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.

Nicotine Addiction and Withdrawal among Orthodox Jews: the Effect of Sabbath Abstinence.

BACKGROUND: Cigarette smoking is a widespread problem around the world. In Israel, the prevalence of smoking is 23%. Smokers who are Orthodox abstain from smoking during the Sabbath, i.e., from sundown Friday to sundown Saturday, due to a religious prohibition. The prevalence of smoking among Orthodox men is 13%. However, there are no data on patterns of smoking or on the addiction profiles in this population. OBJECTIVES: To explore the smoking patterns, motivation for smoking and nicotine addiction among Orthodox Jewish men, compared to non-Orthodox men, as well as the differences in the urge to smoke and withdrawal symptoms on Saturday versus weekdays in the Orthodox group. METHODS: The participants completed the Fagerstrom test for nicotine dependence, questionnaires on reasons for smoking and smoking patterns, as well as two brief questionnaires on the urge to smoke and withdrawal symptoms after overnight abstinence on a weekday and after the end of the Sabbath. RESULTS: Both groups were strongly addicted to nicotine and there were no differences in the reasons for smoking, withdrawal symptoms and nicotine craving after an overnight abstinence on weekdays. However, religious smokers had low levels of craving for nicotine and few withdrawal symptoms during Sabbath abstinence when compared to weekdays. CONCLUSIONS: Although we found no difference in the baseline characteristics with regard to nicotine addiction, smoking motivation, urge to smoke and withdrawal symptoms between religious and non-religious groups, the former are able to abstain from smoking during 25 hours of the Sabbath every week with significantly fewer withdrawal symptoms compared to week days.

Anti-Factor Xa Activity of Prophylactic Enoxaparin Regimens in Critically Ill Patients.

BACKGROUND: Enoxaparin is frequently used as prophylaxis for deep venous thrombosis in critically ill patients. OBJECTIVES: To evaluate three enoxaparin prophylactic regimens in critical care patients with and without administration of a vasopressor. METHODS: Patients admitted to intensive care units (general and post-cardiothoracic surgery) without renal failure received, once daily, a subcutaneous fixed dose of 40 mg enoxaparin, a subcutaneous dose of 0.5 mg/kg enoxaparin, or an intravenous dose of 0.5 mg/kg enoxaparin. Over 5 days anti-activated factor X levels were collected before the daily administration and 4 hours after the injection. RESULTS: Overall, 16 patients received the subcutaneous fixed dose, 15 received the subcutaneous weight-based dosage, and 8 received the dose intravenously. Around two-fifths (38%) of the patients received vasopressors. There was no difference between anti-activated factor X levels regarding vasopressor administration. However, in all three groups the levels were outside the recommended range of 0.1 IU/ml and 0.3 IU/ml. CONCLUSIONS: Although not influenced by vasopressor administration, the enoxaparin regimens resulted in blood activity levels outside the recommended range.

Prosthetic valve endocarditis due to Streptococcus pneumoniae.

INTRODUCTION: In the pre-antibiotic era up 10% of cases of infective endocarditis were due to Streptococcus pneumoniae, but this association is currently exceedingly rare. CASE DESCRIPTION: Since 1997 we have diagnosed three patients, all aged >70, with endocarditis due to S. pneumoniae. One of these three cases involved a prosthetic valve, another a prosthetic ring. All three patients completely recovered with antibiotic treatment only. DISCUSSION AND EVALUATION: During the same period there were 1694 cases of pneumococcal bacteremia, of whom 395 (23%) after age 70. Therefore, after age 70 the prevalence of endocarditis out of all cases of pneumococcal bacteremia was 0.7%. A literature review detected another 16 cases of pneumococcal PVE. The mean age of these 17 patients was 64±14; 10 were female and 7 male. In most instances, symptom duration was short, < 6 days. Valve surgery was performed in 5 cases (29%) and 13 patients (76%) survived. CONCLUSIONS: Endocarditis due to S. pneumoniae is rare in the antibiotic era; even in patients with prosthetic valves its course is evidently not more virulent than with other low-virulent organisms.

Relationship between CYP2A6 genetic polymorphism, as a marker of nicotine metabolism, and ulcerative colitis.

BACKGROUND: Ulcerative colitis (UC) is a common and difficult-to-treat disease. In non-smokers the relative risk of developing UC is 2.9 compared with smokers, who tend to have a later onset and a milder disease. Nicotine is the component of cigarette smoke responsible for the favorable effects in UC. Nicotine is metabolized by the enzyme CYP2A6. Subjects who are homozygotes for CYP2A6*4 gene polymorphism are poor nicotine metabolizers, while homozygotes for CYP2A6*1A polymorphism are extensive metabolizers. OBJECTIVES: To compare the frequency of CYP2A6 and CHRNA3 polymorphisms among smokers and non-smokers with UC, and their effect on disease severity. METHODS: Data on the age at onset of disease, disease activity, and treatment were obtained from questionnaires completed by the 69 subjects in our study group. CYP2A6 *1A,*4A and CHRNA3 polymorphisms were determined by polymerase chain reaction and restriction enzyme analysis. RESULTS: Nine percent of the patients were current smokers, 30% were former smokers and 61% non-smokers. Among smokers and former smokers 63% were homozygotes for CYP2A6*1A and 4% were homozygotes for CYP2A6*4A, whereas among non-smokers 66% were homozygotes for CYP2A6*4A (P < 0.0001). There was no significant effect of CYP2A6 or CHRNA3 genotype on UC activity. CONCLUSIONS: We found a very high proportion of poor nicotine metabolizers among non-smoking patients with UC and a very low proportion among current and former smokers, making it difficult to determine the effect of poor metabolizer genotype on disease activity in smokers with UC. However, it may be possible to identify UC patients who are poor metabolizers of nicotine and who may benefit from nicotine or nicotine-like pharmacological treatment.

Nicotiana glauca (tree tobacco) intoxication--two cases in one family.

We present two cases of rare human poisoning in one family following ingestion of cooked leaves from the tobacco tree plant, Nicotiana glauca. The toxic principle of N. glauca, anabasine (C10H14N2), is a small pyridine alkaloid, similar in both structure and effects to nicotine, but appears to be more potent in humans. A 73-year-old female tourist from France, without remarkable medical history, collapsed at home following a few hours long prodrome of dizziness, nausea, vomiting, and malaise. The symptoms developed shortly after eating N. glauca cooked leaves that were collected around her daughter's house in Jerusalem and mistaken for wild spinach. She was found unconscious, with dilated pupils and extreme bradycardia. Following resuscitation and respiratory support, circulation was restored. However, she did not regain consciousness and died 20 days after admission because of multi-organ failure. Anabasine was identified by gas chromatography/mass spectrometry method in N. glauca leaves and in the patient's urine. Simultaneously, her 18-year-old grandson developed weakness and myalgia after ingesting a smaller amount of the same meal. He presented to the same emergency room in a stable condition. His exam was remarkable only for sinus bradycardia. He was discharged without any specific treatment. He recovered in 24 h without any residual sequelae. These cases raise an awareness of the potential toxicity caused by ingestion of tobacco tree leaves and highlight the dangers of ingesting botanicals by lay public. Moreover, they add to the clinical spectrum of N. glauca intoxication.

Emergency treatment of life-threatening intrathecal methotrexate overdose.

A male 34-year-old patient with aggressive diffuse malignant lymphoma was hospitalized for treatment. Because of high likelihood of CNS involvement, intrathecal methotrexate (MTX) 15 mg was administered with hydrocortisone 100mg. Shortly after the intrathecal injection the patient became agitated, and complained of severe low back pain and 2h later he became confused and developed generalized seizures. At this stage, it was realized that the dose contained 1200 mg of MTX (80-fold overdose). The patient developed ARDS and was comatose; he was intubated and transferred to ICU. The patient was immediately treated with intravenous leucovorin 1200 mg, and 15 mg every 6h, thereafter, for 72 h. In addition, CSF exchange with warm normal saline was initiated via intrathecal catheter, and a total of 200 ml of CSF were replaced during 48 h. Finally, at the end of the exchange 2 mg of leucovorin with 2 mg of dexamethasone were administered intrathecally. MTX levels in CSF 7h post-injection were 770 microM, and increased to 1250 microM 2h later. Thereafter, the levels in CSF declined, and 48 h post-injection were 47 microM. The plasma levels of MTX 7h post-injection were 10 microM, and declined to 0.7 microM at 68 h. The patient regained consciousness and underwent successful weaning from ventilator after tracheostomy. The highest reported intrathecal dose after which the patient survived was 625 mg. Due to the rarity of reported cases, there are no clear guidelines for treatment of massive intrathecal overdose. There is a controversy regarding the toxicity of intrathecal injection of leucovorin. We propose CSF exchange and intravenous leucovorin as the mainstay of treatment.

Clinical effects of locally delivered nicotine in obstructive sleep apnea syndrome.

Obstructive sleep apnea (OSA) is a common disorder characterized by disordered breathing and associated with increased mortality and cardiovascular morbidity. A factor in the pathogenesis of OSA is hypotonia of the upper airway muscles during sleep, resulting in occlusion of the upper airway. Nicotine may be a suitable drug because it is a stimulant of breathing and activity of oropharyngeal muscles. A novel delivery system, a nicotine tooth patch (NTP) that releases nicotine continuously, has been developed by Perio Products (Jerusalem, Israel). A 2-mg NTP achieved low plasma levels of nicotine with high saliva levels (62 microg/mL), presumably resulting in high nicotine levels in the oropharynx. The aim of this study was to evaluate the effect of two doses of NTP, 2 mg and 4 mg, on the clinical features in OSA. Ten subjects with OSA were admitted overnight and monitored by polysomnography at baseline and during two treatments. The treatments were blind and in a randomized order. After a 4.3-mg NTP, T(max) was 40 +/- 16 minutes, C(max) was 123 +/- 43 microg/mL, and terminal T(1/2) was 29 +/- 11 minutes in saliva. Substantial nicotine levels persisted in saliva for approximately 4 hours. There was no effect of nicotine on the apnea-hypopnea index, even during the first 4 hours when there were high levels of nicotine in saliva (26.4 +/- 11.6, 26.8 +/- 19.5, and 26.8 +/- 23), or on sleep stages. Eppworth Sleepiness Scale scores were lower with a 4.3-mg NTP (9.1 +/- 4.5, 9.1 +/- 7.7, and 5.9 +/- 6.5). Locally delivered nicotine at the doses used had no significant effect on OSA.