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.

[CASE REPORT: LEGAL, PSYCHOLOGICAL AND ETHICAL ASPECTS OF THE DYING PATIENT ACT].

INTRODUCTION: We present a patient with amyotrophic lateral sclerosis (ALS), dependent on noninvasive ventilation, whose advance directives precluded life-prolonging measures. The patient was found in cardiac arrest and in accordance with the directives of her surrogate decision maker, underwent intubation and mechanical ventilation. Later, an additional surrogate decision maker disapproved of ventilation and when the ventilator was disconnected for bronchial suctioning, she asked the nurse not to reconnect the patient to the ventilator. We discuss the legal, psychological and ethical aspects of implementation of Israeli law in this complex patient.

Reducing blood culture contamination using an initial specimen diversion device.

OBJECTIVES: False positive blood cultures result from contamination, consuming laboratory resources and causing unnecessary antibiotic treatment and prolonged hospital stay. Skin disinfection reduces contamination; however, bacteria colonizing human skin are also found in tissues deep into the skin surface. A diversion device diverts the initial 1-2 mL of blood to remove any potentially contaminated skin plug. This study investigates the effect of the device on culture contamination in hospitalized patients. METHODS: In this prospective controlled pragmatic study, blood cultures were obtained using an initial specimen diversion device, either via integrated needle or attachment to a newly placed intravenous catheter. Cultures taken using standard methods served as the control. RESULTS: Six hundred seventy-one blood cultures were obtained. Two hundred seven cultures were taken using an initial specimen diversion device, with 2 (1.0%) contaminated cultures. Four hundred sixty-four cultures were taken without the device, with 24 (5.2%) contaminated cultures (P < .008). No significant difference was shown in the rate of true-positive cultures. CONCLUSIONS: The use of a diversion device was associated with reduced culture contamination in hospitalized patients over a 6-month period, without concomitant reduction in true-positive cultures. This intervention may result in a reduction in costs, antibiotic use, and duration of hospital stay.

[MONITORING UNITS IN DEPARTMENTS OF INTERNAL MEDICINE: FREQUENCY, IMPACT AND SATISFACTION].

BACKGROUND: Due to increasing numbers of elderly, seriously ill patients and shortage of ICU beds, many hospitals have established monitoring units (MU) in their medical departments. OBJECTIVES: (1) To assess the national prevalence of MUs in medical departments; (2) to determine the outcome of consecutively admitted MU patients; (3) to evaluate patient/ family satisfaction with care. METHODS: The case control study included all 123 patients hospitalized in the MU during a 5-month period, compared with two control groups: (1) 123 patients admitted to medical departments, matched at a ratio of 1:1 by gender, age±10 years and mechanical ventilation; (2) all 52 medical patients treated in the ICU. The main endpoint was 28-day survival. RESULTS: A total of 76/99 (77%) directors of medical departments in Israel responded: 70 (92%) reported the presence of a MU, 64 (92%) have 5-7 beds and 47 (67%) have one nurse per shift. Baseline characteristics of enrolled MU and medical department patients were similar, although 52 medical ICU patients were younger (56±21 vs. 73±14, p<0.001) and had a lower incidence of kidney failure (11.5% vs. 41.5%, p<0.001). The predicted mortality rates were higher for MU patients compared to medical department patients, but 28-day survival rates were similar (64-70%, NS). The questionnaire showed high rates of satisfaction (from 0=low to 5=high): highest with MU care: (4.79±0.48), followed by ICU (4.41±1.06) and lowest for medical department nursing care (4.27±0.84)(p=0.017). CONCLUSIONS: Monitoring units are ubiquitous in Israeli hospitals and contribute to survival and satisfaction with care.

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.

Operating a Monitoring Unit in the Geriatric Department: Effects on Outcomes.

OBJECTIVES: To compare the effect of a five-bed geriatric monitoring unit (MU) on in-hospital mortality and length of stay with the effect of usual care in a geriatric hospital department and a medical MU. DESIGN: Prospective, case-control, noninterventional study. PARTICIPANTS: All individuals hospitalized for 24 hours or longer in the geriatric MU (n = 89, aged 53-101, mean age 82.2 ± 9.6) over a period of 5 months (January-May 2015); individuals admitted to the geriatric department (n = 178, aged 55-100, mean age 83.2 ± 9.8), matched at a ratio of 1:2 according to sex, age ±5 years, and need for mechanical ventilation; and individuals admitted to a similar five-bed medical MU (n = 95, aged 35-90, mean age 68.2 ± 14.4) during the same period. MEASUREMENTS: Primary outcome was in-hospital mortality. RESULTS: The predicted death rate was 49 ± 26 for participants in the geriatric MU, 39.6 ± 27 for those in the medical MU (P = .02), and 36.7 ± 27 for those in the geriatric department (P < .001). Observed in-hospital mortality was higher for geriatric MU participants (n = 40, 44.9%) than for the department control group (n = 48, 27%) (P = .002), although the mortality ratios (actual divided by predicted death rates) of these two groups were similar, indicating that the more severely ill participants in the geriatric MU did better than control participants in the departments, in particular those requiring hemodynamic pressure support and those with acute renal failure. CONCLUSION: For elderly, severely ill adults, care in a geriatric MU was associated with lower in-hospital mortality than care in the hospital geriatric ward and a longer stay and may be an alternative to medical MU admission.

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.

Prokinetic drugs for gastric emptying in critically ill ventilated patients: Analysis through breath testing.

PURPOSE: The prupose was to identify, through the BreathID automatic breath-testing device, the best prokinetic therapy to enhance gastric-emptying rate (GER) in ventilated intensive care unit patients. MATERIALS AND METHODS: This was a prospective, crossover, nonrandomized study. Consecutive ventilated patients who could be fed enterally and expected to require 5 days of ventilation were included. (13)C-labeled-acetate in 100 mL Osmolite (BreathID; Exalenz Bioscience Ltd, Jerusalem, Israel) was administered intragastrically and followed by a 4-hour continuous recording of expiratory (13)CO2 by the BreathID. Prokinetics were changed daily: (1) baseline (no prokinetic), (2) intravenous (IV) metoclopramide (10 mg every 6 hours), (3) IV metoclopramide (10 mg every 6 hours) and continuous low-dose erythromycin (10 mg/h), (4) IV continuous low-dose erythromycin alone (10 mg/h), and (5) IV bolus erythromycin (200 mg every 12 hours). Gastric-emptying rate was assessed by the percentage dose recovered (PDR)-change from time 0 of the recording in the ratio of (13)CO2/(12)CO2 in exhaled gases (%/h). We used PDR peak values and time to peak (minutes to reach PDR peak) to express GER. RESULTS: In the first 17 patients (group A), baseline GER measurements preceded prokinetic therapy. In the subsequent 14 patients (group B), 2 prokinetic regimens preceded baseline. No order-time effect was observed, justifying pooled analysis of all 31 patients. Combined metoclopramide-continuous low-dose erythromycin yielded significantly higher PDR peak and shorter time to peak vs baseline (P = .0001, P = .005, respectively). The PDR peak was also significantly higher from baseline during continuous low-dose administration of erythromycin alone (P = .004). Metoclopramide alone did not improve GER significantly. CONCLUSIONS: Combined metoclopramide-continuous low-dose erythromycin was found to be the best protocol in the current study to increase GER in ventilated patients. It should be tested as a first-line prokinetic therapy in ventilated patients with poor gastric emptying in further randomized controlled studies. The breath-test device presented in this study can be a user-friendly and practical method to monitor GER, enabling individual tailoring of prokinetic therapy. Further studies to explore its utility are warranted.

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.

[Shaare Zedek Medical Center's model of an integrated division of internal medicine].

BACKGROUND: The specialty and practice of internal medicine have been subject to serious challenges in the last two decades. METHODS: We describe the integrative model of internal medicine as developed in our hospital, providing solutions to some major challenges. RESULTS: Major components include: (1) Senior physicians and residents are employed by the Division rather than individual Departments of Medicine, allowing for balanced distribution of professional capabilities. (2) Two medical departments specialize in geriatric medicine, while the other departments take care of younger, more intellectually challenging patients. Senior and junior staff members rotate through these departments, allowing for exposure to different patient populations and professional expertise. (3) The backbone of senior physicians is rewarded by a set of incentives, including dedicated time for research. (4) Senior staff from the subspecialties contributes annually 1-2 months as senior physicians in the departments and receive academic and other compensation for their efforts. (5) In cases where medical departments elsewhere are flooded with corridor admissions (a source of frustration and burnout), a short admission unit in the emergency department relieves internal medicine pressures and shortens evaluation and therapy for many patients. CONCLUSION: Our integrative model of internal medicine allows for improved patient and staff distribution, greater satisfaction among patients and family members, greater professional satisfaction among physicians, while resident vacancies are filled with competent residents.

[Impact of a monitoring unit in the medical department on patient outcome].

PURPOSE: Many hospitals have established monitoring units (MU) in their medical departments, with operating costs that are significantly lower than Intensive Care Units, but with no data on their effectiveness. We determined the outcome of patients, who were treated in a new MU during their hospitalization, compared with that of a control group. METHODS: We included all patients, who were admitted to the MU during a five months period. The control group consisted of patients, who were admitted to medical departments and did not stay in the MU during their hospitalization. Patients and controls were matched according to gender, age +/- 10 years, and need for mechanical ventilation. The main endpoint was the 28-day survival rate. RESULTS: There were minor differences between baseline characteristics of patients and controls. The patient cohort included a higher rate of acute renal failure (20/100, 20%) and chronic renal failure (23/100, 23%), compared to the control group (respectively, 10/100, 10%, p < 0.05 and 8/100, 8%, p < 0.05), and a higher rate of respiratory support (83/94, 82% and 72/99, 72%, p < 0.05). Contrarily, a GLasgow coma scale of 3-5 was found in 10/100 (10%) of MU patients and in 20/100 (20%) of control patients (p < 0.05). Despite these differences, there was no difference in predicted mortality score. Nevertheless, the observed survival rate of patients who stayed in the monitoring unit (76/100, 76%) was higher than that of the control group (64/100, 64%) (p < 0.05). CONCLUSIONS: The results of this pilot study indicate that a monitoring unit may contribute to improved survival.

Use of non-vitamin, non-mineral (NVNM) supplements by hospitalized internal medicine patients and doctor-patient communication.

OBJECTIVE: To study non-vitamin, non-mineral (NVNM) supplements use and disclosure of among hospitalized internal medicine patients. METHODS: A convenience sample of patients completed an interviewer-administered questionnaire examining use of and perceptions regarding NVNM supplements, and disclosure to medical personnel. RESULTS: 280 patients were interviewed (54% female), 15.4% reporting NVNM supplement use. This practice was more prevalent among female patients (p=0.045), more educated (p<0.001) and patients with more impaired quality-of-life, measured by the SF-12 tool (p<0.020). The most common factor influencing NVNM supplement use was a physician's recommendation. Most (74%) patients using NVNM supplements reported having disclosed this practice to community-based physicians, with only 23.7% disclosing to hospital staff. Six patients reported using supplements at the exclusion of conventional medication, with potentially serious implications. CONCLUSION: While the majority of patients using NVNM supplements are sharing this information with their primary-care physicians, there is little disclosure of this practice to hospital staff. This may be due to a perceived negative attitude of medical professionals to complementary medicine, and a lack of awareness by hospital staff regarding such practices. PRACTICE IMPLICATIONS: Hospital-based medical professionals need to be aware of the use of NVNM supplements and the resulting implications by their internal medicine patients.

A safety trial of high dose glyceryl triacetate for Canavan disease.

Canavan disease (CD MIM#271900) is a rare autosomal recessive neurodegenerative disorder presenting in early infancy. The course of the disease is variable, but it is always fatal. CD is caused by mutations in the ASPA gene, which codes for the enzyme aspartoacylase (ASPA), which breaks down N-acetylaspartate (NAA) to acetate and aspartic acid. The lack of NAA-degrading enzyme activity leads to excess accumulation of NAA in the brain and deficiency of acetate, which is necessary for myelin lipid synthesis. Glyceryltriacetate (GTA) is a short-chain triglyceride with three acetate moieties on a glycerol backbone and has proven an effective acetate precursor. Intragastric administration of GTA to tremor mice results in greatly increased brain acetate levels, and improved motor functions. GTA given to infants with CD at a low dose (up to 0.25 g/kg/d) resulted in no improvement in their clinical status, but also no detectable toxicity. We present for the first time the safety profile of high dose GTA (4.5 g/kg/d) in 2 patients with CD. We treated 2 infants with CD at ages 8 months and 1 year with high dose GTA, for 4.5 and 6 months respectively. No significant side effects and no toxicity were observed. Although the treatment resulted in no motor improvement, it was well tolerated. The lack of clinical improvement might be explained mainly by the late onset of treatment, when significant brain damage was already present. Further larger studies of CD patients below age 3 months are required in order to test the long-term efficacy of this drug.

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.

[Quinines--past and present].

Quinines are known to mankind and have been in medical use against malaria for over 350 years. The revelation of quinines' activity against malaria in the 17th century brought a revolution to the medical world and had dramatic implications on the political arena of Europe at that time. The source of these materials is the bark of the Cinchona trees indigenous to remote mountain areas of Latin America. Great efforts were made in the search for the trees, and in growing them in other areas of the world. Today quinines are produced both synthetically and from the tree bark. Beside malaria, they are pivotal in the treatment of autoimmune disorders such as Lupus and rheumatoid arthritis.

Enoxaparin dosage adjustment in patients with severe renal failure: antifactor xa concentrations and safety.

STUDY OBJECTIVE: To evaluate the safety and efficacy, by measuring antifactor Xa levels, of enoxaparin 1 mg/kg subcutaneously once every 24 hours in patients with severe renal failure. DESIGN: Prospective study. SETTING: Emergency, internal medicine, geriatrics, and cardiology departments of a medical center in Israel. PATIENTS: Nineteen patients with stage 4 or 5 chronic kidney disease who required full anticoagulation. INTERVENTION: Patients received enoxaparin 1 mg/kg subcutaneously every 24 hours for 2 or more days, as determined by a treating physician. MEASUREMENTS AND MAIN RESULTS: Data on patients' demographic and clinical characteristics were collected. Blood samples for peak and trough antifactor Xa levels were obtained during the enoxaparin treatment period. Of the 19 study patients, 14 (74%) had peak antifactor Xa levels within the recommended range for full anticoagulation of 0.5-1.0 U/ml after their first enoxaparin dose; no concentration exceeded 1.0 U/ml. The mean peak antifactor Xa level was not significantly different after the first enoxaparin dose compared with the second and third doses. The mean +/- SD trough antifactor Xa level, thought to be an indicator of drug accumulation, was 0.12 +/- 0.12 U/ml; its clinical significance and target range are still unknown. No major bleeding events were noted. CONCLUSION: Enoxaparin 1 mg/kg once every 24 hours in patients with stage 4 or 5 chronic kidney disease who required full anticoagulation was safe, and this dose did not exceed recommended concentrations. The significance of enoxaparin trough levels remains unclear and should be investigated in future studies. Other dosing regimens of enoxaparin for specific patient populations should also be assessed for safety and efficacy.

Oral maintenance clinical trial with miglustat for type I Gaucher disease: switch from or combination with intravenous enzyme replacement.

Enzyme replacement therapy (ERT) with imiglucerase reduces hepatosplenomegaly and improves hematologic parameters in Gaucher disease type 1 within 6-24 months. Miglustat reduces organomegaly, improves hematologic parameters, and reverses bone marrow infiltration. This trial evaluates miglustat in patients clinically stable on ERT. Tolerability of miglustat and imiglucerase, alone and in combination, pharmacokinetic profile, organ reduction, and chitotriosidase activity were assessed. Thirty-six patients stable on imiglucerase were randomized into this phase II, open-label trial. Statistically significant changes from baseline were assessed (paired t test) on primary objectives with secondary analyses on biochemical and safety parameters. Liver and spleen volume were unchanged in switched patients. No significant differences were seen between groups regarding mean change in hemoglobin. Mean change in platelet counts was only significant between miglustat and imiglucerase groups (P = .035). Chitotriosidase activity remained stable. In trial extension, clinical endpoints were generally maintained. Miglustat was well tolerated alone or in combination. Miglustat's safety profile was consistent with previous trials; moreover, no new cases of peripheral neuropathy were observed. Gaucher disease type 1 (GD1) parameters were stable in most switched patients. Combination therapy did not show benefit. Findings suggest miglustat could be an effective maintenance therapy in stabilized patients with GD1.

Desensitization to hydroxychloroquine--experience of 4 patients.

Hydroxychloroquine (HCQ) is an antimalarial agent with immunomodulatory effects. It is widely used in rheumatologic diseases, and has a very high efficacy/toxicity ratio. It is particularly important in the treatment of systemic lupus erythematosus (SLE) since it reduces new organ involvement and disease flares, and relieves skin and joint symptoms. Some patients develop hypersensitivity rash in response to HCQ. In such patients the drug is withdrawn and replaced by another medication. All the alternative medications for rheumatological patients are significantly more toxic than HCQ. We describe our initial experience of HCQ slow oral desensitization. All 4 patients who were recruited completed the procedure successfully without significant difficulty. Our results suggest that HCQ slow oral desensitization is safe, effective, and easy to perform.

Intrathecal methotrexate neurotoxicity: clinical correlates and antidotal treatment.

The neurotoxicity of methotrexate (MTX) is more severe when administered intrathecally (IT) than by the oral and intravenous (IV) routes, and has been reported even with a single administration of therapeutic doses of 12 or 15mg. Prompt recognition and treatment are essential to improve the outcome after massive IT-MTX overdose. Treatment options include CSF drainage or CSF exchange, ventriculolumbar perfusion, IT corticosteroids to reduce CSF inflammation and IV leucovorin to reduce systemic toxicity. Toxicity resulting from IT injection of leucovorin is controversial. CSF drainage and exchange are particularly effective if performed soon after the overdose. In this paper we describe a protocol of treatment for severe cases of IT-MTX overdose in excess of 100mg. The mainstay of treatment is dilution and removal from CSF of excessive methotrexate alongside with specific antidotal therapy.