pulmonary disease

ABSTRACT Background Despite potential benefits and widespread prescription of aspirin among chronic obstructive pulmonary disease (COPD) patients, limited research has investigated its adverse effects (AEs) in COPD population. Methods We conducted a retrospective analysis of adverse drug events (ADEs) reported in the US Food and Drug Administration Adverse Event Reporting System (FAERS) between Q1 2013 and Q2 2022. COPD patients were categorized into two groups based on aspirin use. ADEs related to aspirin use were identified using combined reporting odds ratio (ROR), proportional reporting ratio (PRR), information component (IC) methods. Results A total of 56,660 ADEs reports associated with COPD patients were included in the study. Among these reports, 144 adverse events were linked to aspirin use in COPD patients, including fatigue (4.12%), diarrhea (3.13%), dyspnea exertional (2.03%), rhinorrhea (1.99%), weight increased (1.89%) and vomiting (1.84%), muscle spasms (1.79%), cardiac disorder (1.74%), heart rate increased (1.69%) and peripheral swelling (1.59%). Subgroup analysis indicates that age and gender might affect the AEs frequency in COPD patients using aspirin. Conclusions Our findings identify 10 most frequently reported ADEs associated with aspirin use in COPD patients, thus offer valuable insights into the AEs of aspirin for safer clinical utilization in COPD management.

Marstacimab, an Anti-Tissue Factor Pathway Inhibitor, in Participants with Hemophilia Α or B, with and without Inhibitors: An Integrated Analysis of Safety

Background: Marstacimab (PF-06741086) targets tissue factor pathway inhibitor (TFPI) to restore hemostasis via the extrinsic pathway of blood coagulation. In phase 1/2 studies, long-term subcutaneous (SC) administration of marstacimab reduced bleeding episodes in adults with severe hemophilia A (HA) or hemophilia B (HB) (factor VIII or factor IX [FIX] ˂1%, respectively), with or without inhibitors. BASIS, the pivotal phase 3 study of marstacimab in adolescents and adults with severe HA (&amp;lt;1%) or moderately severe to severe (FIX ≤2%) HB, is ongoing. Given the potential risk for thrombotic and thromboembolic complications with novel non-factor-based agents, integrated safety analysis of studies of such agents are of interest. Wereport an integrated analysis of marstacimab safety in participants with HA or HB. Methods: Data from participants in the phase 1b/2 study (NCT02974855), its long-term follow-up (LTFU; NCT03363321), the pivotal phase 3 BASIS study (NCT03938792), and its long-term extension (LTE; NCT05145127) were included. In the phase 1b/2 study, male participants (N=26) with severe HA or HB, with or without inhibitors, were assigned to escalating weekly SC doses of marstacimab based on inhibitor status (without inhibitors: 300 mg, a single 300-mg loading dose with subsequent 150-mg doses, or 450 mg; with inhibitors: 300 mg). In the BASIS study, male participants (N=163) with severe HA or moderately severe to severe HB, with or without inhibitors, received a single SC 300-mg loading dose followed by once-weekly 150 mg in the 12-month active treatment phase (ATP). Adverse events (AEs), serious adverse events (SAEs), and AEs of special interest (AESI), including thromboembolic events and injection site reactions (ISRs), were monitored. Results: Overall, 144 unique participants received marstacimab and were included in this analysis: 28 in the phase 1b/2 study (median treatment duration, 2.8 [range, 1.2-3.0] months) and its LTFU (15.0 [1.2-16.4] months) and 116 in the BASIS study (12.1 [0.9-13.1] months) and its LTE (6.4 [1.1-16.1] months; overall BASIS + LTE, 17.3 [0.9-28.2] months). Demographics, baseline characteristics, and marstacimab treatment and dosing ( Table 1) and a summary of safety are shown in Table 2. There were no treatment-related SAEs in the phase 1b/2 study and 1 treatment-related SAE (peripheral swelling) in the BASIS study and its LTE. There were no deaths in any study. There were no AEs related to thromboembolism during treatment in participants with HA or HB across the marstacimab clinical program. Adverse drug reactions were consistent across studies. In the BASIS study and its LTE, ISRs (n=13, 11.2%) tended to be transient and mild in severity and did not lead to discontinuation from the study: other reactions were also mild: pruritus (n=4, 3.4%); rash (n=1, 0.9%) and headache (n=8, 6.9%). One participant, with a history of hemorrhoids, in the BASIS ATP had a grade 2 event of thrombosed hemorrhoids considered related to marstacimab (a local inflammation event, not related to any other thromboembolic event; dose was not interrupted or changed due to this event). No clinically important findings in laboratory values were associated with marstacimab. In the BASIS ATP, antidrug antibodies (ADAs) developed in 23/112 participants (20.5% incidence; titers were low and resolved in 22/23 participants by end of study); 6/23 were positive for neutralizing antibodies (NAbs; titers were transient and resolved by the end of study). In the LTE, ADA developed in 1/44 (2.3%) participants; the ADA titer was negative prior to marstacimab but positive at the end of the main study (titer = 2.48), positive at Day 180 in the LTE (titer = 2.41), and the participant tested negative for NAbs at both timepoints. No differences in the marstacimab safety profile, as determined by AEs, SAEs, AESIs, and discontinuations due to AEs, were reported in ADA positive or negative participants. Across the BASIS study and its LTE, 18 participants had a marstacimab dose escalation from 150 mg to 300 mg; 8/18 (44.4%) had AEs, all mild or moderate in severity and there were no AEs or SAEs leading to treatment discontinuation. Conclusion: Once-weekly SC marstacimab was well tolerated in participants with severe HA or moderately severe to severe HB, without inhibitors, with a low rate and mild severity of ISRs, transient ADAs, and no thromboembolic events with continuous treatment up to 28 months in the phase 3 program.

Cardiovascular Safety Evaluation of Febuxostat and Allopurinol: Findings from the FDA Adverse Event Reporting System.

Febuxostat and allopurinol are the most commonly used uric acid-lowering medications, and their safety is of great concern, especially the cardiovascular adverse reactions associated with febuxostat. We propose to study the cardiovascular toxicity of febuxostat and allopurinol using the FDA Adverse Event Reporting System (FAERS) database. A total of 64 quarters of FAERS data were downloaded from 2004 to 2019. Febuxostat- and allopurinol-related cardiovascular adverse events were extracted after data cleaning. Signal detection was conducted by reporting odds ratio (ROR) and proportional reporting ratio (PRR). There were 2939 and 25,219 reports of febuxostat- and allopurinol-related cardiovascular adverse events (CVAEs), respectively. The most frequent CVAEs with febuxostat and allopurinol were edema peripheral (14.38%) and peripheral swelling (8.76%), respectively. In elderly gout patients, febuxostat is associated with an increased risk of heart failure, ischemic heart disease, hypertension, and cardiomyopathy. Febuxostat in combination with acetic acid derivatives nonsteroidal anti-inflammatory drug (NSAIDS) also increases the risk of cardiovascular adverse events. Compared with allopurinol, febuxostat may increase cardiovascular toxicity in patients with gout.

Two Posterior Mitral Leaflets or a Feature of Degenerative Valve Disease That Contributes to Mitral Regurgitation?

A 79-year-old, 77 kg, 170 cm man with ischemic cardiomyopathy, hypertension, hyperlipidemia, type 2 diabetes mellitus, and chronic renal insufficiency presented to the authors’ institution after his son and daughter reported that their father's activity level had decreased and he was observed to be more fatigued. The patient disagreed with this assessment of his condition, denying chest pain or pressure, dyspnea at rest or on exertion, exercise intolerance, fatigue, malaise, or peripheral swelling, but his children commented that he often intentionally minimized his symptoms. The patient suffered an anterior wall myocardial infarction two years before the current admission. Three stents were placed in the left anterior descending coronary artery during this previous hospitalization. The physical examination was notable for a grade III of VI systolic murmur heard best at the apex that radiated into the axilla. Transthoracic echocardiography suggested the presence of severe mitral regurgitation. Transesophageal echocardiography (TEE) was performed as part of the diagnostic evaluation and the following images were obtained (Figure 1, Figure 2; video clips 1 and 2). What is the diagnosis? Figure 2Midesophageal four-chamber color Doppler TEE view View Large Image Figure Viewer Download Hi-res image

A Five-Leaf Clover or an Exceptionally Rare Cause of Severe Aortic Insufficiency?

A 56-YEAR-old, 68- kg, 165- cm woman with a history of Crohn's disease presented to the authors’ institution with dyspnea and exercise intolerance of several months’ duration. More recently, her symptoms had progressed to occasional dyspnea at rest. She denied fever, chills, chest pain or pressure, palpitations, orthopnea, paroxysmal nocturnal dyspnea, syncope, and peripheral swelling. The physical examination was notable for a grade III of VI holodiastolic murmur. The electrocardiogram and laboratory analysis were noncontributory.

Diagnosis of pulmonary hypertension associated with congenital heart disease. Part 1. Definition, classification and initial examination of patients

Having discussed current definitions and classification of pulmonary hypertension associated with congenital heart defects, the authors consider characteristic clinical symptoms and data of physical examination separately for every subgroup. An increase in pulmonary vascular resistance after radical correction and with small / concomitant defects leads to insufficient filling of the systemic ventricle and the progression of symptoms of low cardiac output , i.e. shortness of breath, palpitations, fatigue, weakness and decreased exercise tolerance. At late stages, due to transient systemic hypotension the patients feel dizziness, lightheadedness and fainting, as well as signs of congestive right ventricular failure – peripheral edema, liver enlargement, ascites and swelling of the cervical veins. The patients with Eisenmenger syndrome develop cyanosis and signs of systemic complications – polycythemia, deformation of the distal phalanges of the fingers like «drumsticks» and «watch glasses», posture disturbance due to osteoarthropathy and scoliosis, pulmonary and paradoxical systemic thrombosis and embolism, bleeding, symptoms of gout and cholelithiasis, impaired renal function. Even mild pulmonary hypertension after Fontaine’s surgery causes venous hypertension with congestive heart failure, hydrothorax, protein deficiency enteropathy and plastic bronchitis, as well as insufficient blood flow to the systemic ventricle with low cardiac output, shortness of breath, palpitations, fatigue, weakness and decreased exercise tolerance. All forms of pulmonary hypertension cause pain in the region of the heart, hemoptysis, pulmonary hemorrhage, arrhythmias, and developmental delay in children. The patient shall be examined «from head to toe.» The diagnostic value of auscultation depends on the complexity of the congenital malformation leading to pulmonary hypertension Pulse oximetry should be performed separately on the arms and legs at rest and exercise.

Evaluation of canine bone marrow-derived mesenchymal stem cells for experimental full-thickness cutaneous wounds in a diabetic rat model

ABSTRACT Background The wound healing potential of canine bone marrow-derived mesenchymal stem cells (BMSCs) was evaluated in the excisional wound of streptozotocin-induced diabetic rats. Research design and methods Xenogenic BMSCs were collected aseptically from the iliac crest of healthy canine donors under general anesthesia. Full-thickness experimental wounds (20 × 20 mm2) on the dorsum of forty-eight adult healthy Wistar white rats. The wounds were assigned randomly to three treatment groups: PBS (Group A) or BMSCs (Group B) injected into the wound margins on days 0, 7, and 14 or BMSCs (Group C) injected into the wound margins on days 7, 14, and 21 post-wounding. The degree of wound healing was evaluated based on macroscopical, hemato-biochemical, histopathological, and histochemical parameters. Results The results indicated granulation tissue formation with reduced exudation and peripheral swelling in the treatment groups compared to the control group A. Similarly, the degree of wound contraction was significantly higher in groups B and C animals than group A on days 14 and 21 post-wounding. The transplantation of BMSCs resulted in early drying of wounds, granulation tissue appearance, and enhanced cosmetic appearance. Conclusion The histopathological, histochemical, and gross findings suggested the therapeutic potential of xenogeneic mesenchymal stem cell therapy in managing diabetic wounds. Abbreviations BMSCs-bone marrow-derived mesenchymal stem cells, PBS-phosphate-buffered saline, MSCs-mesenchymal stem cells, FBS-fetal bovine serum, ECM-extracellular matrix

A Case of Bleeding During Infection With COVID-19

Dr. Patrick Lowe: Our case today is that of a 47-year-old woman who was referred to our emergency department (ED) due to bloody urine, dark tarry stools, red spots on her skin, and bruising throughout her body. Fourteen days prior to presentation, she began exhibiting intermittent fevers, headache, shortness of breath, and a dry cough, and she tested positive for SARS-CoV-2 (the virus that causes COVID-19 pneumonia). Over the 3 days prior to her ED presentation, she experienced a headache that was more intense than the headaches she had been having in the preceding 2 weeks. She reported episodes of both dark urine as well as bright red blood in her urine. In addition, she had multiple dark stools described as tar-like when asked. On the day of her ED presentation, the patient noted a red rash throughout her body. In addition, earlier in the day, she had atraumatic self-limited epistaxis. She denied any falls or head strikes, vision changes, focal weakness or numbness, shortness of breath, chest pain, abdominal pain, or peripheral swelling.

Safety and Efficacy of Switching Injected Peptide Long-Acting Somatostatin Receptor Ligands to Once Daily Oral Paltusotine: ACROBAT Edge Phase 2 Study

Patients with acromegaly not cured by surgery are often initially treated with injected peptide long-acting somatostatin receptor ligands (SRLs). Non-peptide small molecules can also activate the somatostatin receptor and do so with a high degree of precision for the target therapeutic receptor subtype. Paltusotine (formerly CRN00808) is a small molecule somatostatin type 2 (SST2) receptor agonist with high oral bioavailability (70%) and pharmacokinetic profile suitable for once daily dosing. In healthy volunteers, paltusotine has been shown to lower growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels. We hypothesized that patients with acromegaly could switch from injected SRLs to once daily oral paltusotine while maintaining baseline IGF-1 levels. ACROBAT Edge (NCT03789656) was a single-arm study designed to evaluate the safety and efficacy of switching from injected SRLs to paltusotine in patients with acromegaly. The primary analysis population consisted of those who had not achieved normal IGF-1 levels despite stable therapy with long-acting octreotide or lanreotide. Eligible patients received their last injection of SRL 4 weeks prior to switching to once daily oral paltusotine monotherapy for a 13-week treatment period. The starting dose of 10 mg per day was uptitrated in 10 mg increments at specified study visits to a maximal dose of 40 mg per day based on protocol specified study drug toleration and IGF-1 criteria. The primary endpoint was change in IGF-1 from baseline to the completion of the 13-week treatment period. Statistical testing was based on non-parametric Wilcoxon Sign Rank test of whether the median change is different from zero. In addition, the rise in IGF-1 during a 4-week washout period was used to provide supportive evidence of efficacy. Twenty-five patients were enrolled in the primary analysis group, three patients discontinued from the study for non-study drug related reasons, two during the treatment period and one during the washout period after completing treatment. The primary endpoint was achieved as paltusotine treatment resulted in no significant change in IGF-1 levels at week 13 compared to baseline [change in IGF-1 =-0.034 (-0.107, 0.107), median (IQR), p>0.6]. Of the 23 patients who completed the dosing period, 20 (87%) achieved IGF-1 levels at the end of treatment that were within 20% of baseline or lower. Median IGF-1 values rose significantly after paltusotine washout (p<0.0001). The most common treatment-emergent adverse events (>10%) included: headache, arthralgia, fatigue, peripheral swelling, paresthesia and hyperhidrosis. There were no discontinuations due to adverse events and no treatment related serious adverse events. These results suggest that patients with acromegaly treated with injected SRLs can switch to oral paltusotine while maintaining IGF-1 and that paltusotine appeared to be well tolerated.

Inconvenient topic: laxative abuse. review and clinical case

Annotation. Laxatives are drugs with different mechanism of action that are used to treat or prevent constipation. Use of laxatives to control body weight is considered a dangerous tendency, especially among young women with eating disorders. Natural or synthetic stimulant purgatives are the most commonly used for weight loss because they are cost-effective, have rapid onset of action, and available in various dosage forms. Excessive use of laxatives results in a gradual efficacy decrease causes specific damage of the gastrointestinal tract, other organs and systems. This condition is known as "laxative abuse". The purpose of this review is to summarize the available scientific data on behavioral characteristics, clinical and diagnostic criteria and tactics of treatment of laxative abuse with a clinical case description. Laxatives abuse should be suspected in case of eating disorders, clinical, laboratory, endoscopic and histological changes in the gastrointestinal tract. Treatment of laxative abuse requires gradual laxatives withdrawal, potassium replacement therapy and mandatory training in the healthy eating principles. The clinical case describes a young woman who tried to stop taking laxatives, but she started to use diuretics due to peripheral swelling. At the time of examination, the daily dose of furosemide was 600 mg (15 tablets a day). Laxative abuse is relatively common among young women and requires monitoring by physicians of various specialties.

Phase 2 Study Evaluating the Efficacy and Safety of Parsaclisib in Patients with Relapsed or Refractory Mantle Cell Lymphoma Previously Treated with Ibrutinib (CITADEL-205)

Phase 2 Study Evaluating the Efficacy and Safety of Parsaclisib in Patients with Relapsed or Refractory Mantle Cell Lymphoma Previously Treated with Ibrutinib (CITADEL-205)

A STUDY OF CLINICAL, SUBCLINICAL FEATURES AND THERAPEUTIC EFFICACY OF SECUKINUMAB IN PATIENTS WITH ACTIVE ANKYLOSING SPONDYLITIS

Objectives: To study clinical, subclinical features and to evaluate therapeutic efficacy of Secukinumab in patients with active Ankylosing Spondylitis (AS). Patients and methods: Descriptive, comparative, retrospective and prospective study, combination with treatment intervention in patients diagnosis with AS, following to modified ACR-1984 criteria (New York criteria) who are inpatient or outpatient in the Department of General Internal Medicine - Endocrinology of Hue University of Medicine and Pharmacy and in the Department of Nephrology and Rheumatology of Hue Central Hospital from May 2018 to August 2019. Results: The study recruited of 38 patients, (76.3% males) with mean age of 29.76 ± 9.75 years old. The age of onset was about 23 years old and the percentage of patients who were diagnosed AS under 30 years old was 73.7%. The majority of patients were hospitalized with severe pain (92.1%), in which 86.8% of patients sufferred from spinal pain, 71.1% of patients showed peripheral joint pain, commonly seen in hip joints (44.7%). Other common symptoms were lumbar Schober (about 3 cm), hand to ground distance (about 20 cm), median BASDAI score: 4.15 ± 1.01, median ASDAS-CRP: 3.81 ± 0.94, increasing CRP (81.58%), increasing erythrocyte sedimentation rate (81.6%), the percentage of HLA-B27 (+): 81.25% (for patients who have received this test). For patients treated with Fraizeron, in general, there were changes in patient global assessment, noctural back pain, peripheral swelling, lumbar Schober, hand to ground distance, BASDAI, ASDAS-CRP, erythrocyte sedimentation rate, CRP. These changes were positive with p &lt; 0.05. When we assessed the safety of Secukinumab, we did not record any clinical or subclinical undesirable effects. Conclusion: At week 16, Secukinumab has been effectively shown to improve clinical symptoms as well as subclinical symptoms in patients with AS. It is also considered safe for use in these patients. Key words: Ankylosing Spondylitis, Secukinumab

Safety and Efficacy of Prophylactic Closed Incision Negative Pressure Therapy after Acute Fracture Surgery

IntroductionSoft tissue swelling after acute fracture surgery is a challenge which may increase wound dehiscence, delay early range of motion, and increase infection rate postoperatively. This study investigates closed incision negative pressure therapy (ciNPT) using wide-range cover over the incision site and the peripheral swelling trauma zone to promote early active motion and to mitigate joint stiffness, bulla formation, and tendon adhesion. MethodsTwenty-nine patients were enrolled between January 2018 and December 2018. Patients with high-energy soft tissue trauma and comminuted fractures over distal end of limbs (hand and foot; wrist and ankle) or muscle scarcity areas (tibial shaft or patella) were included. ciNPT was applied over closed incisions in the operating room and subatmospheric pressure (-125 mmHg) initiated continuously for 5~7 days. ResultsIn hand and foot patients (n= 8), active motion over all fingers or toes occurred after post-operative Day 2. Mild swelling without any bullous formation was observed over the dorsal aspect of hand. In wrist and ankle patients (n= 16), flexion angle over the finger joints over 90 degrees was observed after 5 days post-surgery. For patients with tibial shaft comminuted fractures with impending compartment syndrome, early active motion of knee and ankle joint was observed as soft tissue swelling and distension pain had subsided after surgery. ConclusionThe prophylactic ciNPT use in the trauma area after surgery reduced postoperative distension pain and improved early range of motion of the tendon and joint in these patients.

MON-314 Analysis of Adverse Events in Adult Patients with Acromegaly Receiving Oral Octreotide Capsules: Results from the Phase 3, Randomized, Double-Blind, Placebo-Controlled CHIASMA OPTIMAL Study

Distinguishing non-specific signs and symptoms of acromegaly from treatment emergent adverse events (TEAEs) in patients treated with somatostatin receptor ligands has proven difficult given limited data from placebo-controlled studies. The phase 3 Octreotide capsules versus Placebo Treatment In MultinationAL centers (OPTIMAL) study provides a novel data set to evaluate the incidence of adverse events from patients randomized to octreotide capsules or placebo. A multinational, randomized, placebo-controlled study was conducted in 56 adult patients with active acromegaly. Eligible patients were ≥18 years of age, had active disease (IGF-I ≥1.3 x ULN after last pituitary surgery), and an average IGF-I ≤1.0 x ULN in response to a stable dose of somatostatin receptor ligand injection. Patients were randomized to octreotide capsule or placebo (28 per group) for 36 weeks, followed by an optional open-label extension for up to 1 year. Safety and tolerability were evaluated based on incidence of AEs, including incidence of new or worsening adverse events of special interest (AESIs). In this study, the safety profile of octreotide capsules was consistent with the known safety profile of injectable octreotide (Melmed et al 2015). No new or unexpected safety signals were detected. Nearly all patients (55/56) experienced a TEAE (28 patients [100.0%] in the octreotide capsule group and 27 patients [96.4%] in the placebo group). Thirty-three patients (58.9%) experienced a TEAE considered to be related to study drug by the blinded PI (64.3% of the octreotide capsule group [18 patients, 40 events] and 53.8% of the placebo group [15 patients, 41 events]). TEAEs with an incidence ≥5% that were more common in the octreotide capsule group vs placebo group included GI disorders, increased blood glucose, sinusitis, osteoarthritis, and cholelithiasis. TEAEs with an incidence ≥5% that were more common in the placebo group vs octreotide capsule group included arthralgia, headache, fatigue, hyperhidrosis, and peripheral swelling. GI disorders were the most common TEAE, reported in 64% of all patients (36/56) and at similar rates between octreotide capsule (68%) and placebo groups (61%). AESIs (defined as new or worsening signs of acromegaly) were observed in 15 patients (53.6%, 34 events total) in the octreotide capsule group and more frequently in 26 patients (92.9%, 82 events total) in the placebo group. In this study, the safety profile of octreotide capsules was consistent with the known safety profile of injectable octreotide. Most patients receiving octreotide capsules or placebo demonstrated TEAEs, although the profile of most common TEAEs varied between groups. TEAEs observed in the placebo group may be indicative of underlying disease activity. Further analysis may elucidate the difference between treatment related AEs and signs/symptoms of active disease in acromegaly.

Human acellular amniotic membrane is adopted to treat venous ulcers.

Venous lower limb ulcers are very common and affect ~1% of the general population. The human acellular amniotic membrane (HAAM), which is isolated from the amniotic membrane (AM) via excluding the majority of cellular components, has lower antigenicity than the AM. The aim of the present study was to evaluate the effectiveness and safety of the HAAM, adopted to treat venous ulcers (VUs) of the lower extremities. The HAMM was isolated from the AM by the Stem Cells and Tissue Engineering laboratory at the West China Hospital of Sichuan University (Chengdu, China). HAMMs were grafted onto VUs in 4 patients, with follow-up evaluations performed on the 3rd day and at the end of the 1st, 2nd and 3rd week, and 2nd, 3rd and 6th month after the HAAMs were applied. The size and depth of the VU (determined based on whether the depth of VU reaches the tibial plane), the proportion of granulation tissue (whether >50%) and the degree of secretion (measured by asessing the degree of satuation in the outer gauze) and infection (assessed qualitatively via the appearance of purulence or peripheral swelling) were assessed. Pain score was monitored at the same intervals using a visual analog scale. Complete epithelialization (healed tissue) occurred in 2 cases: The first at the end of the 3rd week and the second, at the 2nd month following HAAM induction. In one of the remaining cases, ulcer size was reduced by >60%; however the ulcer size of the remaining case only reduced by <20%. Overall, the size of ulcer in cases 1, 2, 3 and 4 decreased to 1.2×1.1 and 1.4×0.4 cm, 1.3×1.8 and 2.3×1.4, respectively, with evident decreases in ulcer depth. The proportion of granulation tissue in each case was >50%. Furthermore, purulence and secretion completely disappeared in all 4 cases. Additionally, the medical cost of HAAM treatment is substantially lower than that of AM treatment, skin autografts and biomaterial transplantation, thus alleviating the patients' financial burden. These findings suggest that HAMM was highly effective in treating VUs in patients.

Investigating the Short-Term Effects of Manual Lymphatic Drainage and Compression Garment Therapies on Lymphatic Function Using Near-Infrared Imaging.

Lymphedema is a chronic peripheral swelling caused by a dysfunction of the lymphatic system, leading to discomfort and loss of upper limb movement. Therapies to treat or manage this swelling have limited evidence, partly because of a paucity in objective lymphatic measures. This study explored the role of near-infrared (NIR) imaging in evaluating interventions. Nine healthy volunteers underwent NIR fluoroscopy using a microdose (50 μL, 0.05% w/v) of indocyanine green to quantify lymphatic behavior before and after a 15-minute period of manual lymph drainage followed by compression garment (CG) therapy for a 10-minute period. Images were taken at the forearm and elbow after each intervention. Lymphatic function was defined by the number, size, displacement, and speed of lymph packets. The lymph parameters were analyzed to assess the effects of the interventions compared with basal values. Baseline (BL) parameters of lymph function revealed high variability in the number, size, and speed of packets between individuals. Despite this variance, both interventions showed statistically significant improvement (p < 0.05) in displacement and speed at the forearm compared with BL. The velocity of transient lymph packets increased from a median of 6.7 mm/s at BL to 13.3 mm/s after manual lymphatic drainage (MLD) and 10.5 mm/s after CG. Lymphatic activity increased significantly after MLD, with relative increases being maintained after a short time period of CG application. NIR fluoroscopy has the potential to both monitor lymph pathology and provide robust parameters in the assessment of interventions.

Hereditary angioedema: epidemiology, management, and role of icatibant

Hereditary angioedema (HAE) is an autosomal dominant, potentially life-threatening condition, manifesting as recurrent and self-limiting episodes of facial, laryngeal, genital, or peripheral swelling with abdominal pain secondary to intra-abdominal edema. The estimated prevalence of HAE in the general population is one individual per 50,000, with reported ranges from 1:10,000 to 1:150,000, without major sex or ethnic differences. Various treatment options for acute attacks and prophylaxis of HAE are authorized and available in the market, including plasma-derived (Berinert®, Cinryze®, and Cetor®) and recombinant (Rhucin® and Ruconest™) C1 inhibitors, kallikrein inhibitor-ecallantide (Kalbitor®), and bradykinin B2 receptor antagonist-icatibant (Firazyr®). Some of these drugs are used only to treat HAE attacks, whereas others are only approved for prophylactic therapies and all of them have improved disease outcomes due to their different mechanisms of action. Bradykinin and its binding to B2 receptor have been demonstrated to be responsible for most of the symptoms of HAE. Thus icatibant (Firazyr®), a bradykinin B2 receptor antagonist, has proven to be an effective and more targeted treatment option and has been approved for the treatment of acute attacks of HAE. Rapid and stable relief from symptoms of cutaneous, abdominal, or laryngeal HAE attacks has been demonstrated by 30 mg of icatibant in Phase III clinical trials. Self-resolving mild to moderate local site reactions after subcutaneous injection of icatibant were observed. Icatibant is a new, safe, and effective treatment for acute attacks of HAE. HAE has been reported to result in enormous humanistic burden to patients, affecting both physical and mental health, with a negative impact on education, career, and work productivity, and with substantial economic burdens. The timely and proper use of disease-specific treatments could improve patients’ quality of life, reduce the disease-specific morbidity and mortality, and, last but not least, reduce costs associated with hospitalizations and emergency room visits. Therefore, the paradigm of HAE treatment has the potential to evolve significantly, thereby exponentially improving a patient’s quality of life.