Require Combination Therapy Research Articles

Neurotrophic Factors as Regenerative Therapy for Neurodegenerative Diseases: Current Status, Challenges and Future Perspectives

Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS), spinal cord injury (SCI), and amyotrophic lateral sclerosis (ALS), are characterized by acute or chronic progressive loss of one or several neuronal subtypes. However, despite their increasing prevalence, little progress has been made in successfully treating these diseases. Research has recently focused on neurotrophic factors (NTFs) as potential regenerative therapy for neurodegenerative diseases. Here, we discuss the current state of knowledge, challenges, and future perspectives of NTFs with a direct regenerative effect in chronic inflammatory and degenerative disorders. Various systems for delivery of NTFs, such as stem and immune cells, viral vectors, and biomaterials, have been applied to deliver exogenous NTFs to the central nervous system, with promising results. The challenges that currently need to be overcome include the amount of NTFs delivered, the invasiveness of the delivery route, the blood-brain barrier permeability, and the occurrence of side effects. Nevertheless, it is important to continue research and develop standards for clinical applications. In addition to the use of single NTFs, the complexity of chronic inflammatory and degenerative diseases may require combination therapies targeting multiple pathways or other possibilities using smaller molecules, such as NTF mimetics, for effective treatment.

Immune-mediated polyarthritis in dogs: Are corticosteroids the best bet?

PICO question In dogs with type I immune-mediated polyarthritis (IMPA), is sole treatment with other immunosuppressive agents as effective as treatment with corticosteroids at reducing clinical signs? Clinical bottom line Category of research question Treatment. Number and type of study designs reviews One pragmatic open-label randomised controlled clinical trial. Strength of evidence Weak. Outcomes reported In the single randomised controlled clinical trial reviewed, 7/10 (70%) of dogs in both treatment groups (prednisone or cyclosporine), were reported to have shown resolution of owner-reported symptoms, clinical symptoms and improved locomotor scores and cytologic signs of disease at the end of the 90 day trial period. Of the remaining dogs, 2/3 cyclosporine treated dogs required change to prednisone, and 2/3 prednisone treated dogs required combination therapy to achieve clinical response. Conclusion There is insufficient evidence to support the use of alternative immunosuppressive agents in place of corticosteroids for the treatment of IMPA type I. Further controlled clinical trials are needed before a change to clinical practice can be considered. How to apply this evidence in practice The application of evidence into practice should take into account multiple factors, not limited to: individual clinical expertise, patient’s circumstances and owners’ values, country, location or clinic where you work, the individual case in front of you, the availability of therapies and resources. Knowledge Summaries are a resource to help reinforce or inform decision making. They do not override the responsibility or judgement of the practitioner to do what is best for the animal in their care.

PS-C22-11: EFFICACY OF TRI-COMBINATION ACEI PLUS AMLODIPINE AND INDAPAMIDE VERSUS ARB AMLODIPINE AND THIAZIDE IN DIABETES WITH HYPERTENSION PATIENTS

Introduction: Global Burden of Disease (GBD) Study has estimated that Hypertension leads to 1.6 million deaths and 118 million disability-adjusted life years in INDIA1 40% of diagnosed Hypertension patients are treated1. The poor control rates among treated Hypertension patients are around 40% in Indian3. Plausible reasons for poor Hypertension control rates in INDIA. This is mainly because most treated patients only receive monotherapy despite guidelines recognizing that most patients require combination therapy 2 and 3. ISH 2020 guidelines support initiating with A+C SPC in Hypertension patients For patients uncontrolled on two drugs, recommended approaches are to increase doses as step 2 and add a third drug as step 3. 4 Every third Hypertension patient needs three or more drugs to reach the BP Perindopril + Amlodipine + Indapamide offers better blood pressure control. In studies such as the ADVANCE CCB study5. Active treatment with Perindopril + Indapamide + CCB reduced the relative risk of death by -28%. -The recent Mazza et al. study provides evidence for Cardiovascular risk reduction with Perindopril + Indapamide + Amlodipine combination. Left ventricular hypertrophy (LVH) regression was greater in the SPC group of Perindopril+ Indapamide+ Amlodipine vs. the FCT group (43.5% vs. 30.4%, P < 0.05).6 In our Indian study from 2019 to 2022, 110 patients with Diabetes with Moderate to severe Hypertension on Perindopril with Amlodipine and Indapamide were able to achieve a blood pressure target of < 130/80 mmHg with Minimum 6 months to a maximum of 2 years on this combination therapy, whereas Target of < 130/80 mmHg with ARB with Amlodipine and thiazide were achieved in 54% only, which was significant (Figure 1). Indian patients are well Tolerated with triple single Pill, and adherence to therapy was Good.

PSAT030 A Clinically Dormant Adrenal Incidentaloma Evolving to A Cortisol Secreting Adenoma, A Ten Year Follow Up Experience

Abstract Intro Adrenal incidentalomas (AIs) are found in approximately 3–4% of abdominal computed tomography (CT) scans performed for other reasons. Most of these masses are found to be nonfunctioning. Studies showed that subtle cortisol secretion in AIs and disruption in the hypothalamic-pituitary-adrenal axis are more frequent than expected. Here we report a case of a small AI progressing to a hormone-secreting adrenal mass causing Cushing's syndrome (CS) after a period of a decade, in which dexamethasone suppression test was the confirmatory diagnostic procedure. Case 66-year-old woman was referred to Endocrinology in 2007 for assessment of abnormal abdominal CT finding indicating minimal nodularity of the right adrenal gland followed by an MRI performed 2 years later with suspicion of a small adenoma measuring 1.4 cm. Patient's past medical history included coronary artery disease, impaired glucose tolerance controlled by diet. No reported family history of relevant endocrine tumors. At time of initial assessment, functional hormonal baseline workup was normal including ACTH: 23 pg/mL [5-27 pg/mL], AM Cortisol level: 13.6 mcg/dL [4-22 mcg/dL], 24h U-Cortisol: 16.4 mcg/24h/1g Cr [4-50 mcg/24h/1g], and DHEAS: 30 mcg/dL [<185 mcg/dL] Patient was re-evaluated annually. Over the course of the follow-up, she was found to have poor healing after surgical repair of ankle fracture in 2012, as well as depression necessitating medical therapy in 2015. Her previously diet-controlled diabetes significantly progressed, requiring combination therapy and ultimately basal/bolus insulin. Moreover, patient developed hypertension with antihypertensive medication doses increased from Valsartan 40mg to Valsartan/HCT 80/12.5 in a 5-year period. The patient was found to have normal ACTH, serum, and urine cortisol levels throughout her follow-up period. Annual CT imaging demonstrated no change in right adrenal mass. In 2017, overnight low dose dexamethasone suppression test was found to be 16.2 mcg/dL[<1.8 mcg/dL], which is significantly increased from 0.9 mcg/dL in 2011. In 2018, CT abdomen showed a marked increase in the adrenal mass size to 2.8 cm. In 2020, she underwent right-sided adrenalectomy with no complications. Both blood pressure and glucose levels improved postoperatively. The preoperative use of mifepristone therapy controlled her blood sugar and pressure and eliminated the need for postoperative glucocorticoid replacement. She is currently controlled on diet and lifestyle modifications alone. Discussion Our case highlights the limitations of current guidelines in the management of AIs that recommend discontinuing annual follow-up if no significant growth occurs after 5 years. Careful long-term follow-up of AIs provides an opportunity to detect the subclinical hormonal alterations, development of new hormonal abnormalities, or any change in mass size. These findings indicate the need for good communication between radiology, primary care, and endocrine providers to assure periodic hormonal and morphological evaluation. This case also suggests that the dexamethasone suppression test may be useful in the evaluation of CS in patients without significant hypercortisolemia. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Identifying Sex Dimorphism in Peripheral Artery Disease with Platelet Mapping

Clinical outcomes in women with peripheral artery disease (PAD) after revascularization procedures are worse compared to men, yet there is little in the existing literature as why this may be the case. Platelet Mapping is an emerging point-of-care viscoelastic technology that measures the comprehensive properties of a blood clot, including fibrin-platelet interactions. This prospective observational study aimed to characterize the clinical and Platelet Mapping profiles of female and male patients undergoing lower extremity revascularization, and to correlate Platelet Mapping distribution to thrombotic potential. All patients with a diagnosis of PAD undergoing named vessel open or endovascular revascularization to re-establish inflow, outflow, or both, during December 2020 and January 2022 were prospectively included. Patients were followed clinically for thrombosis for up to 1year. Platelet Mapping assays were performed in 3 clinical phases: preoperative, postoperative inpatient, and postoperative outpatient. Inferential analysis between female and male patient was performed. The quartile distribution of Platelet Mapping metrics associated with thrombosis was used to infer to thrombotic potential. One hundred seven patients were enrolled, of which 37 (34.6%) were female. Female patients had significantly lower rates of uncontrolled diabetes (2.7% vs. 18.6%), hypertension requiring combination therapy (37.8% vs. 58.6%), chronic kidney disease (27.0% vs. 51.4%), coronary artery disease (29.7% vs. 57.1%), and myocardial infarction (16.2% vs. 35.7%) (all P<0.05). Platelet reactivity was significantly higher in female patients with greater platelet aggregation (75.9±23.3 vs. 63.5±28.8) and lower platelet inhibition (23.8±23.4 vs. 36.8±28.9) (all P<0.01). This trend was consistent over time when stratified by the postoperative inpatient and postoperative outpatient clinical phases. There was no statistically discernible difference in the use of antiplatelet therapy between groups, yet female patients continued to exhibit greater platelet reactivity when analyzed by the type of pharmacologic regimen (platelet aggregation on mono-antiplatelet therapy: 80.6±21.0 in women versus 69.4±25.0 in men; platelet aggregation on dual antiplatelet therapy: 67.9±23.8 in women versus 44.8±31.8 in men) (all P<0.01). Twenty-one patients experienced postoperative graft/stent thrombosis within the study period. In relation to the overall study population, patients with thrombosis had Platelet Mapping metrics above the 50th percentile of overall platelet aggregation distribution. There is a growing appreciation for the differences in etiology, disease progression, and outcomes of cardiovascular conditions as they relate to sex. In this cohort, traditional cardiovascular risk factors were in lower prevalence in female patients. Platelet reactivity was found to be higher across clinical phases and antiplatelet regimens. High platelet reactivity was also associated with an increased incidence of thrombosis after lower extremity revascularization. These hypothesis-generating findings provide the basis for further exploration of sex-specific coagulation profiling in PAD patients.

A lymphatic-absorbed multi-targeted kinase inhibitor for myelofibrosis therapy

Activation of compensatory signaling nodes in cancer often requires combination therapies that are frequently plagued by dose-limiting toxicities. Intestinal lymphatic drug absorption is seldom explored, although reduced toxicity and sustained drug levels would be anticipated to improve systemic bioavailability. A potent orally bioavailable multi-functional kinase inhibitor (LP-182) is described with intrinsic lymphatic partitioning for the combined targeting of phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways without observable toxicity. We demonstrate selectivity and therapeutic efficacy through reduction of downstream kinase activation, amelioration of disease phenotypes, and improved survival in animal models of myelofibrosis. Our further characterization of synthetic and physiochemical properties for small molecule lymphatic uptake will support continued advancements in lymphatropic therapy for altering disease trajectories of a myriad of human disease indications.

Efficacy and Safety of Ivabradine in Combination with Beta-Blockers in Patients with Stable Angina Pectoris: A Systematic Review and Meta-analysis.

IntroductionBeta-blockers are recommended by the European Society of Cardiology as first-line antianginal therapy for reducing heart rate (HR) and symptoms in patients with chronic coronary syndrome, despite a lack of data showing superiority to other antianginal agents. Most patients with angina pectoris require combination therapy to manage symptoms, with a second-line agent chosen to manage the predominant cardiovascular problem. Ivabradine, a selective sinus node If channel inhibitor shown to reduce HR and protect against anginal symptoms, has previously demonstrated noninferior anti-ischaemic and antianginal efficacy to beta-blockers.MethodsThis systematic review and meta-analysis assessed the efficacy and safety of ivabradine in patients with stable angina pectoris who remained symptomatic despite receiving beta-blockers. Keyword searches of PubMed, The Cochrane Central Library Register, ClinicalTrials.gov, The World Health Organization International Clinical Trials Registry Platform (ICTRP) and Google Scholar identified studies comparing ivabradine plus beta-blockers with placebo or other first- or second-line antianginal agents in patients with stable angina pectoris. No date limits or language restrictions were applied. Outcomes were evaluated after 1 and 4 months of treatment, including changes in HR, angina attacks, use of short-acting nitrates, quality of life and safety. Risk of bias was evaluated on the basis of recommendations of the Cochrane Handbook for Systematic Reviews of Interventions.ResultsSeven relevant studies were identified (N = 6821). Ivabradine plus a beta-blocker consistently reduced HR, anginal symptoms and short-acting nitrate consumption within 1 month of initiating therapy, with continued reductions for up to 4 months. Furthermore, ivabradine plus beta-blocker therapy was well tolerated, with bradycardia rarely reported (0.1% of patients overall). This study is limited by the inclusion of only two randomised studies, which may lead to result interpretation bias.ConclusionsIvabradine may be valuable for tailoring early antianginal treatment when used in combination with beta-blockers for chronic stable angina inadequately controlled by beta-blockers.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-022-02222-1.

A Case Report of CultureNegative Burkholderia Prosthetic Valve Endocarditis Identified by Metagenomic NextGeneration Sequencing (mNGS)

Burkholderia cepacia complex is a group of closely related opportunistic Gram-negative species that can be found in soil and water. Burkholderia cepacia complex is commonly associated with pulmonary infections in patients with cystic fibrosis, hospital-borne outbreaks related to contaminated medicines and devices, and, rarely, prosthetic valve endocarditis. The treatment of Burkholderia cepacia remains challenging because of the organism’s intrinsic resistance to several antibiotics, and often requires combination therapy. Through this clinical vignette, we review an interesting case of culture-negative Burkholderia prosthetic valve endocarditis identified through metagenomic next-generation sequencing (mNGS) and the challenges associated with the diagnosis and selection of an appropriate treatment.

Restoration of Euglycemia in Type 2 Diabetes Patients with Pioglitazone as Fourth Drug in Oral Combination Therapy: An Experimental Study

The global burden of Type 2 diabetes mellitus (T2DM) is on the increase with over 500 million individuals of the world’s population being affected and diabetes associated deaths reaching over a million yearly. The progressiveness of the disease coupled with poor adherence to treatment requirements and lifestyle modifications T2DM very challenging as patients on single drug treatment may eventually require combination therapy up to the level of triple therapy without achieving euglycemia. In this study we hypothesize that the addition of pioglitazone as a fourth drug, may restore euglycemia and prevent the use of insulin. A total of 107 T2DM patients already on triple combination therapy were recruited and pioglitazone was introduced as a fourth drug in 66 patients (experimental group) while 41 patients served and as control. After 3 months, the mean post-treatment HbA1c in the experimental group was 7.00 ± 0.50% which showed statistically significant difference compared with the experimental group’s mean baseline HbA1c of 8.47 ± 0.51% at p is less than 0.05. Also, the mean post-treatment HbA1c of the experiment group showed statistically significant difference when compared with the post-treatment HbA1c of the control group at p is less than 0.05, i.e. 7.00 ± 0.50% (experimental group) vs. 8.55 ± 0.73% (control group). Our findings indicate that the addition of pioglitazone significantly improved the glycemic profile of the experimental subjects without necessitating the adoption of complex insulin-dependent strategies.

MEDB-85. Transcriptional complexes as resistance drivers to BET inhibition

BET-bromodomain inhibition (BETi) is a promising therapeutic strategy to target MYC-driven cancers, including Group 3 medulloblastoma, a deadly childhood brain tumor. We have shown that BET inhibitors exhibit preclinical efficacy against MYC¬-amplified medulloblastoma, providing motivation to evaluate this drug class in early phase clinical trials. However, our work has also found that MYC-amplified medulloblastoma cells can acquire resistance to BETi, suggesting that curative responses for this disease will require combination therapy. To guide the development of such combination therapies, we have focused our efforts on elucidating the mechanisms through which medulloblastoma cells acquire resistance to BETi. We found that medulloblastoma cells can develop tolerance to BETi by reinstating the expression of cell-essential “rescue genes,” which include bHLH transcription factors, cell-cycle regulators, and anti-apoptosis genes. This transition to the resistant cell state is mediated through changes in chromatin structure including the upregulation of H3K4me3 promoters. Our preliminary results suggest that BETi-resistant cells maintain mRNA transcription and protein translation of important mediators of resistance. Importantly, we observe that BETi-resistant medulloblastoma cells are more dependent on specific protein complexes involved in transcriptional regulation. This project explores the mechanisms through which these transcriptional regulators help maintain transcription of rescue genes that drive BETi resistance and evaluates the potential of targeting these drivers of BETi resistance. These results will help guide the development of combination approaches to improve the efficacy of BETi for the treatment of MYC-driven medulloblastoma.

Black phosphorus-Au-thiosugar nanosheets mediated photothermal induced anti-tumor effect enhancement by promoting infiltration of NK cells in hepatocellular carcinoma

BackgroundHepatocellular carcinoma (HCC) is a heterogeneous cancer required combination therapy, such as photothermal therapy and chemotherapy. In recent years, cancer immunotherapies are rapidly evolving and are some of the most promising avenues to approach malignancies. Thus, the combination of the traditional therapies and immunotherapy in one platform may improve the efficacy for HCC treatment.ResultsIn this work, we have prepared a black phosphorus (BP)-Au-thiosugar nanosheets (BATNS), in which Au-thiosugar coating and functionalization improved the stability of both black phosphorus nanosheets (BPNS) and gold ions in different simulated physiological environments. The compression of the BATNS band gap can convert more photon energy to heat generation compared with BPNS, resulting in higher photothermal conversion efficiency. The in vitro and in vivo results also revealed a stronger reduction on the hepatocellular carcinoma of mice and prolonged survival of disease models compared with BPNS. More importantly, BATNS showed an additional immune effect by increasing local NK cell infiltration but not T cell on the liver cancer treatment, and this immune effect was caused by the thermal effect of BATNS photothermal treatment.ConclusionsThe novel BATNS could improve the stability of BPNS and simultaneously combine the cancer thermotherapy and immunotherapy leaded by local NK cell infiltration, resulting in a better therapeutic efficacy on hepatocellular carcinoma. This work also provided a new path to design BP-based materials for biomedical applications.Graphical

Natural Killer Cells: the Missing Link in Effective Treatment for High-Grade Serous Ovarian Carcinoma.

Ovarian cancer (OC), especially high-grade serous cancer (HGSC), is a highly heterogeneous malignancy with limited options for curative treatment and a high frequency of relapse. Interactions between OC and the immune system may permit immunoediting and immune escape, and current standard of care therapies can influence immune cell infiltration and function within the tumor microenvironment. Natural killer (NK) cells are involved in cancer immunosurveillance and immunoediting and can be activated by therapy, but deliberate approaches to maximize NK cell reactivity for treatment of HGSC are in their infancy. NK cells may be the ideal target for immunotherapy of HGSC. The diverse functions of NK cells, and their established roles in immunosurveillance, make them attractive candidates for more precise and effective HGSC treatment. NK cells' functional capabilities differ because of variation in receptor expression and genetics, with meaningful impacts on their anticancer activity. Studying HGSC:NK cell interactions will define the features that predict the best outcomes for patients with the disease, but the highly diverse nature of HGSC will likely require combination therapies or approaches to simultaneously target multiple, co-existing features of the tumor to avoid tumor escape and relapse. We expect that the ideal therapy will enable NK cell infiltration and activity, reverse immunosuppression within the tumor microenvironment, and enable effector functions against the diverse subpopulations that comprise HGSC.

Antihyperglycemic Effect of Fenugreek and Ginger in Patients with Type 2 Diabetes: A Double-Blind, Placebo-controlled Study

Background: Type 2 diabetes mellitus (T2DM) is a worldwide chronic, complex, and progressive disease that usually requires combination therapy for improved glycemic control. Although conventional medicine showed more potency than herbal medicine, a combination of both may result in better therapeutic outcomes with fewer side effects. Objective: This study was conducted to investigate the antihyperglycemic potential of fenugreek seeds (Trigonellafoenum-graecum L.) and ginger root (Zingiber officinalis) in patients with T2DM along with their usual antidiabetic medications. Methods: double-blind, placebo-controlled study was conducted using 33 cases, who were randomly divided into three groups. The first group received oral placebo capsules (1 g 3 times a day) and served as a control group, while the other two groups each received capsules of either fenugreek or ginger powder of the same dosage (1 g 3 times a day). The study was conducted for 8 weeks and treatment effects in patients were assessed through the measurements of serum’s fasting blood sugar (FBS), HbA1c, lipid profile, as well as kidney and liver functions. Results and Discussion: After 8 weeks of intervention, fenugreek and ginger induced a significant reduction in FBS by 19.1 ± 3.8% and 16.0 ± 8.0% compared to their baselines, respectively (p ≤ 0.05). Moreover, fenugreek significantly reduced HbA1c by 15.9 ± 4.9% compared to the baseline, while ginger did not. Creatinine and triglyceride levels were also reduced significantly (p ≤ 0.05) compared to their baselines in both fenugreek and ginger groups. However, all the other parameters did not significantly change. Conclusion: This study provides evidence that using fenugreek and ginger may enhance glycemic control in T2DM patients. Additionally, they might improve kidney function and lipids profile. Clinical Trial Registeration: The clinical trial has been registered with the number (2015-03‐229) at King Fahd University Hospital, Dammam, Saudi Arabia.

Comparative Pharmacokinetics Between a Fixed‐Dose Combination of Pitavastatin/Valsartan 4/160 mg and the Corresponding Individual Components Through a Partial Replicated Crossover Design in Healthy Male Subjects

Hypertension and hyperlipidemia are often comorbid, requiring combination therapies of antihypertensive drugs and antihyperlipidemia drugs. Taking 1 fixed-dose combination (FDC) may increase patient compliance rather than taking each of the drugs separately. This study aimed to evaluate the pharmacokinetic bioequivalence between an FDC of pitavastatin/valsartan 4/160mg and the corresponding individual components. Considering that valsartan is a highly variable drug for maximum plasma concentration (Cmax ), an open-label, randomized, partial replicated crossover study was conducted in 54 healthy subjects. The subjects received a single oral dose of the FDC of pitavastatin/valsartan 4/160mg in 1 period or the corresponding individual components in the other 2 periods. The geometric mean ratios and their 90%CIs of the FDC to the corresponding individual components for Cmax and area under the concentration-time curve from time 0 to the last measurable time point were 1.05 (90%CI, 0.96-1.15) and 0.10 (90%CI, 0.95-1.04) for pitavastatin and 1.15 (90%CI, 1.06-1.25) and 1.06 (0.99-1.14) for valsartan, respectively. The geometric mean ratios (90%CIs) for area under the concentration-time curve from time 0 to the last measurable time point and Cmax of both drugs were included in the bioequivalence criteria. In conclusion, the FDC of pitavastatin/valsartan 4/160mg showed pharmacokinetic equivalence with the corresponding individual components.

RETROSPECTIVE CHART ANALYSIS OF PATIENTS DIGNOSED WITH ACANTHOLYTIC PEMPHIGUS FOR THE PERIOD 2008-2018

The aim: Determine the clinical and anamnestic criteria that cause the аcantholytic pemphigus (AP) morbidity in the course of the treatment. Materials and methods: Analysis of medical histories of patients who underwent the therapy on the basis of the clinic for 10 years. In the analysis of 174 medical case histories were determined the factors provoking the onset and exacerbation of the disease. The disease severity was assessed using the IKEDA index. Results: During the analysis, patients were divided into two groups. The I group - patients who required combination therapy - systemic glucocorticosteroids (SGCs) and immunosuppressant (azathioprine (AZA)). For patients of group II used SGCs - according to the indications. The presence of intoxication and signs of pyoderma were more common in patients of group I. The number of exacerbations per year for an unknown reason in group I was almost 3 times higher. The ineffectiveness of high starting doses of SGCs was 20.2% of cases compared with those in group II. Conclusions: According to clinical and anamnestic data, during the retrospective analysis of case histories, the criteria determining the severity of acantholytic pemphigus during treatment were determined: the age of patients, the diagnosis period, the prevalence of lesions and severity of dermatosis according to the IKEDA index, the selection of adequate treatment tactics, taking into the complications caused as a result of the systemic glucocorticosteroids therapy.

Outcomes of eosinophilic esophagitis in patients managed in a multidisciplinary clinic.

Background: Eosinophilic esophagitis is a complex disease with an increasing prevalence. Multidisciplinary teams are often needed to manage this difficult-to-treat condition. Objective: To observe the clinical and histologic outcomes of patients with eosinophilic esophagitis after management in a multidisciplinary clinic. Methods: An observational, retrospective chart review was conducted to include all patients referred to the Walter Reed National Military Medical Center multidisciplinary eosinophilic esophagitis clinic between August 2012 and February 2021. Only patients who had at least one esophagogastroduodenoscopy before referral, one or more visits and endoscopy after multidisciplinary management, and documented clinical symptoms were included. Statistical analysis was performed by using McNemar and Wilcoxon tests. Results: A total of 103 patients were included in the study, with a mean age at diagnosis of 17.9 years. Management in the multidisciplinary clinic was associated with a reduction in solid-food dysphagia by 70.9%, poor growth by 70.8%, and emesis or regurgitation by 87.5%. We observed that 48.5% and 62.1% had histologic remission (<15 eosinophils/hpf) on the initial and any post-multidisciplinary endoscopy, respectively. Only seven patients (5.8%) with two or more visits and endoscopies did not achieve histologic remission. More than two-thirds of the patients (68.9%) required combination therapy to achieve remission. Conclusion: Although an observational study, these findings may suggest that the management of patients with eosinophilic esophagitis in a multidisciplinary clinic may improve the likelihood of clinical and histologic remission. Targeted management with a multidisciplinary approach may reduce overall morbidity and slow disease progression; however, more research is needed.

Three-dimensional printing of ramipril tablets by fused deposition modeling

Introduction. Arterial hypertension is one of the main risk factors for the development of cardiovascular diseases. Drug treatment of arterial hypertension is associated with a number of difficulties: often requires combination therapy, also a possible change in either dosages or drugs during treatment during the patient's life. Three-dimensional printing allows to create individual medicines on-demand.Aim. Study suitability of Kollidon® VA 64 as a matrix-polymer for the preparation of immediate release ramipril printing tablets.Materials and methods. Substance: ramipril; excipients: Kollidon® VA 64, Kollidon® CL-F, Soluplus®, PEG 1500, sodium carbonate anhydrous, Poloxamer 188, sodium stearyl fumarate, mannitol; reagents: hydrochloric acid, acetonitrile for ultra-HPLC, sodium octanesulfonate for HPLC, orthophosphoric acid 85 %, sodium perchlorate analytical grade, triethylamine, standard: ramipril USP (№1598303). Ramipril filaments were prepared by hot melt extrusion on the extruder Haake™ miniCTW (Thermo Fisher Scientific). The tablets were printed on a hand-made 3D printer. The printlets were studied for friability and hardness. Uniformity and quantitative determination of ramipril and impurities in tablets and filaments were determined by high performance liquid chromatography on a Shimadzu Prominence LC liquid chromatograph. Stability of ramipril was studied on a DSC 3+ Mettler Toledo by differential scanning calorimetry. Also, the stability of ramipril was determined by the Raman spectroscopy on an analytical system ORTES-785TRS-2700.Results and discussion. Ramipril filaments with a diameter of 1.75 mm were obtained by melt extrusion at a temperature of 105 °C. They were homogeneous in quantitative content of the active substance. From the resulting filaments, tablets were printed in five configurations with three filling densities: 30 %, 50 % and 100 %. Degradation of ramipril in filaments and tablets is not observed. The melting point of the selected mixture is lower than the melting point of matrix-polymer. It makes possible to lower the processing temperature. Tablets with 100 % filling provide an immediate release of ramipril.Conclusion. Kollidon® VA 64 is suitable as a matrix-polymer for the development of immediate release ramipril printlets. Kollidon® VA 64 provides the necessary physical and processing properties of the filament required for FDM printing.

Systematic measurement of combination-drug landscapes to predict in vivo treatment outcomes for tuberculosis

SummaryLengthy multidrug chemotherapy is required to achieve a durable cure in tuberculosis. However, we lack well-validated, high-throughput in vitro models that predict animal outcomes. Here, we provide an extensible approach to rationally prioritize combination therapies for testing in in vivo mouse models of tuberculosis. We systematically measured Mycobacterium tuberculosis response to all two- and three-drug combinations among ten antibiotics in eight conditions that reproduce lesion microenvironments, resulting in >500,000 measurements. Using these in vitro data, we developed classifiers predictive of multidrug treatment outcome in a mouse model of disease relapse and identified ensembles of in vitro models that best describe in vivo treatment outcomes. We identified signatures of potencies and drug interactions in specific in vitro models that distinguish whether drug combinations are better than the standard of care in two important preclinical mouse models. Our framework is generalizable to other difficult-to-treat diseases requiring combination therapies. A record of this paper’s transparent peer review process is included in the supplemental information.

Epidemiology of urinary tract infections in children: Causative bacteria and antimicrobial therapy.

Urinary tract infections (UTIs) are the most common bacterial infections in children. This study aimed to review characteristics of causative bacteria and the effectiveness of antimicrobial therapy in children with febrile UTIs. Clinical records of 108 patients (130 episodes) with febrile UTIs admitted to the Kawasaki Medical School Hospital between July 2009 and October 2016 were retrospectively reviewed. The characteristics of the causative bacteria, antibacterial therapy, and therapeutic effect were verified. Patients were aged between 0 and 183months (median age: 3months). Seventy-three (67.6%) were males. Sixty-three episodes (48.5%) were diagnosed with complicated UTIs. Forty-seven episodes (36.2%) were observed in patients aged <3months; 15 of them had complicated UTIs. Escherichia coli (E.coli) was the most common pathogen, followed by Enterococcus faecalis (E.faecalis). Blood cultures were positive in three episodes. Among the 130 episodes, 62 (47.7%) were treated with a combination of ampicillin and third-generation cephalosporins, followed by third-generation cephalosporins (31 episodes, 23.8%) and sulbactam sodium / ampicillin sodium (15 episodes, 11.5%). In case of patients with uncomplicated/complicated UTIs and patients aged <3 and ≥3 months, the most common pathogen was E.coli, followed by E. faecalis. There was no difference in therapeutic effects between "combination ampicillin and third-generation cephalosporins" and "third-generation cephalosporin monotherapy" administered for the treatment of UTIs caused by E.coli. Escherichia coli is the most common pathogen among pediatric UTIs. For antibacterial therapy, third-generation cephalosporin monotherapy is effective and may not require combination therapy with ampicillin.

Biofilm Time-Kill Curves to Assess the Bactericidal Activity of Daptomycin Combinations against Biofilm-Producing Vancomycin-Resistant Enterococcusfaecium and faecalis.

Introduction: E. faecium and E. faecalis are responsible for 13.9% of hospital-acquired infections with frequent resistance to vancomycin (82.6% of E. faecium, 9.5% of E. faecalis). Medical device infections secondary to enterococci often require combination therapy due to impaired activity against biofilm embedded cells. In vitro data demonstrate synergistic activity of daptomycin combinations. Using a novel, biofilm time-kill approach, we evaluated whether daptomycin combinations maintained synergy against biofilm-producing E. faecium and E. faecalis. Methods: Broth microdilution (BMD) and biofilm MIC (bMIC) values for daptomycin, ampicillin, ceftriaxone, fosfomycin, and rifampin were determined against biofilm-producing E. faecium and E. faecalis. Daptomycin combination bMIC values were determined in the presence of biologic concentrations of other antimicrobials. Synergy was evaluated against two E. faecalis (R6981, R7808) and two E. faecium (5938 and 8019) using a previously described biofilm time-kill method. Synergy was defined as ≥2 log10 CFU/cm2 reduction over the most active agent alone. Bactericidal activity was defined as ≥3 log10 CFU/cm2 reduction. Results: Daptomycin bMICs were 2–8-fold higher than BMD. In the presence of other antimicrobials, daptomycin bMICs were reduced ≥ two-fold in dilutions. Ceftriaxone and ampicillin demonstrated the most potent combinations with daptomycin, yielding synergy against three of four strains. Daptomycin plus rifampin was synergistic against E. faecium 5938 and E. faecalis 6981 and produced bactericidal kill. The combination of daptomycin plus fosfomycin displayed synergy solely against E. faecalis 6981. Conclusions: Daptomycin combinations with beta-lactams demonstrated promising synergistic activity against both E. faecium and E. faecalis. While daptomycin plus rifampin yielded bactericidal results, the effect was not seen across all organisms. These combinations warrant further evaluation to determine the optimal dose and response.