Group Received Combination Therapy Research Articles

Evaluation of Zinc Sulfate and Canagliflozin as Therapeutic Agents in a Type-2 Diabetes Rat Model

Introduction: Diabetes mellitus (DM) poses a growing global health concern due to increasing prevalence, leading to substantial economic burdens. While current therapeutic options control hyperglycemia, their side effects can reduce patient compliance. Canagliflozin, an SGLT-2 inhibitor and zinc supplementation have individually demonstrated potential in managing diabetes mellitus. Aims & Objectives: This study aimed to assess the synergistic effects of Zinc Sulphate and Canagliflozin in a combination therapy on a type-2 diabetic model of rats. Material & Methods: The study utilized a rat model, inducing type-2 diabetes through a high-fat diet and streptozotocin injection. Rats were divided into six groups: normal control, disease control, zinc-treated, canagliflozin-treated and two groups receiving combination therapy with different doses. Parameters such as fasting blood glucose and serum insulin were measured over an 8-week period. Results: Blood glucose and serum insulin levels were significantly altered in diabetic groups but showed improvement with zinc and canagliflozin treatment. HOMA-IR and HOMA-B changes in diabetic rats were mitigated with both agents individually and exhibited further improvement in combination therapy groups. Conclusion: The combination of zinc and canagliflozin demonstrated superior efficacy in improving blood glucose, insulin levels and Insulin resistance compared to individual treatments. This suggests a potential synergistic effect of the two agents in managing type-2 diabetes. Further studies are warranted to explore the underlying mechanisms and potential clinical applications of this combination therapy. Key words: Zinc sulphate, Insulin, Canagliflozin, Diabetes.

Dupilumab and House Dust Mite Immunotherapy in Patients with Atopic Dermatitis: A Preliminary Study.

Severe atopic dermatitis (AD) is a complex disease requiring systemic treatment. This study aimed to assess the effectiveness of combined therapy consisting of dupilumab and sublingual dust mite allergen immunotherapy (SLIT-HDM) in patients with severe AD and HDM allergies. Patients diagnosed with severe AD were included in this randomised, placebo-controlled, double-blind 12-month trial; they received SLIT for HDMs and/or dupilumab for 12 months and were compared with patients on cyclosporine. The primary outcomes for the treatment arms were changes in the Eczema Area and Severity Index (EASI), body surface area (%BSA), and Investigator Global Assessment (IsGA) over 12 months. The secondary outcomes were the proportion of patients who achieved IsGA success and reduced medication scores. Significant improvements were observed in all analysed groups after 12 months of therapy based on the EASI, %BSA, and IsGA. However, the most substantial changes were observed in the groups treated with dupilumab or a combination of SLIT-HDM and dupilumab. Additionally, the proportion of patients who achieved an IsGA reduction was significantly greater in the group receiving combination therapy than in the other groups (9/14 [64% of the group receiving SLIT-HDM] vs. 11/14 [73% of the group receiving dupilumab] vs. 15/17 [88% of the group receiving dupilumab and SLIT-HDM] vs. 7/13 [53% of the group receiving cyclosporine]) (p < 0.05). In patients with severe AD and HDM allergies, combination treatment with dupilumab and allergen immunotherapy for HDMs may increase the therapeutic benefit over treatment with these methods separately.

Antibiotic-induced severe cutaneous adverse reactions: a single-center retrospective study over ten years.

Severe cutaneous adverse reactions (SCARs) are rare but life-threatening, with antibiotics being the main cause. This retrospective study from a single center was designed to analyze the culprit drugs, clinical features and treatment outcomes of antibiotic-induced SCARs. We analyzed cases of antibiotic-induced SCARs in a tertiary hospital in China between January 2013 and January 2024, including Steven-Johnson syndrome (SJS) or Stevens-Johnson syndrome-toxic epidermal necrolysis (SJS-TEN) overlap, toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP). Descriptive analysis of the demographic characteristics, clinical manifestations, treatment and prognosis were carried out. Among 354 cases of SCARs, 63 validated antibiotic-related cases were included. Cephalosporins (31.7%), penicillins (25.4%), and quinolones (19.0%) were the most common triggers for SCARs. Overall, liver (50.8%), lungs (31.7%), and kidneys (23.8%) were the most frequently affected organ in SCARs cases. Eight patients (28.6%) in the SJS/SJS-TEN overlap group and 8 patients (80.0%) in the TEN group received combination therapy of corticosteroids and IVIG. Patients with SCARs caused by penicillins or cephalosporins could receive alternative treatments such as lincomamides, quinolones, and tetracyclines. The mortality rate in the TEN group was the highest at 20.0%, followed by the SJS/SJS-TEN overlap group (7.1%), and no deaths were observed in the DRESS and AGEP groups. The identification of the culprit antibiotics and the application of alternative antibiotic therapies are crucial for the management of antibiotic-induced SCARs. If complicated underlying conditions and complications like advanced age, cancer and pneumonia coexist with SCARs, patients might be more at risk for mortality.

Stereotactic radiosurgery versus combined stereotactic radiosurgery and bevacizumab for recurrent glioblastoma; a systematic review and meta-analysis of survival.

Recurrent glioblastoma (rGBM) is a brain tumor that is resistant to standard treatments. Although stereotactic radiosurgery (SRS) is a non-invasive radiation technique, it cannot fully prevent tumor recurrence and progression. Bevacizumab blocks tumor blood supply and has been approved for rGBM. However, the best way to combine SRS and bevacizumab is still unclear. We did a systematic review and meta-analysis of studies comparing SRS alone and SRS plus bevacizumab for rGBM. We searched three databases for articles published until June 2023. All statistical analysis was performed by STATA v.17. Our meta-analysis included 20 studies with 926 patients. We found that the combination therapy had a significantly lower rate of overall survival (OS) than SRS alone at 6-month 0.77[95%CI:0.74-0.85] for SRS alone and (100%) for SRS plus bevacizumab. At 1-year OS, 0.39 [95%CI: 0.32-0.47] for SRS alone and 0.61 [95%CI:0.44-0.77] for SRS plus bevacizumab (P-value:0.02). However, this advantage was not seen in the long term (18 months and two years). Additionally, the combination therapy had lower chances of progression-free survival (PFS) than SRS alone at the 6-month and 1-year time points, but the differences were insignificant. Our study indicates that incorporating bevacizumab with SRS may lead to a short-term increase in OS for rGBM patients but not long-term. Additionally, the PFS rate did not show significant improvement in the group receiving combination therapy. Further clinical trials are necessary to validate the enhanced overall survival with combination therapy for rGBM.

PPARγ and AKt gene modulation following pregabalin and duloxetine combination for painful diabetic polyneuropathy.

Aim: Diabetic peripheral neuropathy (DPN) induces chronic neuropathic pain in diabetic patients. Current treatments like pregabalin and duloxetine offer limited efficacy. This study evaluates combining pregabalin and duloxetine versus pregabalin alone for DPN pain relief, and explores gene modulation (PPARγ and Akt) to understand neuropathic pain's molecular basis.Materials & methods: Diabetic patients with DPN were randomized into groups receiving combination therapy or pregabalin alone for 4weeks. Pain intensity, gene expressionand quality of life were assessed.Results: Combination therapy significantly reduced pain, improved quality of lifeand upregulated PPARγ and Akt genes compared with monotherapy.Conclusion: Pregabalin and duloxetine combination therapy in DPN led to PPARγ mRNA upregulation and negative correlation of Akt gene expression with pain scores. This combination therapy effectively reduced pain and improved quality of life.Clinical Trial Registration: CTRI/2021/02/031068.

Impacts of trelagliptin and remogliflozin alone and in combination with Alpha Lipoic Acid on cardiac function in streptozotocin-induced diabetes mellitusinrats.

This study investigated the effects of trelagliptin and remogliflozin, alone and in combination with alpha lipoic acid (ALA), on cardiac biomarkers in diabetic cardiomyopathy (DCM). We aimed to assess the management of glucotoxicity consequences in streptozotocin-induced diabetic rats by measuring serum levels of pharmacologically active endogenous ligands. Forty-eight male rats were divided into different treatment groups, including negative control, positive control, and four experimental groups. After inducing diabetes, the rats were treated for 28 days, and serum levels of biomarkers associated with oxidative stress (malondialdehyde and thioredoxin-interacting protein), inflammation (nuclear factor NF-kappa-B p105 and lipoprotein-associated phospholipase A2), and myopathy (neprilysin and high selective cardiac troponin T) were measured. Immunohistochemical analysis of heart cells was also performed. The results showed that inducing hyperglycemia increased serum glucose levels and biomarkers associated with DCM. However, all treatment groups exhibited a significant decrease in these biomarkers and an increase in insulin levels compared to the diabetic control group. The groups receiving combination therapy with ALA showed greater improvements in cardiac biomarkers compared to the individual treatments. The immunohistochemical analysis supported these findings by demonstrating a reduction in the percentage area of cathepsin B, a protein involved in DCM pathophysiology. In conclusion, supplementing the base treatments with ALA showed promise in enhancing cardiac biomarkers associated with DCM. The combination of trelagliptin, remogliflozin, and ALA may have additional clinical value in managing DCM by targeting oxidative stress, inflammation, and glucotoxicity. However, further research is needed to validate these findings and explore their potential clinical applications.

Orthovoltage X-Ray Therapy Significantly Reduces Disability Risk In Knee Osteoarthritis Patients: A Decade-Long Cohort Study

Introduction — Osteoarthritis (OA) of the knee and hip joints affects 13% of the adult population in the Russian Federation. While medications can provide some relief from the pain associated with OA, they are often not enough. An alternative treatment option is orthovoltage radiation therapy (OVRT), which not only relieves pain, but can also help prevent disability. However, there is little evidence for the long-term effectiveness of OVRT. Objective — We compared the incidence of disability among patients with OA who received standard treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) in combination with the symptomatic slow-acting drugs for osteoarthritis (SYSADOA), or in combination with OVRT for knee OA in the setting of an open randomized controlled trial with long-term follow-up. Material and Methods — The sampling frame included patients with confirmed OA of the knee sensu Altman (1991), with radiographic grades of OA from 0 to 2 sensu Kellgren-Lawrence. A total of 292 patients were randomly distributed among two groups of equal sizes. The control group received combination therapy with NSAIDs and SYSADOA. In the experimental group, OVRT was additionally performed at a total dose of 4.5 Gy. Relationships between treatment regimen and time to disability were studied using actuarial analysis, Kaplan-Meier plots. Crude and adjusted hazard ratios (HR) with 95% confidence intervals (CI), as well as attributable fraction (AF) and population attributable fraction (PAF) were calculated. Results — The cumulative time at risk for disability was 2,304.9 person-years. In total, 9.5% of patients in the experimental group became disabled during the observation period vs. 17.8% in the control group. In the experimental group, the level of disability was lower (HR=0.49, 95% CI: 0.26-0.95). Differences became more pronounced after adjusting for sex, age, radiographic grade of OA, pain intensity, and duration of OA before treatment (HR=0.24, 95% CI: 0.11-0.48). AF and PAF were 49.9% and 25.8%, respectively. Conclusion — It has been shown that the introduction of OVRT in the treatment regimen can reduce the disability of patients with knee OA by almost 50%. One in four disability cases could be prevented if OVRT were used universally in the treatment of knee OA. Our results indicate that combining OVRT with standard care is a more effective approach to preventing disability in patients with knee OA than standard treatment alone.

Effectiveness of Compassion-Enriched Acceptance and Commitment Treatment with and Without Sertraline on Depression, Stress, and Anxiety in Methadone-Containing Substance Abuse Patients: A Clinical Trial

Introduction: This study aimed to evaluate the effectiveness of combination therapy with sertraline and compassion-enriched act on depression, stress, and anxiety in opioid abuse patients treated with methadone compared to intervention based on compass-enriched acceptance and commitment treatment alone.Methods: This study was a clinical trial with a pre-test and post-test design. Forty people were selected by voluntary sampling method; after matching, they were divided into two groups with 15 participants. The first group received compassion-enriched acceptance and commitment treatment and the second group received combination therapy with compassion-enriched acceptance and commitment treatment and sertraline for 28 days. Patients were evaluated based on the Anxiety-Stress-Depression Questionnaire (DASS-21). Data were analyzed using SPSS version 16, multivariate analysis of covariance test at the level of 0.05.&#x0D; Results: The results showed that both interventional methods effectively treat depression, stress, and anxiety (p&lt;0.01), while the combined treatment of enriched acceptance and commitment treatment with compassion plus sertraline has the most significant effect on the studied parameters (p&lt;0.01).&#x0D; Conclusion: Acceptance and commitment treatment enriched with compassion plus drug therapy effectively reduces depression, stress, and anxiety in opioid addicts under methadone maintenance treatment and can be used as an effective method in the treatment of addiction.

Efficacy and association of hyperbaric oxygen therapy combined with butylphthalide and oxiracetam with serum levels of inflammatory markers in vascular cognitive impairment after acute ischemic stroke.

This study evaluated the efficacy of hyperbaric oxygen therapy (HBOT) combined with butylphthalide (NBP) and oxiracetam (OXR) for vascular cognitive impairment after acute ischemic stroke and investigated the association between such combination therapy and the serum levels of inflammatory markers. This was a prospective study which included eighty patients with post-AIS cognitive impairment (PAISCI) treated in Dongguan City People's Hospital from January 2020 to January 2022. They were randomized into study group and control group. The control group was provided with conventional therapy consisting of NBP for intravenous transfusion and oral OXR, while the study group received combination therapy of HBOT, NBP, and OXR. A comparison was drawn between the two groups regarding clinical outcomes, levels of recovery of cognitive and neurological function and intelligence, changes in inflammatory markers, and incidence of adverse drug reactions (ADRs). The response rate of the study group was significantly higher than that of the control group (p=0.04). The cognitive function scores of the study group were significantly better than those of the control group at the end of treatment (p<0.05). The post-treatment levels of inflammatory markers were significantly reduced in the study group when compared with the control group (p<0.05). At two weeks after treatment, the ADR rate of study group was significantly lower than the control group (p=0.03). The combination therapy of HBOT, NBP, and OXR demonstrates robust efficacy in patients with PAISCI. It is deemed to be a safe and effective treatment regimen.

Результаты проспективного сравнительного рандомизированного исследования по изучению эффективности и безопасности биологически активного комплекса «Нефробак»® в комплексном лечении пациентов с хроническим пиелонефритом.

Introduction. Chronic pyelonephritis is the most common kidney disease. In accordance with the chronic nature of the infection, an important aspect of the treatment of recurrent uncomplicated urinary tract infections is antibiotic resistance. The aim of this work is to evaluate dynamics of the number of relapses and severity of symptoms of chronic pyelonephritis against the background of the complex drug «Nephrobac»®. Materials and methods. The study included 60 patients aged 24 to 56 years with complaints of pain in the lumbar area, fever, and dysuria. Based on the examination, the patients were diagnosed with chronic pyelonephritis. The patients were randomized into two groups: the first group received only antibacterial therapy, the second group received antibacterial therapy in combination with the biologically active complex «Nephrobac»® 1 capsule 2 times a day for 1 month. Patients of both groups were observed for 6 months from the start of therapy. Results. Fewer cases of leukocyturia were observed in the group receiving the antibiotic in combination with «Nephrobac»®, 45% and 75% after 3 and 6 months, respectively. In addition, in the same group, there were significantly fewer patients with bacteriuria after 3 visits in the main group compared with the control group receiving antibiotic therapy. There were no relapses registered 6 months after the start of the study in the group receiving combination therapy, including «Nephrobac»®, there were three patients with 1 relapse each in the control group. Conclusions. «Nephrobac»® can be recommended as a part of the complex therapy of chronic pyelonephritis, which has an anti-relapse and anti-inflammatory effect, enhancing antibiotics.

Asthenic post-COVID syndrome

To evaluate the efficacy and safety of combination therapy for post-COVID asthenic syndrome with multicomponent bioregulatory drugs Traumeel S, Ubichinon compositum and Coenzyme compositum. The study included 104 patients (averaged age 39.5 [30.8; 48] years) after COVID-19, clinically recovered from an acute infectious process, with asthenic syndrome lasting from 2 weeks to 6 months; the severity of asthenic syndrome on the asthenia VAS scale was at least 30 points. Before the start of the study, in addition to a physical examination, the patient's condition was assessed using the following questionnaires and scales: VAS for asthenia, subjective scale for assessing asthenia (MFI-20), L.D. Malkova, a questionnaire for the quality of life (EQ-5D), a questionnaire for identifying signs of autonomic disorders (Vayne A.M.). The patient's condition was monitored during follow-up visits 2 weeks, 1 month after the start of treatment and 1 month after the end of treatment. Patients of the main group received combination therapy, which included Traumeel S 1 tablet x 3 times a day, Ubichinone compositum and Coenzyme compositum 2.2 ml intramuscularly, alternating every other day, for 1 month (15 injections of each drug per course of treatment). Patients of the comparison group received eleutherococcus extract 100 mg during 30 days, 2 tablets x 2 times a day before mealsand vitamins B. The effectiveness of therapy was assessed by analysis of the asthenia severity (VAS scale), quality of life (EQ-5D questionnaire), patient satisfaction with treatment on a 5-point scale, which was carried out 1 month after the end of the course of treatment. As a result of the treatment was positive. The general asthenia severity, low activity and motivation significantly decreased in patients of both groups without significant differences. At the same time, in patients of the comparison group, there was no correlation between the quality of life and physical and mental asthenia, while in the main group there was an inverse correlation with the asthenia severity, which indicates an increase in the quality of life with a decrease in the severity of asthenia. One of the significant differences was the regression of headache and musculoskeletal pain in patients of the main group. The advantage of combined therapy of post-COVID asthenic syndrome with bioregulation therapy Traumeel S, Ubichinone compositum and Coenzyme compositum was shown in comparison with one of the common treatment regimens, including eleutherococcus extract and combined preparations of B vitamins.

Additional Effect of Luseogliflozin on Semaglutide in Nonalcoholic Steatohepatitis Complicated by Type 2 Diabetes Mellitus: An Open-Label, Randomized, Parallel-Group Study.

IntroductionUntreated nonalcoholic fatty liver may progress to nonalcoholic steatohepatitis (NASH) and cirrhosis and induce hepatocellular carcinoma and liver failure. Type 2 diabetes mellitus (T2DM), often complicated with nonalcoholic fatty liver disease (NAFLD), is a driver of NAFLD progression. Thus, efficacious treatment strategies for patients with coexisting NAFLD and T2DM are important for preventing NAFLD progression. Although previous studies have demonstrated that either sodium-glucose transporter 2 inhibitors (SGLT2is) or glucagon-like peptide 1 receptor agonists (GLP-1 RAs) benefit NASH patients with T2DM, the rate of NASH resolution has not sufficiently improved. Therefore, we developed a protocol for a randomized controlled trial to examine whether the addition of an SGLT2i to the treatment regimen of patients receving a GLP-1 RA (combination therapy), within the therapeutic dose range for T2DM, increases the rate of NASH resolution in patients with coexisting NASH and T2DM.MethodsThis open-label, randomized, parallel-group study commenced in June 2021, will conclude recruitment in May 2023, and will end by March 2025. Sixty patients with NASH complicated by T2DM are enrolled at the Ehime University Hospital in Toon, Japan. Participants will be randomized into: (1) an intervention group receiving combination therapy with the SGLT2i luseogliflozin 2.5 mg, once daily (Taisho Pharmaceutical, Tokyo, Japan) and the GLP-1 RA semaglutide 0.5 mg, once per week (Novonordisk, Copenhagen, Denmark); and (2) a control group receiving monotherapy with the GLP-1 analog semaglutide. The primary endpoints, which will be ascertained by liver biopsy, are: (1) NASH resolution rate from baseline without worsening of liver fibrosis after 52 weeks of intervention; (2) rate of improvement from baseline of at least 1 point in the NAFLD activity score without worsening of liver fibrosis after 52 weeks of intervention; and (3) rate of improvement from baseline of at least one fibrosis stage without worsening of NASH after 52 weeks of intervention.Trial RegistrationUniversity Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR) number: UMIN000045003. Japan Registry of Clinical Trials registration number: jRCTs061210009.

Correlation between Level of Serum Transaminases and Duration of Antiepileptic Drugs in Epilepsy Children in Sanglah Hospital

BACKGROUND: Some antiepileptic drugs (AEDs), particularly sodium valproate, phenytoin, phenobarbital, and carbamazepine induce and increase production of hepatic enzymes. The adverse metabolic effects of AEDs treatments have become main concern, however data about evaluation of serum transaminases and duration of AEDs in Indonesia still limited. AIM: The aim of the study was to investigate correlation of AEDs and serum transaminases in children with epilepsy. METHODS: This cross-sectional research was conducted in pediatric neurology outpatient clinic in Sanglah Hospital. The target was children with epilepsy who had taken AEDs for at least 6 months. Data were collected from January 2020 to the number of samples were achieved. The exclusion criteria were concomitant liver disease, taking drugs which induce elevated serum transaminase or alcohol abuse. Data including age, gender, nutritional status, type, and duration of AEDs were obtained from medical record. Correlation was analyzed by Pearson’s or Spearman’s correlation, p &lt; 0.05 was considered significant. RESULTS: Total 148 epileptic children enrolled in this study. Aspartate transaminase (AST) and alanine aminotransferase (ALT) level were highest in the group receiving combination therapy (34.37 ± 24.9 U/L and 35.96 ± 23.3 U/L). There was a significant negative correlation between duration of carbamazepine and AST (r = –0.723, p = 0.0001) and ALT (r = –0.457, p = 0.009), as well as duration of valproic acid with AST and ALT (r = –0.689 and –0.677, p = 0.0001). Duration of phenobarbital administration was positively correlated with AST and ALT (r = 0.546 and 0.425, p = 0.0001). Combination therapy also had positive correlation with AST and ALT (r = 0.815 and 0.781, p = 0.0001, respectively). CONCLUSION: Duration administration of carbamazepine and valproic acid had negative correlation with AST and ALT; however, phenobarbital and combination therapy were positively correlated with AST and ALT.

Impact of Postoperative Radiotherapy on Overall Survival in Patients with pN1 Non-Small Cell Lung Cancer

Objective: to comparatively analyze overall survival (OS) in patients with non-small cell lung cancer (NSCLC) with affected lymph nodes (pN1) of the lung root after surgical and combination treatment with postoperative radiotherapy (PORT). Subjects and methods. OS was studied in 310 patients with grade 2-3 NSCLC. (pT1a-4N1M0): in 101 patients after lobectomy/bilobectomy, pulmonectomy with ipsilateral mediastinal lymphadenectomy and in 209 patients after combination treatment with the similar surgical volume and hypofractionated PORT (a single focal dose (SFD) of 3 Gy; 5 fractions per week, a cumulative focal dose (CFD) of 36-39 Gy (43.2-46.8 Gy-eq)) or classical fractionation (SFD2 Gy, 5 fractions per week, CFD44 Gy). An analysis was carried out in the groups of patients younger and older than 60 years with central or peripheral cancer, squamous cell carcinoma or adenocarcinoma, with different tumor grading according to the T criterion (T1-4). Results. PORT in radically operated patients with NSCLC increased 5- and 10-year OS rates only in central squamous cell lung cancer (56.1% and 39.5% vs.25.4% and 4.3%, p = 0.002). This group receiving combination therapy showed a statistically significant increasing trend in 5-year OS rates for both pT1-2 tumors (57.5% vs. 21.3%, respectively, p = 0.013) and pT3-4 tumors (53.9% versus 26.0%; p = 0.044), so did patients younger than 61 years (65.5% vs.29.4%, p = 0.008) and those over 60 years old (47.5% vs.21.3%, p = 0.047). Patients with peripheral squamous cell carcinoma or lung adenocarcinoma at any site exhibited no statistically significant increase in OS after PORT. In general, the 5- and 10-year OS rates in the compared groups were statistically significantly higher in the PORT group (47.9% and 28.9% vs. 27.1% and 11.4, p = 0.006). None of the analyzed subgroups showed a decrease in OS after PORT. Conclusion. In patients with pN1 NSCLC who had radical surgery via lobectomy/bilobectomy or pulmonectomy with ipsilateral mediastinal lymphadenectomy, PORT can be recommended only for those with central squamous cell carcinoma, regardless of tumor size and age group. In other subgroups of patients with pN1 NSCLC, PORT can only be performed within the scientific protocols. The expediency of PORT after bilateral mediastinal lymph node dissection needs to be investigated.

Combination Therapy of Metadichol Nanogel and Lipocalin-2 Engineered Mesenchymal Stem Cells Improve Wound Healing in Rat Model of Excision Injury

Purpose: Currently, several disorders including burns, trauma, excisional and diabetic wounds, and bedsores threaten the human health. Application of mesenchymal stem cells (MSCs) is recommended for treatment of skin disorders. However, because of oxidative stress and inflammation after skin injury, survival of transplanted MSCs is low which in turn negatively affects the efficiency of the MSCs-based therapy. In an attempt to address the aforementioned challenge and introducing a novel potential therapeutic strategy, we employed combination therapy by lipocalin 2 (Lcn2)-engineered MSCs and a Metadichol (an inverse agonist of vitamin D receptor (VDR)) nanogel in a rat model of excisional wound. Methods: First, human umbilical cord MSCs (hUC-MSCs) was transfected by a recombinant plasmid encoding Lcn2 gene. Next, a combination of Metadichol nanogel and the engineered MSCs was co-applied on wound in rat model of excision injury. Finally the improvement of wound healing in experimental groups was evaluated by photography and histological assessments (hematoxylin and eosin staining). Results: Our findings revealed that the repair rate was higher in the group received combination therapy comparing to control groups. Notably, Metadichol+Lcn2-MSCs showed significantly higher wound contraction rate compared to control group at all time points (P value < 0.001). Furthermore, wound repair rate was 95% 14 days after surgery, and 100% after 21 days in the treatment groups. Our results also revealed that the combination therapy improved and accelerated the wound healing process. Conclusion: Our findings suggest a novel potential therapeutic strategy i.e. Lcn2-engineered MSCs and Metadichol for wound healing. However, further preclinical and clinical studies are required.

Multicenter study of ceftolozane/tazobactam for treatment of Pseudomonas aeruginosa infections in critically ill patients

BackgroundThis study aimed to assess the efficacy of ceftolozane-tazobactam (C/T) for treating infections due to Pseudomonas aeruginosa (P. aeruginosa) in critically ill patients. Patients and MethodsA multicenter, retrospective and observational study was conducted in critically ill patients receiving different C/T dosages and antibiotic combinations for P. aeruginosa infections. Demographic data, localisation and severity of infection, clinical and microbiological outcome, and mortality were evaluated. ResultsNinety-five patients received C/T for P. aeruginosa serious infections. The main infections were nosocomial pneumonia (56.2%), intra-abdominal infection (10.5%), tracheobronchitis (8.4%), and urinary tract infection (6.3%). Most infections were complicated with sepsis (49.5%) or septic shock (45.3%), and bacteraemia (10.5%). Forty-six episodes were treated with high-dose C/T (3 g every 8 hours) and 38 episodes were treated with standard dosage (1.5 g every 8 hours). Almost half (44.2%) of the patients were treated with C/T monotherapy, and the remaining group received combination therapy with other antibiotics. Sixty-eight (71.6%) patients presented a favourable clinical response. Microbiological eradication was documented in 42.1% (40/95) of the episodes. The global ICU mortality was 36.5%. Univariate analysis showed that 30-day mortality was significantly associated (P < 0.05) with Charlson Index at ICU admission and the need of life-supporting therapies. ConclusionsC/T appeared to be an effective therapy for severe infections due to P. aeruginosa in critically ill patients. Mortality was mainly related to the severity of the infection. No benefit was observed with high-dose C/T or combination therapy with other antibiotics.

Evaluation of low doses effect of systemic isotretinoin in monotherapy and combination on qualitative and quantitative composition of microbiota in patients with acne

Objective.To evaluate the effect of low doses of systemic isotretinoin in monotherapy and combination on the qualitative and quantitative composition of the microbiota in patients with acne with moderate papulo-pustular acne.Materials and methods. 78 patients were monitored on an outpatient basis. Group 1 consisted of 38 patients. This group was divided into two age subgroups: A (12–24 years; n = 18) and B (25–45 years; n = 20). All patients in group 1 received monotherapy in the form of systemic administration of isotretinoin at a dose of 0.5–0.7 mg per 1 kg of body weight per day daily for 6 months. Group 2 consisted of 40 patients who were also divided into two age groups: A (12–24 years; n = 21) and B (25–45 years; n = 19). This group received combination therapy with isotretinoin at a dose of 0.1–0.3 mg per kg of body weight per day daily for 6 months in combination with phototherapy with broadband incoherent light (wavelength 440–950 nm) once every two weeks, a course of 4–6 procedures. To study the features of the qualitative and quantitative composition of the skin microbiota of acne patients, all patients were scraped and smeared with a sterile cotton swab before and after therapy, followed by analysis of microbial markers by chromatography-mass spectrometry.Results. Against the background of monotherapy in patients of different age groups, there was a positive dynamic in relation to the majority of microbiota indicators, its severity in subgroup A (12–24 years) was statistically more significant (p &lt; 0.05). However, the complete normalization of the composition of the facial skin microbiota in both subgroups did not occur. After combination therapy, there was a pronounced positive dynamics and normalization of most indicators of the microbiota of the skin, regardless of age. However, the number of some targeted microorganisms turned out to be slightly higher than normal and after therapy.Conclusions. The use of low-dose isotretinoin monotherapy, as well as its combination with broadband incoherent light, does not allow to completely normalize the composition of the microbiota in patients suffering from acne papulo-pustular form of moderate severity, which requires further study and analysis.

IVMP+IVIG raises platelet counts faster than IVIG alone: results of a randomized, blinded trial in childhood ITP

Children with immune thrombocytopenia (ITP) rarely suffer from life-threatening bleeds (eg, intracranial hemorrhage). In such settings, the combination of IV methylprednisolone (IVMP) with IV immune globulin (IVIG) is used to rapidly increase platelet counts (PCs). However, there are no controlled data to support using combination therapy over IVIG alone. We conducted a randomized, double-blind, placebo-controlled study to evaluate the rapidity of the PC increment and associated adverse events (AEs) between 2 regimens: A (IV placebo) and B (IVMP 30 mg/kg), both given over 1 hour, followed in both cases by IVIG (Gamunex 10%) 1 g/kg over 2-3 hours in children 1-17 years old with primary ITP and PCs <20×109/L in whom physicians had decided to treat with IVIG. Thirty-two children (ages: median, 8 years; range, 1.2-17.5 years) with a mean baseline PC of 9.2×109/L participated. Eighteen were randomized to regimen A and 14 to regimen B. By 8 hours after initiating therapy, 55% of all children had a PC≥20×109/L (no group difference). By 24 hours, mean PCs were 76.9×109/L (B) vs 55×109/L (A) (P= .06;P= .035 when adjusted for intergroup differences in patient ages). No patient experienced severe bleeding/unexpected severe AEs. There were statistically fewer IVIG-related headaches in the group receiving combination therapy (P= .046). Our findings show a rapid response to IVIG with/without steroids and provide evidence to support the use of IVMP+IVIG in life-threatening situations. This trial was registered at www.clinicaltrials.gov as #NCT00376077.

Effect of Combination l-Citrulline and Metformin Treatment on Motor Function in Patients With Duchenne Muscular Dystrophy

Nitric oxide precursors, such as the amino acid l-arginine and the biguanide antidiabetic drug metformin, have been associated with metabolism and muscle function in patients with Duchenne muscular dystrophy (DMD). The treatment of DMD remains an unmet medical need. To evaluate the benefits and harms of a combination of l-citrulline and metformin treatment among patients with DMD. A single-center randomized double-blind placebo-controlled parallel-group clinical trial was conducted between December 12, 2013, and March 30, 2016, at the University Children's Hospital Basel in Switzerland. A total of 47 ambulant male patients aged 6.5 to 10 years with genetically confirmed DMD were recruited locally and from the patient registries of Switzerland, Germany, Austria, and France. Data were analyzed from April 6, 2016, to September 5, 2019. Patients in the treatment group received 2500 mg of l-citrulline and 250 mg of metformin (combination therapy) 3 times a day for 26 weeks compared with patients in the control group, who received placebo. The primary end point was the change in transfer and standing posture, as assessed by the first dimension of the Motor Function Measure, version 32, from baseline to week 26. Secondary end points included assessments of timed function, quantitative muscle force, biomarkers for muscle necrosis, and adverse events. The 2 prespecified subgroups comprised patients who were able to walk 350 m or more in 6 minutes (stable subgroup) and patients who were not able to walk 350 m in 6 minutes (unstable subgroup) at baseline. Among 49 ambulant male children with DMD who were screened for eligibility, 47 patients with a mean (SD) age of 8.2 (1.1) years were randomized to a treatment group receiving combination therapy (n = 23) or a control group receiving placebo (n = 24), and 45 patients completed the study. No significant differences between groups were found in the results of timed function and muscle force tests for overall, proximal and axial, and distal motor function. Among patients receiving combination therapy, the Motor Function Measure first dimension subscore decrease was 5.5% greater than that of patients receiving placebo (95% CI, -1.0% to 12.1%; P = .09). The administration of combination therapy had significantly favorable effects on the first dimension subscore decrease among the 29 patients in the stable subgroup (6.7%; 95% CI, 0.9%-12.6%; P = .03) but not among the 15 patients in the unstable subgroup (3.9%; 95% CI, -13.2% to 20.9%; P = .63). Overall, the treatment was well tolerated with only mild adverse effects. Treatment with combination therapy was not associated with an overall reduction in motor function decline among ambulant patients with DMD; however, a reduction in motor function decline was observed among the stable subgroup of patients treated with combination therapy. The statistically nonsignificant difference of distal motor function in favor of combination therapy and the reduced degeneration of muscle tissue appear to support the treatment concept, but the study may have lacked sufficient statistical power. Further research exploring this treatment option with a greater number of patients is warranted. ClinicalTrials.gov identifier: NCT01995032.

Evaluation of cardioprotective effect of exenatide in type 2 diabetes mellitus and acute myocardial infarction in the clinic and experiment

Background. Insulin therapy is associated with the risk of hypoglycemia, high variability of glycemia. Therefore, therapy with analogues GLP1 becomes relevant for patients with myocardial infarction and diabetes mellitus type 2. These drugs can reduce glycemic variability and risk of hypoglycemia. Objective. The effects of combination therapy analogue GLP1 and insulin should be studied in rats with experimental myocardial infarction and the impact of such therapy should be studied on the level of markers of myocardial damage, BNP, dynamics of the echocardiographic parameters and level of glycemia in patients with diabetes mellitus type 2 and myocardial infarction. Design and methods . Neonatal streptozotocin diabetes mellitus was modeled in an experiment in rats. Groups of animals were formed depending on the time of the beginning of insulin therapy, analogue GLP1(exenatide) or a combination of these drugs — before or after experimental myocardial infarction. Morphological assessment of ischemia and necrosis areas was carried out and glycemic variability was assessed. Two groups of patients with type 2 diabetes mellitus and myocardial infarction were formed in the clinical part. The first group received standard insulin therapy, the second group received combination therapy with insulin and exenatide. Parameters of glycemia, markers of myocardial damage, BNP, dynamics of echocardiography were evaluated. Results. The decrease of the area of necrosis, was observed in the combination therapy group in the experiment. Troponin I and CPK MV levels did not differ initially in all groups of patients. Reducing glycemic variability, a positive trend of level BNP, and EF was noted in patients with exenatide. Conclusion. Exenatide has the most pronounced positive effect on the course of myocardial infarction at the introduction before the start of reperfusion. Exenatide had no effect on the dynamics of markers of myocardial damage, but reduced the glycemic variability, improved the dynamics of laboratory parameters in patients.