Corrected QT interval in hospitalized patients with coronavirus disease 2019: Focus on drugs therapy.

ABSTRACT: Corrected QT (QTc) interval prolongation has been associated with poor patient prognosis. In this study, we assessed the effects of different drugs and cardiac injury on QTc interval prolongation in patients with coronavirus disease 2019 (COVID-19).The study cohort consisted of 395 confirmed COVID-19 cases from the Wuhan Union Hospital West Campus. All hospitalized patients were treated with chloroquine/hydroxychloroquine (CQ/HCQ), lopinavir/ritonavir (LPV/r), quinolones, interferon, Arbidol, or Qingfei Paidu decoction (QPD) and received at least 1 electrocardiogram after drug administration.Fifty one (12.9%) patients exhibited QTc prolongation (QTc ≥ 470 ms). QTc interval prolongation was associated with COVID-19 severity and mortality (both P < .001). Administration of CQ/HCQ (odds ratio [OR], 2.759; 95% confidence interval [CI], 1.318-5.775; P = .007), LPV/r (OR, 2.342; 95% CI, 1.152-4.760; P = .019), and quinolones (OR, 2.268; 95% CI, 1.171-4.392; P = .015) increased the risk of QTc prolongation. In contrast, the administration of Arbidol, interferon, or QPD did not increase the risk of QTc prolongation. Notably, patients treated with QPD had a shorter QTc duration than those without QPD treatment (412.10 [384.39-433.77] vs 420.86 [388.19-459.58]; P = .042). The QTc interval was positively correlated with the levels of cardiac biomarkers (creatine kinase-MB fraction [rho = 0.14, P = .016], high-sensitivity troponin I [rho = .22, P < .001], and B-type natriuretic peptide [rho = 0.27, P < .001]).In conclusion, QTc prolongation was associated with COVID-19 severity and mortality. The risk of QTc prolongation was higher in patients receiving CQ/HCQ, LPV/r, and quinolones. QPD had less significant effects on QTc prolongation than other antiviral agents.

Interferon therapy in patients with SARS, MERS, and COVID-19: A systematic review and meta-analysis of clinical studies.

Concern regarding coronavirus (CoV) outbreaks has stayed relevant to global health in the last decades. Emerging COVID-19 infection, caused by the novel SARS-CoV2, is now a pandemic, bringing a substantial burden to human health. Interferon (IFN), combined with other antivirals and various treatments, has been used to treat and prevent MERS-CoV, SARS-CoV, and SARS-CoV2 infections. We aimed to assess the clinical efficacy of IFN-based treatments and combinational therapy with antivirals, corticosteroids, traditional medicine, and other treatments. Major healthcare databases and grey literature were investigated. A three-stage screening was utilized, and included studies were checked against the protocol eligibility criteria. Risk of bias assessment and data extraction were performed, followed by narrative data synthesis. Fifty-five distinct studies of SARS-CoV2, MERS-CoV, and SARS-CoV were spotted. Our narrative synthesis showed a possible benefit in the use of IFN. A good quality cohort showed lower CRP levels in Arbidol (ARB) + IFN group vs. IFN only group. Another study reported a significantly shorter chest X-ray (CXR) resolution in IFN-Alfacon-1 + corticosteroid group compared with the corticosteroid only group in SARS-CoV patients. In a COVID-19 trial, total adverse drug events (ADEs) were much lower in the Favipiravir (FPV) + IFN-α group compared with the LPV/RTV arm (P = 0.001). Also, nausea in patients receiving FPV + IFN-α regimen was significantly lower (P = 0.03). Quantitative analysis of mortality did not show a conclusive effect for IFN/RBV treatment in six moderately heterogeneous MERS-CoV studies (log OR = -0.05, 95% CI: (-0.71,0.62), I2 = 44.71%). A meta-analysis of three COVID-19 studies did not show a conclusive nor meaningful relation between receiving IFN and COVID-19 severity (log OR = -0.44, 95% CI: (-1.13,0.25), I2 = 31.42%). A lack of high-quality cohorts and controlled trials was observed. Evidence suggests the potential efficacy of several combination IFN therapies such as lower ADEs, quicker resolution of CXR, or a decrease in inflammatory cytokines; Still, these options must possibly be further explored before being recommended in public guidelines. For all major CoVs, our results may indicate a lack of a definitive effect of IFN treatment on mortality. We recommend such therapeutics be administered with extreme caution until further investigation uncovers high-quality evidence in favor of IFN or combination therapy with IFN.

[Topical chemotherapy for conjunctival tumours - the medical and legal bearings of the case]. / Lokale Chemotherapie von Tumoren der Bindehaut - interdisziplinär medizinische und administrative Aspekte.

The treatment management of malignant tumours is characterised and limited by specific features of the topographical structure of the eye. The anatomic characteristics of the conjunctival sac, the movable tissue structures and the need to take care of corneal transparency and conjunctival stability are the main concerns of the experts. Clinical studies have revealed adjuvant chemotherapy to have a positive effect as a therapeutic treatment for neoplasia of the conjunctiva and cornea. Although mitomycin and interferon are widely used, there are no phase III studies on local adjuvant chemotherapy (interferon, mitomycin, 5-fluorouracil) that evaluate the proof of effectiveness, potential adverse effects or interactions with other drugs. For this reason, the currently available studies fail to comply with the jurisdiction of the German Federal Social Court. Hence, the Medical Service of the Health Insurance Funds (MDK) regionally does not accept the medical preconditions for reimbursement of the costs in adjuvant local chemotherapy. A doctor's unquestioned acceptance of such an MDK decision could have legal consequences. An off-label use is acceptable by law if there is no alternative treatment available with a higher evidence level that conforms to the medical standard. It is therefore recommendable for the Joint Federal Committee commissions the experts in ophthalmology and oncology on off-label use, to review the scientific evidence regarding adjuvant therapy of malignant tumours of the ocular surface. Only in this way can regional disparities in patient care, and intrusions on the doctor-patient relationship, be avoided.

Efectos adversos metabólicos y nutricionales asociados a la terapia biológica del cáncer / Associated metabolic and nutritional side effects to biological cancer therapy

Introducción: Los diferentes tipos de cáncer constituyen una de las principales causas de morbi-mortalidad en el mundo. La terapia clásica antitumoral (cirugía, quimioterapia, radioterapia) ha incrementado notoriamente la supervivencia. Las terapias biológicas, con mecanismos de acción selectivos y frecuentemente específicos, constituyen una incorporación relativamente reciente al tratamiento oncológico; entre las más utilizadas se incluyen: citoquinas, anticuerpos monoclonales e inhibidores de tirosin kinasa y de mTOR. Si bien están adecuadamente documentados los efectos adversos nutricionales y metabólicos asociados a la terapia clásica, tanto en literatura como en guías clínicas, no ocurre igual con la terapia biológica. Objetivo: Revisar la literatura al respecto y detallar de modo organizado los resultados obtenidos. Métodos: Se revisó la literatura indizada así como todas las fichas técnicas de los fármacos incluidos en las distintas familias mediante la Agencia Española del Medicamento y Productos Sanitarios a Julio de 2013. Se registran los síntomas y signos clínicos con teórica acción sobre el estado nutricional o metabólico. Resultados: Se describe la acción específica de cada familia. Se agrupan los posibles efectos adversos de cada una sobre el estado nutricional y metabolismo, detallando y diferenciándolos en tablas para una más fácil y cómoda revisión y consulta. Se observan como posibles efectos secundarios más prevalentes los relacionados con el apetito, aparato digestivo y alteraciones electrolíticas. Conclusiones: Los posibles efectos secundarios asociados a terapias biológicas son múltiples y aparecen con diferente frecuencia y gravedad. Es importante al utilizarlas conocer el impacto nutricional y metabólico que pueden presentar, para su prevención y tratamiento (AU)

Introduction: The different types of cancer represent one of the main causes of morbimortality worldwide. Classical anti-tumor therapy (surgery, chemotherapy, radiotherapy) has notably increased the survival rate. Biological therapies, with selective and frequently specific mechanisms of action, are a relatively recent acquisition in oncologic therapy; among the most commonly used ones are: cytokines, monoclonal antibodies, tyrosine kinase inhibitors, and mTOR inhibitors. The nutritional and metabolic adverse effects of classical therapy are well documented in the literature and the clinical guidelines, which is not the case for biological therapy. Objective: To review the literature in this field and to detail in an organized manner the results obtained. Methods: Indexed literature and the technical data sheets of the drugs included in the different families were revised through the Spanish Agency of Medicines and Health Care Products until July of 2013. The symptoms and clinical signs of a theoretical action on the nutritional and metabolic status were recorded. Results: The specific action of each family is described. The possible adverse effects of each one of them on the nutritional and metabolic status are grouped, detailing and differentiating them in tables for easier and more friendly-user consultation. The most prevalent possible side effects observed are those related with the appetite, the gastrointestinal tract, and electrolytic impairments. Conclusions: the possible side effects associated to biological therapies are plenty and occur with different frequency and severity. It is important to know the nutritional and metabolic impact when using these therapies for preventing and managing them (AU)

A meta-analysis of adjuvant therapy after potentially curative treatment for hepatocellular carcinoma.

BACKGROUND: The high recurrence rate of hepatocellular carcinoma (HCC) after potentially curative treatment determines the long-term prognosis. OBJECTIVE: To evaluate the efficacy and safety of adjuvant therapies in patients with HCC who have undergone hepatic resection, transplantation or locoregional ablation therapy. METHODS: Several databases were searched to identify randomized controlled trials (RCTs) fulfilling the predefined selection criteria. Meta-analyses were performed to estimate the effects of adjuvant therapies of any modality on recurrence-free survival (RFS) and overall survival (OS). RESULTS: Eight adjuvant modalities were identified from 27 eligible RCTs conducted predominantly in Asian populations comparing adjuvant with no adjuvant therapy. Adjuvant chemotherapy, internal radiation and heparanase inhibitor PI-88 therapy failed to improve RFS or OS, while interferon (IFN) therapy yielded significant survival results. The findings of adjuvant vitamin analogue therapy required further examination. Adjuvant adoptive immunotherapy conferred significant benefit for RFS but not for OS. Although cancer vaccine therapy and radioimmunotherapy may improve survival after radical surgery, the results were from single, small-scale trials. Severe side effects were observed in the studies of adjuvant chemotherapy and of IFN therapy. CONCLUSIONS: Adjuvant IFN therapy can improve both RFS and OS; however, the benefits of using this agent should be weighed against its side effects. Combination of systemic and transhepatic arterial chemotherapy is not recommended for HCC after potentially curative treatment. Other adjuvant therapies produce limited success for survival. Additional RCTs with proper design are required to establish the role of adjuvant therapies for HCC.

Approach to the treatment-experienced patient with hepatitis C virus genotype 1 infection.

A significant proportion of treatment-experienced hepatitis C virus genotype 1 (GT1) patients will not achieve sustained virologic response [corrected] with protease inhibitor-triple therapy, and so the need for alternative therapies for these patients remains high. The aim of this article is to provide a critical evaluation of the available data, highlighting the knowledge gaps and providing a practical framework for making treatment decisions in treatment-experienced GT1 patients with currently approved drugs.

Regulators of innate immunity as novel targets for panviral therapeutics.

Interferons (IFNs) have long been used as an immunomodulatory therapy for a large array of acute and chronic viral infections. However, IFN therapies have been plagued by severe side effects. The discovery of pathogen recognition receptors (PRR) rejuvenated the interest for immunomodulatory therapies. The successes obtained with Toll-like receptor (TLR) agonists in activating immune cells and as adjuvant for prophylactic vaccines against different viruses paved the way to targeted immunomodulatory therapy. Better characterization of pathogen-induced immune disorders and newly discovered regulators of innate immunity have now the potential to specifically withdraw prevailing subversion mechanisms and to transform antiviral treatments by introducing panviral therapeutics with less adverse effects than IFN therapies.

Classical and emerging roles of vitamin D in hepatitis C virus infection.

According to the Institute of Medicine, the risk of clinically significant vitamin D deficiency increases at 25-hydroxyvitamin D levels below 20 ng/mL. By this standard, most cirrhotic hepatitis C virus- (HCV-) positive patients and many noncirrhotic patients are vitamin D-deficient. The high prevalence of vitamin D deficiency among HCV patients is a cause for concern for several specific reasons. Classic studies established the importance of vitamin D and calcium in maintaining bone. Vitamin D's beneficial effects on bone are likely to be vital for HCV-infected patients because these individuals have a high prevalence of low bone mineral density. Many pharmaceutical agents reduce bone density and exposure to these drugs may increase bone disease in HCV-positive patients. Bone loss occurs following liver transplantation and bone density is often low in patients with HIV/HCV co-infection who are on combination antiretroviral therapy. Some evidence suggests that ribavirin reduces bone density, underscoring the special need to monitor vitamin D in patients receiving HCV treatment and to prescribe supplements, as appropriate. In addition to its role in calcium metabolism, vitamin D is also an immune modulator that reduces inflammation while enhancing protective immune responses. Higher vitamin D levels are associated with less liver fibrosis and less inflammation in HCV patients. Recent studies show that low vitamin D levels are associated with treatment failure among HCV-infected patients receiving pegylated-interferon and ribavirin. If confirmed, these findings will provide an additional reason to ensure adequate levels of vitamin D. Information about how to monitor vitamin D status and how to use vitamin D supplements most effectively in HCV-infected patients is provided.

Benefits of Reiki therapy for a severely neutropenic patient with associated influences on a true random number generator.

BACKGROUND: Reiki therapy is documented for relief of pain and stress. Energetic healing has been documented to alter biologic markers of illness such as hematocrit. True random number generators are reported to be affected by energy healers and spiritually oriented conscious awareness. METHODS: The patient was a then 54-year-old severely ill man who had hepatitis C types 1 and 2 and who did not improve with conventional therapy. He also suffered from obesity, the metabolic syndrome, asthma, and hypertension. He was treated with experimental high-dose interferon/riboviron therapy with resultant profound anemia and neutropenia. Energetic healing and Reiki therapy was administered initially to enhance the patient's sense of well-being and to relieve anxiety. Possible effects on the patient's absolute neutrophil count and hematocrit were incidentally noted. Reiki therapy was then initiated at times of profound neutropenia to assess its possible effect on the patient's absolute neutrophil count (ANC). Reiki and other energetic healing sessions were monitored with a true random number generator (RNG). RESULTS: Statistically significant relationships were documented between Reiki therapy, a quieting of the electronically created white noise of the RNG during healing sessions, and improvement in the patient's ANC. The immediate clinical result was that the patient could tolerate the high-dose interferon regimen without missing doses because of absolute neutropenia. The patient was initially a late responder to interferon and had been given a 5% chance of clearing the virus. He remains clear of the virus 1 year after treatment. CONCLUSIONS: The association between changes in the RNG, Reiki therapy, and a patient's ANC is the first to the authors' knowledge in the medical literature. Future studies assessing the effects of energetic healing on specific biologic markers of disease are anticipated. Concurrent use of a true RNG may prove to correlate with the effectiveness of energetic therapy.

Chronic cough associated with interferon/ribavirin therapy for hepatitis C.

WHAT IS KNOWN AND OBJECTIVE: The combination of pegylated interferon and ribavirin has become standard therapy for chronic hepatitis C infection. The occurrence of chronic cough associated with this treatment regimen has been reported, but the mechanism by which cough occurs has not previously been investigated. We measured cough reflex sensitivity, during and after completion of therapy, in four patients who developed chronic cough associated with interferon/ribavirin therapy. CASE SUMMARY: Four patients without history of respiratory symptoms developed chronic cough temporally related to initiation of therapy with pegylated interferon and ribavirin for chronic hepatitis C infection. Cough resolved within 2-6 weeks after completion of a 48-week course of therapy. To measure cough reflex sensitivity, capsaicin cough challenge testing was performed 1 month prior to cessation of therapy, and 1 and 2 months after completion of treatment. In all patients, cough reflex sensitivity, as measured by C(5) , the concentration of capsaicin inducing 5 or more coughs, was significantly enhanced during treatment compared to 1 month after completion of therapy (P = 0·016). WHAT IS NEW AND CONCLUSION: Previous studies have observed that cough occurs more commonly in patients receiving the combination of interferon and ribavirin compared to interferon alone, thus implicating ribavirin as the causal agent. Our data demonstrate that it does so by reversible enhancement of cough reflex sensitivity. Clinicians should be aware of this potential treatment-related effect, so as to avoid unnecessary and costly diagnostic evaluations seeking an alternative aetiology of cough.

Evaluation of oral cannabinoid-containing medications for the management of interferon and ribavirin-induced anorexia, nausea and weight loss in patients treated for chronic hepatitis C virus.

OBJECTIVES: The systemic and cognitive side effects of hepatitis C virus (HCV) therapy may be incapacitating, necessitating dose reductions or abandonment of therapy. Oral cannabinoid-containing medications (OCs) ameliorate chemotherapy-induced nausea and vomiting, as well as AIDS wasting syndrome. The efficacy of OCs in managing HCV treatment-related side effects is unknown. METHODS: All patients who initiated interferon-ribavirin therapy at The Ottawa Hospital Viral Hepatitis Clinic (Ottawa, Ontario) between August 2003 and January 2007 were identified using a computerized clinical database. The baseline characteristics of OC recipients were compared with those of nonrecipients. The treatment-related side effect response to OC was assessed by c2 analysis. The key therapeutic outcomes related to weight, interferon dose reduction and treatment outcomes were assessed by Student's t test and c2 analysis. RESULTS: Twenty-five of 191 patients (13%) initiated OC use. Recipients had similar characteristics to nonrecipients, aside from prior marijuana smoking history (24% versus 10%, respectively; P=0.04). The median time to OC initiation was seven weeks. The most common indications for initiation of OC were anorexia (72%) and nausea (32%). Sixty-four per cent of all patients who received OC experienced subjective improvement in symptoms. The median weight loss before OC initiation was 4.5 kg. A trend toward greater median weight loss was noted at week 4 in patients eventually initiating OC use (-1.4 kg), compared with those who did not (-1.0 kg). Weight loss stabilized one month after OC initiation (median 0.5 kg additional loss). Interferon dose reductions were rare and did not differ by OC use (8% of OC recipients versus 5% of nonrecipients). The proportions of patients completing a full course of HCV therapy and achieving a sustained virological response were greater in OC recipients. CONCLUSIONS: The present retrospective cohort analysis found that OC use is often effective in managing HCV treatment-related symptoms that contribute to weight loss, and may stabilize weight decline once initiated.

[The use of hepatoprotector LiverPro in combined therapy of chronic viral hepatitis C].

We analysed clinical characteristics, laboratory findings, nature and frequency of side effects, and positive virologic response rate in 20 patients with chronic viral hepatitis C (HCV) given combined antiviral therapy with PEG-Intron, ribavirin, and LiverPro hepatoprotector (Santegra, USA, two capsules twice daily) during 3 months. The results were compared with those obtained in the control group of HCV patients receiving the same treatment excepting the hepatoprotector. Clinical manifestations of HCV in the former group disappeared 7-10 days earlier than in control. Also, cytolytic syndrome resolved in these patients, the positive virologic response rate was 20% higher and the frequency of severe side effects of interferon therapy that required its withdrawal was 10% lower. The authors recommend to include LiverPro in combined therapy of HCV.

[Damage to retinal vasculature]. / Les dommages vasculaires rétiniens.

The use of interferon increased these last years. Cotton wool-spots, retinal hemorrhages, and microaneurysms are common manifestations of interferon retinopathy. The frequency of this retinopathy is underestimated as it is often asymptomatic. Screening and a multidisciplinary approach are therefore recommended.

Neuroendocrine tumors. Biotherapy.

This review gives an introduction to the classification and staging of neuroendocrine tumors, as the prognostic implications of these classifications influence therapeutic decisions. The indications for biotherapy are given, together with a short update on the mechanism of somatostatin analogs and interferon-alpha therapy. This is followed by an in-depth description of the use of biotherapy, its results with respect to symptomatic and antiproliferative treatment, as well as its side-effects.

Relative hypoparathyroidism induced by interferon treatment in a hemodialysis patient.

Several authors have documented beneficial effects of interferon (IFN) in chronic hepatitis C virus (HCV) infection among the dialysis population. Reports about mineral metabolism disturbances during IFN treatment are scarce, especially in dialysis patients. We report the case of a 49-year-old woman on hemodialysis with chronic HCV infection who developed significant decrease in serum calcium (Ca) and phosphorus (P) levels accompanied by relative hypoparathyroidism while being under treatment with alpha-IFN. These changes were closely related to IFN treatment, because they disappeared after INF was discontinued, reaching Ca and P levels which were similar to those of the pre-IFN period. Because IFN may induce immune disorders, several autoimmune markers were analyzed. All of them were negative or within the normal range. To further explore these mineral metabolism disturbances, a number ofparathyroid hormone (PTH) secretion-inhibiting factors, such as aluminum, magnesium, 25-hydroxyvitamin D, and calcitriol were excluded as a cause for these changes. We suggest that mineral metabolism should be carefully observed during interferon treatment in dialysis patients.

Evidence-informed assessment and treatment of depression in HCV and interferon-treated patients.

More than 4 million people are currently infected with Hepatitis C an RNA virus that may ultimately result in complete hepatic failure and is often a silent infection until late in the course of disease. Hepatitis C patients have increased rates of major depression (as well as substance abuse) and treatment of hepatitis with interferon, the current standard treatment, provokes episodes of depression in as many as a third of patients treated. Immune-dysfunction mediated mechanisms for the depression in these patients have been proposed and have increasing experimental support. The resulting depression has interfered with treatment for many patients, but several standard treatments for depression have been shown to be effective in patients with interferon-associated depression, suggesting that this should not be a barrier to effective treatment. In this paper, we review the evidence for associations between depression and Hepatitis C and interferon treatment, as well as the evidence supporting an immune mechanism for the association, and finally the data showing effective treatment and recommendations for prophylactic use of anti-depressants.