ABSTRACT
BACKGROUND: The aim of this review is to elucidate the type and frequency of ocular adverse events associated with selinexor with a goal to quantify the occurrence of these events in our investigator-initiated trial. METHODS: We retrospectively reviewed medical records of 174 patients treated with at least one dose of selinexor in combination with multiple standard chemotherapy or immunotherapy agents between July 2015 and July 2020 at a comprehensive cancer center in the U.S. All reported ocular adverse events were assessed. RESULTS: A total of 174 patient medical records were reviewed. All patients received at least one dose of selinexor in combination with multiple standard chemotherapy or immunotherapy agents in our cohort of patients with advanced malignancies. A total of 34 (19.54%) patients experienced 37 ocular adverse events. The most frequently reported ocular symptom was blurred vision, which was reported in 22 (12.64%) patients. The most frequently reported treatment-related adverse event was dry eye syndrome reported in 21 (12.1%) patients, and 19 (10.9%) of them were diagnosed with mild dry eye. The second most common treatment-related adverse event was the progression of age-related nuclear sclerosis (cataract) reported in 7 (4.0%) patients. None of the ocular adverse events required therapy discontinuation. CONCLUSION: Our findings highlight that ocular adverse events associated with oral selinexor were mild. The most frequently reported ocular treatment-related adverse events were mild dry eye and progression of age-related nuclear sclerosis. None of the ocular adverse events required therapy discontinuation. IMPLICATIONS FOR PRACTICE: Patients receiving selinexor in combination with multiple standard chemotherapy or immunotherapy agents were reviewed, with a total of 34 patients experiencing 37 ocular adverse events. Findings highlight that ocular adverse events associated with oral selinexor were mild. The most frequently reported ocular treatment-related adverse events were mild dry eye and progression of age-related nuclear sclerosis. None of the ocular adverse events required therapy discontinuation.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Hydrazines , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Humans , Hydrazines/adverse effects , Retrospective Studies , Triazoles/adverse effectsABSTRACT
Introduction: Despite unprecedented advances in the treatment of multiple myeloma (MM), almost all patients develop a disease that is resistant to the five most commonly used and active anti-MM agents. The prognosis for this patient population is particularly poor resulting in an unmet need for additional therapeutic options. Exportin-1 (XPO-1) is a major nuclear export protein of macromolecular cargo frequently overexpressed in MM. Selinexor is a first-in-class, oral Selective-Inhibitor-of-Nuclear-Export (SINE) compound that impedes XPO-1. Based on results of the STORM-trial, selinexor in combination with dexamethasone was granted accelerated FDA approval for patients with penta-refractory MM in July 2019.Areas covered: This article summarizes our up-to-date knowledge on the pathophysiologic role of XPO-1 in MM. Furthermore, it reviews the most recent clinical data on selinexor in combination with dexamethasone and other anti-MM agents; and discusses its safety profile, management strategies; and potential future developments.Expert opinion: Selinexor represents a next-generation-novel agent with an innovative mechanism of action that marks a significant advance in the treatment of heavily pretreated MM patients. Ongoing studies investigate its therapeutic potential also in earlier lines of therapy. Additional data is needed to confirm that selinexor and other SINE compounds are a valuable addition to our current therapeutic armamentarium.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Hydrazines/therapeutic use , Karyopherins/antagonists & inhibitors , Multiple Myeloma/drug therapy , Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors , Triazoles/therapeutic use , Active Transport, Cell Nucleus/drug effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Cell Line, Tumor , Cell Nucleus/drug effects , Cell Nucleus/metabolism , Clinical Trials as Topic , Dexamethasone/therapeutic use , Drug Evaluation, Preclinical , Humans , Hydrazines/administration & dosage , Hydrazines/adverse effects , Hydrazines/pharmacokinetics , Karyopherins/genetics , Multiple Myeloma/metabolism , Prognosis , Receptors, Cytoplasmic and Nuclear/genetics , Triazoles/administration & dosage , Triazoles/adverse effects , Triazoles/pharmacokinetics , Exportin 1 ProteinSubject(s)
Benzoates/adverse effects , Hydrazines/adverse effects , Ischemia/etiology , Purpura, Thrombocytopenic, Idiopathic/drug therapy , Pyrazoles/adverse effects , Thrombosis/chemically induced , Aged , Biopsy , Clopidogrel/therapeutic use , Computed Tomography Angiography , Conservative Treatment , Female , Humans , Hyperbaric Oxygenation , Ischemia/pathology , Ischemia/therapy , Platelet Count , Purpura, Thrombocytopenic, Idiopathic/blood , Skin/blood supply , Skin/diagnostic imaging , Skin/pathology , Thrombosis/complications , Thrombosis/diagnosis , Thrombosis/drug therapy , Tibial Arteries/diagnostic imaging , Tibial Arteries/pathology , Toes/blood supply , Toes/diagnostic imaging , Toes/pathology , Treatment Outcome , Warfarin/therapeutic useABSTRACT
BACKGROUND: Cancer anorexia-cachexia syndrome is associated with increased morbidity and mortality. Anamorelin is an oral ghrelin-receptor agonist with appetite-enhancing and anabolic activity. We assessed the effects of anamorelin on body composition, strength, quality of life, biochemical markers, and safety in patients with cancer anorexia-cachexia. METHODS: Data were pooled, a priori, from two completed phase 2, multicentre, placebo-controlled, double-blind trials in patients with advanced or incurable cancer and weight loss of 5% or more. Patients were stratified by weight loss severity (5-15%, >15%) and randomly allocated (1:1) with a computer-generated randomisation schedule to anamorelin hydrochloride 50 mg or placebo once-daily for 12 weeks. Primary outcome was lean body mass by dual-energy x-ray absorptiometry over the 12 week treatment period in eligible patients who had at least one dose of study drug and post-treatment efficacy assessment. We assessed safety in all patients who received at least one dose of study drug. The trials are registered with ClinicalTrials.gov, numbers NCT00219817 and NCT00267358. FINDINGS: Between June 29, 2005, and Oct 26, 2006, we enrolled 44 patients in the anamorelin group and 38 patients in the placebo group. 74 patients were eligible for the efficacy analyses. Over 12 weeks, lean body mass increased in 38 patients in the anamorelin group by a least-squares mean of 1.89 kg (95% CI 0.84 to 2.95) compared with a decrease of a least-squares mean of -0.20 kg (-1.23 to 0.83) for 36 patients in the placebo group (difference 2.09 kg [0.94-3.25]; p=0.0006). 42 (95%) of 44 patients treated with anamorelin and 33 (87%) of 38 patients treated with placebo had adverse events. The most common grade 3-4 adverse events (treatment-related or not) in the anamorelin group were fatigue, asthenia, atrial fibrillation, and dyspnoea (two [5%] each); in the placebo group, such events were pneumonia (three [8%]) and anaemia, thrombocytopenia, abdominal pain, anxiety, and dyspnoea (two [5%] each). INTERPRETATION: Anamorelin treatment for 12 weeks had a favourable clinical response profile in patients with cancer anorexia-cachexia syndrome. These findings support further investigation in this setting. FUNDING: Helsinn Therapeutics (US), Helsinn Healthcare SA.
Subject(s)
Anabolic Agents/therapeutic use , Appetite Stimulants/therapeutic use , Cachexia/drug therapy , Hydrazines/therapeutic use , Neoplasms/complications , Oligopeptides/therapeutic use , Absorptiometry, Photon , Adult , Aged , Aged, 80 and over , Anabolic Agents/adverse effects , Analysis of Variance , Appetite Stimulants/adverse effects , Body Composition/drug effects , Cachexia/diagnosis , Cachexia/etiology , Cachexia/physiopathology , Clinical Trials, Phase II as Topic , Female , Humans , Hydrazines/adverse effects , Least-Squares Analysis , Male , Middle Aged , Muscle Strength/drug effects , Oligopeptides/adverse effects , Quality of Life , Randomized Controlled Trials as Topic , Time Factors , Treatment Outcome , United States , Weight Gain/drug effects , Young AdultABSTRACT
BACKGROUND: The purpose of this study was to evaluate the activity of Selective Inhibitors of Nuclear Export (SINE) compounds that inhibit the function of the nuclear export protein Exportin 1 (XPO1/CRM1) against canine tumor cell lines and perform a Phase I clinical trial of KPT-335 in dogs with spontaneous cancer to provide a preliminary assessment of biologic activity and tolerability. METHODS AND FINDINGS: Canine tumor cell lines derived from non-Hodgkin lymphoma (NHL), mast cell tumor, melanoma and osteosarcoma exhibited growth inhibition and apoptosis in response to nanomolar concentrations of SINE compounds; NHL cells were particularly sensitive with IC50 concentrations ranging from 2-42 nM. A Phase I clinical trial of KPT-335 was performed in 17 dogs with NHL (naive or relapsed), mast cell tumor or osteosarcoma. The maximum tolerated dose was 1.75 mg/kg given orally twice/week (Monday/Thursday) although biologic activity was observed at 1 mg/kg. Clinical benefit (CB) including partial response to therapy (PR, n = 2) and stable disease (SD, n = 7) was observed in 9/14 dogs with NHL with a median time to progression (TTP) for responders of 66 days (range 35-256 days). A dose expansion study was performed in 6 dogs with NHL given 1.5 mg/kg KPT-335 Monday/Wednesday/Friday; CB was observed in 4/6 dogs with a median TTP for responders of 83 days (range 35-354 days). Toxicities were primarily gastrointestinal consisting of anorexia, weight loss, vomiting and diarrhea and were manageable with supportive care, dose modulation and administration of low dose prednisone; hepatotoxicity, anorexia and weight loss were the dose limiting toxicities. CONCLUSIONS: This study provides evidence that the novel orally bioavailable XPO1 inhibitor KPT-335 is safe and exhibits activity in a relevant, spontaneous large animal model of cancer. Data from this study provides critical new information that lays the groundwork for evaluation of SINE compounds in human cancer.
Subject(s)
Acrylamides/pharmacokinetics , Acrylamides/therapeutic use , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Cell Nucleus/metabolism , Drug Evaluation, Preclinical , Hydrazines/pharmacokinetics , Hydrazines/therapeutic use , Neoplasms/drug therapy , Neoplasms/veterinary , Acrylamides/administration & dosage , Acrylamides/adverse effects , Active Transport, Cell Nucleus/drug effects , Administration, Oral , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Biological Availability , Cell Line, Tumor , Cell Nucleus/drug effects , Dogs , Dose-Response Relationship, Drug , Female , Humans , Hydrazines/administration & dosage , Hydrazines/adverse effects , Inhibitory Concentration 50 , Male , Quality of LifeABSTRACT
Field experiments were conducted during April and May of 2011 in Valparai, Coonoor and Gudalur (Tamil Nadu, India) to determine the residues of bifenazate in black tea. From this study, residue levels of bifenazate at different harvest intervals, persistence, dissipation pattern during processing, rate constant and half-life values were calculated. Residues of bifenazate dissipated exponentially after spraying and at Gudalur trial, on the 16th day after application residues were below the maximum residue level of 0.02 mg/kg set by the European Union. However, no residues were detected in the tea brew. Regression lines drawn for bifenazate showed that it followed first order dissipation kinetics. Half-life values varied from 1.03 to 1.36 days for bifenazate and a pre-harvest interval of 16 days is suggested.
Subject(s)
Camellia sinensis/chemistry , Carbamates/analysis , Crops, Agricultural/chemistry , Food Contamination/prevention & control , Hydrazines/analysis , Pesticide Residues/analysis , Pesticides/analysis , Tea/chemistry , Aerosols , Camellia sinensis/growth & development , Camellia sinensis/metabolism , Carbamates/adverse effects , Carbamates/chemistry , Carbamates/metabolism , Crops, Agricultural/growth & development , Crops, Agricultural/metabolism , Crops, Agricultural/standards , Diffusion , European Union , Food Contamination/legislation & jurisprudence , Food Handling , Food Inspection , Half-Life , Hydrazines/adverse effects , Hydrazines/chemistry , Hydrazines/metabolism , India , Kinetics , Legislation, Food , Pesticide Residues/adverse effects , Pesticide Residues/chemistry , Pesticide Residues/metabolism , Pesticides/adverse effects , Pesticides/chemistry , Pesticides/metabolism , Plant Leaves/chemistry , Plant Leaves/growth & development , Plant Leaves/metabolism , Regression Analysis , Solubility , Tea/standards , Tropical ClimateABSTRACT
PURPOSE: To develop a tool to assist the decision-making for selection of Thrombopoyetin Receptor Agonists of adult patients with chronic immune primary thrombocytopenia (PTI). METHODS: Stochastic cost-effectiveness analysis with a 6-Health- States Markov model: stable, bleeding type 2, 3 or 4, post-type 4 bleeding and death. Each simulation analyzes a randomly generated scenario that describes patients characteristics, results measured in quality adjusted life years (QALYs) and costs (in ?2011). Distributions were obtained from the Spanish data of the European health survey of 2009, the INE estimate of population for 2011 and the 6-months clinical studies for Eltrombopag and Romiplostim. Utility values were obtained from the literature and the costs from Spanish official rates lists. A set of 10.000 random scenarios were generated and the patients evolution of each scenario was simulated during a time horizon of five years (in 2-weeks cycles). National Health System Perspective was used and the annual discount rate was set at 3%. RESULTS: Eltrombopag showed more effectiveness in 9.983 scenarios and there was no difference in 17. In 7.048 scenarios the alternative Eltombopag was dominant. It was cost-effective in another 19 (threshold 30,000 ??/AVAC). CONCLUSIONS: Eltrombopag was the most cost-effective alternative in 70,67% of the simulated scenarios and its use could produce lower costs to the NHS.
Objetivo: Desarrollar una herramienta de apoyo a la decisión en la selección de agonistas del receptor de trombopoyetina en el tratamiento de pacientes adultos con trombocitopenia inmune primaria crónica (PTI) refractaria. Métodos: Análisis coste-efectividad estocástico con un modelo de Markov de seis estados: estable, sangrado tipo 2, 3 ó 4, post-sangrado 4 y muerte. Cada simulación analiza un escenario aleatoriamente generado que describe las características del paciente, los resultados medidos en años de vida ajustados a calidad (AVACs) y los costes (en ?2011). Se obtuvieron distribuciones a partir de los datos para España de la Encuesta Europea de Salud de 2009, de la estimación de población para 2011 del INE, de los estudios a 6 meses de Eltrombopag y Romiplostim, de las utilidades obtenidas de la bibliografía y de las tarifas oficiales en España para procesos y actividad. Se generaron 10.000 escenarios aleatorios y se simuló la evolución de los pacientes de cada escenario durante un horizonte temporal de cinco años (ciclos de dos semanas). Perspectiva del Sistema Nacional de Salud (SNS). Tasa de descuento anual del 3% para costes y efectos. Resultados: En 9.983 escenarios Eltrombopag mostró mayor efectividad y en 17 no hubo diferencias. Eltombopag fue la alternativa dominante en 7.048 escenarios y la más coste efectiva en otros 19 (umbral 30.000 ?/AVAC). Conclusiones: Eltrombopag es la alternativa más coste-efectiva en el 70,67% de los escenarios simulados, por lo que su uso podría producir menores costes al SNS.
Subject(s)
Benzoates/economics , Computer Simulation , Drug Costs/statistics & numerical data , Hydrazines/economics , Models, Economic , Purpura, Thrombocytopenic, Idiopathic/economics , Pyrazoles/economics , Receptors, Thrombopoietin/agonists , Recombinant Fusion Proteins/economics , Thrombopoietin/economics , Administration, Oral , Adult , Benzoates/adverse effects , Benzoates/therapeutic use , Combined Modality Therapy , Cost Savings , Cost-Benefit Analysis , Female , Hemorrhage/economics , Hemorrhage/etiology , Hemorrhage/prevention & control , Humans , Hydrazines/adverse effects , Hydrazines/therapeutic use , Injections, Subcutaneous , Male , Markov Chains , Middle Aged , National Health Programs/economics , Purpura, Thrombocytopenic, Idiopathic/drug therapy , Purpura, Thrombocytopenic, Idiopathic/epidemiology , Purpura, Thrombocytopenic, Idiopathic/surgery , Pyrazoles/adverse effects , Pyrazoles/therapeutic use , Receptors, Fc/therapeutic use , Recombinant Fusion Proteins/adverse effects , Recombinant Fusion Proteins/therapeutic use , Severity of Illness Index , Spain , Splenectomy , Stochastic Processes , Thrombopoietin/adverse effects , Thrombopoietin/therapeutic use , Time FactorsABSTRACT
BACKGROUND: The Internet has revolutionized the manner in which patients obtain information about health care. This technology has also allowed patients to obtain directly both prescription and nonprescription therapies. OBJECTIVE: To report a case of fulminant hepatorenal failure associated with the use of hydrazine sulfate, an unregulated alternative remedy for cancer marketed on the Internet. DESIGN: Case report. SETTING: Academic medical center. PATIENT: A 55-year-old man with maxillary sinus cancer. INTERVENTION: Self-medication with hydrazine sulfate. MEASUREMENTS: Serum liver and renal function tests; histologic evaluation of liver and kidney tissue. RESULTS: The patient developed hepatic encephalopathy, renal failure, and profound coagulopathy. He died after severe gastrointestinal hemorrhage developed. Autopsy revealed autolysis of the kidneys and submassive bridging necrosis of the liver. CONCLUSION: Fatal hepatorenal failure may occur after the use of hydrazine sulfate. This fatal complication must be considered in anyone taking or contemplating the use of hydrazine sulfate.
Subject(s)
Antineoplastic Agents/adverse effects , Carcinoma, Squamous Cell/drug therapy , Complementary Therapies , Hepatic Encephalopathy/chemically induced , Hydrazines/adverse effects , Maxillary Sinus Neoplasms/drug therapy , Renal Insufficiency/chemically induced , Self Medication/adverse effects , Fatal Outcome , Hepatic Encephalopathy/pathology , Humans , Internet , Liver/pathology , Male , Middle Aged , Renal Insufficiency/pathologySubject(s)
Antineoplastic Agents/therapeutic use , Complementary Therapies , Neoplasms/drug therapy , Antineoplastic Agents/adverse effects , Antioxidants/therapeutic use , Ascorbic Acid/therapeutic use , Attitude to Health , Canada , Clinical Trials as Topic , Cooperative Behavior , Government Agencies , Humans , Hydrazines/adverse effects , Voluntary Health AgenciesABSTRACT
Occupational and environmental medicine affords encounters with many unusual toxins, ranging from exotic metals to rocket fuels. Twelve of the most unusual industrial toxins are reviewed here and their clinical manifestations and treatments explored: acetonitrile, acrylonitrile, boron hydrides, dimethylaminopropionitrile, dimethylformamide, hydrazines, methyl isocyanate, 2-nitropropane, phosphine, Stalinon, tellurium, and vanadium.
Subject(s)
Isocyanates , Occupational Diseases/chemically induced , Acetonitriles/adverse effects , Acrylonitrile/adverse effects , Aminopropionitrile/adverse effects , Aminopropionitrile/analogs & derivatives , Cyanates/adverse effects , Humans , Hydrazines/adverse effects , Nitroparaffins/adverse effects , Occupational Exposure/adverse effects , Phosphines/adverse effects , Propane/adverse effects , Propane/analogs & derivatives , Tellurium/adverse effects , Vanadium/adverse effectsABSTRACT
This randomized, prospective, placebo-controlled clinical trial compares the influence on nutritional status and survival of hydrazine sulfate with placebo addition to cisplatin-containing combination chemotherapy in patients with unresectable non-small-cell lung cancer (NSCLC). The trial consisted of 65 patients with advanced, unresectable NSCLC who had had no prior chemotherapy, were at least partially ambulatory (Eastern Cooperative Oncology Group [ECOG] performance status [PS] level 0-2), and who had adequate hematologic, renal, and hepatic function. All patients received the same defined combination chemotherapy (cisplatin, vinblastine, and bleomycin) and the same defined dietary counseling with the addition of either three times daily oral hydrazine sulfate (60 mg) or placebo capsules. Hydrazine sulfate compared with placebo addition to chemotherapy resulted in significantly greater caloric intake and albumin maintenance (P less than .05). Considering all patients, survival was greater for the hydrazine sulfate compared with placebo group (median survival, 292 v 187 days), but the difference did not achieve statistical significance. In favorable PS patients (PS 0-1), survival was significantly prolonged (median survival, 328 days v 209 days; P less than .05) for hydrazine sulfate compared with placebo addition. In a multifactor analysis, PS, weight loss, and liver involvement were the final variables. Objective response frequency and toxicity were comparable on both arms. Hydrazine sulfate may favorably influence nutritional status and clinical outcome of patients with NSCLC. Further definitive studies of hydrazine sulfate addition to therapeutic regimens in NSCLC are warranted.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Drugs, Investigational/therapeutic use , Hydrazines/therapeutic use , Lung Neoplasms/drug therapy , Nutritional Status/drug effects , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bleomycin/administration & dosage , Carcinoma, Non-Small-Cell Lung/mortality , Cisplatin/administration & dosage , Drugs, Investigational/adverse effects , Humans , Hydrazines/adverse effects , Lung Neoplasms/mortality , Nutrition Assessment , Prospective Studies , Randomized Controlled Trials as Topic , Research Design , Vinblastine/administration & dosageABSTRACT
In conclusion, there are several drug types that can interfere with vitamin B6 metabolism. In most cases, the interaction involves a complex formation between the drug (or a derivative) and the reactive coenzyme PLP, resulting in a Schiff base. Such an interaction leads to an inactivation of PLP (and also of the drug). Other types of interaction involve (a) stimulation of vitamin B6-dependent pathways and (b) competition with PLP for the binding site on the enzyme. Examples of the above are the steroid hormones (oral contraceptives). In most instances, overt symptoms of vitamin B6 deficiency due to chronic ingestion of these drugs are observed, and neurological problems seem to be rather frequent. Because of the reactive nature of the coenzyme PLP and the ease with which it can interact with drugs, sub-clinical (marginal) vitamin B6 deficiency should be suspected in the absence of overt clinical signs. Once the vitamin B6 problem has been identified, the condition can usually be treated by judicious use of large doses of vitamin B6 without compromising the clinical efficacy of the drug.