Process of drug registration in Israel: the correlation between the number of discussions within the Ministry of Health and postapproval variations by EMA and/or FDA.

OBJECTIVES: US FDA and EMA allow facilitated regulatory pathways to expedite access to new treatments. Limited supportive data may result in major postapproval variations. In Israel, partly relying on Food and Drug Administration (FDA) and European Medicines Agency (EMA), clinical data are reviewed independently by the Advisory Committee of Drug Registration (ACDR). In this study, the correlation between the number of discussions at the ACDR and major postapproval variations is examined. DESIGN: This is an observational retrospective comparative cohort study. SETTING: Applications with FDA and/or EMA approval at time of assessment in Israel were included. The timeframe was chosen to allow a minimum of 3 years of postmarketing approval experience for potential major label variations. Data regarding the number of discussions at ACDR were extracted from protocols. Data on postapproval major variations were extracted from the FDA and EMA websites. RESULTS: Between 2014 and 2016, 226 (176 drugs) applications, met the study criteria. 198 (87.6%) and 28 (12.4%) were approved following single and multiple discussions, respectively. A major postapproval variation was recorded in 129 (65.2%) compared with 23 (82.1%) applications approved following single and multiple discussions, respectively (p=0.002). Increased risk for major variation was found for medicines approved following multiple discussions (HR=1.98, 95% CI: 1.26 to 3.09) with a median time of 1.2 years, applications approved based on phase II trials (HR=2.58, 95% CI: 1.72 to 3.87), surrogate endpoints (HR=1.99, 95% CI: 1.44 to 2.74) and oncologic indications (HR=2.48, 95% CI: 1.78 to 3.45). CONCLUSIONS: Multiple ACDR discussions associated with limited supportive data are predictive for major postapproval variations. Moreover, our findings demonstrate that approval by the FDA and/or EMA does not pave the way to automatic approval in Israel. In a substantial per cent of the cases, submission of the same clinical data resulted in different safety and efficacy considerations, requiring additional supporting data in some cases or even rejection of the application in others.

Autoimmune Neutropenia Associated With HHV-6 Virus Infection: A Case Report.

Background: Autoimmune neutropenia (AIN) is divided into primary and secondary forms. The former is more prevalent in children and is usually a self-limiting disease. Secondary AIN is more common in adults and often occurs in the setting of another autoimmune disorder or secondary to infections, malignancies or medications. Several viral and bacterial pathogens were described to trigger AIN. Here we report a case of AIN in an adult woman associated with human herpesvirus-6 (HHV-6) infection. Case Presentation: We report a case of AIN in an adult woman associated with HHV-6 infection. The patient presented to the emergency department with fever and painful genital ulcers. Upon arrival, her laboratory workup demonstrated severe neutropenia and elevated inflammatory markers. She was hospitalized and underwent a thorough infectious, hematological, autoimmune and inflammatory workup. Malignancy was also excluded using an advanced whole body radiological scan. Serological tests confirmed the presence of both acute and chronic types of HHV-6 antibodies, at very high titers. Polymerase chain reaction demonstrated a numerous copies of the virus in the patient's blood. Specific immunofluorescence test confirmed the diagnosis of autoimmune neutropenia. Conclusion: Secondary AIN is a rare disease that may affect all range of ages. The adult type is a challenging disorder that has different etiologies and may be triggered by a variable infectious pathogen. The finding of HHV-6 as a possible culprit pathogen may warrant physicians into widening the evaluation and include HHV-6 in the analysis.

Human Kidney Spheroids and Monolayers Provide Insights into SARS-CoV-2 Renal Interactions.

BACKGROUND: Although coronavirus disease 2019 (COVID-19) causes significan t morbidity, mainly from pulmonary involvement, extrapulmonary symptoms are also major componen ts of the disease. Kidney disease, usually presenting as AKI, is particularly severe among patients with COVID-19. It is unknown, however, whether such injury results from direct kidney infection with COVID-19's causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or from indirect mechanisms. METHODS: Using ex vivo cell models, we sought to analyze SARS-CoV-2 interactions with kidney tubular cells and assess direct tubular injury. These models comprised primary human kidney epithelial cells (derived from nephrectomies) and grown as either proliferating monolayers or quiescent three-dimensional kidney spheroids. RESULTS: We demonstrated that viral entry molecules and high baseline levels of type 1 IFN-related molecules were present in monolayers and kidney spheroids. Although both models support viral infection and replication, they did not exhibit a cytopathic effect and cell death, outcomes that were strongly present in SARS-CoV-2-infected controls (African green monkey kidney clone E6 [Vero E6] cultures). A comparison of monolayer and spheroid cultures demonstrated higher infectivity and replication of SARS-CoV-2 in actively proliferating monolayers, although the spheroid cultures exhibited high er levels of ACE2. Monolayers exhibited elevation of some tubular injury molecules-including molecules related to fibrosis (COL1A1 and STAT6) and dedifferentiation (SNAI2)-and a loss of cell identity, evident by reduction in megalin (LRP2). The three-dimensional spheroids were less prone to such injury. CONCLUSIONS: SARS-CoV-2 can infect kidney cells without a cytopathic effect. AKI-induced cellular proliferation may potentially intensify infectivity and tubular damage by SARS-CoV-2, suggesting that early intervention in AKI is warranted to help minimize kidney infection.

Unprovoked pulmonary embolism in older adults: incidence and prognosis.

INTRODUCTION: Unprovoked pulmonary embolism (UPE) is not rare and it is associated with an unfavorable prognosis in adults. However, the incidence and the prognosis of UPE in older adults have never been studied. MATERIAL AND METHODS: This was a historical prospective study. We reviewed all the medical charts of all older adults (aged 70 years or more) with UPE, provoked pulmonary embolism (PPE), and malignancy-associated PE (MAPE), admitted to a tertiary medical center between 2010 and 2012. The all-cause 3-year mortality rates and cumulative survival following admission were compared between the groups. RESULTS: The final cohort included 249 patients with PE: 161 (64.7%) were women; the mean age was 79.8 ±5.7 years. Overall, 36 (14.5%) patients had UPE, 81 (32.5%) patients had MAPE, and 132 (53.0%) patients had PPE. Overall, 39 (15.7%) patients died within 30 days, 76 (30.5%) patients died within 6 months, 101 (40.6%) patients died within 1 year, and 136 (54.6%) patients died within 3 years of admission. Relative to PPE and MAPE patients, the cumulative survival was significantly higher in UPE patients at each time point within 1 year of admission (p < 0.05 and p < 0.001, respectively). However, 3 years after admission, the cumulative survival was comparable between PPE patients and UPE patients, and was significantly lower in MAPE patients (p < 0.001). CONCLUSIONS: UPE is not rare in older adults with PE, and it is associated with a favorable prognosis within 1 year of admission in this population.

Renal Mg handling, FXYD2 and the central role of the Na,K-ATPase.

This article examines the central role of Na,K-ATPase (α1ß1FXYD2) in renal Mg handling, especially in distal convoluted tubule (DCT), the segment responsible for final regulation of Mg balance. By considering effects of Na,K-ATPase on intracellular Na and K concentrations, and driving forces for Mg transport, we propose a consistent rationale explaining basal Mg reabsorption in DCT and altered Mg reabsorption in some human diseases. FXYD2 (γ subunit) is a regulatory subunit that adapts functional properties of Na,K-ATPase to cellular requirements. Mutations in FXYD2 (G41R), and transcription factors (HNF-1B and PCBD1) that affect FXYD2 expression are associated with hypomagnesemia with hypermagnesuria. These mutations result in impaired interactions of FXYD2 with Na,K-ATPase. Renal Mg wasting implies that Na,K-ATPase is inhibited, but in vitro studies show that FXYD2 itself inhibits Na,K-ATPase activity, raising K0.5 Na. However, FXYD2 also stabilizes the protein by amplifying specific interactions with phosphatidylserine and cholesterol within the membrane. Renal Mg wasting associated with impaired Na,K-ATPase/FXYD2 interactions is explained simply by destabilization and inactivation of Na,K-ATPase. We consider also the role of the Na,K-ATPase in Mg (and Ca) handling in Gitelman syndrome and Familial hyperkalemia and hypertension (FHHt). Renal Mg handling serves as a convenient marker for Na,K-ATPase activity in DCT.

Hypermagnesuria in Humans Following Acute Intravenous Administration of Digoxin.

BACKGROUND: Hypomagnesemia is a known predisposing condition for the appearance of digitalis toxicity. The detection of a genetic form of Mg urinary wasting with hypomagnesemia being caused by a mutation in the γ subunit (FXYD2) of the Na,K-ATPase, the pharmacological target of Digoxin, prompted us to investigate whether Digoxin administration increases urinary Mg excretion. METHODS: Two groups of subjects, with rapid atrial fibrillation, received intravenous Digoxin (n = 9) or verapamil (n = 8), for heart rate control. During the following 4 h, blood and urinary creatinine, sodium, potassium, calcium, and magnesium levels were determined, and fractional excretion (Fex) values for Na, K, Ca, and Mg were calculated. RESULTS: In the Digoxin group, at 60 min Fex Mg rose from 3.07 ± 1.21 to 7.58 ± 2.51% (an increase of 269 ± 107% of baseline, p < 0.001), and at 240 min to 6.05 ± 2.30% (204 ± 56% of baseline, p < 0.01). No significant change was observed for Fex Na, Fex K, and Fex Ca. A striking correlation was found between individual values of Fex Mg and serum Digoxin concentration (r = 0.678, p < 0.0001). No significant correlation was found between Fex Na or Fex K and serum Digoxin. A correlation of borderline significance was found between Fex Ca and serum Digoxin (r = 0.349, p = 0.073). CONCLUSIONS: The hypermagnesuric effect of acute Digoxin treatment is reminiscent of the effect of the missense mutation in FXYD2, which assumes that FXYD2 is a positive regulator of Na,K-ATPase in the distal convoluted tubule (DCT). The borderline calciuric effect of Digoxin may point to an additional site of action, more proximal to the DCT, that is, the thick ascending limb.

Gender differences in mortality among statin users aged 80 years or more.

BACKGROUND: Little is known about the prognosis associated with statin therapy and its gender differences in older adults aged ≥80 years. OBJECTIVE: To study the mortality and survival associated with statin therapy and their gender differences in older adults aged ≥80 years. METHOD: This was a historical prospective study conducted at a tertiary medical center. The medical charts of all older adults aged ≥80 years who had been admitted to a single internal medicine department during 1 year were reviewed. All-cause 3­year mortality and survival rates following hospital admission in men and in women using statins were investigated. RESULTS: The final cohort included 216 patients: 122 (56.5%) women, mean age 85.3 ± 3.9 years. Overall, 66 (53.2%) women and 58 (46.8%) men used statins for 3 years or more following hospital admission. During this time 48 (39.3%) women and 48 (51.1%) men died. The all-cause 3­year mortality rates were significantly lower only in women who had used statins compared with women who had not used statins (24.2% vs. 57.1%; relative risk = 0.2; 95% confidence interval 0.1-0.5; p < 0.0001). The 3­year cumulative survival rates were significantly higher in women who had used statins as part of primary as well as secondary cardiovascular prevention (p < 0.0001 and p = 0.014, respectively). A Cox regression analysis showed that statin therapy was independently associated with low 3­year cumulative mortality rates in women (hazard ratio=0.3; 95% confidence interval=0.1-0.6; p = 0.001). CONCLUSION: In older adults aged ≥80 years, statin therapy is associated with high 3­year cumulative survival rates only in women.

Clinical characteristics and risk factors for low dose methotrexate toxicity: a cohort of 28 patients.

OBJECTIVE: Low dose (10-25 mg/week) methotrexate is widely used for the management of systemic inflammatory diseases, and is considered to be relatively safe. Toxicity due to low dose MTX has been reported but is poorly characterized. We describe the clinical features, risk factors, and outcomes of low dose MTX toxicity in a large case series at our center. PATIENTS AND METHODS: We conducted a retrospective case series of all adult (>18 years) patients hospitalized at Sheba Medical Center, between 2005 and 2012 for low dose MTX toxicity. RESULTS: We identified 28 patients (age: 70.4±13.7 years, range: 33-88; 20 (71%) females) hospitalized for low dose MTX toxicity. Indications for MTX therapy included: rheumatoid arthritis (39.2%), psoriasis±arthritis (21.5%), polymyalgia rheumatica (10.8%) and other inflammatory conditions (28.5%). Pancytopenia was the most common manifestation of low dose MTX toxicity detected in 78.5% of the patients. Potential risk factors included acute renal failure, hypoalbuminemia, concurrent use of drugs known to interact with MTX, and dose errors. Serum MTX concentrations (n=20, mean 0.04±0.07 µg/mL range: 0-0.3) did not correlate with the degree of either neutropenia (r=-0.36; p=0.18) or thrombocytopenia (r=0.44; p=0.10). Seven (25%) patients died, all from pancytopenia followed by sepsis. Serum MTX concentrations did not differ between the patients who died from MTX toxicity (n=6; mean: 0.05±0.04 µg/mL) and those who survived the toxicity (n=14 mean 0.04±0.08; p=0.45). CONCLUSIONS: Low-dose MTX toxicity can be life threatening, mainly due to myelosuppression. There is no rationale for MTX therapeutic drug monitoring in the setting of low-dose toxicity.

Nilotinib-associated acute pancreatitis.

OBJECTIVE: To report a case of acute pancreatitis in a patient receiving nilotinib for chronic myelogenous leukemia (CML). CASE SUMMARY: A 69-year-old man recently diagnosed with chronic phase CML received nilotinib 300 mg twice daily and was admitted with acute pancreatitis that appeared the day after the first dose. The patient had normal levels of triglycerides and denied alcohol use. Serum pancreatic enzymes were within normal limits the day before nilotinib initiation. Abdominal computed tomography demonstrated a normal liver, bile duct without stones, and findings that were consistent with focal pancreatitis. The patient's history was significant for concomitant use of enalapril and simvastatin; both have been associated with pancreatitis, but the patient had been taking these medications for at least 5 years without adverse effects. Nilotinib was immediately discontinued. Abdominal pain resolved and serum pancreatic enzymes levels returned to normal 2 weeks later. DISCUSSION: One of the adverse effects of some tyrosine kinase inhibitors is increased levels of serum pancreatic enzymes. Accordingly, nilotinib labeling includes "high lipase levels in serum" as an adverse event. There are few case reports of acute pancreatitis associated with nilotinib in the literature and some are incomplete. We present a well-documented case of nilotinib-associated acute pancreatitis. Consistent with Badalov's new classification system for drug-induced acute pancreatitis and with the Naranjo probability scale, this case represents a possible adverse reaction of pancreatitis associated with nilotinib therapy. As rechallenge is unethical, treatment with nilotinib has not been resumed. CONCLUSIONS: This case demonstrates a possible association between acute pancreatitis and nilotinib use. Although a rare phenomenon, clinicians should be alert for signs and symptoms of pancreatitis, as treatment with nilotinib for CML is becoming more common.

The serotonin syndrome: initial misdiagnosis.

BACKGROUND: The selective serotonin reuptake inhibitors are major drugs used in psychiatry today. While serotonin syndrome has become more frequent in an overdose situation and when an interacting drug is given, the toxicity of SSIRs is less than that of most other psychiatric drugs. Although the characteristics of toxicity are defined, it seems that physicians are not aware of the phenomenon. OBJECTIVES: To investigate patients with serotonin syndrome who were initially misdiagnosed. METHODS: We conducted a retrospective chart review of seven patients admitted in the last 2 years with mild to severe serotonin syndrome who were initially diagnosed as having other diseases. RESULTS: Most patients (5/7) were initially diagnosed with exacerbation of their psychiatric disorder. Gastroenteritis was diagnosed in two patients. One patient was suspected of having a metastatic lesion in the brain, and severe drug overdose was diagnosed in one patient. They all recovered after withholding the culprit drugs. CONCLUSIONS: This report is an addition to the growing literature on misdiagnosis of psychiatric patients. Serotonin toxicity should be considered in patients in whom the combination of mental changes, neuromuscular abnormalities and autonomic hyperactivity are features of acute disease.