Intermittent therapy with levosimendan in patients with advanced heart failure

Introduction Therapeutic options for patients with advanced heart failure on the high-urgent (HU) heart transplant (HTx) waiting list are limited. In view of the limited data on the usefulness of classic inotropes, the calcium sensitizer levosimendan (Lev) may be a possible alternative for patients in need of a repetitive therapy with an inotropic agent as a bridge to HTx. Method In a single-center open-label study we retrospectively analyzed data from 34 HU-listed patients (from a total collective of 95 HU patients) who repetitively received Lev (12.5 mg; 0,05–0.1 μg/kg/min over 24–48h) in 2–8 weeks intervals due to cardiac instability and/or progressive second organ dysfunction. Potential side effects as well as changes of kidney, liver and heart functional parameters were evaluated (0–6 days before, 4–8 days and 14–20 days after Lev infusion). Patient collective: age 51±10 years, 6 women, 28 men; NYHA stage III-IV. 11 Patients with ischemic cardiomyopathy (32%), 19 patients with dilated cardiomyopathy (56%), 4 patients with arrhythmogenic right ventricular cardiomyopathy (12%). Results The waiting time for HTx was up to 12 months (6±5 months). There were no adverse, serious events (resuscitation, defibrillation for ventricular tachycardia (VT), intubation and ventilation, renal replacement therapy) up to 7 days after Lev infusion. Transient cardiac arrhythmias (ventricular bursts or non-sustained VTs) occurred in 11 patients (32%) with spontaneous termination and no need of urgent anti-arrhythmic therapy. The values for sodium, potassium, Hb and CRP did not change significantly after Lev. In contrast, there was a significant reduction in creatinine after 4–8 days (initially 1.43±0.4 mg/dl; after 4–8 days 1.28±0.3; p<0.0005) with an increase again after 14–20 days (1.43±0.3 mg/dl). The bilirubin value was significantly reduced after 4–8 days (initially 1.63±0.7 mg/dl; after 4–8 days 1.30±0.5; p<0.0005) with only partial (non-significant) increases again over the course (1.34±0.5 mg/dl). The BNP value was significantly reduced 4–8 days after administration of Lev (initially 1565±1136 ng/l; after 4–8 days 1103±895; p<0.0001) and increased again in the longer time course (1462±1001 ng/l; p<0.001 versus 4–8 days). 28 patients were successfully transplanted (82%). 6 patients remained without HTx (18%), of which 1 patient (3%) with clinical improvement could be discharged. 2 patients (6%) received an LVAD and 3 patients (9%) died during the waiting period. Conclusion Intermittent therapy with Lev as “a bridge to transplant” is safe and effective concerning deterioration of heart failure and prevention of progressive kidney/hepatic dysfunction. However, a prospective randomized multi-center trial is necessary to underscore the encouraging data of this observational, single center study. FUNDunding Acknowledgement Type of funding sources: None.

Treatment Outcomes of Mycobacterium Avium Complex Pulmonary Disease According to Disease Severity

Mycobacterium avium complex pulmonary disease (MAC-PD) requires long-term treatment. We analyzed the outcomes of 992 MAC-PD patients according to disease severity and compared the outcomes of intermittent and daily therapy for mild disease. Patients were divided into groups according to severity using the body mass index, age, cavity, erythrocyte sedimentation rate, and sex (BACES) system, and culture conversion rates were evaluated. We also evaluated the effects of intermittent treatment on the culture conversion rates in mild disease group. Using the BACES, 992 patients were divided into mild (n=331), moderate (n=503), and severe (n=158) disease groups, and culture conversion at the end of treatment was achieved in 85% (282/331), 80% (403/503), and 61% (97/158), respectively. Differences in culture conversion among the severity groups were significant (p<0.001). In patients with mild disease, culture conversion rates were similar between intermittent (84%, 166/198) and daily (87%, 116/133) treatment (p=0.396), and intermittent antibiotic therapy did not negatively impact culture conversion (adjusted hazard ratio 1.08; confidence interval 0.83–1.15; p=0.552). MAC-PD patients with mild disease had higher culture conversion rates. Daily and intermittent therapy yielded similar culture conversion rates for mild disease. Treatment strategies with lower pill burden may be applicable in mild MAC-PD.

Five-year microevolution of a multidrug-resistant Mycobacterium tuberculosis strain within a patient with inadequate compliance to treatment

Background Whole-genome sequencing has shown that the Mycobacterium tuberculosis infection process can be more heterogeneous than previously thought. Compartmentalized infections, exogenous reinfections, and microevolution are manifestations of this clonal complexity. The analysis of the mechanisms causing the microevolution —the genetic variability of M. tuberculosis at short time scales— of a parental strain into clonal variants with a patient is a relevant issue that has not been yet completely addressed. To our knowledge, a whole genome sequence microevolution analysis in a single patient with inadequate adherence to treatment has not been previously reported. Case presentation In this work, we applied whole genome sequencing analysis for a more in-depth analysis of the microevolution of a parental Mycobacterium tuberculosis strain into clonal variants within a patient with poor treatment compliance in Argentina. We analyzed the whole-genome sequence of 8 consecutive Mycobacterium tuberculosis isolates obtained from a patient within 57-months of intermittent therapy. Nineteen mutations (9 short-term, 10 fixed variants) emerged, most of them associated with drug resistance. The first isolate was already resistant to isoniazid, rifampicin, and streptomycin, thereafter the strain developed resistance to fluoroquinolones and pyrazinamide. Surprisingly, isolates remained susceptible to the pro-drug ethionamide after acquiring a frameshift mutation in ethA, a gene required for its activation. We also found a novel variant, (T-54G), in the 5′ untranslated region of whiB7 (T-54G), a region allegedly related to kanamycin resistance. Notably, discrepancies between canonical and phage-based susceptibility testing to kanamycin were previously found for the isolate harboring this mutation. In our patient, microevolution was mainly driven by drug selective pressure. Rare short-term mutations fixed together with resistance-conferring mutations during therapy. Conclusions This report highlights the relevance of whole-genome sequencing analysis in the clinic for characterization of pre-XDR and MDR resistance profile, particularly in patients with incomplete and/or intermittent treatment.

Five-year Microevolution of a Multidrug-Resistant Mycobacterium Tuberculosis Strain within a Patient with Inadequate Compliance to Treatment.

BackgroundWhole-genome sequencing has shown that the Mycobacterium tuberculosis infection process can be more heterogeneous than previously thought. Compartmentalized infections, exogenous reinfections, and microevolution are manifestations of this clonal complexity. The analysis of the mechanisms causing the microevolution —the genetic variability of M. tuberculosis at short time scales— of a parental strain into clonal variants with a patient is a relevant issue that has not been yet completely addressed. To our knowledge, a whole genome sequence microevolution analysis in a single patient with inadequate adherence to treatment has not been previously reported.Case Presentations In this work, we applied whole genome sequencing for a more in-depth analysis of the microevolution of a parental Mycobacterium tuberculosis strain into clonal variants within a patient with poor treatment compliance in Argentina. We analyzed the whole-genome sequence of 8 consecutive Mycobacterium. tuberculosis isolates obtained from a patient within 57-month of intermittent therapy. Nineteen mutations (9 short-term, 10 fixed variants) emerged, most of them associated with drug resistance. The first isolate was already resistant to isoniazid, rifampicin, and streptomycin, thereafter the strain developed resistance to fluoroquinolones and pyrazinamide. Surprisingly, isolates remained susceptible to the pro-drug ethionamide after acquiring a frameshift mutation in ethA, a gene required for its activation. We also found a novel variant, (T-54G), in the 5' untranslated region of whiB7 (T-54G), a region allegedly related to kanamycin resistance. Notably, discrepancies between canonical and phage-based susceptibility testing to kanamycin were previously found for the isolate harboring this mutation. In our patience, microevolution was mainly driven by drug selective pressure. Rare short-term mutations fixed together with resistance-conferring mutations during therapy.ConclusionsThis report highlights the relevance of whole-genome sequencing in the clinic for characterization of pre-XDR and MDR resistance profile, particularly in patients with incomplete and/or intermittent treatment.

Intermittent Versus Continuous Androgen Deprivation in Prostate Cancer

This chapter summarizes the findings of an important non-inferiority trial comparing intermittent androgen-deprivation therapy to continuous systemic androgen-deprivation therapy. The results favored continuous androgen-deprivation therapy to a small degree but favored intermittent therapy in terms of potency and mental health. This and similar trials have informed the potential trade-offs of intermittent versus continuous therapy.

Relugolix: a novel androgen deprivation therapy for management of patients with advanced prostate cancer

Androgen deprivation therapy (ADT) is the foundation of treatment for patients with locally advanced, recurrent and metastatic prostate cancer, most commonly using luteinizing releasing hormone (LHRH) agonists. More recently, a new approach to ADT has emerged with the development of gonadotropin-releasing hormone (GnRH) antagonists, which aim to overcome some of the potential adverse physiologic effects of LHRH agonists. This article focuses on the newest GnRH antagonist, relugolix – a once-daily treatment and the only oral GnRH antagonist that has now been approved for the treatment of advanced prostate cancer. In phase II and III studies, relugolix achieved rapid and sustained castration without the testosterone surge associated with LHRH agonists, thus avoiding the potential clinical consequences of tumor flare and the necessity for concomitant anti-androgen therapy. Relugolix also achieved rapid testosterone recovery, which may potentially reduce ADT-related adverse events and offer opportunities for combination and intermittent therapy strategies. Cardiovascular safety is a particular concern in men with prostate cancer and ADT further increases cardiovascular risk: indeed, LHRH agonists are required to have a drug label warning about an increased risk of cardiovascular disease. Data from the phase III HERO study demonstrate an improved cardiac safety profile for the GnRH antagonist relugolix compared with the LHRH agonist leuprolide, including a significantly reduced risk for a major adverse cardiovascular event. Taken together, the data indicate that relugolix may mitigate some of the cardiovascular concerns surrounding ADT and has the potential to become a new standard of care for men with prostate cancer. In summary, relugolix represents a novel and recently available prostate cancer management strategy, incorporating the mechanistic advantages of GnRH antagonists and the potential benefits of oral administration.

Management of acneiform rash associated with anti-EGFR monoclonal antibody treatment

Introduction. Dermatologic adverse events (DAEs) occur in 50-90% of cases during anti-EGFR monoclonal antibody treatment. Positive correlation between the severity of acneiform rash (AR) and the effectiveness of anti-EGFR management is established. Low effectiveness of traditional treatment for AR impairs patients’ compliance, leads to dose reduction or drug discontinuation, affecting treatment results.Objective. To assess the effectiveness of traditional and proposed combined treatment for AR associated with anti-EGFR monoclonal antibody therapy.Materials and methods. 44 patients with grade I-II acneiform rash were included in a 12-week study. Patients were divided into 3 equal groups and received different treatment: group 1a – traditional therapy, group 1b – combined continuous therapy, and group 1c – combined intermittent therapy. Assessment of clinical outcomes was performed with DLQI, IGA score, and the NCI CTCAE v. 4.03.Results. The severity of AR in groups 1b and 1c improved by the end of week 1, and this trend was kept until the end of the study. The improvement was more prominent in group 1c comparing to group 1b. The severity of AR in group 1a improved by the end of week 1. During weeks 2 and 3 there was no significant change. At week 4 a deterioration of the evaluated parameters was registered, and the treatment regimen in group 1a was changed according to the treatment protocols of group 1c with rapid improvement of AR.Conclusion. Combined intermittent therapy with systemic doxycycline and topical therapy with metronidazole 1% gel and cream with hydrocortisone acetate 1% and fusidic acid 2% showed the best effectiveness and tolerability in patients with anti-EGFR monoclonal antibody-related AR.

Seborrheic dermatitis: comparative effectiveness of standard and intermittent external therapy

Background. The chronic and recurrent nature of seborrheic dermatitis, its wide prevalence and multifactorial etiopathogenesis require a comparison of the effectiveness of different treatment strategies. Aim. In a randomized controlled trial to evaluate the effectiveness of standard and intermittent therapy with topical corticosteroids and activated zinc pyrithione (Skin-cap cream) in reducing the severity of clinical manifestations, the duration of remission of the disease, and compliance with treatment. Methods. The effectiveness of external therapy in patients with seborrheic dermatitis of the face and scalp was studied. All the examined patients had at least two episodes of exacerbation per year. Doctor's prescription Mometasone furoate cream 0.1% 1 time/day externally for 14 days, activated zinc pyrithione (Skin-cap cream) 2 times/day externally for 14 days, further 1 time a day 2 times a week for 14 days. Results. There was a comparable clinical effectiveness of antiinflammatory therapy in the short term with more stable results of intermittent therapy with the use of (Skin-cap cream) in the long term. Conclusions. Usage of activated zinc pyrithione (Skin-cap cream) according to the intermittent scheme in the treatment of seborrheic dermatitis of the face with the transition to the scalp is associated with long-term results. Safety of medicine allows to use it pro re nata by patients, e.g., in case of increased stress levels, diet incompliance, with no risks of adverse events, specific to topical corticosteroids, those increases treatment compliance.

Modulating proteasome inhibitor tolerance in multiple myeloma: an alternative strategy to reverse inevitable resistance

Background Resistance to proteasome inhibitors (PIs) is a major obstacle to the successful treatment of multiple myeloma (MM). Many mechanisms have been proposed for PI resistance; however, our mechanistic understanding of how PI resistance is inevitably acquired and reversed remains incomplete. Methods MM patients after bortezomib relapse, MM cell lines and mouse models were used to generate matched resistant and reversed cells. RNA sequencing and bioinformatics analyses were employed to assess dysregulated epigenetic regulators. In vitro and in vivo procedures were used to characterise PI-tolerant cells and therapeutic efficacy. Results Upon PI treatment, MM cells enter a slow-cycling and reversible drug-tolerant state. This reversible phenotype is associated with epigenetic plasticity, which involves tolerance rather than persistence in patients with relapsed MM. Combination treatment with histone deacetylase inhibitors and high-dosage intermittent therapy, as opposed to sustained PI monotherapy, can be more effective in treating MM by preventing the emergence of PI-tolerant cells. The therapeutic basis is the reversal of dysregulated epigenetic regulators in MM patients. Conclusions We propose an alternative non-mutational PI resistance mechanism that explains why PI relapse is inevitable and why patients regain sensitivity after a ‘drug holiday’. Our study also suggests strategies for epigenetic elimination of drug-tolerant cells.