Navigating Treatment Dilemmas: Recalcitrant Pemphigus and the Burden of Multiple Comorbidities.

Pemphigus vulgaris is a chronic autoimmune disease of the skin caused by the production of autoantibodies targeting desmogleins 1 and 3 usually presenting in individuals with an average age of onset of approximately 40 years. A 35-year-old obese, diabetic woman presented with fluid-filled lesions over her body for three months along with erosions and painful ulcers in her mouth and genital area for two months. Based on clinical and histopathological studies, the patient was diagnosed as a case of pemphigus vulgaris. She was started on conventional treatment with oral corticosteroids followed by pulse therapy and mycophenolate mofetil. Rituximab infusion was scheduled but could not be administered due to elevated D-dimer values. The patient underwent screening for deep vein thrombosis (DVT) and received subcutaneous enoxaparin and oral rivaroxaban. She developed severe sepsis for which she was treated with systemic antibiotics. She subsequently developed acute renal failure and underwent hemodialysis. The patient's clinical condition further deteriorated, which necessitated therapeutic plasma exchange (TPE). Collagen, colloidal silver, and silicone foam dressings were done to hasten wound healing. Two distinct approaches were employed to eliminate the pseudomembrane on the wounds. One portion was treated with hydrogen peroxide (H2O2), while the other was with hyaluronidase. The hyaluronidase treatment resulted in considerable improvement of the lesions. Intravenous immunoglobulin (IVIG) infusion was scheduled. However, the treatment could not be administered as the patient succumbed to death due to pulmonary thromboembolism (PTE) secondary to DVT.

Clinical Management With High-Frequency Ultrasound of Recurrent Submental Abscess Formation After Filler Placement: Bacterial Contamination or Immune-Mediated Adverse Event?

The authors present a case of a 29-year-old female patient with a recurrent submental abscess formation after chin augmentation with highly reticulated hyaluronic acid filler. We evaluate the possible cause of this complication and the result after clinical management with ultrasound-guided injection of hyaluronidase. We highlight the prevention, assessment and treatment with real-time imaging of hyaluronidase injection in the affected area, as a predictable approach for both the patient and the physician.

Garcinol: A novel and potent inhibitor of hyaluronidase enzyme.

Extracellular matrix (ECM) contains hyaluronic acid (HA) as its integral part that is involved in numerous functional activities within the body. Degradation of HA by hyaluronidase enzyme involved in many pathophysiological conditions such as asthma, arthritis, COPD and in venom spreading during envenomation. Inhibitor of hyaluronidase enzyme has a wide range of application along with the hyaluronan-hyaluronidase system. In this present study, we have evaluated the inhibitory effect of garcinol against hyaluronidase from Hippasa partita spider venom (HPHyal), bovine testicular hyaluronidase (BTH) and human serum hyaluronidase. Garcinia indica fruit rind has been used to isolate the active component garcinol. Garcinol has been used in treatment of diverse ailments. Garcinol has exhibited anti-oxidant, anti-inflammatory, HAT inhibition and miRNA deregulator in development and progression of cancers. Experimental data have shown that garcinol completely inhibited all the three tested hyaluronidase enzymes. The inhibition was found to be non-competitive pattern with reversible type. In the docking study, garcinol with hyaluronidase enzyme has been stabilized by hydrogen bonding and hydrophobic interactions. Thus, garcinol could be a potent novel inhibitor of hyaluronidase enzyme which can be further used for pharmacotherapeutic applications.

Efficacy of Oral Colchicine and Intralesional Hyaluronidase with and without Ultrasound Therapy in the Management of Oral Submucous Fibrosis-A Comparative Study.

Aim: To determine the therapeutic effect and efficacy of oral colchicine tablet and intralesional injection of hyaluronidase with and without ultrasound therapy in the clinical course of oral submucous fibrosis. Materials and Methods: This comparative study involving 45 human participants was divided into three equal groups. The participants in group 1 received oral colchicine and intralesional hyaluronidase. The participants in group 2 received oral colchicine, intralesional hyaluronidase, and ultrasound therapy. The group 3 participants were treated with intralesional dexamethasone and hyaluronidase. Intergroup assessments were done using repeated measures of ANOVA test, where P value of <0.05 was considered as statistically significant difference. Results: Group 2 patients had maximum improvement with respect to all the parameters. Conclusion: Therapeutic ultrasound can be given effectively as an adjunct therapy along with conventional therapy in OSMF patients.

Hyaluronidase: A New and Powerful Ally for Post-Rhinoplasty Fibrosis.

Rhinoplasty outcome may depend on different factors: patient's selection, technique, surgeons' skills and patient's healing. Different surgical maneuvers can be performed in order to reduce post-operative risk of fibrosis such as dead spaces' closure, sub-perichondral and subperiosteal dissection and nasal ligaments preservation or reconstruction. However, in some patients, especially the ones with thick and sebaceous skin, these maneuvers may not be enough. Here we propose a new alternative to treat post-rhinoplasty fibrosis using a combination of Triamcinolone Acetonide and Hyaluronidase. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Comparative assessment of the efficacy of an intralesional injection of placentrex, hyaluronidase and dexamethasone in the management of oral submucous fibrosis: A randomized controlled trial.

The prevalent symptoms of oral submucous fibrosis (OSMF) are a burning sensation and trismus. The aim of the present study was to compare the efficacy of placentrex, hyaluronidase and dexamethasone, and their combination in the treatment of OSMF. For this purpose, 160 patients with OSMF were divided into four groups (each with 40 patients at a 1:1:1:1 allocation ratio). The patients in group 1 (control) received only oral supplements, along with regular mouth-opening exercises; patients in group 2 received an injection of placental extract; patients in group 3 were injected with hyaluronidase and dexamethasone; and patients in group 4 received a combination of injections from groups 2 and 3. The injections were administered once weekly for 12 weeks and patients were followed-up for 12 months. The data of the patients (mouth opening ability and a burning sensation) were analyzed using ANOVA and the Kruskal-Wallis test. The maximum increase in mouth opening (7.30±0.80 mm) was noted in group 4, and the lease increase was observed in the control group (0.37±0.16 mm), from baseline levels to the end of the 12th week. The maximum relapse in mouth opening of 1.62±0.45 mm was noted in group 2, and a minimum relapse of 0.20±0.08 mm was noted in group 4. On the whole, the present study demonstrates that the intralesional injection of a combination of the three drugs (placentrex, hyaluronidase and dexamethasone) in addition to the use of oral supplements and mouth opening exercises has a high level of efficacy in improving trismus and burning sensation in patients with OSMF.

Hyaluronidase inhibitor sHA2.75 alleviates ischemia-reperfusion-induced acute kidney injury.

Hyaluronidases (HAases) are enzymes that degrade hyaluronic acid (HA) in the animal kingdom. The HAases-HA system is crucial for HA homeostasis and plays a significant role in biological processes and extracellular matrix (ECM)-related pathophysiological conditions. This study aims to explore the role of inhibiting the HAases-HA system in acute kidney injury (AKI). We selected the potent inhibitor "sHA2.75" to inhibit HAase activity through mixed inhibitory mechanisms. The ischemia-reperfusion mouse model was established using male BALB/c mice (7-9 weeks old), and animals were subjected to subcapsular injection with 50 mg/kg sHA2.75 twice a week to evaluate the effects of sHA2.75 on AKI on day 1, 5 and 14 after ischemia-reperfusion or sham procedure. Blood and tissue samples were collected for immunohistochemistry, biochemical, and quantitative analyses. sHA2.75 significantly reduced blood urea nitrogen (BUN) and serum creatinine levels in AKI mouse models. Expression of kidney injury-related genes such as Kidney injury molecule-1 (KIM-1), Neutrophil Gelatinase-Associated Lipocalin (NGAL), endothelial nitric oxide synthase (eNOS), type I collagen (Col1), type III collagen (Col3), alpha-smooth muscle actin (α-SMA) showed significant downregulation in mouse kidney tissues after sHA2.75 treatment. Moreover, sHA2.75 treatment led to decreased plasma levels of Interleukin-6 (IL-6) proteins and reduced mRNA levels in renal tissues of AKI mice. Inhibitor sHA2.75 administration in the AKI mouse model downregulated kidney injury-related biomarkers and immune-specific genes, thereby alleviating AKI in vivo. These findings suggest the potential use of HAase inhibitors for treating ischemic reperfusion-induced kidney injury.

Enzyme-responsive design combined with photodynamic therapy for cancer treatment.

Photodynamic therapy (PDT) is a noninvasive cancer treatment that has garnered significant attention in recent years. However, its application is still hampered by certain limitations, such as the hydrophobicity and low targeting of photosensitizers (PSs) and the hypoxia of the tumor microenvironment. Nevertheless, the fusion of enzyme-responsive drugs with PDT offers novel solutions to overcome these challenges. Utilizing the attributes of enzyme-responsive drugs, PDT can deliver PSs to the target site and selectively release them, thereby enhancing therapeutic outcomes. In this review, we spotlight recent advances in enzyme-responsive materials for cancer treatment and primarily delineate their application in combination with PDT.

Hyaluronidase impacts exposures of long-acting injectable paliperidone palmitate in rodent models.

A significant challenge in the development of long-acting injectable drug formulations, especially for anti-infective agents, is delivering an efficacious dose within a tolerable injection volume. Co-administration of the extracellular matrix-degrading enzyme hyaluronidase can increase maximum tolerable injection volumes but is untested for this benefit with long-acting injectable formulations. One concern is that hyaluronidase could potentially alter the tissue response surrounding an injection depot, a response known to be important for drug release kinetics of long-acting injectable formulations. The objective of this pilot study was to evaluate the impact of co-administration of hyaluronidase on the drug release kinetics, pharmacokinetic profiles, and injection site histopathology of the long-acting injectable paliperidone palmitate for up to four weeks following intramuscular injection in mouse and rat models. In both species, co-administration of hyaluronidase increased paliperidone plasma exposures the first week after injection but did not negate the overall long-acting release nature of the formulation. Hyaluronidase-associated modification of the injection site depot was observed in mice but not in rats. These findings suggest that further investigation of hyaluronidase with long-acting injectable agents is warranted.

Methods for the induction of labor: efficacy and safety.

This review assessed the efficacy and safety of pharmacologic agents (prostaglandins, oxytocin, mifepristone, hyaluronidase, and nitric oxide donors) and mechanical methods (single- and double-balloon catheters, laminaria, membrane stripping, and amniotomy) and those generally considered under the rubric of complementary medicine (castor oil, nipple stimulation, sexual intercourse, herbal medicine, and acupuncture). A substantial body of published reports, including 2 large network meta-analyses, support the safety and efficacy of misoprostol (PGE1) when used for cervical ripening and labor induction. Misoprostol administered vaginally at doses of 50 µg has the highest probability of achieving vaginal delivery within 24 hours. Regardless of dosing, route, and schedule of administration, when used for cervical ripening and labor induction, prostaglandin E2 seems to have similar efficacy in decreasing cesarean delivery rates. Globally, although oxytocin represents the most widely used pharmacologic agent for labor induction, its effectiveness is highly dependent on parity and cervical status. Oxytocin is more effective than expectant management in inducing labor, and the efficacy of oxytocin is enhanced when combined with amniotomy. However, prostaglandins administered vaginally or intracervically are more effective in inducing labor than oxytocin. A single 200-mg oral tablet of mifepristone seems to represent the lowest effective dose for cervical ripening. The bulk of the literature assessing relaxin suggests this agent has limited benefit when used for this indication. Although intracervical injection of hyaluronidase may cause cervical ripening, the need for intracervical administration has limited the use of this agent. Concerning the vaginal administration of nitric oxide donors, including isosorbide mononitrate, isosorbide, nitroglycerin, and sodium nitroprusside, the higher incidence of side effects with these agents has limited their use. A synthetic hygroscopic cervical dilator has been found to be effective for preinduction cervical ripening. Although a pharmacologic agent may be administered after the use of the synthetic hygroscopic dilator, in an attempt to reduce the interval to vaginal delivery, concomitant use of mechanical and pharmacologic methods is being explored. Combining the use of a single-balloon catheter with dinoprostone, misoprostol, or oxytocin enhances the efficacy of these pharmacologic agents in cervical ripening and labor induction. The efficacy of single- and double-balloon catheters in cervical ripening and labor induction seems similar. To date, the combination of misoprostol with an intracervical catheter seems to be the best approach when balancing delivery times with safety. Although complementary methods are occasionally used by patients, given the lack of data documenting their efficacy and safety, these methods are rarely used in hospital settings.

Triterpenoids from Juglans mandshurica with anti-hyaluronidase activities.

Phytochemical study on 90% ethanol extract from the green walnut husks of Juglans mandshurica Maxim. resulted into the isolation of three undescribed triterpenoids, juglansmanoids A-C (1-3). Structural elucidation of all the compounds were performed by spectral methods such as 1D and 2D (1H-1H COSY, HMQC, and HMBC) NMR spectroscopy, in addition to high resolution mass spectrometry. The isolated components were evaluated in vitro for anti-hyaluronidase activities. As a result, triterpenoid 1 exhibited potent anti-hyaluronidase activity (IC50 = 9.78 µg/ml) three times more than the positive control drug oleanolic acid (IC50 = 40.12 µg/ml).

Hyaluronan degradation by HYAL2 is essential for odontoblastic differentiation and migration of mouse dental papilla cells.

The coordination between odontoblastic differentiation and directed cell migration of mesenchymal progenitors is necessary for regular dentin formation. The synthesis and degradation of hyaluronan (HA) in the extracellular matrix create a permissive niche that directly regulates cell behaviors. However, the role and mechanisms of HA degradation in dentin formation remain unknown. In this work, we present that HA digestion promotes odontoblastic differentiation and cell migration of mouse dental papilla cells (mDPCs). Hyaluronidase 2 (HYAL2) is responsible for promoting odontoblastic differentiation through degrading HA, while hyaluronidase 1 (HYAL1) exhibits negligible effect. Silencing Hyal2 generates an extracellular environment rich in HA, which attenuates F-actin and filopodium formation and in turn inhibits cell migration of mDPCs. In addition, activating PI3K/Akt signaling significantly rescues the effects of HA accumulation on cytodifferentiation. Taken together, the results confirm the contribution of HYAL2 to HA degradation in dentinogenesis and uncover the mechanism of the HYAL2-mediated HA degradation in regulating the odontoblastic differentiation and migration of mDPCs.

Modular preparation of biphenyl triazoles via click chemistry as non-competitive hyaluronidase inhibitors.

Hyaluronidase is a promising target in drug discovery, given its overexpression in a range of physiological and pathological processes, including tumor migration, skin aging, sagging, and wrinkling, as well as inflammation and bacterial infections. In this study, to identify novel hyaluronidase inhibitors, we applied click chemistry for the modular synthesis of 370 triazoles in 96-well plates, starting with biphenyl azide. Utilizing an optimized turbidimetric screening assay in microplates, we identified Fmoc-containing triazoles 5 and 6, as well as quinoline-containing triazoles 15 and 16, as highly effective hyaluronidase inhibitors. Subsequent research indicated that these triazoles potentially interact with a novel binding site of hyaluronidase. Notably, these inhibitors displayed minimal cytotoxicity and showed promising anti-inflammatory effects in LPS-stimulated macrophages. Remarkably, compound 6 significantly reduced NO release by 74 % at a concentration of 20 µM.

Size-Switchable Ru Nanoaggregates for Enhancing Phototherapy: Hyaluronidase-Triggered Disassembly to Alleviate Deep Tumor Hypoxia.

Hypoxia is a critical factor for restricting photodynamic therapy (PDT) of tumor, and it becomes increasingly severe with increasing tissue depth. Thus, the relief of deep tumor hypoxia is extremely important to improve the PDT efficacy. Herein, tumor microenvironment (TME)-responsive size-switchable hyaluronic acid-hybridized Ru nanoaggregates (HA@Ru NAs) were developed via screening reaction temperature to alleviate deep tumor hypoxia for improving the tumor-specific PDT by the artful integration multiple bioactivated chemical reactions in situ and receptor-mediated targeting (RMT). In this nanosystem, Ru NPs not only enabled HA@Ru NAs to have near infrared (NIR)-mediated photothermal/photodynamic functions, but also could catalyze endogenous H2O2 to produce O2 in situ. More importantly, hyaluronidase (HAase) overexpressed in the TME could trigger disassembly of HA@Ru NAs via the hydrolysis of HA, offering the smart size switch capability from 60 to 15 nm for enhancing tumor penetration. Moreover, the RMT characteristics of HA ensured that HA@Ru NAs could specially enter CD44-overexpressed tumor cells, enhancing tumor-specific precision of phototherapy. Taken together these distinguishing characteristics, smart HA@Ru NAs successfully realized the relief of deep tumor hypoxia to improve the tumor-specific PDT.

Causes and management of sight threatening complications of dermal filler injections: A review.

Injectable dermal fillers continue to increase in popularity in aesthetic medicine. Although rare, vision loss secondary to filler injections is a devastating complication associated with a poor visual prognosis. The mechanism for vision loss is thought to be related to retrograde embolization of the dermal filler from peripheral vessels in the face into the ophthalmic arterial system. Early recognition and prompt management are essential if vision is to be salvaged. The use of retrobulbar hyaluronidase is still contentious, however when administered by a specialist, this treatment gives the best chance at visual recovery and should be considered for all cases.

Understanding the complexity of Tityus serrulatus venom: A focus on high molecular weight components.

Tityus serrulatus scorpion is responsible for a significant number of envenomings in Brazil, ranging from mild to severe, and in some cases, leading to fatalities. While supportive care is the primary treatment modality, moderate and severe cases require antivenom administration despite potential limitations and adverse effects. The remarkable proliferation of T. serrulatus scorpions, attributed to their biology and asexual reproduction, contributes to a high incidence of envenomation. T. serrulatus scorpion venom predominantly consists of short proteins acting as neurotoxins (α and ß), that primarily target ion channels. Nevertheless, high molecular weight compounds, including metalloproteases, serine proteases, phospholipases, and hyaluronidases, are also present in the venom. These compounds play a crucial role in envenomation, influencing the severity of symptoms and the spread of venom. This review endeavors to comprehensively understand the T. serrulatus scorpion venom by elucidating the primary high molecular weight compounds and exploring their potential contributions to envenomation. Understanding these compounds' mechanisms of action can aid in developing more effective treatments and prevention strategies, ultimately mitigating the impact of scorpion envenomation on public health in Brazil.

Complications of Injectables.

The field of non-surgical esthetic procedures has witnessed a significant surge in demand in recent years, with neuromodulators, skin treatments, and dermal fillers contributing significantly to the industry's growth. These procedures have become increasingly popular, reflecting the broader acceptance of esthetic enhancements in society. Neuromodulators play a pivotal role in facial rejuvenation, but they require precise knowledge of facial anatomy to optimize results and prevent complications. They include rare hypersensitivity reactions, local injection reactions, and brow and eyelid ptosis. Dermal fillers, both non-permanent and permanent, are widely used to restore volume and improve facial contours. However, they also carry risks, including bruising, temporary edema, and lumps. Permanent fillers present higher complication rates, and their use should be approached with caution. Vascular occlusion is a rare but severe complication associated with dermal fillers. To mitigate these risks, practitioners must have a comprehensive understanding of their compositions and potential complications. Overall, while non-surgical esthetic procedures offer remarkable results with minimal downtime, the importance of training, anatomic knowledge, and effective complication management cannot be overstated in ensuring patient safety and satisfaction in this evolving field of medicine.

Facilitated subcutaneous immunoglobulin treatment patterns in pediatric patients with primary immunodeficiency diseases.

Aim: This retrospective study investigated real-world hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) treatment patterns in pediatric patients with primary immunodeficiency diseases (PIDs) in Poland. Methods: Clinical and demographic information, fSCIG treatment parameters and clinical outcomes were extracted from medical records of 28 participants (aged ≤18 years) with PIDs who received fSCIG. Results: 18 participants (64.3%) started fSCIG with a ramp-up (median duration: 35.5 days). 27 patients (96.4%) were administered fSCIG every 4 weeks and one patient every 3 weeks. 25 patients (89.3%) used one infusion site. No serious bacterial infections occurred. Conclusion: Data support the feasibility of administering fSCIG to children and adolescents with PIDs every 3-4 weeks using a single infusion site and indicate flexibility in modifying fSCIG infusion parameters. Clinical Trial Registration: NCT04636502 (ClinicalTrials.gov).

Antibodies, also known as immunoglobulins, are proteins that are made by the immune system to help fight infections. In primary immunodeficiency diseases (PIDs), part of the immune system may be missing or not working properly. This study looked at the use of an antibody treatment called hyaluronidase-facilitated subcutaneous immunoglobulin (or fSCIG) in Polish children aged 18 years or younger with PIDs. Information on patients, their disease, how fSCIG was being used and how patients responded to treatment was taken from medical records. Out of 28 patients, 18/28 (64.3%) had their fSCIG dose slowly increased, which took an average of 35.5 days. Overall, 27/28 patients were treated with fSCIG every 4 weeks (96.4%), and 25/28 patients used one place to inject fSCIG (89.3%). No serious infections caused by bacteria happened during the study. The study results suggest that children with PIDs could be treated every 3 to 4 weeks with fSCIG, and that flexibility in how fSCIG is injected may offer options suited to individual patients.

Efficacy and safety of the enzymatic mixture - Lipase, collagenase and hyaluronidase - In the treatment of moderate to severe submental fat: A prospective cohort study.

Purpose: To study the effect of the enzymatic mixture: Lipase, Collagenase and Hyaluronidase in the treatment of submental fat. Methods: A monocentric prospective cohort study including 10 female patients, aged between 18 and 65 years old, who received treatment for submental fat with a mixture of Lipase, Collagenase, and Hyaluronidase. The treatment protocol consisted of one treatment session every 21 days for a total of 3 sessions. In each session, 4 ml of the enzymatic mixture (1 ml of Collagenase GH PB20, 1 ml of Hyaluronidase PB 3000 and 2 ml of Lipase PB 500) + 2 ml of Lidocaine 2% were injected in the submental fat (SMF). Efficacy was assessed four weeks after the last session. Co-Primary Outcome was defined as the improvement of ≥ 1-point in Clinician-Reported and Patient-Reported Sub-mental Fat Rating Scales (CR-SMFRS and PR-SMFRS). Secondary Outcomes included score reductions in Patient-Reported Sub-mental Fat Impact Scale (PR-SMFIS), ≥10% reduction in submental fat pad thickness by ultrasound, and Subject Self-Rating Scale (SSRS) responses of 4, 5, or 6. Results: The Co-Primary outcome was achieved in 9 out of 10 patients. A considerable reduction of 22.8% in the PR-SMFIS was observed. Furthermore, 9 out of 10 patients expressed overall satisfaction with the treatment. Submental fat reduction of more than 10% was observed in 9 out of 10 patients in neutral position and in all patients in flexed position. Adverse effects were only limited to local reactions. Conclusion: The enzymatic mixture of Lipase, Collagenase and Hyaluronidase is an effective and safe minimally-invasive method for the reduction of SMF that can be used alone or in conjunction with other treatment modalities.

Highly Concentrated Stabilized Hybrid Complexes of Hyaluronic Acid: Rheological and Biological Assessment of Compatibility with Adipose Tissue and Derived Stromal Cells towards Regenerative Medicine.

Cells and extracts derived from adipose tissue are gaining increasing attention not only in plastic surgery and for aesthetic purposes but also in regenerative medicine. The ability of hyaluronan (HA) to support human adipose stromal cell (hASC) viability and differentiation has been investigated. However, the compatibility of adipose tissue with HA-based formulation in terms of biophysical and rheological properties has not been fully addressed, although it is a key feature for tissue integration and in vivo performance. In this study, the biophysical and biochemical properties of highly concentrated (45 mg/mL) high/low-molecular-weight HA hybrid cooperative complex were assessed with a further focus on the potential application in adipose tissue augmentation/regeneration. Specifically, HA hybrid complex rheological behavior was observed in combination with different adipose tissue ratios, and hyaluronidase-catalyzed degradation was compared to that of a high-molecular-weight HA (HHA). Moreover, the HA hybrid complex's ability to induce in vitro hASCs differentiation towards adipose phenotype was evaluated in comparison to HHA, performing Oil Red O staining and analyzing gene/protein expression of PPAR-γ, adiponectin, and leptin. Both treatments supported hASCs differentiation, with the HA hybrid complex showing better results. These outcomes may open new frontiers in regenerative medicine, supporting the injection of highly concentrated hybrid formulations in fat compartments, eventually enhancing residing staminal cell differentiation and improving cell/growth factor persistence towards tissue regeneration districts.