Clinical Pharmacology and Toxicology Unit


Clinical Pharmacology and Toxicology Unit

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Lavon O.,Clinical Pharmacology and Toxicology Unit | Lavon O.,Technion - Israel Institute of Technology | Avrahami A.,Technion - Israel Institute of Technology | Eisenkraft A.,Hebrew University of Jerusalem
BMC Pharmacology and Toxicology | Year: 2017

Background: Better and safer antidotes against cyanide poisoning are needed. Prior study has shown a favorable effect of isosorbide dinitrate (ISDN) on the survival of cyanide-poisoned rabbits when administered as early as 1 min after poisoning. The aim of the current study was to further evaluate the efficacy of intravenous ISDN administered in clinically relevant timing for first responders. Methods: A comparative animal study using 24 rabbits in 4 randomized study groups was performed. Animals were poisoned with intravenous potassium cyanide (1 mg/kg). Animals in Group 1 served as controls and received no treatment. Groups 2-4 animals were treated intravenously with ISDN (50 μg/kg) after poisoning; one group after 3 min, another group after 5 min and the last after 7 min. Animals were observed for 30 min after poisoning. The study endpoints included survival rate, clinical status, blood pressure, pulse per minute, blood lactate and pH. Results: Five of 6 animals (83.3%) from every treatment group survived the whole observation period while all control untreated animals died. All the rabbits collapsed immediately after exposure, showing rapidly deteriorated vital signs with lactic metabolic acidosis (peak blood lactate levels of 18.1 to 19.0 mmol/L on average at 10 min post exposure). Vital signs, clinical scores, and blood gases of treated rabbits gradually improved. Conclusion: Poisoned rabbits showed improved short-term survival following the administration of ISDN up to 7 min after lethal cyanide poisoning of. We see a potential for ISDN as an antidote against cyanide poisoning. © 2017 The Author(s).

Abu-Kishk I.,Pediatric Intensive Care Unit | Goldman M.,Assaf Harofeh Medical Center | Mordish Y.,Assaf Harofeh Medical Center | Berkovitch M.,Clinical Pharmacology and Toxicology Unit | Kozer E.,Pediatric Emergency Unit
Archives of Disease in Childhood | Year: 2010

Aim: To describe the incidence of acute renal insufficiency after dipyrone overdose in children. Methods: The medical records of all patients ≤18 years of age during a 3-year period presenting at Assaf Harofeh Medical Center due to toxic exposure were retrospectively reviewed. Patients suffering from dipyrone overdose were compared with all the other patients. Results: 235 cases were included in the fi nal analysis. Of these, 26 (11%) patients were exposed to dipyrone (median age 15 years). Three of the 26 patients (12%) had transient non-oliguric renal insuffi ciency. One other patient who did not receive dipyrone also developed transient renal insuffi ciency. Conclusions: Dipyrone overdose is frequent and may cause acute non-oliguric renal insuffi ciency. Renal function should be monitored in such patients.

Rosenfeld-Yehoshua N.,Pediatric Intensive Care Unit | Rosenfeld-Yehoshua N.,Tel Aviv University | Klin B.,Tel Aviv University | Klin B.,Assaf Harofeh Medical Center | And 4 more authors.
Pediatric Critical Care Medicine | Year: 2016

Objectives: In Israel, the recommendation for the use of propofol is age limited. Furthermore, procedural sedations involving propofol must be performed only by anesthesiologists. Propofol is frequently used in the PICUs in Israel. Design: Questionnaire survey. Setting: PICUs in Israel. Subjects: None. Interventions: None. Measurements and Main Results: Physicians from 13 PICUs (86.6%) responded to the questionnaire. Propofol was used for induction, procedural sedation, and ongoing ICU sedation in 100%, 70%, and 12% of cases, respectively. Eighty-eight percent of the participants limited the duration of propofol infusion to 24 hours at a dose of less than or equal to 4 mg/kg/1 hr, but 40% administered propofol as needed without specifying an upper dose limit. Twenty-five percent encountered adverse effects such as apnea, desaturation, and bradycardia, but only two of the participants suspected propofol infusion syndrome, each in one patient. All the participants agreed to expand the indications for propofol use in the pediatric age group. Ketamine was the drug mostly used instead of propofol (50%), followed by fentanyl (30%), midazolam (30%), and remifentanil (5%). Apart from anesthesiologists, PICU physicians support the use of propofol by physicians who have the technical skills for rapid-sequence intubation and advanced airway management. Conclusions: Off-label use of propofol is an accepted practice in Israeli PICUs. Propofol has a unique profile that makes it an attractive sedative agent in many clinical settings. PICU physicians may want to prescribe it, at least for short periods and at low doses. © 2016 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.

Kozer E.,Pediatric Emergency Unit | Kozer E.,Tel Aviv University | Lotem Z.,Pediatric Ambulatory Center | Elgarushe M.,Clalit Health Services | And 6 more authors.
Pediatrics | Year: 2012

BACKGROUND: Infections with viruses causing upper respiratory tract infection (URI) are associated with increased leukotriene levels in the upper airways. Montelukast, a selective leukotriene-receptor antagonist, is an effective treatment of asthma and allergic rhinitis. OBJECTIVE: To determine whether prophylactic treatment with montelukast reduces the incidence and severity of URI in children. METHODS: A randomized, double-blind, placebo-controlled study was performed in 3 primary care pediatric ambulatory clinics in Israel. Healthy children aged 1 to 5 years were randomly assigned in a 1:1 ratio to receive 12-week treatment with 4 mg oral montelukast or look-alike placebo. Patients were excluded if they had a previous history of reactive airway disease. A study coordinator contacted the parents by phone once a week to obtain information regarding the occurrence of acute respiratory episodes. The parents received a diary card to record any acute symptoms of URI. The primary outcome measure was the number of URI episodes. RESULTS: Three hundred children were recruited and randomly assigned into montelukast (n = 153) or placebo (n = 147) groups. One hundred thirty-one (85.6%) of the children treated with montelukast and 129 (87.7%) of the children treated with placebo completed 12 weeks of treatment. The number of weeks in which URI was reported was 30.4% in children treated with montelukast and 30.7% in children treated with placebo. There was no significant difference in any of the secondary variables between the groups. CONCLUSIONS: In preschool-aged children, 12-week treatment with montelukast, compared with placebo, did not reduce the incidence of URI. Copyright © 2012 by the American Academy of Pediatrics.

Lavon O.,Israel Information Poison Center | Lavon O.,Clinical Pharmacology and Toxicology Unit | Ben-Zeev A.,Israel Information Poison Center | Bentur Y.,Israel Information Poison Center | Bentur Y.,Technion - Israel Institute of Technology
Basic and Clinical Pharmacology and Toxicology | Year: 2014

Medication errors (ME) are a major concern to healthcare systems. Most studies evaluated ME occurring in healthcare facilities; only few focused on ME outside them. The objective was to characterise ME occurring outside healthcare facilities. A prospective observational follow-up study evaluating all ME occurring outside healthcare facilities reported to a national poison information centre during a 5-month period. For each ME case, a detailed questionnaire was filled and a follow-up call was made within 7 days. The collected data included demographics, circumstances, type of error and outcome. Of 1381 consecutive ME cases were included; 97.8% involved a single incident and 88.3% one drug. The main characteristics of the ME were as follows: children younger than 6 years old (58.9%), parents responsible for 55.6% of cases, wrong dose 34.5% and different medication 30.1%. Analgesics (27.4%) and antimicrobials (12.2%) were the most common pharmaceuticals. The main reasons for the ME were look-alike packaging (31.4%) and misunderstood instructions (28%). Most followed up patients (97.1%) were asymptomatic or mildly affected; there was one severe case and no mortality. Most ME occurring outside healthcare facilities are single incidents, involving young children who were administered a wrong dose or medication due to look-alike packaging or misunderstood instructions with asymptomatic or mild outcome. Improved packaging, labelling and patient education are suggested to reduce ME. © 2013 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Lubart E.,Shmuel Harofeh Medical Center | Berkovitch M.,Clinical Pharmacology and Toxicology Unit | Leibovitz A.,Shmuel Harofeh Medical Center | Orly D.,Clinical Pharmacology and Toxicology Unit | Segal R.,Shmuel Harofeh Medical Center
Therapeutic Drug Monitoring | Year: 2010

Many medications administered to frail geriatric patients are not in a liquid form, but are crushed and dissolved in water before their administration through a nasogastric tube (NGT). Some medications are enteric coated and others are extended release. Only sparse information is available on their pharmacokinetics when administered through NGT. The aim of our study was to evaluate the pharmacokinetics of phenytoin administered through an NGT and to compare these with the pharmacokinetics of a group of patients receiving the drug orally. Twenty patients were studied in a stable clinical condition, from the long-term care ward of the Geriatric Medical Center Shmuel Harofeh. They were consistently treated with phenytoin for the prevention of seizure disorders. Patients in group 1 (n = 12) had oropharyngeal dysphagia and received feeding and medications by NGT. Group 2 (n = 8), included age-matched orally fed patients from the same department, who received phenytoin orally. Blood samples for phenytoin concentration were taken at baseline, time 0, and at 1, 3, 4, 6, and 8 hours postdrug administration; phenytoin was measured using the AxSYM assay. The mean daily dose was not statistically different between the 2 groups: 291 ± 28 (200-300) mg/d and 300 ± 53 (200-400) mg/d, in the NGT, and the orally fed group, respectively, in one dose. Pharmacokinetic parameters of phenytoin were not significantly different between the 2 groups; trough concentrations, 1.9 ± 1.7 (0.5-4.9) versus 2.2 ± 1.8 (1.0-6.5) μg/mL; Cmax, 6.6 ± 3.4 (2.5-9.1) versus 7.3 ± 6.7 (2.7-8.4) μg/mL; tmax, 5.1 ± 3.1 (3.1-8.2) versus 4.6 ± 2.7 (2.3-8.4) hours; area under the curve, 52.2 ± 40.1 (41.1-61.2) versus 62.3 ± 84.7 (30.2-77.2) μg/h/mL, in the NGT fed versus the oral fed, respectively. Phenytoin pharmacokinetic parameters are not significantly different between patients receiving the drug through NGT as compared with those who received it orally, but the implication of the low concentrations measured should be evaluated carefully. Copyright © 2010 by Lippincott Williams & Wilkins.

Goldstein L.H.,Haemek Medical Center | Goldstein L.H.,Technion - Israel Institute of Technology | Goldstein L.H.,Clinical Pharmacology Unit | Berlin M.,Clinical Pharmacology and Toxicology Unit | And 3 more authors.
Journal of Clinical Pharmacology | Year: 2013

Adverse drug reactions (ADR) are underreported by doctors despite numerous efforts. We aimed to determine if establishing an gADR reporting doctorfs networkh within a hospital would increase the quantity of ADRs reported by hospital doctors. One hundred hospital doctors joined the network. Email reminders were sent to network members during the 1 year study period, conveying information about ADRs reported, amusingly and pleasantly reminding them to report ADRs in minimal detail, by phone, email, text message or mail to the Clinical Pharmacology Unit, who would further complete the report. A total of 114 ADRs were reported during the study period in comparison to 48, 26, and 17 in the previous 3 years (2008, 2009, 2010, respectively). In the 3 years prior, doctors reported 41.7% of the reported ADRs whereas in the study period, doctors reported 74.3% of ADRs (P.001), reflecting an 80% increase in doctors reports. Ninety seven percent of doctorsf reports were of ADR network members. Thirty]four (34%) network members reported an ADR during the study period and 31 of the 34 reporters had never reported ADRs before becoming network members. Establishing an ADR network of doctors substantially increases ADR reporting amongst its members. © 2013, The American College of Clinical Pharmacology.

Lavon O.,Clinical Pharmacology and Toxicology Unit
Clinical Toxicology | Year: 2015

Context. More effective, rapidly delivered, safer antidotes are needed for cyanide poisoning. Previous study has demonstrated a beneficial effect of isosorbide dinitrate on the survival of cyanide-poisoned mice. Objective. To evaluate the effectiveness of isosorbide dinitrate compared with that of sodium nitrite in cyanide poisoning. Materials and methods. A comparative animal study was performed using 18 rabbits, randomized into 3 study groups. Animals were poisoned intravenously with potassium cyanide (1 mg/kg). The first group was not given any further treatment. The second and third groups were treated intravenously 1 min after poisoning with sodium nitrite (6 mg/kg) and isosorbide dinitrate (50 μg/kg), respectively. The primary outcome was short-term survival of up to 30 min. Secondary outcomes included time to death, a clinical score, mean blood pressure, pulse, blood pH, and lactate and methemoglobin levels. Results. Rabbits treated with isosorbide dinitrate or sodium nitrite survived while only one untreated rabbit survived. Median time to death of the 5 poisoned and untreated animals was 10 min. All the animals collapsed soon after poisoning, exhibiting rapidly disturbed vital signs and developed lactic metabolic acidosis; average peak blood lactate levels were 15.5-19.1 mmol/L at 10 min after poisoning. The treated animals improved gradually with practically full recovery of the clinical scores, vital signs, and blood gas levels. Sodium nitrite administration raised methemoglobin to an average peak of 7.9%, while isosorbide dinitrate did not change methemoglobin levels. Conclusion. Early administration of isosorbide dinitrate improved the short-term survival of cyanide-poisoned rabbits. Isosorbide dinitrate shows potential as an antidote for cyanide poisoning and may exert its effect using a nitric-oxide-dependent mechanism. © 2014 Informa Healthcare USA, Inc.

Aviner S.,Barzilai Medical Center | Aviner S.,Ben - Gurion University of the Negev | Berkovitch M.,Clinical Pharmacology and Toxicology Unit | Berkovitch M.,Tel Aviv University | And 4 more authors.
Pediatrics | Year: 2010

OBJECTIVE: An apparent life-threatening event (ALTE) caused by ingestion of drugs or toxins has been reported rarely among infants. None of these agents was homeopathic medication. We report 11 infants who presented with an ALTE after ingestion of Gali-col Baby, a homeopathic agent indicated for "infantile colic." METHODS: A retrospective case-control study was conducted. Charts of all infants who were younger than 1 year and were admitted with an ALTE from January 2005 through August 2008 to the pediatric division at the Barzilai Medical Center were reviewed. Age-matched infants who were admitted on the same dates for a reason other than ALTE served as a control group. Information on medications administered before admission was recorded. RESULTS: During the study period, 36 635 children visited the pediatric emergency department of the Barzilai Medical Center. There were 11 057 admissions to the pediatric division during this period, 115 of which were because of an ALTE. Eleven of these infants received Gali-col Baby before the event as opposed to none in the control group (P < .005). Three infants received a significant overdose, compared with the manufacturer's recommended dosage. After a thorough investigation, no other presumptive causes for ALTE were found among the 11 infants. CONCLUSIONS: Gali-col Baby is associated with an ALTE in some infants. There are no published controlled trials on the efficacy or safety of its use; therefore, better control and supervision of Gali-col Baby and probably other homeopathic medications are needed to prevent possible serious adverse effects. Copyright © 2010 by the American Academy of Pediatrics.

Perl S.,Pediatric Emergency Unit | Goldman M.,Assaf Harofeh Medical Center | Berkovitch M.,Clinical Pharmacology and Toxicology Unit | Kozer E.,Pediatric Emergency Unit
Israel Medical Association Journal | Year: 2011

Background: Diarrhea is a leading cause of child mortality worldwide. Rotavirus is one of the most common causes of severe diarrhea and dehydration in children. Objectives: To compare the demographic, clinical and laboratory characteristics of patients with rotavirus gastroenteritis to those with other causes of gastroenteritis. Methods: The medical records of children aged 0-18 years hospitalized with acute gastroenteritis in our facility between 1 January 2004 and 31 March 2006 were retrieved. Patients with rotavirus gastroenteritis were compared with patients who were rotavirus negative. Results: The study group comprised 533 patients; 202 tested positive for rotavirus and 331 tested negative. Compared to patients with rotavirus-negative gastroenteritis, patients with rotavirus-positive gastroenteritis had a higher incidence of vomiting (185/202 vs. 212/331, 92% vs. 64%, P < 0.001), lethargy (67/202 vs. 51/331, 33% vs. 15%, P < 0.001), and dehydration (81/202 vs. 78/331, 40% vs. 24%, P < 0.001). The need for intravenous rehydration therapy and the duration of hospitalization were higher in patients with rotavirus gastroenteritis. Conclusions: Vomiting and dehydration are more common in hospitalized children with rotavirus gastroenteritis than in children with gastroenteritis due to other causes.

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