Vladimir Gavrilov

Signs and symptoms of carbamazepine overdose in young children.

Objective To examine common signs and symptoms of mild to moderate carbamazepine (CBZ) overdose in young children. Methods The medical records of previously healthy children admitted to the pediatric departments for acute accidental CBZ poisoning during the years 1993–1998 were evaluated retrospectively. Information was retrieved on serum CBZ levels, signs and symptoms on admission and during hospitalization, ECG findings, and chemical laboratory test. Results There were 14 exposed children all under the age of 5 years. These children accidentally took CBZ prescribed for a family member. The diagnosis of CBZ poisoning in seven children was unknown on admission because of inadequate history and was revealed only on toxicology screen. Nystagmus and drowsiness occurred in 8 of the 14 children, nystagmus and ataxia in 4 children, and drowsiness and tachycardia in another 2 children. The peak CBZ serum levels in these children ranged from 18 μg/ml to 32 μg/ml, mean + SD; 25 μg/ml + 4.64 μg/ml (therapeutic range: 5–10 μg/ml). Conclusion Based on a certain group of young pediatric patients with mild to moderate CBZ poisoning, it is concluded that, nystagmus is the most common sign of this overdose. Other common signs are drowsiness and ataxia. The presence of nystagmus and CNS depression of unknown etiology, in a young child should suggest the possibility of CBZ toxicity.

Central nervous system toxicity and early peripheral neuropathy following dermal exposure to methyl bromide.

Case Report: We describe a case of early peripheral neuropathy and central nervous system toxicity as a result of acute predominantly dermal exposure to methyl bromide. A 32-year-old male was admitted after an accidental predominantly dermal exposure to methyl bromide while fumigating soil for pest control. The patient suffered dermal burns and vesicles on the upper and lower limbs. One week following exposure, he developed progressive weakness of the lower limbs, ataxia, paresthesiae of both legs and the left arm, hyperactive tendon reflexes in the lower limbs, and left Babinski sign. Nerve conduction velocity testing was compatible with axonal neuropathy. The patient recovered gradually from his burns. Three months postexposure he showed no signs of central nervous system toxicity, but the peripheral neuropathy was still present. Discussion: Neurological effects primarily referable to the central nervous system following severe inhalation of methyl bromide have frequently been reported. The patient described in this study developed an unusual early peripheral neuropathy following dermal exposure. Peripheral neuropathy can be an outcome of methyl bromide intoxication, but is usually a late sequela of acute central nervous system toxicity or an aftereffect of repetitively inhaled chronic exposure. In this case, exposure to methyl bromide through abraded skin caused early peripheral neuropathy and central nervous system toxicity.

Transdermal delivery of paracetamol for paediatric use: effects of vehicle formulations on the percutaneous penetration

Paracetamol is a safe and effective analgesic and antipyretic agent, and is one of the most widely used medications for infants and children. The formulations currently available have been designed for oral and rectal administration. However, they are not practical in young patients with vomiting and diarrhoea, or in those who refuse to take the full dose. An alternative route of administration would be a significant contribution to the paediatric pharmacopoeia. The aim of this study was to develop a new transdermal system for optional therapeutic administration of paracetamol in infants and children. In‐vivo studies were carried out in animals using a transdermal system of high‐loaded, soluble paracetamol in a hydrogel patch, which was also tested in‐vitro for 8 h. Although the beneficial contribution of glyceryl oleate to the transdermal penetration of paracetamol seemed to be significant in‐vitro, it was shown to be insufficient in‐vivo. To improve the penetration of the drug, 4% PEG‐40 stearate and 10% ethanol were incorporated as absorption enhancers into the dermal patches. A few hours after application of the improved patches to rats, plasma drug concentrations were elevated to levels comparable with those obtained after oral and subcutaneous administration of a high dose of paracetamol. Since plasma drug concentrations did not reach a constant steady state (as a peak or plateau) during the short‐term animal experiments, longer pharmacokinetic studies in conscious animals are necessary.

Unapproved Prescription Practices in Primary Pediatric Clinics in Israel: A Prospective Analysis

Abstract Background: Many medications have not been approved for children because of a lack of data that can ensure acceptable standards of safety, efficacy, and optimal dose. Objective: The purpose of this study was to determine the extent of unlicensed and off-label medications used in primary pediatric clinics in Israel. Methods: This study was a prospective analysis of medications prescribed during consecutive clinic visits to children from different ethnic communities and different regions of Israel, during different seasons of the year. Pediatricians completed forms with patient and medication data for each patient visit included in the study. The product licenses for age, dose, indication, and route of administration of medications prescribed to children aged Results: The study was carried out in the clinical practices of 6 board-certified pediatricians treating a total of ∼9300 children in 2000–2001. A total of 1925 prescriptions for 160 different medications were given to 1802 children (959 boys, 843 girls, mean [SD] age, 4.8 [3.9] years). Of the 298 (15.5%) of unapproved prescriptions given, 1 (0.3%) was for an unlicensed medication, and 297 (99.7%) were given in an off-label manner to 280 children (15.5%). Antibiotic and antiashmatic agents were the most frequently prescribed off-label medications. Infants received more unapproved medications than did children ( P P Conclusions: Based on the results of the present survey, many medications prescribed to children have not passed the licensing process as exists for adults. A large number of children in primary pediatric clinics in Israel as well as in other countries receive a myriad of unapproved medication, prescriptions.

Unapproved prescriptions in two pediatric intensive care units in Israel.

BACKGROUND Many medications prescribed to children worldwide have not been approved for pediatric use because the necessary clinical trials have not yet been performed. Children given these drugs have been shown to be at increased risk for adverse drug reactions. OBJECTIVE The aim of this study was to assess the extent of unapproved (off label and/or unlicensed) use of medications in pediatric intensive care units (PICUs) in Israel. METHODS Medications administered to patients treated in the PICUs of Soroka University Medical Center (SMC) and Assaf Harofe Medical Center (AHMC) were reviewed. Analyses were retrospective at SMC and prospective at AHMC. RESULTS The records of 158 patients were included in the study-116 patients at SMC (73.4%; 62 boys, 54 girls; mean [SD] age, 38.9 [50.4] months) and 42 at AHMC (26.6%; 26 boys, 16 girls; mean [SD] age, 63.3 [69.3] months). They received a total of 123 different medications. Sedatives and antibiotics were the most frequently prescribed drug classes at SMC (15.2% and 6.5%, respectively), and antibiotics, acetaminophen, and antiasthmatic drugs were most frequently prescribed at AHMC (14.4%, 13.6%, and 6.8%, respectively). Sympathomimetic drugs, sedatives, and antibiotics were the drugs most commonly prescribed in an unlicensed or off-label manner at SMC (11.4%, 11.4%, and 6.5%, respectively); at AHMC, they were antiinfectives, sympathomimetics, antiasthmatic drugs, and acetaminophen (18.7%, 16.9%, 12.7%, 6.8%, respectively). The percentage of patients receiving unapproved medications (SMC, 93 [80.2%]; AHMC, 38 [90.5%]) and the percentage of unlicensed and off-label prescriptions (SMC, 243 [41.5%]; AHMC, 118 [41.0%], respectively) were similar between the 2 PICUs. Inappropriate age was the most common off-label category, followed by different dose, different indication, and different route. CONCLUSION The results of this study of unapproved prescriptions in 2 PICUs in Israel show a high number of such prescriptions and indicate an urgent need to investigate the use of those medications in children.

Acetaminophen (paracetamol) levels in human tears

This study was designed to measure acetaminophen (paracetamol) levels in tears, and to compare it to serum levels. Paracetamol levels were measured in 20 paired tears and serum samples from 10 healthy volunteers, 1 and 2 hours after ingesting 1.5 g paracetamol. Tears were collected using glass microcapillary tubes while stimulating the conjunctiva with a small sponge placed in the lower fornix. Blood samples were taken simultaneously. The samples were analyzed for paracetamol levels using homogeneous enzyme immunoassay. Tears and serum paracetamol levels 1 hour after ingestion were 16.3 microg/mL +/- 7.2 (mean +/- SD), and 21.4 microg/mL +/- 7.7 (mean +/- SD) respectively. Tears and serum levels 2 hours after ingestion were 14.4 microg/mL +/- 7.8 (mean +/- SD), and 17 microg/mL +/- 7.6 (mean +/- SD) respectively. Tears and serum paracetamol levels of all the 20 paired samples (1 h and 2 h after ingestion) were 15.35 microg/mL +/- 7.4, and 19.25 microg/mL +/- 7.8, respectively (mean +/- SD). There was a strong and highly significant correlation between paracetamol levels in serum and in tears 1 and 2 hours after ingestion (r = 0.8, p = 0.005, r = 0.85, p = 0.002 respectively). Mean +/- SD ratio of tears/serum paracetamol levels 1 hour and 2 hours after ingestion were 0.77 +/- 0.21 and 0.81 +/- 0.25 respectively. Delta tears (difference in mean levels at 1 and 2 hours) paracetamol levels is significantly correlated with delta serum levels (r = 0.7, p = 0.025). A reliable, convenient, and feasible noninvasive method is described for measuring paracetamol in tears. There is no information in the literature about tears paracetamol secretion, and little information of tears drugs concentration.

A combined pretreatment of 1,25-dihydroxyvitamin D3 and sodium valproate enhances the damaging effect of ionizing radiation on prostate cancer cells ☆

Radiotherapy is one of the curative treatment options for prostate cancer (PCa). However, effective doses of ionizing radiation (IR) have a high risk of side effects. To increase sensitivity of PCa to IR we pretreated human androgen-refractory DU145 PCa cells with a combination of sodium valproate (VPA), a well-tolerated drug with histone deacetylases inhibiting activity, and 1,25-dihydroxyvitamin D3, 1,25(OH)2D3, the active metabolite of vitamin D, a well known anticancer agent. The results show that irradiation (4Gy) of DU145 PCa cells pretreated with a combination of 1 mM VPA and 100 nM 1,25(OH)2D3 efficiently suppressed (87.9%) PCa cell proliferation. IR after combined pretreatment resulted in increased DNA double-strand breaks expressed as levels of phosphorylated histone H2A.X, compared with non-treated cells the increase was 58.1% in pretreated cells and 11.8% in non-pretreated cells (p<0.002). Combined pretreatment enhanced IR-induced activation of DNA damage checkpoint kinase Chk2, 39.0% in pretreated cells compared to 23.8% in non-pretreated cells (p<0.05). These molecular changes led to DNA replication blockade, S-phase cell-cycle arrest and enhanced apoptosis. Cumulatively, the results indicate that combined pretreatment with VPA and 1,25(OH)2D3 followed by IR is a highly effective treatment for human PCa cells. This observation may have important implications for reducing doses of radiation administered to cancer patients thus limiting the severity of side effects.

LF 16-0687 Ms, a new bradykinin B2 receptor antagonist, improves neurologic outcome but not brain tissue prostaglandin E2 release in a rat model of closed head trauma combined with ethanol intoxication.

BACKGROUND LF 16-0687 Ms previously was reported to improve Neurological Severity Score (NSS) and decrease cerebral edema and prostaglandin E(2) (PGE(2)) release after closed head trauma (CHT) in rats. Here, we examined whether these beneficial effects of LF 16-0687 Ms are altered when CHT is accompanied by acute ethanol administration. METHODS Six groups of rats (n = 8 per group) were examined during combination of the following experimental conditions: CHT versus sham operation, LF 16-0687 Ms 3 mg/kg subcutaneously versus saline, and ethanol 2 g/kg versus saline. RESULTS After CHT, brain water content decreased and NSS improved with ethanol + LF 16-0687 Ms as compared with values after saline or ethanol. PGE(2) release decreased with ethanol (147 +/- 59 pg/mg tissue) but not with ethanol + LF 16-0687 Ms (286 +/- 194 pg/mg tissue). CONCLUSION Ethanol does not affect the improvement of NSS and the decrease of cerebral edema seen with LF 16-0687 Ms after CHT, but does reverse the ability of LF 16-0687 Ms to minimize the increase of PGE(2) release. In intoxicated patients, bradykinin antagonist therapy may improve post-CHT outcome without altering PGE(2) release.

Urinary excretion of vitamin A in critically ill patients complicated with acute renal failure.

Objective. Study the possible excretion of vitamin A in urine of critically ill patients complicated with acute renal failure. Patients and Methods. Nine Intensive z`Care Unit patients, age 71.2 ± 15.7 (mean ± SD) with acute renal failure were studied. Urinary retinol, creatinine, protein, albumin, and serum creatinine were measured. Results. All patients excreted retinol in urine; individual values ranged from 0.007 to 0.379 µmol retinol/mmol creatinine. There was no correlation of urinary retinol/creatinine ratio with serum creatinine or with urinary protein/creatinine and albumin/creatinine ratios. Conclusion. Excretion of retinol in urine may be indicative of acute renal failure in critically ill patients.

Acute Valproic Acid Poisoning in Young Children

Objective: To assess the signs and symptoms of acute valproic acid (VPA) overdose in young children. Methods: The medical records of previously healthy children admitted to the pediatric department for accidental acute VPA poisoning during the years 1995–1999 were evaluated retrospectively. Information was retrieved on serum VPA concentrations, signs and symptoms on admission and during hospitalization, electrocardiography findings, and laboratory tests. Results: All 16 children included in the study were in the age range of two to six years. In 13 cases, the drug had been intended for use by a family member and was ingested accidentally by the child. Three children were receiving VPA to treat a seizure disorder and had an adverse reaction due to unintentional overdose. For four children, a diagnosis of VPA poisoning was not made on admission because of inadequate history and was revealed only on toxicology screening. Drowsiness occurred in all the children, hypotonia in 11, ataxia in eight, miosis in six, and mild hypernatremia in five. Only two children had mildly elevated hepatic enzymes. The peak VPA serum concentrations in the study group ranged from 128 to 142 μg/mL (mean ± SD 135 ± 4.25; therapeutic range 50–100). Conclusions: Drowsiness was the most common symptom in young children with mild to moderate VPA poisoning. Other symptoms included hypotonia, ataxia, and miosis. A third of the patients had hypernatremia, most probably due to VPA formulated as sodium valproate. Unlike in cases of chronic toxicity, hepatic damage was not a characteristic finding.