Enzyme Therapy Research Articles

Evaluate the Clinical and Laboratory Manifestations of Children With Type 6 of Mucopolysaccharidosis Before and After Enzyme Therapy: A Quasi-Experimental One Group Study

The purpose of this study is to evaluate the clinical and laboratory manifestations of children with mucopolysaccharidosis type 6 before and after enzyme therapy. In this quasi-experimental study, 8 patients with MPS-6 referred to the pediatric endocrinology department of Imam Reza Hospital in Mashhad were followed up for 12 months. The level of urinary glycosaminoglycan was measured to check the response to the treatment. The range of motion of the shoulder and elbow joints was evaluated using a goniometer, and abdominal ultrasound was performed to check the size of the liver and spleen in the midclavicular line. The 6-minute walking test and the 3-minute stair climbing test were performed for the patients at the mentioned times. The height and weight of the patients were also measured, and echocardiography was performed. Then patients underwent weekly enzyme treatment. One of the patients (seventh patient) was excluded from the study. Patients were treated with enzyme from the beginning of the study. The patients were evaluated at 12 months later. Statistical analysis showed that changes in urinary GAG level, height, weight, changes in 6-minute walk and range of motion (extension and flexion) of the shoulder were significant (P<0.05). Changes in liver and spleen size compared to height, climbing stairs, corneal opacity and heart changes after 12 months of enzyme therapy were not significant. It is suggested that even though this method of treatment is not definitive, that can be continued to improve the current condition of the patient.

Machine Learning Model Predictors of Intrapleural tPA and DNase Failure in Pleural Infection: A Multicenter Study.

Intrapleural enzyme therapy (IET) with tissue plasminogen activator (tPA) and deoxyribonuclease (DNase) has been shown to reduce the need for surgical intervention for complicated parapneumonic effusion/empyema (CPPE/empyema). Failure of IET may lead to delayed care, and increased length of stay. The goal of this study was to identify risk factors for failure of IET. We performed a multicenter, retrospective study of patients who received IET for the treatment of CPPE/empyema. Clinical and radiological variables at the time of diagnosis were included. We compared four different machine learning classifiers (L1-penalized logistic regression, support vector machine (SVM), XGBoost and LightGBM) by multiple bootstrap-validated metrics, including F-beta to demonstrate model performances. 466 participants who received IET for pleural infection were included from five institutions across the United States. Resolution of CPPE/empyema with IET was achieved in 78% (n=365). SVM performed superior with median F-beta of 56%, followed by L1-penalized logistic regression, LGBM and XGBoost. Clinical and radiological variables were graded based on their ranked variable importance. The top two significant predictors of IET failure using SVM were the presence of an abscess/necrotizing pneumonia (17%) and pleural thickening (13%). Similarly, LightGBM identified abscess/necrotizing pneumonia (35%) and pleural thickening (26%) and XGBoost indicated pleural thickening (36%) and abscess/necrotizing pneumonia (17%) as the most significant predictors of treatment failure. Predictors identified by L1-penalized logistic regression model were pleural thickening (18%) and pleural fluid LDH (9%). The presence of abscess/necrotizing pneumonia and pleural thickening consistently ranked among the strongest predictors of IET failure in all machine learning models. The difference in rankings between models may be a consequence of the different algorithms used by each model. These results indicate that the presence of abscess/necrotizing pneumonia, and pleural thickening may predict IET failure. These results should be confirmed in larger studies.

Emerging Bioengineering Approaches for Cancer and Tumor Therapy

Cancer has become a significant socioeconomic burden globally, with millions of new cases and deaths each year. The promising field of bioengineering has recently undergone significant advancements, providing new methods for combating cancer. Increasing attention has been directed toward understanding the molecular mechanisms of human diseases, supported by the availability of various genetic tools and rapid technological advancements. These developments have enabled the use of the latest gene therapy techniques for cancer treatment, including gene editing, gene deletion, and correcting defective genes through methods such as TALENs, Zinc fingers, RNAi, CRISPR, site-directed mutagenesis (SDM), and enzyme therapy to modulate catalytic activity. In addition, bioengineering vaccines like mRNA vaccines, bioinformatics, computational tools, artificial intelligence (AI), nanotechnology, and chemotherapy are emerging as significant cancer treatment strategies. Among these, gene editing and gene therapy have gained particular attention in recent years and are often used in combination with other therapeutic approaches. The engineering of enzymes and advancements in nanotechnology have also significantly progressed. AI and bioinformatics have contributed to more precise diagnosis, prediction, and prognosis, enabling tailored treatment of cancer and tumors. Imaging and radiotherapy, enhanced by AI, have improved surgical outcomes, even from remote locations. Precision oncology has emerged, using bacteria and viruses to target tumors directly. In this review, we discuss recent advancements and challenges in various cancer therapies.

Fabry cardiomyopathy: myocardial fibrosis, inflammation and reduced mannose6phosphate receptors cause low accessibility to enzyme therapy

Abstract Background Clinical impact of enzyme replacement therapy (ERT) on advanced Fabry disease cardiomyopathy (FDCM) appears limited. Purpose Clarify the pathologic mechanisms responsible of ERT inefficacy in the advanced FDCM. Methods Ten male patients with advanced FDCM (echocardiographic maximal wall thickness 19.3 ± 2.1 mm) underwent left ventricular endomyocardial biopsy before and 4 hours after beta-agalsidase infusion. Comparative studies between pre and post infusion samples included: histology and electron microscopy; assessment of myocardial alpha-galactosidase A activity; immunohistochemistry for alpha-galactosidase A and semiquantitative evaluation (from 0 to 3) of its cardiomyocyte content; Ultrastructural immunogold analysis with anti-alpha-galactosidase A ab. Western Blot (WB) quantification of mannose-6-phosphate receptors (M6Pr). Controls were surgical left ventricular biopsies from patients with mitral stenosis. Results Histologic and Ultrastructural evaluation showed no removal of storage material while myocardial fibrosis was 9.8 ± 6.8 vs 3.8 ± 2.0 of controls and virus-negative lymphocytic inflammation was observed in 7 out of 10 patients. At Ultrastructural immunogold analysis, Myocardial alpha-galactosidase A activity increased in post infusion samples by overall 1.89-fold. Alpha-galactosidase A immunostaining in cardiomyocytes was absent at baseline in all patients and did not significantly improve in post-infusion samples. Immunogold particles increased by 1.33-fold remaining far from normal controls (86.9 ± 6.6). Protein analysis showed M6Pr in advanced FDCM to be 81% lower than in normal heart. Conclusions Our study shows a low accessibility to ERT of cardiomyocytes affected by advanced FDCM. It is sustained by myocardial fibrosis, inflammation and severe down-regulation of M6Pr. Figure Legend Histologic and ultrastructural and mannose6phosphate receptors characteristics of patients with severe Fabry Disease Cardiomyopathy. Panel A shows severe cellular glycolipid infiltration associated with diffuse interstitial fibrosis (Masson trichrome, 100x). Panel B reveals an overlapping lymphocytic CD45Ro+ myocardial inflammation with focal necrosis of adjacent cardiomyocytes. Insert(i), Ultrastructural detail showing vacuoles (black arrows) to consist of myelin bodies,( scale bar=3μm). Panel C (upper) Western blot analysis of all 10 patients of Mannose-6-phosphate Receptor, molecular weight 275 Kd. Alpha sarcomeric actin (43 kDa) was used as a loading control. (Panel C -lower) Panel D: Graphs document western blot of Mannose-6-phosphate Receptor, in all 10 patients with severe FDCM showing 3-fold lower of Mannose-6-phosphate Receptor values in patients versus normal heart (4.830 ± 1116,724 vs 14.737± 1145,386; p < 0.001).

Perspectives for using serratiopeptidase in systemic enzyme therapy for low-intensity chronic inflammation and pain syndromes: from mechanisms of action to practical implementation (literature review)

Background. Recent experimental and clinical stu­dies have confirmed the effectiveness and safety of serratiopeptidase (SRP) as a powerful anti-inflammatory agent, highlighting its potential benefits across various fields of medicine. The ­purpose was to analyze current literature on the mechanisms of action of SRP as a means of systemic enzyme therapy for low-intensity chronic inflammation and pain syndromes, its clinical applications, and prospects for implementation in general medical practice. ­Materials and methods. To identify relevant literature sources, a comprehensive search was conducted in electronic databases, inclu­ding PubMed, Scopus, Web of Science, and the Cochrane Library. ­Results. According to modern literature data, SRP demonstrates quite powerful anti-inflammatory, analgesic, reparative, fibrinoly­tic, and mucolytic properties, and exhibits a certain antimicrobial activity, especially against biofilm-forming bacteria. The combination of this enzyme with traditional antibiotics provides a more effective treatment of infectious processes. SRP has significant potential in the treatment of conditions and diseases associated with the development of low-intensity chronic inflammation and pain syndromes (especially in comorbid ones) due to its anti-inflammatory, anti-edematous, antithrombotic, and analgesic properties associated with the inhibition of cyclooxygenase 1 and 2, 5-lipoxygenase activity, myeloperoxidase and elastase, suppression of the formation and/or release of bradykinin, biogenic amines, pro-inflammatory cytokines, cell adhesion molecules, cleavage of bradykinin-related peptides, limitation of oxidative-nitrosative stress. The effectiveness of the enzyme notably increases when it is combined with some prebiotics and/or probiotics. Conclusions. The development of new dosage forms of SRP, along with further preclinical and clinical trials, could lead to new strategies for the prevention and treatment of inflamatory diseases.

Exopeptidase combination enhances the degradation of isotopically labelled gluten immunogenic peptides in humans.

Celiac disease is a common autoimmune-like enteropathy caused by an aberrant response to incompletely digested dietary gluten. Gluten immunogenic peptides including the immunodominant 33-mer are thought to be resistant to proteolytic digestion by human gastrointestinal peptidases. We developed a novel enzyme therapy approach to support gluten peptide digestion using a combination of two tandem-acting exopeptidases, AMYNOPEP, that complement the intrinsic enzymatic activity of intestinal brush border enterocytes. We evaluated the effects of AMYNOPEP supplementation on 33-mer degradation in vitro and in vivo. In a cross-over clinical study, healthy volunteers with no gastrointestinal disorders were given stable isotope (SI) labelled 33-mer peptides in the presence of varying peptide substrates and caloric loads, with and without AMYNOPEP. 33-mer degradation products (SI-labelled single amino acids) were measured in the blood plasma using LC-MS/MS. AMYNOPEP achieved rapid, complete amino-to-carboxyl terminal degradation of the 33-mer in vitro, generating single amino acids and dipeptides. In healthy volunteers, AMYNOPEP supplementation significantly increased 33-mer degradation and absorption of SI-labelled amino acids even in the presence of competing substrates. Specifically, we observed a 2.8-fold increase in the Cmax of stable isotope-labelled amino acids in the presence of wheat gluten. The absorption kinetics of labelled amino acids derived from 33-mer digestion with AMYNOPEP closely resembled that of SI-labelled X-Proline dipeptides administered without enzyme supplementation, highlighting the rapid hydrolytic activity of AMYNOPEP on polypeptides. AMYNOPEP achieved complete degradation of the 33-mer into single amino acids and dipeptides in vitro and significantly improved 33-mer degradation kinetics in healthy volunteers, as measured by labelled amino acid detection, warranting further investigation into the potential therapeutic benefits of exopeptidase combinations for patients with gluten-related health disorders including celiac disease.

Prescribing of pancreatic enzyme therapy for malabsorption in unresectable pancreatic cancer: Cross-sectional survey across New Zealand and Australia

ObjectiveTo investigate the practices of clinicians prescribing pancreatic enzyme replacement therapy (PERT) for unresectable pancreatic cancer in Aotearoa New Zealand and Australia. MethodsA mixed media advertising campaign was used to recruit appropriate clinicians to complete a questionnaire that collected demographic data, information regarding prescribed medication, and awareness of PERT guidelines. ResultsThe study recruited 161 clinicians, with 93 and 68 respondents from Aotearoa New Zealand and Australia respectively. Most respondents from both countries were experienced gastrointestinal surgeons and dietitians. Aotearoa New Zealand clinicians and dietitians used faecal elastase more frequently to diagnose PEI than other groups. Clinicians had a tendency to under-prescribe PERT, and to advise incorrectly on the timing of the medication. The majority of clinicians from Aotearoa New Zealand and Australia were not aware of any best practice clinical guidelines for PERT (70 % and 77 %, respectively). ConclusionThis study suggests clinicians are over-reliant on faecal elastase to diagnose PEI and are uncertain about the correct dose and timing of PERT for optimal patient benefit in those with unresectable pancreatic cancer. Most clinicians were not aware of best practice guidelines.

Novel treatment for PXE: Recombinant ENPP1 enzyme therapy

Pseudoxanthoma elasticum (PXE) is a genetic multisystem ectopic calcification disorder caused by inactivating mutations in the ABCC6 gene encoding ABCC6, a hepatic efflux transporter. ABCC6-mediated ATP secretion by the liver is the main source of plasma inorganic pyrophosphate (PPi), a potent endogenous calcification inhibitor. The deficiency of plasma PPi underpins PXE. Recent studies demonstrated that INZ-701, a recombinant human ENPP1, the principal PPi-generating enzyme, restored plasma PPi levels and prevented ectopic calcification in the muzzle skin of an Abcc6-/- mouse model of PXE. This study examined the pharmacokinetics, pharmacodynamics, and potency of a new ENPP1-Fc isoform, BL-1118, in Abcc6-/- mice. When Abcc6-/- mice received a single subcutaneous injection of BL-1118 at 0.25, 0.5, or 1 mg/kg, they had dose-dependent elevations in plasma ENPP1 enzyme activity and PPi levels, with an enzyme half-life of approximately 100 hours. When Abcc6-/- mice were injected weekly from 5 to 15 weeks of age, BL-1118 dose-dependently increased steady-state plasma ENPP1 activity and PPi levels and significantly reduced ectopic calcification in the muzzle skin and kidneys. These results suggest that BL-1118 is a promising enzyme therapy for PXE, a disease currently lacking preventive or therapeutic options.

The effectiveness and acceptability of systemic enzyme therapy in the complex treatment of vulvovaginitis caused by opportunistic microorganisms: Open-label single-center prospective comparative randomized study

Background. Vulvovaginal infections are the most common, studied, and still causing many questions. It has been established that the disturbance of the ratio of the vaginal microbiota components does not always lead to a disorder since the development and outcome of the disorder largely depend on the state of the macroorganism, including the state of its immune system. To date, the only method for assessing the state of local immunity is smear microscopy with counting leukocytes. An alternative to leukocyte counting is the assessment of immunological parameters (e.g., the transcriptional profile of cytokine genes). An integrated approach to assessing the state of microbiocenosis (the ratio of lactobacilli and opportunistic pathogens) and local mucosal immunity, considering the individual genetic characteristics of patients and microorganisms, makes it possible to optimize treatment methods for vaginitis. One of the ways to increase the effectiveness of treatment and prevention of the recurrence of infectious and inflammatory diseases in gynecology is systemic enzyme therapy based on the complex effect of a specially selected combination of plant and animal origin enzymes on key physiological and pathophysiological processes in the body. Aim. To study the clinical effect and the effect of combined therapy with an antibiotic and a medicinal product, including a complex of enzymes of plant and animal origin (Wobenzym) on the state of the vaginal microbiota, the expression of cytokine genes, and the recurrence rate in patients with bacterial vulvovaginitis. Materials and methods. An open-label, single-center, prospective, comparative, randomized study enrolled 88 patients according to inclusion criteria. After randomization of patients into 2 groups, the main group received combination therapy (clindamycin vaginal cream 2% and Wobenzym), and patients of the comparison group received standard therapy only (clindamycin vaginal cream 2%). Short-term and long-term endpoints were defined. The primary endpoints included the assessment of symptoms, the change over time of the number of leukocytes in Gram-stained smears, and the recurrence rate; the secondary endpoints were the study of the change over time of the inflammation index, the results of the assessment of the state of the vaginal microbiota by real-time quantitative polymerase chain reaction using the Femoflor 16 reagent kit and a microbiological study. Results. When used in combination, Wobenzym potentiates the antibacterial properties of clindamycin, reduces the inflammation index, promotes the growth of the normal microbiota of the vagina (Lactobacillus spp.), prevents the growth of opportunistic microorganisms and, as a result, prevents the recurrence of vulvovaginitis. Conclusion. The results support the use of combination therapy (antibiotic + Wobenzym) to improve the effectiveness of therapy and maintain normocenosis.

Real-world data of in-hospital administration of alglucosidase alfa in French patients with Pompe disease: results from the National Claims Database.

Pompe disease is caused by a rare biallelic mutation in the GAA gene resulting in acid α-glucosidase deficiency and glycogen accumulation. We analyzed hospital admissions associated with the administration of Myozyme®, utilizing the French hospital discharge database, known in France as the Programme de Médicalisation des Systèmes d'Information (PMSI), which comprehensively captures all hospital activity within the country. In this observational study, we examined hospitalization records from April 4, 2012, to December 31, 2019, within the PMSI database, focusing on admissions where Myozyme® was administered. We particularly investigated the incidence of critical care admissions and adverse events (AEs) related to Myozyme®. From 2012 to 2019, approximately 26,714 hospital stays involving Myozyme® administration were recorded for 239 patients. Most (96.6%) of these were outpatient stays, with only 3.2% in critical care. Furthermore, hospitalizations without critical care needs increased from 96% in 2012 to 99% in 2019. Of the patients receiving at least one infusion, 997 critical care admissions were recorded, with 781 (78.3%) occurring concurrent with or the day after the Myozyme® treatment without directly correlating to adverse effects of enzyme therapy. The analysis of the French hospital discharge database indicated that Myozyme® was associated with a low incidence of AEs and complications in a hospital context, supporting the consideration of its safe use in home-infusion settings.

The natural history of Gaucher disease type 1 in 31 patients over a median of 15 years: a retrospective study.

The natural history of untreated patients with type 1 Gaucher disease (GD1) is not well documented, and there is controversy over when and how to treat such patients, especially if they are only mildly symptomatic. Treatment of GD1 is inconvenient, very costly, and may result in undesirable side effects. We documented the clinical history of 31 untreated patients with GD1 followed in our clinic for 4-26 (median 15) years. This was a retrospective, observational study of the progress of untreated adult patients with GD1 followed by blood tests (haemoglobin, platelet counts, ferritin and chitotriosidase), organ volumes (spleen and liver), bone manifestations (through magnetic resonance imaging and dual X-ray absorptiometry scans) and neurological and quality of life issues. Statistical analyses were performed with the use of the Student paired t test and the modified Wald test for 95% confidence intervals. We found that the above parameters remained stable in most patients over a period of 4-26 (median 15) years. Five patients progressed from normal bone density to osteopenia and two from osteopenia to osteofibrosis; six were peri- or post-menopausal females. The DS-3 was stable over time. Only four of the 31 patients were started on enzyme or substrate reduction therapy. Our results demonstrate that many patients with GD1, provided with close follow-up by a specialist centre, can be followed for many years without requiring treatment and with no or minimal worsening of their GD1 manifestations.

Therapeutic Potential of a Biodynamic Supplement on Skin Pressure Ulcers: A Randomized Clinical Study.

Pressure ulcers (PUs) are a debilitating and often painful condition. They are localized lesions on the skin and/or underlying tissues and are common in the elderly, people with mobility difficulties, diabetics, and vascular disease or malnutrition, as well as in those requiring intensive or palliative care. The prevention and treatment of PUs involve strategies to optimize hydration, circulation, and nutrition. Nutrition plays a key role in pressure ulcer care because wounds require macronutrients and micronutrients to heal. Reports relating to the effectiveness of "Complementary Enzyme Therapy" also in the vulnological field led us to this study, the aim of which was to test the activity of a biodynamic food supplement (Citozym®) rich in carbohydrates, vitamins, and amylase and lactase and characterized by marked antioxidant activity. Citozym® administered topically and/or systemically, and in particular in both administrations, in patients suffering from Pus, has shown a marked reduction in bedsores and, in many cases, complete healing. Furthermore, it was possible to observe a lower incidence of side effects compared to conventional therapies. The results obtained, confirmed by various tests and recognized by the scientific community, allow us to conclude that treatment with Citozym® could represent a new and effective strategy for the treatment of PUs.

Ultrasound and Intrapleural Enzymatic Therapy for Complicated Pleural Effusion: A Case Series with a Literature Review.

Pleural effusion is the most common manifestation of pleural disease, and chest ultrasound is crucial for diagnostic workup and post-treatment monitoring. Ultrasound helps distinguish the various types of pleural effusion and enables the detection of typical manifestations of empyema, which presents as a complicated, septated effusion. This may benefit from drainage and the use of intrapleural enzyme therapy or may require more invasive approaches, such as medical or surgical thoracoscopy. The mechanism of action of intrapleural enzymatic therapy (IPET) is the activation of plasminogen to plasmin, which breaks down fibrin clots that form septa or the loculation of effusions and promotes their removal. In addition, IPET has anti-inflammatory properties and can modulate the immune response in the pleural space, resulting in reduced pleural inflammation and improved fluid reabsorption. In this article, we briefly review the literature on the efficacy of IPET and describe a case series in which most practical applications of IPET are demonstrated, i.e., as a curative treatment but also as an alternative, propaedeutic, or subsequent treatment to surgery.

Abbreviation of Desensitization Protocol for Pediatric Patients with Lysosomal Storage Diseases Receiving Enzyme Replacement Therapy

Introduction: Lysosomal storage diseases (LSDs) constitute a group of metabolic disorders characterized by the accumulation of substrates within lysosomes. For their treatment, disease-specific enzyme replacement therapy (ERT) is employed. In cases of hypersensitivity reactions that may occur during these treatments, desensitization of enzyme therapy becomes necessary. Repeated desensitization procedures may result some degree of tolerance. This study presents cases of patients received abbreviated desensitization protocols following repeated desensitization procedures. Method: During the period between September 2019 and January 2024, pediatric patients who experienced anaphylactic reactions to ERT and whose desensitization protocols were abbreviated after receiving uneventful treatment with desensitization for at least a year were included in the study. Result: Six patients, four with Pompe disease, one with mucopolysaccharidosis type 2, and one with mucopolysaccharidosis type 4, had been receiving uninterrupted ERT by desensitization for at least 1 year. The mean age of the patients was 117.6 months (median: 104.5, IQR: 85.2–144). All patients experienced anaphylaxis as the initial reaction. Skin and intradermal tests were repeated on patients prior to protocol abbreviation. Premedication previously given to all patients was discontinued, and desensitization protocols were subsequently shortened by increasing the infusion rate and/or reducing the number of steps. Conclusion: The study investigated patients whose desensitization protocols were abbreviated. It demonstrated that some level of tolerance could be attained through repeated applications. This approach aims to identify concise, safe, and efficient protocols, thereby reducing hospitalizations, nosocomial infections, and treatment expenses.

Challenges of enzyme therapy: Why two players are better than one.

Enzyme-based therapy has garnered significant attention for its current applications in various diseases. Despite the notable advantages associated with the use of enzymes as therapeutic agents, that could have high selectivity, affinity, and specificity for the target, their application faces challenges linked to physico-chemical and pharmacological properties. These limitations can be addressed through the encapsulation of enzymes in nanoplatforms as a comprehensive solution to mitigate their degradation, loss of activity, off-target accumulation, and immunogenicity, thus enhancing bioavailability, therapeutic efficacy, and circulation time, thereby reducing the number of administrations, and ameliorating patient compliance. The exploration of novel nanomedicine-based enzyme therapeutics for the treatment of challenging diseases stands as a paramount goal in the contemporary scientific landscape, but even then it is often not enough. Combining an enzyme with another therapeutic (e.g., a small molecule, another enzyme or protein, a monoclonal antibody, or a nucleic acid) within a single nanocarrier provides innovative multidrug-integrated therapy and ensures that both the actives arrive at the target site and exert their therapeutic effect, leading to synergistic action and superior therapeutic efficacy. Moreover, this strategic approach could be extended to gene therapy, a field that nowadays has gained increasing attention, as enzymes acting at genomic level and nucleic acids may be combined for synergistic therapy. This multicomponent therapeutic approach opens opportunities for promising future developments. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies.

Complex anti-relapse therapy of various variants of the course of the vulvar lichen sclerosus: A randomized prospective study

Aim. To develop and evaluate the effectiveness of complex therapy of vulvar lichen sclerosus (VLS), considering the clinical and immunological variant (CIV) of the disease. Materials and methods. A randomized prospective study included 292 patients 20-70 years old with different CIVs of the VLS course: atrophic (n=101), sclerosing (n=154), scleroatrophic (n=37), as well as 35 females with VLS in the comparison group of the same age category. Based on the clinical, immunological, and morphological features of the VLS course, a complex anti-relapse therapy was developed, the effectiveness of which was evaluated after a year of follow-up in comparison with the standard of care (SoC) of patients (from the comparison group) based on the number of disease relapses and the results of the Vulvar Quality of Life Index Questionnaire (VQLI) survey of women with vulvar diseases. Results. In patients with the sclerosing variant of VLS, short courses of topical glucocorticoids during exacerbations are justified; in patients with the scleroatrophic variant – topical calcineurin inhibitors, in the atrophic variant – a protein-peptide complex from porcine blood leukocytes (vaginal suppositories and cream-balsam with lanolin) containing interleukin-1, 6, tumor necrosis factor α, transforming growth factor, macrophage migration inhibitory factor. Patients with any variant of VLS are instructed to follow household and hygienic recommendations, use emollients daily, take prophylactic doses of vitamins A, E, and D to correct its deficiency or insufficiency, as well as use local enzyme therapy, as indicated, aimed at preventing or treatment of cicatricial changes. Local estrogens were prescribed only to women with genitourinary menopausal syndrome in the peri- and postmenopausal period. The developed complex anti-relapse therapy of VLS showed greater clinical efficacy compared to SoC: 3.7-fold decrease in episodes of disease exacerbation, as well as a significant (p=0.001) 1.3-fold decrease in the negative effect of VLS on the QoL of patients in the main clinical group (15.4 points according to the VQLI assessment – a mild effect on QoL) compared to SoC with the average score of 27.6, which corresponded to a strong negative effect of the disease on QoL. Conclusion. The results of the study support the distinction of VLS CIVs and the need to consider their features when choosing an effective therapy for the disease. Properly selected complex, supportive therapy of VLS can significantly increase the QoL of patients, minimize the number of relapses, and prevent the development of complications, including, probably, the risk of malignant transformation.

A lava-inspired proteolytic enzyme therapy on cancer with a PEG-based hydrogel enhances tumor distribution and penetration of liposomes

The enhanced permeability and retention (EPR) effect has become the guiding principle for nanomedicine against cancer for a long time. However, several biological barriers severely resist therapeutic agents’ penetration and retention into the deep tumor tissues, resulting in poor EPR effect and high tumor mortality. Inspired by lava, we proposed a proteolytic enzyme therapy to improve the tumor distribution and penetration of nanomedicine. A trypsin-crosslinked hydrogel (Trypsin@PSA Gel) was developed to maintain trypsin’s activity. The hydrogel postponed trypsin’s self-degradation and sustained the release. Trypsin promoted the cellular uptake of nanoformulations in breast cancer cells, enhanced the penetration through endothelial cells, and degraded total and membrane proteins. Proteomic analysis reveals that trypsin affected ECM components and down-regulated multiple pathways associated with cancer progression. Intratumoral injection of Trypsin@PSA Gel significantly increased the distribution of liposomes in tumors and reduced tumor vasculature. Combination treatment with intravenous injection of gambogic acid-loaded liposomes and intratumoral injection of Trypsin@PSA Gel inhibited tumor growth. The current study provides one of the first investigations into the enhanced tumor distribution of liposomes induced by a novel proteolytic enzyme therapy.Graphic

Организация профилактики и терапии угревой болезни у подростков на современном этапе.

The organization of prevention and treatment of acne in adolescents, necessary to improve the quality of medical dermatological care, has not been studied enough. The purpose of the study: аnalysis of current and potential opportunities for organizing the prevention and treatment of acne in adolescents. Results. The pathophysiological mechanisms of acne development are being reviewed, considering the characteristics of the puberty period, however, the trends in introducing new approaches to the organization of prevention and treatment of acne in adolescents are not expressed, with the exception of antiandrogen therapy. The official organization of treatment for adolescents with acne considers that any stage of acne development is multifactorial and is based on an inflammatory process. The officially recommended main method of treating acne in adolescents is the combined use of topical agents, especially the combination of benzoyl peroxide and the retinoid adapalene. In complex cases, topical treatment is supplemented with systemic therapy with retinoids (isotretinoin). Prevention of side effects of topical treatment (dry skin, hyperemia or cheilitis) is achieved through the use of moisturizing cosmetics or cream with dexpanthenol, respectively. Officially, in the field of acne prevention and therapy, such methods of influencing acne vulgaris as dermatocosmetics and corneo-or enzyme therapy are not used. The use of local and systemic pre- and probiotics for the treatment of acne has not been introduced. This reveals a connection between the development of acne and the intestinal microbiome. The use of local antiandrogens and insulin-like growth factor 1 inhibitors to control sebum production, as well as selective retinoic acid receptor agonists with a better safety profile compared to retinoid therapy for acne, may be promising for the prevention and treatment of acne in adolescents. Findings. Organization of effective treatment of acne in adolescents should include their clear instructions and correction of dietary habits. Prevention of acne today is practically not organized in the field of medical services.

Endocrinological and metabolic profile of Gaucher disease patients treated with enzyme replacement therapy.

Gaucher disease (GD) is a lysosomal storage disease caused by glucocerebrosidase (GCase) enzyme deficiency. Gaucher cells transformed from the macrophages by progressive sphingolipid accumulation and infiltrate bone marrow, spleen, liver, and other organs. The accumulation of substrate causes inflammation, compromised cellular homeostasis, and disturbed autophagy. It has been hypothesized that this proinflammatory state of GD leads cytokines and chemokines release. As a result of inflammatory process, the cellular dysfunction caused by disruption of cellular signaling, organelle dysfunction, or autoimmune antibodies may affect endocrine profile of GD patients such as hormone levels, lipid profile, and bone mineral density status. A total of 13 patients confirmed to have GD, 12 non-neuronopathic type and one subacute neuronopathic type, were enrolled in our study. The median treatment duration in the enzyme therapy was 13.33 years (9-26 years). At least one endocrinological abnormality was detected in blood tests of nine patients. Hyperinsulinism was the most common finding although fasting blood glucose levels HgbA1c levels were normal in all patients. Two patients had osteopenia, and osteoporosis was detected in two patients. Low HDL levels were detected in six patients, but HDL levels below 23 mg/dL associated with disease severity have been detected in two patients who have not receiving enzyme replacement therapy. None of patients had thyroidal dysfunction. This study had revealed endocrinological abnormalities in GD patients that have not led any severe morbidity in our patients. However, thyroid hormone abnormalities, insulin resistance, or lipid profile abnormalities may cause unpredictable comorbidities. Endocrinological assessment in GD patients in routine follow-up may prevent possible clinical manifestation in long term as well as can define efficacy of ERT on endocrine abnormalities.

A New Mutation of Pompe Disease in a 2-Month-Old Infant

Pompe disease, also known as type 2 glycogen storage disease (GSD), is an autosomal recessive disorder. It occurs due to the deficiency of an enzyme, acid maltase, which degrades glycogen in lysosomes. This deficiency leads to glycogen accumulation in several tissues, such as cardiac muscle cells [1]. The disease is classified into infantile and late-onset types. Infantile Pompe disease (IPD) can manifest with feeding problems, hepatomegaly, generalized muscle weakness, hypotonia, macroglossia, and hypertrophic cardiomyopathy [1-3], from the first day to weeks of life [1]. If left untreated, IPD leads to cardiorespiratory failure and death within one year. Late-onset Pompe disease (LOPD), which includes juvenile-, childhood-, and adult-onset disease, is characterized by proximal muscle weakness, respiratory muscle involvement (especially the diaphragm), and arrhythmia. The prognosis of LOPD is less severe than that of IPD [1]. Diagnosis can be made by gene sequencing of the acid alpha-glucosidase (GAA) gene and enzyme assay in dried blood, muscle, skin, and blood cells [5,6]. During pregnancy, diagnosis can also be made by amniocentesis [1]. Treatment with enzyme replacement using recombinant human acid α-glucosidase is effective. As IPD is rapidly progressive, treatment should be initiated as soon as possible. Enzyme therapy can prevent and reverse cardiac and muscle involvement [1]. According to the information the authors have about Pompe disease, in most cases, the initial signs and symptoms are common with other diseases. In these cases, genetic testing significantly helps to definitively diagnose the disease. With the progress made in genetic tests, sometimes new mutations are added to the existing genetic bank. In this case report, the authors introduce a Pompe patient with a new genetic mutation of pathogenic types. This patient had presented with signs of severe hypotonia and cardiomegaly, increased cardiac enzymes, and abnormal liver tests. Despite enzyme therapy immediately after diagnosis, the patient died.