Alternative Treatment Regimens Research Articles

Comparative efficacy and safety of mycophenolate mofetil and azathioprine in combination with corticosteroids in the treatment of lymphocytic myocarditis

Aim. To study the efficacy and safety of mycophenolate mofetil (MM) in combination with corticosteroids in the treatment of lymphocytic myocarditis in comparison with a standard combination of corticosteroids and azathioprine.Material and methods. The study included 46 patients aged 18 years and older with severe and moderate lymphocytic myocarditis (men, 34; women 12; mean age, 53,5±13,0 years). The diagnosis was verified using endomyocardial biopsy. Symptom duration averaged 9,5 [4; 20.25] months. All patients had class 3 [2,75; 3] heart failure (HF). The main group included 29 patients who received MM 2 g/day, including six patients — instead of azathioprine, which was canceled due to cytopenia (n=3) or insufficient effect (n=3). The comparison group included 17 patients who received azathioprine 150 [100; 150] mg/day. Patients of both groups also received methylprednisolone at a starting dose of 24 [24; 32] and 24 [24; 24] mg/day and standard HF therapy. In 7/2 patients, the parvovirus B19 genome was detected in the myocardium. In all cases, an increase in anticardiac antibody titers was evidence of immune activity. The average follow-up period was 24 [12; 54] months (at least 6 months).Results. The groups were completely comparable in age, initial characteristics and standard drug therapy. In both groups, a comparable significant increase in the ejection fraction (EF) was noted as follows: from 31,2±7,6 to 44,7±8,3% and from 29±9,1 to 46±11,9% (p<0,001). An excellent response to treatment (an increase in EF by 10% or more) was noted in 68,2% and 66,7% of patients, a good response (by 9-5%) — in 27,3% and 14,3%, a poor response (an increase in less than 5% or a decrease in EF) — in 4,5% and 19,0%, respectively. In both groups, we noted the same significant (p<0,01) decrease in pulmonary artery systolic pressure (36,3±12 to 28,1±6,1 mm Hg in the MM group and from 44,1±8,5 to 30,7±12,1 mm Hg in the azathioprine group), left ventricular (LV) end-diastolic dimension (from 6,4±0,6 to 6±0,7 cm and from 6,2±0,5 to 5,8±0,6 cm), LV end-diastolic volume (from 188,7±55,2 to 178,8±57,1 ml and from 167,8±47,5 to 163,3±61,8 ml), LV end-systolic volume (from 130,3±44,1 to 98,4±32 ml and from 118,1±39 to 94,1±46 ml), left atrial volume (from 98,3±30,3 to 86,7±32,6 ml and from 105±27,4 to 91,2±47,3 ml, p<0,05), as well as mitral regurgitation grade. The incidence of deaths was 2 (6,9%) and 2 (8,7%), transplantation — 1 (3,4%) and 1 (4,3%) patients, death+transplantation end point — 3 (10,3%) and 2 (11,8%) without significant differences between the groups. The presence of the parvovirus B19 genome did not affect the results of treatment. The incidence of infectious complications was comparable in both groups (in one case, MM was completely canceled), no new cytopenia cases were noted during the follow-up period.Conclusion. In patients with moderate and severe virus-negative (except for parvovirus B19) lymphocytic myocarditis, the combination of moderate-dose corticosteroids with mycophenolate mofetil 2 g/day is at least no less effective than the standard regimen of immunosuppressive therapy. There was a tendency towards a more pronounced decrease in anticardiac antibody titers in combination with better tolerance (no cases of cytopenia) in MM group. MM in combination with corticosteroids can be recommended as an alternative treatment regimen for lymphocytic myocarditis.

Efficacy of Magnesium Sulfate on Maternal Mortality in Eclampsia.

Eclampsia is a common complication of preeclampsia patients and can be life-threatening for both the mother and the fetus. Hence, timely intervention and appropriate management of this detrimental condition are extremely crucial. Eclampsia is described as the occurrence of generalized convulsions in patients with preeclampsia. Magnesium sulfate (MgSO4) is the drug of choice for treating and preventing eclampsia. This review aims to study and analyze the available literature on the pathogenesis of eclampsia, the pharmacology of MgSO4, and its effectiveness in the management of eclampsia. Other proposed treatments and their comparative study with MgSO4 are also discussed. Additionally, we examine the data regarding the impact of eclampsia, its public health burden, and the cost-effectiveness of MgSO4. One of the major drawbacks associated with the use of MgSO4 in low-income countries has been the cost of treatment and the lack of resources. We have analyzed the trials that have proposed alternate treatment regimens which could shape new guidelines to resolve these issues. For this review, we extensively studied abstract and full-text articles from multiple databases. This article discusses the pathophysiology of eclampsia, the pharmacology of MgSO4, the issues surrounding eclampsia management, and how MgSO4 benefits these patients.

Three-year study to evaluate an anthelmintic treatment regimen with reduced treatment frequency in horses on two study sites in Belgium

In the present study, an anthelmintic treatment regimen with reduced treatment frequency was evaluated in horses on two study sites in Belgium during three consecutive summer pasture seasons. Historically, the horses on both study sites were treated up to 6 times a year with ivermectin (IVM) or up to 4 times a year with moxidectin (MOX), and previous efficacy evaluations indicated a reduced egg reappearance period in some of the treated horses for both IVM (28 days) and MOX (42 days). In the present study, all horses were treated with IVM or MOX in the spring and in autumn. Faecal egg counts (FEC) were conducted every two weeks during the summer pasture season and whenever the individual FEC exceeded 250 eggs per gram of faeces, the specific horse was treated with pyrantel embonate. No increase in parasitic disease over the three-year period of the study was observed. The FEC data collected in the study as well as the age of the animals and local weather data were then imported into a cyathostomin life-cycle model, to evaluate long term effects of the newly applied treatment regimen on the selection pressure for anthelmintic resistance, and compare to the previous high frequency treatment regimen. The model simulations indicated that the whole-herd treatment regimen with at least 4 macrocyclic lactone treatments annually led 2–3 times faster resistance development than any of the alternative treatment regimens evaluated under the specific conditions of these two study sites. Further lowering the treatment frequency or applying even more selective treatments enhanced the delay in resistance development, but to a lesser extent.

The outcome of re-treatment of relapsed hepatitis C virus infection in a resource-limited setting.

The aim of this study was to compare efficacy and safety of different combination regimens in re-treatment of HCV in the setting of inaccessibility of resistance testing. This real-life prospective study included 86 chronic HCV infected patients who experienced failure of treatment treated at Faculty of Medicine Ain shams Research Institute (MASRI) since 2018. 64% of the patients were males, with median age 50.2years. They were re-treated using 1 of 3 proposed regimens of DAA combinations. One group received PAR/OMB/SOF/RBV for 12weeks, another group received SOF/DAC/SIM/RBV for 12weeks and a third received SOF/DAC/RBV for 24weeks. Response to different regimens was assessed by comparing sustained virologic response (SVR) of each. Monitoring the occurrence of adverse events was performed. SVR was achieved in all but 3 patients (96.5% SVR), one in the SOF/DAC/SIM/RBV group and two in the SOF/DAC/RBV group. The group receiving RBV had more anaemia and hyperbilirubinemia. The first treatment regimen used was a significant predictor to SVR achievement. This study presents alternative treatment regimens for re-treatment of HCV patients in areas with limited resources in the case of non-availability of other regimens as velpatasvir, voxilaprevir, grazoprevir, elbasvir.

Immunological tumor heterogeneity and diagnostic profiling for advanced and immune therapies

Immunotherapies have changed the way how we treat cancer at all stages. The understanding of the immune system in individual tumor specimens guides the selection of immune-modulating agents such as immune checkpoint inhibitors alone or in combination with other therapeutic agents that target, modulate or unleash the patient's immune system. Despite the similar histopathological diagnosis, each tumor is unique at its primary site and site of metastasis, also depending on previous treatment regimens or genetic alterations, such as chromosomal instability or acquired mutations. The clinically well-established use of PD-1/PD-L1 inhibitors already requires the assessment of its target molecules in different cells (viable tumor cells alone or in combination with immune cells or immune cells alone) with different thresholds in various indications. Anyhow, checkpoint inhibitors show the best overall response rate when immune effector cells like tumor-infiltrating lymphocytes are in close spatial proximity without being suppressed by other humoral or cellular regulatory mechanisms. Therefore, immune cell-rich tumors (“hot tumors”) are usually quite reactive to immune-modulating agents, whereas other immune-depleted or immune-excluded tumor areas are less responsive and require alternative treatment regimens such as modified immune effectors cells or immune-stimulating agents, for example, oncolytic viruses. Here, we summarize the relevance to understand the entire tumor heterogeneity and its environment, the contextual relationship and spatial quantification of all immune and tumor cells along with the genetic background of the individual cancer through the application of multiplex in-situ technologies and the application of machine learning tools.

Comparative Efficacy and Safety of Diacerein in Patients with Knee Osteoarthritis: A Pilot Study

Background Osteoarthritis (OA) is the most common chronic rheumatic disease. The prevalence of OA is skyrocketing with time. Providing a proper treatment regimen for OA is also growing as a major public health challenge. Conventional pharmacological treatments are mainly for alleviating pain and have some severe adverse effects. Diacerein is a new oral anti-inflammatory drug especially developed for the management of OA having only mild to moderate adverse effects. However, the evidence of efficacy and safety of Diacerein in OA is not well documented and yet to be explored.
 Objective To compare the efficacy and safety of Diacerein in knee OA with conventional nonsteroidal anti-inflammatory drugs (NSAIDs).
 Method A comparative study was conducted among knee OA patients attending Out- Patient Orthopedic department in Dhulikhel Hospital, Nepal from December 2019 to September 2020, using self-structured and standard questionnaire. The patients were randomized to receive either a conventional standard treatment (Treatment Group I: NSAIDs) or alternative treatment regimen (Treatment Group II: NSAIDS+ Diacerein). Patients were followed-up after two months and data were analyzed using SPSS 21.0.
 Result Among 72 patients enrolled in this study, majority (44.44%) were between 51-60 years of age in which 81.94% of the patients were female. Post treatment data was collected from 15 participants. The mean KOOS-PS score of the participants in Treatment Group I decreased from 35.56 ± 14.33 to 35.14 ± 12.65 while that of the Treatment Group II participants reduced from 63.31 ± 12.08 to 49.99 ± 13.10 in two months. Similarly, the mean WOMAC score decreased from 46.87 ± 17.80 to 34.37 ± 16.83 in Treatment Group I and from 54.23 ± 14.66 to 46.22 ± 12.16 in Treatment Group II. The mean Lysholm score in Treatment Group I increased from 55.57 ± 8.16 to 60.86 ± 15.01 and in Treatment Group II, it increased from 46.62 ± 13.01 to 60.25 ± 17.598.
 Conclusion Diacerein treatment group had better functional outcome compared to the patients in the treatment group with conventionally used drugs. Also, the adverse effects faced by the patients were minor. The current study are suggestive of better efficacy and safety of Diacerein compared to other drugs.

Effect of Immunomodulatory Drugs (IMiDs) on Immune Effectors after Autologous Stem Cell Transplantation (ASCT) in Multiple Myeloma

INTRODUCTION: Patients with multiple myeloma have several phenotypic and functional immune aberrations that suppress host anti-myeloma immune responses. The degree and type of immune dysfunction can be targeted and reversed in many patients with active treatment. Therapies that result in deep and sustained remissions play a part in immunological control of disease in long-term responders. IMiD-mediated immunomodulatory effects conferring immune system reactivation have been reported in MM in the maintenance setting. We hypothesized that the circulating effector immune cell profile post-ASCT will be impacted by depth of response and IMiD based maintenance therapy.METHODS: Thirty multiple myeloma patients who underwent ASCT and IMiD based maintenance and consented for specimen collection protocol were included in this study. Blood and bone marrow samples were collected before starting IMiD based maintenance therapy on Day 60+ post ASCT (time point defined as baseline). Blood samples were then serially collected after 1 month (n=24), 3 months (n=26) and 6 months (n=19) of maintenance treatment. Multicolor flow cytometry was used for NK, NK-T and T cell distribution/activation immunotyping, and for measurement of bone marrow minimal residual disease (MRD) status. Threshold for MRD positivity was established as 1.5x10-5 abnormal/clonal plasma cells. Clinical response assessment was performed post-ASCT at baseline per IMWG guidelines. Welch's t-test was used to compare each immune variable between MRDpos and MRDneg groups and one-way ANOVA was used to analyze changes of each immune variable over time. The association of individual immune variable with progression free survival (PFS) was assessed by Cox regression analysis.RESULTS: In total, 16 patients achieved CR/sCR, 13 VGPR and 1 PR. MRD status was determined for 20 of 30 patients, 5 were MRDneg and 15 MRDpos. MRDpos patients had an immunotype characterized by higher expression of KIR2DS4 on NK (p=0.002) and NK-T cells (p=0.048) at baseline, compared with MRDneg patients. Twenty-six patients received single agent IMiD maintenance, 4 received IMiD/proteasome inhibitor combination. During IMiD maintenance therapy, NK and NK-T cell acquired phenotypes associated with greater effector functions as shown by increase in NK NKG2D+ (p=0.04), NK Tim3+ (p=0.049) and NK-T Tim3+ (p=0.01). T cells were marked by a NKG2D loss (p<0.001) and Tim3 gain (p<0.001) of expression. The median follow-up of the cohort was 19.3 months (IQR 14.8-21.3). Seven patients (5 MRDpos, 2 MRD status unknown) relapsed within 12 to 24 months post-ASCT. High KIR2DS4 (HR=1.072, 95% CI: 1.019-1.128; p=0.008), NKp46 (HR=1.05, 95% CI: 1.004-1.098; p=0.031) and NKG2A (HR=1.222, 95% CI: 1.018-1.466; p=0.032) expression by NK-T cells at baseline were associated with shorter PFS. NK and NK-T cells retained higher KIR2DS4 expression after 1, 3 and 6 months of IMiD maintenance therapy in relapsing patients compared with those in remission (Figure1).CONCLUSIONS: Our results demonstrate that KIR2DS4 expression by NK and NK-T cells is associated with MRD status post-transplant, as well as PFS in multiple myeloma patients treated with IMiD maintenance therapy. This simple blood-based immunotype, if validated in larger studies, could be used for longitudinal assessment to predict early on after starting IMiD maintenance treatment whether to continue this treatment or change to different treatment. Patients predicted to derive less clinical benefit from IMiDs could be offered alternative treatment regimens such as monoclonal antibodies, other immunotherapies or epigenetic therapy. [Display omitted] DisclosuresBhutani:Amgen: Speakers Bureau; Prothena Therapeutics: Research Funding; BMS: Speakers Bureau; Takeda Oncology: Speakers Bureau. Voorhees:Amgen: Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Novartis: Consultancy; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy; Oncopeptides: Consultancy. Usmani:Array BioPharma: Honoraria, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Novartis: Speakers Bureau; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Mutation Patterns Identify Adult Patients with De Novo Acute Myeloid Leukemia (AML) Aged 60 Years or Older Who Respond Favorably to Standard Chemotherapy: an Analysis of Alliance Studies

Abstract Background: Despite changes in treatment regimens, the patient's age (and the corresponding treatment intensity) remains one of the most important prognostic factors in AML. Thus far, only 5-15% of AML patients aged ≥60 years (y) are cured with chemotherapy. Identification of patients who are more (or less) likely to respond to standard cytarabine/daunorubicin-based chemotherapy might help to enable early risk stratification toward alternative treatment regimens. Aims: To provide a comprehensive molecular profile of a large cohort of adults with de novo acute myeloid leukemia (AML) aged ≥60 y, and to determine if specific molecular and/or cytogenetic features could identify patients who are more likely to respond to standard chemotherapy. Methods: We used a next-generation sequencing panel of 80 cancer- and/or leukemia-associated genes to profile molecularly 423 patients aged ≥60 y with de novo AML and available cytogenetic data similarly treated on Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology. Results: Overall, we detected 1377 mutations, with a median of 3 mutations per patient (range: 0-8). The outcome of the whole patient cohort was poor, with complete remission (CR) rate of 55% and disease-free (DFS) and overall survival (OS) 3y-rates of 14%. In multivariable analyses (MVA), mutated NPM1 was the only factor positively associated with achieving CR (P Summary: We identified combinations of mutations whose presence is associated with favorable outcome in older AML patients treated with standard chemotherapy. Patients with intermediate and adverse molecular features should be considered for alternative treatment regimens. Download : Download high-res image (186KB) Download : Download full-size image Figure 1 . Disclosures Stone: Otsuka: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Ono: Membership on an entity's Board of Directors or advisory committees; Orsenix: Membership on an entity's Board of Directors or advisory committees; Cornerstone: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Argenix: Other: DSMB; Arog: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Actinium: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Fujifilm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Jazz: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Seattle genetics: Membership on an entity's Board of Directors or advisory committees; Sumitomo: Membership on an entity's Board of Directors or advisory committees. Kolitz: Gilead, Magellan, Novartis, Pharmacyclics, and Seattle Genetics: Consultancy; Gilead, Magellan, and Novartis: Honoraria; Celgene, Jazz: Equity Ownership; Boehringer Ingelheim, Cantex, Erytech, and Millennium: Research Funding; Gilead, Novartis, and Seattle Genetics: Other: Travel Support. Powell: Rafael Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Byrd: Janssen: Research Funding; Genentech: Research Funding; Acerta Pharma: Research Funding; Pharmacyclics: Research Funding; The Ohio State University: Patents & Royalties: OSU-2S.

Hypofractionated Volumetric-Modulated Arc Radiotherapy for Patients With Non-Small-Cell Lung Cancer Not Suitable for Surgery or Conventional Chemoradiotherapy or SBRT.

BackgroundHypofractionated radiotherapy (HypoRT) has been used to pursue an alternative treatment regimen for patients with non-small-cell lung cancer (NSCLC) who are not eligible for stereotactic ablative radiotherapy (SABR), surgery or concurrent chemoradiotherapy (CCRT) and has shown good local control and safety. We analyzed the feasibility of using volumetric-modulated arc radiotherapy (VMAT) with the simultaneous integrated boost (SIB) technique to achieve high local control with few treatment-related toxicities.Patients and MethodsA total of 55 patients with stage I-IV NSCLC who were not candidates for SABR, surgery or CCRT were included in the present study. All patients received a prescribed dose of 60 to 66 Gy in 15 fractions. Local progression-free survival (LPFS), PFS, overall survival (OS), and toxicities were retrospectively analyzed.ResultsThirty-three patients (60.0%) had stage IV or recurrent disease in this study. The median follow-up time was 8 months (interquartile range: 5.0-16.3 months). The 1-year and 2-year OS rates were 84.3% and 69.9%, and the 1-year and 2-year LPFS rates were 91.0% and 63.0%. The median OS (mOS) and median LPFS (mLPFS) were not reached, and median PFS (mPFS) was 15 months. Twenty-eight (51.9%) patients had disease progression at the time of analysis. Of these, 7 (13.0%), 7 (13.0%) and 21 (38.9%) had local recurrence, locoregional failure and distant metastasis, respectively. All cases of local recurrence were found within the SIB region. Four patients had grade 2-3 pneumonitis, and 8 patients had grade 2-3 esophagitis. Patients with grade 2-3 esophagitis had significantly higher maximum dose and dose to 5 cm3 volume to esophagus than those with grade 0-1 esophagitis. No grade 4 or higher toxicity was observed.ConclusionThe 60 to 66 Gy in 15 fractions RT regimen provides favorable local control and survival with well-tolerated toxicities. Hypofractionated VMAT+SIB is an alternative treatment option for patients with NSCLC who cannot tolerate standard definitive therapy.

Current understanding of nonsurgical interventions for refractory differentiated thyroid cancer: a systematic review.

Thyroid cancer incidence and related mortality is increasing year-on-year, and although treatment for early disease with surgery and radioiodine results in a 98% 5-year survival rate, recurrence and treatment refractory disease is evident in an unacceptable number of patients. Alternative treatment regimens have therefore been sought in the form of tyrosine kinase inhibitors, immunotherapy, vaccines, chimeric antigen receptor T-cell therapy and oncolytic viruses. The current review aims to consolidate knowledge and highlight the latest clinical trials using secondary therapies in thyroid cancer treatment, focusing on both in vitro and in vivo studies, which have investigated therapies other than radioiodine.

Benznidazole Treatment: Time- and Dose-Dependence Varies with the Trypanosoma cruzi Strain.

As the development of new drugs for Chagas disease is not a priority due to its neglected disease status, an option for increasing treatment adherence is to explore alternative treatment regimens, which may decrease the incidence of side effects. Therefore, we evaluated the efficacy of different therapeutic schemes with benznidazole (BNZ) on the acute and chronic phases of the disease, using mice infected with strains that have different BNZ susceptibilities. Our results show that the groups of animals infected by VL-10 strain, when treated in the chronic phase with a lower dose of BNZ for a longer period of time (40 mg/kg/day for 40 days) presented better treatment efficacy than with the standard protocol (100 mg/kg/day for 20 days) although the best result in the treatment of the animals infected by the VL-10 strain was with100 mg/kg/day for 40 days. In the acute infection by the Y and VL-10 strains of T. cruzi, the treatment with a standard dose, but with a longer time of treatment (100 mg/kg/day for 40 days) presented the best results. Given these data, our results indicate that for BNZ, the theory of dose and time proportionality does not apply to the phases of infection.

Stress Cardiomyopathy Due to Exogenous Thyrotoxicosis From T3 Supplementation

Background: Wilson’s Temperature Syndrome (WTS) refers to a constellation of nonspecific symptoms, some of which include a low-normal body temperature, headaches, and fatigue. WTS was rejected by the American Thyroid Association as a valid medical diagnosis in 2005. Originally proposed in 1990 by Dr. E Denis Wilson, the etiology was theorized to be an impaired ability to convert T4 to T3, although this was not corroborated in thyroid lab abnormalities. Despite being publicly rebuffed as a true medical diagnosis, WTS has continued to gain traction amongst certain alternative medical groups and is treated with T3 supplementation. The development of a stress cardiomyopathy due to T3 supplementation is rare. Extrapolating from endogenous thyroid mediated stress cardiomyopathy and T4 supplementation induced stress cardiomyopathy, the pathophysiologic mechanism is likely excessive sympathetic activation. Clinical Case: A 58-year old female with no prior cardiac history presented to the emergency department with chest pain. Physical exam revealed a euvolemic appearing women, with intact and symmetric distal pulses, and a normal cardiac exam without murmurs or other abnormal heart sounds. There were no abnormal lung sounds. Her O2 sats were normal on room air. EKG and CXR were unremarkable. Her troponin was elevated (3.7 ng/mL, n< 0.034 ng/mL) and her BNP was elevated (4,568 pg/mL, n< 150 pg/mL). The patient was given aspirin and started on therapeutic heparin given concern for NSTEMI. Echocardiogram revealed an ejection fraction of 30% with hypokinesis of the entire apex and mid ventricle, raising concern for a stress cardiomyopathy.Coronary angiogram was performed which demonstrated no coronary artery disease. The patient underwent a cardiac MRI which confirmed a stress cardiomyopathy. Meanwhile, her laboratory workup was completed which revealed an undetectable TSH, a low T4 (0.53 ng/dL, n 0.7-1.8 ng/dL), and an elevated T3 (6.37 pg/mL, n 1.71-3.71 pg/mL). Patient endorsed taking oral liothyronine (T3) at doses of 5-40 mcg BID over the past 6 weeks per her alternative medicine provider for treatment of WTS. Her stress cardiomyopathy was presumed to be due to her exogenous thyrotoxicosis from T3 supplementation. She was counseled on the importance of cessation of T3 supplementation, and was started on heart failure medications. On hospital day 3, her T3 normalized to 2.73 pg/mL, and T4 remained low (0.4 pg/mL). Follow-up echocardiogram four months later demonstrated an ejection fraction that had improved to 45%. Conclusion: This case highlights the importance of physician awareness of alternative medicine diagnoses and treatment regimens that affect thyroid hormones and may cause harm to patients. This case is an important reminder of the effect thyroid hormones have on coronary vasculature, myocytes and myocardial function.

Artemether and lumefantrine dissolving microneedle patches with improved pharmacokinetic performance and antimalarial efficacy in mice infected with Plasmodium yoelii

Malaria affects more than 200 million people annually around the world, killing a child every 2 min. Artemether (ART) and lumefantrine (LUM) are the gold standard choice to treat uncomplicated Plasmodium falciparum malaria; however, they are hydrophobic compounds with low oral bioavailability. Microneedle (MN) arrays consist of micron-sized needles on one side of a supporting base and have the ability to bypass the skin's stratum corneum barrier in a minimally invasive way, creating temporary channels through which drugs can diffuse, including those with poor water solubility. Herein, we report the development of dissolving MNs (DMNs) containing ART (MN-ART) and LUM (MN-LUM) as an alternative treatment regimen for malaria in low-resource settings. To incorporate the drugs into the MNs, nanosuspensions (NSs) for both molecules were developed separately to enhance drug solubility. The NSs were freeze-dried and the powder form was incorporated directly in an aqueous polymeric blend with poly-vinyl-pyrrolidone for MN-ART and a sodium hyaluronate hydrogel for MN-LUM. The in vivo bioavailability studies were performed using a MN reapplication scheme (1 × a day for 3 days), illustrating that an extended-release profile was achieved for both drugs when MNs were applied intradermally, and when compared to conventional oral treatment. The ART-LUM oral treatment was used as a positive control. For antimalarial activity, studies with animals infected with 106Plasmodium yoelii 17XNL (12 days) were also conducted using female C57BL/6JUnib mice, demonstrating a 99.5% reduction in parasitemia by day 12 post-infection. By abolishing the infection, MN-ART and MN-LUM may serve as a promising controlled intradermal delivery device for antimalarial drugs to be explored in endemic areas.

Targeting B cells in multiple sclerosis

Treatments targeting B cells are increasingly used for patients with multiple sclerosis (MS). We review the mechanisms of action, clinical effectiveness and safety of treatment, with emphasis on recently published studies. Several monoclonal antibodies targeting the surface molecule CD20 on B cells are approved or being developed for treatment of MS. Overall, they seem comparable in terms of strongly suppressing radiological disease activity and relapse biology. Novel approaches include anti-CD19 antibody therapy and treatment with oral drugs targeting Bruton's tyrosine kinase (BTK). The main safety issue with persistent B cell depletion is an increased risk of infections - possibly including an increased risk of severe COVID-19. Vaccine responses are also blunted in patients treated with anti-CD20 antibodies. Lower doses or longer infusion intervals may be sufficient for control of disease activity. Whether this might also improve the safety of treatment and increase vaccination responses remains to be determined. Available data support the widespread use of therapies targeting B cells in MS. Whether novel approaches targeting CD19 or BTK will have advantages compared to anti-CD20 antibody therapy remains to be established. Furthermore, trials investigating alternative dosing regimens for anti-CD20 antibody treatment are warranted.

Ten-day bismuth-containing quadruple therapy versus 7-day proton pump inhibitor-clarithromycin containing triple therapy as first-line empirical therapy for the Helicobacter pylori infection in Korea: a randomized open-label trial

BackgroundThis randomized, open-label trial aimed to compare the efficacy of 10-day bismuth-containing quadruple therapy (BQT) with 7-day proton-pump inhibitor-clarithromycin containing standard triple therapy (STT) as an empirical first-line Helicobacter pylori therapy.MethodsParticipants with H. pylori infection were randomly assigned to either 10-day BQT (daily doses of bismuth 300 mg, four times; lansoprazole 30 mg, twice; metronidazole 500 mg, three times; and tetracycline 500 mg, four times) or 7-day STT (lansoprazole 30 mg; amoxicillin 1,000 mg; and clarithromycin 500 mg; each given twice daily). Participants who failed initial therapy were crossed over to the alternative treatment regimen. Primary outcome was the eradication rates of first-line treatment by intention-to-treat analysis.ResultsStudy participants (n = 352) were randomized to receive either 10-day BQT (n = 175) or 7-day STT (n = 177). The BQT-group achieved a significantly higher eradication rate than the STT-group in the intention-to-treat analysis (74.3% vs 57.1%, respectively; P = 0.001), modified intention-to-analysis (87.2% [130/149] vs 68.7% [101/147], respectively; P < 0.001) and per-protocol analysis (92.9% [105/113] vs 70.1% [94/134], respectively; P < 0.001). Although there was no serious adverse event, the compliance was lower with BQT than STT as a higher proportion of participants in the BQT-group discontinued therapy because of adverse events than those in the STT-group (23.1% vs 9.1%, respectively; P = 0.001)ConclusionsTen-day BQT had higher eradication rates compared to that of the 7-day STT as an empirical first-line treatment for H. pylori eradication in Korea.Trial registration: ClinicalTrials.gov, NCT02557932. Registered 23 September 2015, https://clinicaltrials.gov/ct2/show/NCT02557932?term=NCT02557932&draw=2&rank=1.

Clinicopathologic Features of Myelodysplastic Syndromes Involving Lymph Nodes.

Lymph nodes (LNs) involved by a myelodysplastic syndrome (MDS) are rare and uncommonly biopsied. In this study, we report 6 MDS patients who underwent an LN biopsy that showed MDS, and we summarize the clinicopathologic features of this cohort. All patients presented with lymphadenopathy (generalized in 5), 5 patients had splenomegaly, and 3 patients had hepatomegaly. Histologically, the LN architecture was distorted without complete effacement. MDS cells, mostly of the myeloid lineage, produced interfollicular expansion. These myeloid cells exhibited a spectrum of maturation, and immature and atypical forms were common, including eosinophils. Scattered megakaryocytes and nucleated erythroid cells were often present. Concurrent bone marrow aspirate and biopsy specimens in these patients showed persistent/resistant MDS. Following the diagnosis of LN involvement, patients did not respond well to therapy and all died by the time of the last follow-up, with a median survival of 6.7 months (range, 4.5 to 21.6 mo). In summary, patients with MDS uncommonly develop clinically evident lymphadenopathy prompting biopsy as a result of infiltration by MDS. MDS in LNs can be subtle, showing incomplete and sometimes mild distortion of the architecture, and ancillary studies including immunohistochemical and flow cytometric immunophenotypic analysis are often needed to establish the diagnosis. These data also suggest that the emergence of lymphadenopathy attributable to MDS is associated with poor treatment response and prognosis in MDS patients and that aggressive therapy or alternative treatment regimens need to be explored in this context.

Drugs that target early stages of Onchocerca volvulus: A revisited means to facilitate the elimination goals for onchocerciasis.

Several issues have been identified with the current programs for the elimination of onchocerciasis that target only transmission by using mass drug administration (MDA) of the drug ivermectin. Alternative and/or complementary treatment regimens as part of a more comprehensive strategy to eliminate onchocerciasis are needed. We posit that the addition of “prophylactic” drugs or therapeutic drugs that can be utilized in a prophylactic strategy to the toolbox of present microfilaricidal drugs and/or future macrofilaricidal treatment regimens will not only improve the chances of meeting the elimination goals but may hasten the time to elimination and also will support achieving a sustained elimination of onchocerciasis. These “prophylactic” drugs will target the infective third- (L3) and fourth-stage (L4) larvae of Onchocerca volvulus and consequently prevent the establishment of new infections not only in uninfected individuals but also in already infected individuals and thus reduce the overall adult worm burden and transmission. Importantly, an effective prophylactic treatment regimen can utilize drugs that are already part of the onchocerciasis elimination program (ivermectin), those being considered for MDA (moxidectin), and/or the potential macrofilaricidal drugs (oxfendazole and emodepside) currently under clinical development. Prophylaxis of onchocerciasis is not a new concept. We present new data showing that these drugs can inhibit L3 molting and/or inhibit motility of L4 at IC50 and IC90 that are covered by the concentration of these drugs in plasma based on the corresponding pharmacological profiles obtained in human clinical trials when these drugs were tested using various doses for the therapeutic treatments of various helminth infections.

Reducing mortality associated with opportunistic infections in Atlantic salmonSalmo salarfry using hydrogen peroxide and peracetic acid

Developing efficacious protocols for applying water disinfectants to reduce opportunistic pathogen-associated mortalities during the Atlantic salmon Salmo salar fry stage would be highly beneficial for producers. Atlantic salmon fry (0.47 g ± 0.02) were exposed to daily stressors over four weeks while providing daily 30-min bath treatments of 15 mg/L hydrogen peroxide (H2O2), 0.2 mg/L peracetic acid (PAA) or 0.5 mg/L PAA. Survival was tracked, and skin and gill samples were collected at 2 and 4 weeks for histopathology. Moribund fish were regularly assessed via wet-mount microscopy, with organisms resembling Saprolegnia spp. routinely observed on gills of affected fish. Tanks treated with H2O2 had significantly (p < 0.05) higher survival (83.7% ± 1.7) compared to controls (69.5% ± 5.2) while no significant differences were observed between either PAA treatments (76.6% ± 0.6 and 77.4% ± 3.0 survival in the 0.2 mg/L and 0.5 mg/L PAA groups, respectively) and controls. Interestingly, no significant differences were noted among treatments for waterborne Saprolegnia spp. concentrations through qPCR quantification. Lower total suspended solids (TSS) were observed in both PAA treatment groups; no other water quality differences were noted. No treatment impacts were observed through histopathology at either sampling point. These results suggest that, at the dosage and treatment regime tested, H2O2 can be a safe and efficacious water treatment for reducing Atlantic salmon fry opportunistic infection-associated mortality during periods of physical and environmental stress. Assessments of alternative PAA treatment regimens should also be considered in future research aimed at reducing early life-stage mortality in Atlantic salmon.

Camel milk as an alternative treatment regimen for diabetes therapy.

Camel milk is a valuable source of nutrition with a wide range of therapeutic effects. Its unique composition helps to regulate the blood glucose level. The current study is aimed to evaluate the antidiabetic and hepatoprotective effects, as well as lipid profile restoration of camel milk in the diabetic mouse model. This innovative study evaluates the therapeutic effects of camel milk in diabetic mice by simultaneous measurement of blood glucose, HbA1c, ALT, AST, TG, cholesterol, and histopathological studies. The results showed that camel milk has significantly reduced blood glucose, HbA1c (p < .001), aspartate transaminase (AST), alanine transaminase (ALT) (p < .01), triglyceride (TG), and cholesterol (p < .01), compared to that in the diabetic control group. Also, the therapeutic effects of camel milk were completely comparable with the antidiabetic drug glibenclamide. The results of this study suggest that camel milk could be used as a proper alternative treatment regimen for diabetes therapy.

A Comparative Study on Depression and Anxiety of Mice (Mus musculus) on a Prebiotic-supplemented Diet Versus a Standard Diet during Unpredictable Chronic Mild Stress (UCMS)

Background. Anxiety and depression are becoming increasingly prevalent today and are often aggravated by day-to-day stresses. Because current management strategies are usually accompanied by unpleasant side effects, there is a need to look into alternative treatment regimens - such as prebiotics - that may provide equally effective anxiolytic and antidepressant effects. Objective. Therefore, the study aims to determine the effect of a combined fructooligosaccharide (FOS) and galactooligosaccharide (GOS) supplemented diet on anxiety and depression levels in mice subjected to Unpredictable Chronic Mild Stress (UCMS). Methods. Forty male BALB/C mice were subjected to UCMS under a pretest-posttest control group design where the treatment group received prebiotic supplementation throughout the study. Repeated measures ANOVA was run to evaluate between, within, and time interactions of the measured anxiety parameters using the light-dark box test, and depression parameter using the fur coat state assessment. Results. Results show that (1) the FOS + GOS treatment did not give the treatment group an advantage over the control group during UCMS, (2) both groups grew more anxious and depressed over time, and (3) the treatment group grew more anxious with time in relation to control in terms of the total time spent in the light side. Conclusion. These imply that the UCMS protocol was successful in inducing stress in mice, but the FOS + GOS regimen failed to provide anxiolytic and antidepressant effects on male BALB/C mice exposed to UCMS.