Start Of Combination Therapy Research Articles

Mexiletine shortened QTc interval in an age-dependent manner but suppressed ventricular arrhythmias at all age in children with long QT syndrome type 8

Abstract Background long QT syndrome (LQTS) type 8 (LQT8) is caused by mutations in CACNA1C, a gene encoding the α-subunit of voltage-gated Ca2+ channels. Mexiletine is sodium channel blocker which is often utilized for patients with LQTS type 3. Recently, the potential QT shortening effect of mexiletine in patients with LQTS type 2, however the efficacy for LQT8 patients have not been elucidated sufficiently. Purpose The study aimed to examine the efficacy of mexiletine for LQT8 children. Methods and Results The study consisted of 5 LQT8 children diagnosed at age <18 years from 4 families (female n=2). Three cases diagnosed on the first day of life, others during school-aged period. The mean age at diagnosis was 3.8 ± 4.9 years. The CACNA1C mutations identified in the patients were R518C (Case No.1), R858H (No.2), M1476R (No3 and 4), and G402S (No.5). We analyzed response in 12-lead electrocardiogram (ECG) parameters to mexiletine (3mg/kg, Max 125mg) intravenous infusion over 10 minutes. 12-lead ECGs were recorded at rest and 10 minutes after infusion. Two of them were received in the school-age period (No.1 and 2), two were in the neonatal period (No.4 and 5), and another was twice in both periods (No.3). QTc was drastically shortened in school-aged children (No.1: 521/456ms, No.2: 691/556, No.3: 568/532ms), while 3 neonatal cases showed no QTc shortening (No.3: 481/479ms, No.4: 600/601ms, No.5: Pre 689ms/Post 714ms) (Figure). T wave alternans (TWA) that had occurred incessantly in the neonatal case No.4 dramatically suppressed a few seconds after mexiletine infusion. In addition, torsades de pointes (TdP) had been recorded in 2 cases (No.2 and 5). Then, case No.2 and 5 started combination therapy of oral mexiletine and β-blocker, and No.4 mexiletine therapy. They had no cardiac event during medication for several years, although case No.2 suffered recurrent cardiac events because of non-compliance to mexiletine. Conclusion Mexiletine shortened QTc interval in school-aged children with LQT8, but not in neonates. Regardless of QTc shortening, mexiletine successfully reduced TWA and TdP at all age of LQT8 children.Mexiletine infusion test

Evaluating the Efficacy of a Pre-Established Lipid-Lowering Algorithm in Managing Hypercholesterolemia in Patients at Very High Cardiovascular Risk.

Recent data from European studies (EUROASPIRE V, DA VINCI, SANTORINI) indicate that achieving the LDL cholesterol (LDL-C) target in patients at very high cardiovascular risk is uncommon. Additionally, using a combination therapy involving statins and ezetimibe remains infrequent. A single-center assessment of a pre-defined lipid lowering treatment algorithm's effectiveness at achieving the LDL-C target in patients at very high cardiovascular risk one month and one year after hospitalization. 81 patients were included, all in secondary prevention. The average age of the patient was 66.9 years, and the main cardiovascular risk factors included hypertension, diabetes mellitus, and smoking history. Following the predefined lipid-lowering algorithm specific to our study, which involves initiating high-intensity statin therapy or a combination of statin and ezetimibe depending on initial LDL-C levels and patient history; 30 (37%) patients initiated high-intensity statin therapy (Atorvastatin (40 mg, 80 mg) or Rosuvastatin (20 mg, 40 mg)), while 51 (63%) started combination therapy with high-intensity statin and ezetimibe 10 mg. After one year, 57 (70.4%) remained adherent to their initial treatment, achieving a mean LDL-C of 49.5 ± 16.9 mg/dL, with 36 (63.2%) of them reaching the LDL-C target of <55 mg/dL. A total of 13 patients discontinued treatment, and 9 were lost to follow-up, withdrew from the study, or died. Initiating dual statin and ezetimibe therapy or high-intensity statin therapy early, based on the expected treatment efficacy, holds the potential to more rapidly and effectively achieve LDL-C targets in a larger proportion of very high-risk cardiovascular patients.

First-line Chemotherapy in Combination With Oral Recombinant Methioninase and a Low-methionine Diet for a Stage IV Inoperable Pancreatic-Cancer Patient Resulted in 40% Tumor Reduction and an 86% CA19-9 Biomarker Decrease.

Pancreatic cancer has a very poor prognosis with a 5-year survival rate of less than 5% among patients with distant metastasis, a figure that has not improved over many decades. Only 10 to 20% patients are candidates for curative surgery at presentation due to the aggressive nature and asymptomatic progression of pancreatic cancer. Although first-line chemotherapy, such as FOLFIRINOX and gemcitabine + nab paclitaxel, improved the median survival from 8.5 to 11.1 months, more effective treatments are immediately needed. The aim of the present study was to evaluate the efficacy of methionine restriction with oral rMETase (o-rMETase) and a low-methionine diet combined with first-line chemotherapy on a patient with stage IV metastatic pancreatic cancer. A 63-year-old female was diagnosed with metastatic pancreatic cancer in October 2023. The patient started FOLFIRINOX as first-line chemotherapy in combination with methionine restriction, which comprised o-rMETase 250 units twice a day and a low-methionine diet. The patient was monitored using computed tomography and CA19-9 blood tests. After five months from the start of combination therapy, the size of the primary tumor decreased by 40% along with liver-metastasis regression. The CA19-9 blood marker decreased by 86%. The patient sustains a high performance status and continues the combination therapy without severe side effects. Methionine restriction consisting of o-rMETase and a low-methionine diet, in combination with first-line chemotherapy, was highly effective in a patient with inoperable stage IV pancreatic cancer.

Effectiveness and safety of mycophenolate mofetil and rituximab combination therapy for immune idiopathic myopathies

IntroductionIdiopathic inflammatory myopathies (IIM) represent a rare and heterogenous group diseases, and their treatment is not fully defined yet. According to previous small case series, the combination of mycophenolate mofetil (MMF) and rituximab (RTX) may be effective in controlling difficult-to-treat patients. Our aim was to further explore the efficacy and safety of this combined approach in patients with IIM.MethodsPatients with IIM treated with the RTX/MMF combination in our Center were retrospectively identified. After the start of combination therapy, the efficacy was evaluated at 12 months (T12) according the 2016 ACR/EULAR response criteria for IIM. Cardiac imaging and pulmonary function tests were used to monitor disease activity in patients with myocarditis and interstitial lung disease, respectively. Adverse events were recorded over the follow-up period.ResultsAmong the 20 patients (median age 61 years; 70% female) included in the study, anti-synthetase syndrome was the most prevalent IIM subgroup (60%). At treatment start, muscle, heart, and lung were the most commonly actively affected organs. After 12 months, a moderate or major response was observed in all patients, and creatine kinase was significantly decreased (p-value = 0.012). Cardiac imaging and enzymes monitoring showed a reduction of heart inflammation, while pulmonary function tests improved in patients with lung involvement. No severe side effects were observed.ConclusionOur data show that combination of RTX and MMF is effective and safe in patients with severe and refractory IIM. Therefore, this combined treatment might represent a feasible approach for difficult-to-treat IIM cases.

Effect of proactive combination therapy with peritoneal dialysis and hemodialysis on technique survival and mortality.

Clinically relevant evidence for the timing of starting combination therapy with peritoneal dialysis and hemodialysis remains scarce. We retrospectively examined whether combination therapy during the induction phase of dialysis prolongs peritoneal dialysis duration. This retrospective study includes 160 patients who underwent combination therapy from 20 dialysis facilities. Four groups were categorized: combination at peritoneal dialysis induction (n = 12, Proactive combination group), and combination following peritoneal dialysis durations of < 2years (n = 65), 2-5years (n = 70), or > 5years (n = 13). Differences in technique survival of dialysis, mortality, and hospitalization due to cardiovascular events in the groups were observed. The Proactive combination group had the longer mean duration of combination therapy (3.18years) comparing to that of combination therapy following peritoneal dialysis (1.45years), but total peritoneal dialysis duration was shorter than in control groups (4.02years). Of the 160 cases in the entire cohort, there were 8 deaths, 18 ischemic heart disease hospitalizations, and 18 stroke hospitalizations. The Proactive group had lower crude mortality rate (0/12 cases, 0.0%) and crude hospitalization rate for ischemic heart disease (1/11, 8.3%) than the other groups. However, this cohort study did not have enough statistical power to adjust for patients' background, and we were unable to fully examine the differences in such clinical outcomes by the timing of initiation of combination therapy. Use of combination therapy in the induction phase might prolong the duration of combination therapy, but is not necessarily effective for prolonging peritoneal dialysis technique survival.

Responses to Combination Chemotherapy with MAPK Pathway Inhibition in Relapsed and Refractory LCH

MAPK pathway inhibition (MAPKi) is associated with high response rates in patients with Langerhans cell histiocytosis (LCH), but monotherapy may not be curative and efficacy in LCH-associated neurodegeneration (LCH-ND) is not known. Based on upregulation of Bcl-xL by MAPK activation, we hypothesize that MAPKi may render LCH cells more sensitive to chemotherapy-induced cytotoxicity. We assessed the safety and efficacy of combination therapy in 10 patients with refractory systemic disease and LCH-ND. Records of patients treated with combination therapy at Texas Children's Hospital from October 2018 to July 2023 were reviewed for clinical responses as well as peripheral blood/tissue BRAFV600E mutation status, ataxia rating scores, and toxicity. The median age at the start of combination therapy was 6.82 years (range, 0.48-20.45 years) with a median of 4 treatments prior to this therapy regimen (range, 1-14). Almost all Clofarabine was administered outpatient (typical starting dose 25 mg/m2/day x 5 days). MAPK inhibitors included BRAFV600E inhibitors (50%) and MEK inhibitors (50%). Overall response was 8/10 (80%), with 5/5 (100%) objective response rate (ORR) for systemic disease. Further, 5/6 (83%) demonstrated reduced or extinguished peripheral BRAFV600E+ fraction by the end of combination therapy. Ataxia rating scores were improved in 2/3 (67%) individuals with clinical neurodegeneration. Common toxicities during treatment included fever, skin rash, arthralgia, and cytopenia. Combining therapy was well-tolerated and associated with clinical and molecular improvement in most patients with highly refractory systemic LCH and LCH-ND. Further prospective multi-center trials are required to optimize this approach, determine potential for combination therapy to achieve cure, and compare risks and benefits to chemotherapy or MAPK inhibitor monotherapy.

Small bowel angioectasia–The clinical and cost impact of different management strategies

BackgroundThe management of patients with recurrent anaemia and small bowel angioectasia (SBA) is costly and challenging. Aims/methodsIn this retrospective cohort study, we examined the clinical and cost implication of a combination therapy of Somatostatin analogues (SA) and endoscopic ablation, endoscopic therapy alone, and conservative management. ResultsMedian number of bleeding episodes reduced from 3.5 (IQR 4) in the year before, to 1 (IQR 2) in the year after starting combination therapy with SA (p = 0.002). There were no differences in number of bed days (13.7 vs. 15.3, p = 0.66) and cost (£10,835 vs £11,653, p = 0.73) in the year before and after starting combination therapy. There was a trend towards a reduction in median number of blood transfusions episodes (17 vs 5, p = 0.07) and therapeutic endoscopies (1 vs. 0, p = 0.05) after starting SA. In patients suitable for endoscopic therapy alone, time spent in hospital was reduced (–3.5 days, p = 0.004), but bleeding episodes, transfusions and cost of treatment were not different. Patients requiring a combination therapy were significantly more co-morbid with a mean (± sd) Charlson comorbidity index (CCI) of 7.1 (± 2.7). Higher CCI (OR 2.1, 95% CI 1.1–3.9) and presence of chronic renal failure (OR 4.1, 95% CI 1.4–12.4) predicted escalation to combination therapy. ConclusionsSAs may be a useful adjunct to endoscopic therapy for transfusion dependent comorbid patients. In the first year they reduce bleeding episodes. Cost in the 1-year before and after adding on SA are no different suggesting additional clinical benefit can be gained without additional cost.

P617 Dual biologic therapy in pediatric Inflammatory Bowel Disease

Abstract Background There is paucity of data on the effectiveness of combination biologic agents as an option for children with refractory inflammatory bowel disease (IBD) that is inadequately controlled by biologic monotherapy. The aims of this study were to determine the effectiveness and safety of combination biologic use in pediatrics IBD. Methods A retrospective cohort study of children with IBD seen at Sidra Medicine and who received combination biologic therapy from October 2018 to April 2022. The diagnosis of IBD was established according to the revised Porto criteria. Children with IBD on two or more biologics were identified from our IBD database and their electronic medical records were reviewed. Patients included in the study must have been on combination biologic therapy for at least two months. Relevant clinical and demographic data were collected. Results Out of the 211 patients in our IBD database, we identified a total of 14 patients who had received dual biologic therapy within the study period. 3 patients were excluded because they had received dual biologic therapy for less than 2 months. 11 patients with IBD met our inclusion criteria and were included in this study. All 11 patients had Crohn’s disease. Overall, 7 patients (63%) were male, the median age at the start of starting combination therapy was 15.1 years (IQR 13.9 to 17.4), and the median disease duration was 2.3 years (IQR 1.4 to 3.2). Patients had been on the first biologic for a median of 20.3 months (IQR 13.0 to 32.3) before the addition of the second biologic. The reasons for dual biologic therapy included active disease, failure of single biological therapy, and development of complications. The patients had failed therapy with a median of two (range 1-3) prior biological medications. Concomitant dermatological disease (psoriasis) was present in one patient (9.1%). After a median follow-up of 5.2 months (IQR 2.9-5.5), median PCDAI significantly reduced from 22.5(IQR 16.75-30) to 5(1.25-13.75) {P&amp;lt;0.001}…Figure 1. Median fecal calprotectin reduced from 1534 (1361-1612) to 489 (379-658) {P&amp;lt;0.001}. No adverse events were noted. Conclusion Dual biologic therapy was associated with clinical and biomarker improvements in patients with Crohn’s disease who previously failed at least one single biologic. Dual biologic treatment was not associated with adverse events during the study period. Dual biologic therapy may be an attractive strategy but the lack of randomized controlled trials as well as long-term safety concerns means that there is a need for further trials on this subject. Future studies should assess risk: benefit ratios, safety, and efficacy of specific combinations of biologic use in IBD.

Comparative renal risk of long-term use of beta-lactams in combination with vancomycin across the continuum of care.

Data are controversial regarding nephrotoxicity risk with vancomycin plus piperacillin-tazobactam (VPT) compared to vancomycin alone or in combination with other beta-lactams (BLs) in acute care use. Furthermore, data are lacking on the incidence of acute kidney injury (AKI) with long-term use of VPT including outpatient parenteral antimicrobial therapy (OPAT). This retrospective study included 826 adult patients on an intravenous vancomycin plus BL for ⩾2 weeks, including cefepime, piperacillin/tazobactam, ertapenem, or meropenem, from August 2017 to January 2022. The primary outcome was incidence of AKI. Univariate and multivariable Cox proportional hazard regression analyses were conducted to adjust for confounding variables. A secondary analysis based on the propensity score (PS)-matched cohort was performed. AKI occurred in 14.4% of patients in the VPT group (n = 15/104) compared to 5.5% in the other BL group (n = 40/722) (p < 0.001). Average time to AKI from start of combination therapy was 9.4 (1.7-12.0) days in the VPT group and 10.9 (5-22.7) days in the other BL group (p = 0.20). The median duration of vancomycin and BL in the overall cohort was approximately 1 month. Beyond BL selection, patient characteristics were not associated with AKI other than the receipt of concomitant acyclovir [hazard ratio (HR) 2.48 (95% confidence interval (CI): 1.33-4.65), p = 0.004]. In the PS-matched cohort, AKI occurred in 14.4% of patients in the VPT group (n = 15/104) and 5.3% in the other BL group (n = 11/208) (p = 0.006). Receipt of VPT [HR: 2.55 (1.36-4.78), p = 0.004] and acyclovir [HR: 2.38 (1.19-4.74), p = 0.014) remained significantly associated with AKI in the multivariable model. Clinicians should exercise caution when using VPT for >2 weeks, including in the OPAT setting, even when no renal dysfunction is observed during the initial week of combination therapy.

Concomitant initiation of combination therapy with macitentan and tadalafil in pulmonary arterial hypertension (PAH) patients with comorbidities: real-world data from OPUS and OrPHeUS

Abstract Background Guidelines for the management of pulmonary arterial hypertension (PAH) recommend early combination therapy of an endothelial receptor antagonist (ERA) and a phosphodiesterase type-5 inhibitor (PDE5i) [1]. There is, however, limited guidance about the management of PAH patients with comorbidities. Purpose To describe the demographics, clinical characteristics, safety, tolerability, and outcomes associated with initiation of the ERA macitentan and the PDE5i tadalafil in patients with comorbidities in the US OPsumit® USers (OPUS) and the OPsumit® Historical USers cohort (OrPHeUS) combined dataset. Methods This analysis reports data from the OPUS registry (Apr 2014–Jun 2020) and OrPHeUS medical chart review (Oct 2013–Mar 2017) on PAH patients initiating macitentan and tadalafil (M+T) combination therapy, in any order, as concomitant initiation (≤60 days apart, concomitant initiation group). The index date was defined as the start date of the second therapy (i.e., the start of combination therapy). Patients were further grouped by the number of comorbidities present prior to or at macitentan initiation: systemic hypertension, diabetes, renal insufficiency, BMI ≥30 kg/m2, other signs of right heart failure and atrial fibrillation. Results are presented descriptively alongside results for all PAH patients receiving M+T combination therapy (overall M+T group). Results Of the 1336 PAH patients that received M+T combination therapy, 431 (32%) were in the concomitant initiation group. In the concomitant initiation and overall M+T groups, respectively: 72% and 68% had ≥1 comorbidity, and the most common were systemic hypertension (47% and 47%), obesity (32% and 26%) and diabetes (23% and 22%). Patients were more likely to be older, male and have idiopathic/heritable PAH with increasing comorbidity burden (Table 1). Patients in the concomitant initiation group were more likely to be incident (median time from diagnosis: 1–2 months vs 9–24 months in the overall M+T group; Table 1). Most patients had ≥1 adverse event (AE); in both groups, patients with a high comorbidity burden (≥3) were more likely to have had an AE and to have discontinued treatment (Table 2). The incidence rate of first all-cause hospitalisation and mortality by comorbidity was comparable between the concomitant initiation and overall M+T groups. Conclusions In the real-world, concomitant initiation of M+T is used in PAH patients with comorbidities, usually shortly after diagnosis. Patient characteristics were similar for the concomitant initiation and overall M+T groups, with the exception of time from diagnosis. At index date, age, gender proportion, and PAH aetiology differed between the comorbidity groups. The safety profile of M+T combination therapy in the concomitant initiation group was consistent with that in the overall M+T group. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Actelion Pharmaceuticals Ltd, a Janssen Pharmaceutical Company of Johnson &amp; Johnson

OA08 A case of Recalcitrant Psoriatic Disease- should new treatment strategies be considered?

Introduction/BackgroundDespite the advent of numerous biologic therapies and small molecular drugs targeting specific immune pathways, at least 40% of PsA patients exhibit poor response.Given the complexity and heterogeneity of signalling pathways resulting in synovio-entheseal disease in PsA; new treatment strategies must be evaluated to induce deep and sustainable clinical responses in all the phenotypic domains.In patients who do not achieve remission in all disease aspects on biologic monotherapy or combination of a biologic therapy with an oral synthetic agent; dual targeted anti-cytokines strategies or combined biologic with a targeted oral small molecule are a possible treatment option.Description/MethodA 40-year-old attended our rheumatology department in 2010 with peripheral synovitis, dactylitis and scalp psoriasis. A clinical diagnosis of PsA was made and she was commenced on combination methotrexate and sulphasalazine.In 2011, therapy was escalated to include etanercept and methotrexate due to persistent active disease clinically and on nuclear medicine bone scan.Between 2011 to 2015, sequential bDMARD switches including certolizumab, infliximab and adalimumab, failed to put the disease in remission.Due to loss of effect, adalimumab was switched to secukinumab in early 2016. A few months later, while on secukinumab, she developed new onset Crohn’s disease and required treatment change to ustekinumab.In August 2018 following a prolonged flare, ustekinumab was stopped and tofacitinib was started. The disease went in LDA until September 2020 when hospital admission for a severe PsA flare was required. She had dactylitis of 3 digits, a left temporomandibular joint effusion on ultrasound and elevated acute phase reactants. A treatment change to abatacept resulted in primary failure and abatacept was replaced with baricitinib.In March 2021, she attended clinic with new nail changes, dactylitis of 3 digits and a large left knee effusion. She underwent a diagnostic arthroscopy of the left knee and wash-out in May 2021 which showed a macroscopic synovitis score and vascularity score of 100% respectively. Synovial histology showed evidence of chronic synovitis with abundant plasma cells.Following the arthroscopy and careful discussion, it was decided to initiate combination therapy with adalimumab biosimilar and tofacitinib in June 2021. The patient was assessed at 2 months following starting combination therapy and a dramatic clinical and biochemical was noted. CRP had improved from 139.9mg/L to 6.3mg/L. She was mobilising without an aid for the first time in years. Both her psoriasis and Crohn’s disease were also well controlled.Discussion/ResultsWhile the outcomes of patients with psoriasis have dramatically improved with monoclonal antibody therapies targeting IL-23 and IL-17A; achieving a measurable low disease activity state such as minimal disease activity (MDA) for musculoskeletal manifestations of psoriatic disease is infrequent. Due to the heterogeneity of disease in PsA, multiple cellular pathways are involved in the pathogenesis resulting in recalcitrant disease in a subgroup of patients. These patients, like our case, exhibit poor response to the current therapeutic paradigm in PsA.In such patients, treating one disease domain, one type of cell or a single pathway at a time is unlikely to result in meaningful disease control and remission may be unachievable thus subjecting patients to sustained joint inflammation and damage seen in PsA. Very little data exist regarding the safety of dual immunomodulator therapies for concomitant psoriasis and psoriatic arthritis. Safety concerns such as infectious risks are important considerations with such strategies; however, the targeted second-generation anti-cytokine biologics and targeted JAK-I have exhibited improved safety profiles with regards to infections.In this case, following careful discussion with our patient, she felt that the prospect of possible reduction in her musculoskeletal symptoms outweighed the potential safety concerns.Multiple cases are reported in the literature regarding the use combined biologic strategies in psoriatic disease; the most common combination reported being anti-TNF therapy and ustekinumab with varying degrees of response. Prospective, high-quality studies are needed to identify safe and efficacious dual strategies in PsA to pinpoint dosages, sequence and frequency of therapies.Key learning points/ConclusionThis case truly highlights the heterogeneity and complexity that accompanies psoriatic disease and as such, modulating a single pathway may not be sufficient to address all the phenotypic domains (skin, synovium, entheses, and axial).While physicians are often, understandably, hesitant to prescribe combined immunomodulatory therapies due to concerns regarding potential complications, such strategies should be considered in debilitating cases of psoriatic disease who fail to respond to conventional treatment as they have the potential to foster deep and long-lasting remission.Our case highlights that a patient-centred approach with patient involvement in clinical decisions regarding their disease is required. With such strategies, patients and clinicians, both, should balance the potential associated risks particularly infectious risk.Further studies are required to better determine the efficacy and safety profile of combined immunomodulatory therapies in psoriatic disease.

Effect of dulaglutide and long-acting insulin combination therapy in patients with type 2 diabetes: a retrospective observational study.

The study aimed to evaluate the long-term effects of combination therapy comprising dulaglutide and long-acting insulin, on glycemic control in patients with type 2 diabetes. This retrospective observational study included 20 patients with type 2 diabetes who underwent blood glucose management with intensive insulin therapy for a limited period. All patients were switched from intensive insulin therapy to combination therapy comprising dulaglutide and long-acting insulin. Hemoglobin A1c was evaluated before and 4, 12, and 24weeks after starting combination therapy. Continuous glucose monitoring was conducted before and 1 and 24weeks after starting combination therapy. Hemoglobin A1c levels were significantly reduced after 4, 12, and 24weeks of combination therapy (- 2.2% ± 0.4%, P < 0.0001; - 3.7% ± 0.8%, P = 0.0003; and - 3.6% ± 0.8%, P = 0.0005, respectively). Glycemic variability (% coefficient of variation) was significantly decreased after 1 and 24weeks of combination therapy (- 5.7% ± 2.1%, P = 0.011; and - 8.7% ± 2.4%, P = 0.003, respectively) and the percentage of readings and time > 250mg/dL at 24weeks was significantly improved (- 2.2% ± 0.8%, P = 0.019). Combination therapy with dulaglutide and long-acting insulin resulted in better blood glucose control than intensive insulin therapy, which persisted for 24weeks. Combination therapy also reduced blood glucose fluctuations and the number of self-injections needed. The online version contains supplementary material available at 10.1007/s13340-022-00592-z.

Vancomycin and Piperacillin-Tazobactam Combination Induced Acute Kidney Injuries

Vancomycin and piperacillin-tazobactam are antibiotics that are commonly used in combination in the hospital setting for patients that are septic due to their broad-spectrum coverage, particularly for coverage of Pseudomonas aeruginosa and Methicillin-resistant Staphylococcus aureus (MRSA). However, this combination has an increased risk of acute kidney injury (AKI), with an incidence of approximately 20%. The mechanism of nephrotoxicity with the combination is not certain, however, it is believed to be synergistic. Risk factors for vancomycin and piperacillin-tazobactam combination induced AKIs include additional use of nephrotoxic agents and certain comorbidities, such as preexisting chronic kidney disease. The onset of AKI occurs about 3-5 days after starting combination therapy, with the majority tending to be non-severe.1 There are two interesting case reports that will be covered to showcase the characteristics of vancomycin and piperacillin-tazobactam AKIs. The most effective way to avoid vancomycin and piperacillin-tazobactam AKIs is to use an alternative regimen that provides adequate coverage, such as vancomycin and cefepime combination or vancomycin and meropenem combination. In cases where vancomycin and piperacillin-tazobactam combination is used, it is important to adopt best practices to minimize the risk of toxicity, such as ensuring appropriate indication and duration and minimizing modifiable risk factors.

Metastasis of breast cancer to the right kidney with a tumor thrombus in the inferior vena cava: a case report

BackgroundIt is quite rare for breast cancer to metastasize to the kidney with a tumor thrombus in the inferior vena cava.Case presentationA Japanese woman in her forties was diagnosed with cancer of the left breast and underwent left mastectomy with sentinel lymph node biopsy. The final pathological diagnosis was pT1aN0M0, stage IA (ER positive, PgR positive, HER2 negative). Thirteen years later, she presented for care with the complaint of abdominal pain. By imaging findings, right renal carcinoma with a tumor thrombus in the inferior vena cava and lung metastases was suspected. However, her tumors were refractory to molecular targeted therapy. In addition, CT-guided needle biopsy of the kidney and lung lesions was done and it was revealed that lesions of the left lung and the right kidney was breast cancer metastases (ER positive, PgR positive, HER2 negative). The patient started combination therapy consisting of abemaciclib, tamoxifen and leuprorelin. Six months later, she died from progression of her metastatic disease.ConclusionsIt is sometimes difficult to differentiate between primary renal cancer and kidney metastases from breast cancer on imaging. Renal biopsy is recommended before commencing treatment.

The role of the presence of fragmented QRS in predicting disease severity in patients with pulmonary hypertension

Pulmonary arterial hypertension is a malignant pulmonary vascular disease primarily caused by increased pulmonary vascular resistance, which leads to right ventricular hypertrophy, fibrosis, right heart failure and death. Fragmented QRS (fQRS) indicates non-homogeneous ventricular activity caused by myocardial fibrosis. This study aims to investigate the importance of fQRS in patients with pulmonary hypertension (PH) and to determine the role of the presence of fQRS in indicating the severity of the disease. The study included 94 (85 patient group 1 PH and 9 patient group 4 PH) patients. The patients were divided into two groups according to the presence of fQRS in their surface electrocardiography (ECG). The patients' laboratory, transthoracic echocardiography, and right heart catheterization parameters were compared between the two groups . FQRS was detected in 55 (58%) patients, and the mean age of these patients was 51.8±18.0, and 29.1% of them were male. Systolic pulmonary arterial pressure (PAP) measured by transthoracic echocardiography (p&lt;0.001), pulmonary vascular resistance (PVR) (p&lt;0.001) and mean, diastolic, systolic PAP (p=0.001, p&lt;0.001, p&lt;0.001) measured by right heart catheterization were found to be higher in patients with fQRS presence in their surface ECGs. Moreover, fQRS was found to be of high significance in predicting PVR. (95% CI 2.147-6.182; p&lt;0.001). In conclusion, when evaluating patients with pulmonary hypertension, it will be helpful in our clinical practice to assume that patients with fQRS on surface ECG are more affected hemodynamically and to start combination therapy early or follow up on these patients at shorter intervals.

Zanubrutinib in Combination with Venetoclax for Patients with Treatment-Naïve (TN) Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) with del(17p): Early Results from Arm D of the SEQUOIA (BGB-3111-304) Trial

Zanubrutinib in Combination with Venetoclax for Patients with Treatment-Naïve (TN) Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) with del(17p): Early Results from Arm D of the SEQUOIA (BGB-3111-304) Trial

Safety and efficacy of combining biologics or small molecules for inflammatory bowel disease or immune-mediated inflammatory diseases: A European retrospective observational study.

Background and aimsFew data are available regarding the combination of biologics or small molecules in inflammatory bowel disease (IBD) patients. We report safety and efficacy of such combinations through a retrospective multicentre series.MethodsCombination therapy was defined as the concomitant use of two biologics or one biologic with a small molecule. Patient demographics, disease characteristics and types of combinations were recorded. Safety was evaluated according to the occurrence of serious infection, opportunistic infection, hospitalisation, life‐threatening event, worsening of IBD or immune‐mediated inflammatory diseases (IMID), cancer and death. Efficacy was evaluated as the physician global assessment of the combination and comparison of clinical/endoscopic scores of IBD/IMID activity prior and during combination.ResultsA total of 104 combinations were collected in 98 patients. Concomitant IMID were present in 41 patients. Reasons for starting combination therapy were active IBD (67%), active IMID or extra‐intestinal manifestations (EIM) (22%), both (10%) and unclassified in 1. Median duration of combination was 8 months (interquartile range 5–16). During 122 patient‐years of follow‐up, 42 significant adverse events were observed, mostly related to uncontrolled IBD. There were 10 significant infections, 1 skin cancer and no death. IBD disease activity was clinically improved in 70% and IMID/EIM activity in 81% of the patients. Overall, combination was continued in 55% of the patients.ConclusionsCombination of biologics and small molecules in patients with IBD and IMID/EIM seems to be a promising therapeutic strategy but is also associated with a risk of opportunistic infections or infections leading to hospitalisation in 10%.

Postoperative medical treatment of lower urinary tract symptoms after benign prostatic hyperplasia surgery. Are we underestimating the problem?

The aim of this study was to determine whether well timed start of medical and surgical treatment of benign prostatic obstruction (BPO) influences the treatment's effectiveness and thus the patients' overall functional outcomes and quality of life. Pharmacological therapy even in high-volume (>80 cm3) BPH typically begins with α-blockers sole and only subsequently are 5ARI added. Several studies showed that acute urinary retention (AUR) developed more frequently in men who suffered severe lower urinary tract symptoms (LUTS) and who did not start combination therapy immediately. Moreover, there are no strict criteria which determine the right time for performing surgery in patients with mild and moderate LUTS, especially when pharmacological therapy fails. However, sometimes, the surgery does not eliminate all the symptoms, as it deals effectively with BPO, but does not treat an overactive bladder. Also, data show that surgery should be performed as soon as possible and be more radical after the first episode of AUR. A combination of α-blockers and 5ARI makes for a good starting point where the treatment of high volume BPH is concerned. Ideally, surgery should be performed immediately or as soon as possible in patients with the first episode of AUR and 'anatomic' BPH tissue removal is preferable (dissection of tissue along the prostate capsule to remove its maximum volume).

Psychiatric disorders of the combination of levetiracetam either with lacosamide or perampanel: a retrospective cohort study.

Background The number of patients with epilepsy receiving perampanel or lacosamide as an add-on treatment following levetiracetam treatment has increased. Although levetiracetam causes psychiatric disorders, it is unclear whether they occur with the combined use of these antiepileptic drugs. Objective To determine the frequency of psychiatric disorders in patients received lacosamide or perampanel in combination with levetiracetam. Setting A single-center retrospective cohort study. Method Patients who received levetiracetam + lacosamide or levetiracetam + perampanel were selected. Medical records from the start of combination therapy contained characteristics of patients and the incidence of psychiatric disorders. Main outcome measure The frequency of psychiatric disorders, the time to onset, dose reduction or discontinuation following psychiatric disorders, and the clinical course following disorder onset. Results Forty-four patients used levetiracetam + lacosamide and 50 used levetiracetam + perampanel. The incidence of psychiatric disorders was significantly lower (p < 0.001) with levetiracetam + lacosamide (6.8%) than with levetiracetam + perampanel (44%). The incidence of affect lability was significantly higher with levetiracetam + perampanel than with levetiracetam + lacosamide (p = 0.018). The time to the onset of psychiatric disorders was within 1 month of dose initiation or increase in one case (33.3%) with levetiracetam + lacosamide and 16 cases (72.7%) with levetiracetam + perampanel. There was no significant difference in clinical characteristics and antiepileptic drug dosages owing to the presence or absence of psychiatric disorders. Conclusion As the frequency of psychiatric disorders was higher with levetiracetam + perampanel therapy, levetiracetam + lacosamide may be preferable. These disorders tended to develop within 1 month of therapy and were not dose-dependent. Antiepileptic drugs should be cautiously prescribed to avoid psychiatric disorders.

Serum potassium changes due to concomitant ACEI/ARB and spironolactone therapy: A systematic review and meta-analysis.

DisclaimerIn an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.PurposeTo provide evidence of serum potassium changes in individuals taking angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs) concomitantly with spironolactone compared to ACEI/ARB therapy alone.MethodsPubMed, Embase, Scopus, and Web of Science were searched for studies including exposure to both spironolactone and ACEI/ARB therapy compared to ACEI/ARB therapy alone. The primary outcome was serum potassium change over time. Main effects were calculated to estimate average treatment effect using random effects models. Heterogeneity was assessed using Cochran’s Q and I 2. Risk of bias was assessed using the revised Cochrane risk of bias tool.ResultsFrom the total of 1,225 articles identified, 20 randomized controlled studies were included in the meta-analysis. The spironolactone plus ACEI/ARB group included 570 patients, while the ACEI/ARB group included 547 patients. Treatment with spironolactone and ACEI/ARB combination therapy compared to ACEI/ARB therapy alone increased the mean serum potassium concentration by 0.19 mEq/L (95% CI, 0.12-0.26 mEq/L), with intermediate heterogeneity across studies (Q statistic = 46.5, P = 0.004; I 2 = 59). Sensitivity analyses showed that the direction and magnitude of this outcome did not change with the exclusion of individual studies, indicating a high level of reliability. Reporting risk of bias was low for 16 studies (80%), unclear for 3 studies (15%) and high for 1 study (5%).ConclusionTreatment with spironolactone in combination with ACEI/ARB therapy increases the mean serum potassium concentration by less than 0.20 mEq/L compared to ACEI/ARB therapy alone. However, serum potassium and renal function must be monitored in patients starting combination therapy to avoid changes in serum potassium that could lead to hyperkalemia.