Effect of hyperbaric oxygen therapy on amphotericin-B induced acute renal failure in rats.

AIM: Acute renal injury may occur after amphotericin B (AmB) administration. The hypothesized injury mechanism is renal vasoconstriction and direct toxic damage. Hyperbaric oxygen therapy (HBO) is indicated for treatment of many ischemic events but not for acute renal failure (ARF). The aim of this study was to investigate the role of HBO therapy in AmB induced ARF. METHODS: ARF was induced in 41 Sprague-Dawley rats by a single dose of 75 mg/kg AmB. The rats were randomly divided into two groups; one group was treated with daily HBO for 3 consecutive days. The control group received no HBO treatment. Parameters of renal function were taken on the 5th day after AmB administration. RESULTS: Forty-one rats were treated with AmB, 21 received HBO and 20 served as controls. Body weight loss following the administration of AmB was 13.5+14.7% in the HBO treated rats, as opposed to 24.6+5% in the control group (P=0.004). Serum creatinine and urea were 0.49+0.13 mg/dL and 200.63+87.82 mg/dL in the treatment group and 0.70+0.22 mg/dL and 368.01+169.35 mg/dL, respectively in the control (P=0.001). CONCLUSION: In this model of AmB-induced ARF, HBO treatment alleviated renal injury as reflected by changes in serum creatinine and urea levels.

Factors associated with empyema in children with community acquired pneumonia.

AIM: Empyema is a potential complication of community acquired pneumonia but factors predicting this complication are lacking. METHODS: A retrospective study of all previously healthy pediatric patients admitted between January 2007 and July 2009 with CAP. Patients with non-lobar pneumonia, RSV bronchiolitis, underlying chronic disease, or hospital-acquired pneumonia were excluded. Preadmission, clinical characteristics on admission, and outcome were compared between patients with and without empyema. Management strategies in patients with empyema were also compared. RESULTS: Overall 356 patients were included. Median age was 3.8 ± 3.54 years and 60.7% were males. A total of 43 patients (12%) were diagnosed with empyema. The development of empyema was independently associated, on multivariate analysis, with older age, female gender and antibiotic therapy prior to admission, and with dyspnea, thrombocytopenia and involvement of more than one lobe on chest radiograph on admission. Patients who developed empyema had a longer and more complicated course. Hypoxemia on admission was significantly less frequent in patients with empyema who were treated with antibiotic therapy alone, compared to those treated with chest tube or video-assisted thoracoscopic surgery. CONCLUSION: Early identification of dyspnea and thrombocytopenia in patients with community acquired pneumonia could alert physicians on the potential development of empyema. Antibiotic therapy alone may be sufficient in patients with empyema who are mildly hypoxemic on admission.

Variation in the CYP2D6 genotype is not associated with carvedilol dose changes in patients with heart failure.

WHAT IS KNOWN AND OBJECTIVE: Carvedilol is the standard of care for heart failure (HF) patients. Carvedilol is partially metabolized by the highly polymorphic enzyme, CYP2D6. To reach an effective dose while avoiding adverse drug reactions (ADRs), testing of CYP2D6 genotype prior to carvedilol initiation may be considered. The objectives of this study were to determine CYP2D6 metabolic genotypes in an Israeli cohort of HF patients and to investigate the relationship between genotype, carvedilol dose and number of ADRs to determine the importance of CYP2D6 genotyping prior to treatment initiation. METHODS: Ninety-three patients with HF on carvedilol were CYP2D6 genotyped and classified as poor (PM), intermediate (IM), extensive (EM) or ultrarapid (UM) metabolizers. Carvedilol dose and ADRs were calculated and correlated with genotype using linear regression statistic analysis. RESULTS AND DISCUSSION: The distribution of the CYP2D6 phenotype in the Israeli population with HF is similar to the European general population. There were no significant differences of carvedilol dose and number of ADRs among genotype groups. Genotype group affiliation and number of adverse drug reactions were not predictive of carvedilol dose changes. WHAT IS NEW AND CONCLUSION: Genotype group affiliation and number of adverse drug reactions were not predictive of carvedilol dose during therapy for patients with HF. The Israeli CYP2D6 phenotype distribution in HF patients was consistent with the frequency in the general European population.

Strategy for increasing detection rates of drug and alcohol abuse in paediatric emergency departments.

AIM: To determine whether implementation of criteria for performing a toxicology screen and increasing staff awareness improve detection of substance abuse among adolescents presenting to the emergency department. METHODS: Patients 12 to 18 years of age presenting to one of three emergency departments in Israel were included in a prospective cohort study. In the 'study' hospital, a set of criteria for urine toxicology screen and measurements of ethanol serum level were implemented. No specific interventions were implemented in the two other hospitals. The main outcome measure was the rate of substance abuse detection. RESULTS: The number of adolescents seen in the participating centres was 3200 at the study hospital, and 3493 and 2792 at the two other hospitals. High blood ethanol concentrations were found in 49 patients at the study hospital compared with 30 and 19 patients at the two other hospitals (p < 0.001). Illicit drugs were detected in 13, 4 and 1 patients, respectively (p = 0.002). CONCLUSIONS: Introducing structured guidelines for ordering toxicological screening increases the detection of alcohol and drug of abuse among adolescents presenting to paediatric emergency departments.

[The risks of combining medicine and herbal remedies].

The risks of using herbal remedies, considered 'natural', should not be disregarded, as some have serious side effects and some interact with and influence conventional medical therapeutics. The effect may be pharmacokinetic by altering absorption or metabolism, and may be pharmacodynamic, by changing the final effect of the drug. St. John's wort, for example, an antidepressant herbal remedy, may pharmacodynamically interact with specific serotonin reuptake inhibitors (SSRI's), causing a serotonin syndrome. St. Johns wort also causes serious pharmacokinetic interactions by activating the cytochrome CYP3A4, dangerously decreasing blood levels of cyclosporin, warfarin, and theophylline, and reducing the efficacy of contraceptive pills and AIDS therapy. The article presents a review of a number of herbal remedies, commonly used in Israel, that have documented drug interactions, providing details of common indications, adverse reactions and drug interactions of each herbal remedy. Physicians should recognize the fact that patients use herbal remedies, purchased directly at pharmacies or health stores, and be aware of the potential interactions of these remedies with conventional drugs.

Pemoline-associated fulminant liver failure: testing the evidence for causation.

BACKGROUND: Pemoline is a central nervous system stimulant used in treating children with attention deficit-hyperactivity disorder. Hepatotoxicity has been commonly reported in association with pemoline; however, only two reports of cases of fatal liver failure have been published. OBJECTIVES: We report on a 14-year-old boy who received concomitant pemoline and methylphenidate in whom fulminant liver failure occurred and for whom liver transplantation failed. Other causes of fulminant liver failure were ruled out, and the liver biopsy was suggestive of drug toxicity. We estimated the probability that these three cases represent an increased risk of fulminant liver failure associated with pemoline. RESULTS: Based on the three known cases of fatal liver failure associated with pemoline use, we calculated that a child receiving pemoline has a relative risk of development of fulminant liver failure of 45.3 (95% confidence interval, 4.1 to 510). This highly significant association (p < 0.001) suggests causation. CONCLUSIONS: Because pemoline has been widely used in recent years, further studies are needed to better quantify this risk in children with attention deficit-hyperactivity disorder.

Safety of the new quinolones in pregnancy.

OBJECTIVE: To investigate the effect on the fetus of intrauterine exposure to quinolones in terms of teratogenicity, with special focus on the musculoskeletal system. METHODS: We studied 38 pregnant women who received quinolones and consulted the Motherisk Program in Toronto from 1989-1992. Perinatal complications, birth weight, birth defects, and developmental milestones, with particular emphasis on the musculoskeletal system, were compared with those of controls matched for both maternal age and indication for antibacterial therapy. RESULTS: Thirty-five women (92%) treated with norfloxacin or ciprofloxacin received therapy during the first trimester. The most common indication for therapy (92%) was urinary tract infection. More pregnancies in the quinolone group resulted in cesarean delivery due to reported fetal distress as compared to the controls (P = .005), without clear reason. Children born to mothers treated with quinolones were significantly heavier (P = .05) than the control infants, possibly because of better control of the urinary tract infection. No malformations were found in the quinolone group, whereas one child in the control group had a ventricular septal defect. No differences were detected between the groups in achievement of developmental milestones or in the musculoskeletal system. CONCLUSION: The use of the new quinolones during the first trimester of pregnancy does not appear to be associated with an increased risk of malformations or musculoskeletal problems; however, longer follow-up and magnetic resonance imaging of the joints may be warranted to exclude subtle cartilage and bone damage.

Use of a eutectic mixture of local anesthetics for prolonged subcutaneous drug administration.

The efficacy of a eutectic mixture of local anesthetics (EMLA) in alleviating the pain associated with subcutaneous needle insertion for infusion of the iron-chelating agent, deferoxamine, was examined in 12 patients with homozygous beta-thalassemia. As reported by the patient using a 100-mm visual analogue scale, the pain of insertion was rated as significantly less after application of EMLA (mean +/- SD, 1.5 +/- 2.2 mm) than the pain associated with needle insertion without EMLA (34.8 +/- 33.5 mm, P = .005). Subsequently, in a double-blind randomized trial of 10 beta-thalassemia patients, EMLA was significantly better (5.7 +/- 8.2 mm) than placebo (27.0 +/- 22.8 mm, P = .01) in reducing the pain of needle insertion for deferoxamine infusion. No adverse effects were reported with the use of EMLA cream. These results suggest that EMLA may be effective in reducing the pain associated with needle insertion for subcutaneous deferoxamine infusion in beta-thalassemia patients, which may lead to improved compliance with this irritating, prolonged therapy. The safety of EMLA use in these patients, and others receiving regular parenteral therapy, should now be examined.

Critical comparison of novel and existing methods of compliance assessment during a clinical trial of an oral iron chelator.

The assessment of compliance is critical in the evaluation of the effectiveness of a new therapeutic agent. Fifteen patients with transfusion-dependent beta-thalassemia, many of whom had previously demonstrated erratic compliance with deferoxamine, were enrolled in a clinical trial of a new oral iron chelator, 1,2-dimethyl-3-hydroxypyrid-4-one (L1). Their compliance with this medication was estimated by several existing methods and the novel Medication Event Monitoring System (MEMS). Overall compliance as assessed by the MEMS was 78.5 +/- 13.0% of prescribed doses taken, significantly lower than the corresponding rates calculated by pill counts and diaries (91.5 +/- 9.2% and 94.1 +/- 4.3%, respectively). However, several serious problems were encountered with the MEMS, mostly in the form of incorrect use of the device by the patients. Disclosure of the nature of the MEMS and the compliance monitoring process did not alter the rate of adherence with L1 therapy. Compliance as determined by pill counts did not differ between the 1st and 2nd 6-month periods. Although not reaching statistical significance, a trend towards better L1 compliance occurred in those patients in whom serum ferritin levels decreased. Patients who filled at least 50% of their diaries had significantly better compliance by pill counts than those who completed less than 50% of their diaries (95.9 +/- 4.1% and 86.5 +/- 11.1%, respectively). Steady-state L1 trough concentrations and 24-hour urinary iron excretion did not correlate with L1 compliance.(ABSTRACT TRUNCATED AT 250 WORDS)

Steady-state pharmacokinetics of isotretinoin and its 4-oxo metabolite: implications for fetal safety.

Isotretinoin is the most potent human teratogen on the market. Women for whom contraception fails may conceive during or soon after discontinuing isotretinoin therapy, making its elimination kinetics a crucial determinant of fetal safety. The steady-state pharmacokinetics of isotretinoin and its major 4-oxo metabolite were studied in 16 adult patients treated for acne who were receiving doses that ranged from 0.47 to 1.7 mg/kg daily. This is the first study of the pharmacokinetics of isotretinoin in women of childbearing age (n = 11). The clinical efficacy and tolerability of isotretinoin was investigated, and the correlation between these data and steady-state serum concentrations of isotretinoin was tested. The concentration-time data best fitted a two-compartment open model with linear elimination. There was no correlation between efficacy and tolerability of isotretinoin and steady-state serum concentrations. There was no correlation between dose of isotretinoin and steady-state concentration, due to the large variability in apparent clearance. Values for elimination half-life (t1/2) of isotretinoin and its metabolite were 29+/-40 hours and 22+/-10 hours, respectively. These data suggest a longer elimination t1/2 of the parent drug than previously reported. This is probably due to the longer sampling time used in this study (as long as 28 days). This study suggests that a greater variability exists in the safe time after discontinuation of the drug for onset of conception.

Hypertension and abdominal pain: uncommon presentation after exposure to a pine caterpillar.

UNLABELLED: The pine caterpillar Thaumatopoea wilkinsoni is found in pine woods all over Israel. Contact with its hair usually results in local reactions. Systemic reactions after contact with caterpillar hairs are known in other caterpillar species, but have been described only once after contact with T. wilkinsoni. We describe a group of adolescents who were exposed to T. wilkinsoni while camping in a pine wood. Three of them were referred to an emergency department. They had severe pruritus, pain and edema at the contact sites, with papular and urticarial rashes. Two of the patients had abdominal pain and one patient had hypertension for several hours. The hypertension resolved spontaneously. CONCLUSION: Skin eruptions are the most common manifestations of T. wilkinsoni contact, however, although systemic manifestations are rare, abdominal pain and hypertension may occur.

Copper and zinc blood levels among children with nonorganic failure to thrive.

BACKGROUND AND AIMS: Copper and zinc deficiency are commonly reported among children with organic failure to thrive. In contrast, reports on copper and zinc status in children with non-organic failure to thrive are scarce. The goal of this study was to evaluate copper and zinc blood levels and nutritional intake among children with non-organic failure to thrive. METHODS: A study group of 32 children with non-organic failure to thrive were investigated and compared with 32 healthy controls. Each child had copper and zinc blood level measurements. In addition, the study group underwent evaluation of thyroid function, immunoglobulins, endomesial antibodies and xylose test. A dietary questionnaire that included a diet history and a 24-h dietary recall was administered to parents by a dietician. Weight for height, height for age and mean daily intake of calories, protein, copper and zinc were calculated. RESULTS: There were no significant differences between the two groups in either socioeconomic status or caloric, copper or zinc intake. Protein intake was significantly lower in the study group (P<0.0001). Plasma copper levels were within the normal range in both groups (P=0.3). Zinc plasma levels were significantly higher in the study group as compared to controls (P=0.03); however, they remained within the normal range in both groups. CONCLUSIONS: Children with non-organic failure to thrive can maintain plasma copper and zinc levels within normal range and similar to normal controls.

Sodium potassium adenosine triphosphatase activity in preterm and term infants and its possible role in sodium homeostasis during maturation.

AIM: To investigate sodium (NA(+)) potassium (K(+)) adenosine triphosphatase (ATPase) activity in newborn infants at different gestational ages, to elucidate the mechanism underlying poor renal sodium conservation in preterm infants. METHODS: Fifty three healthy newborn infants, gestational age 30-42 weeks, were studied. Umbilical cord red blood cell Na(+) K(+)ATPase activity, plasma renin activity, and plasma aldosterone activities were measured in all of them. Red blood cell Na(+) K(+)ATPase activity was re-examined in eight preterm infants, one and two weeks after birth. Total and ouabain sensitive ATPase activity was measured spectrophotometrically using a method that couples ATP hydrolysis with NADH oxidation. RESULTS: Red blood cell Na(+) K(+)ATPase activity was significantly lower (p<0.01) in preterm babies with a gestational age below 35 weeks, compared with those with aged 35 weeks and above: 2.3 (0.8) and 6.7 (1.3) nmol NADH/minute/mg protein, respectively. There was no correlation between gestational age, Na(+) K(+)ATPase, plasma renin activity and aldosterone values either in the preterm or term babies. Two weeks after birth, irrespective of gestational age, the enzyme activity of the preterm babies increased to values similar to those observed in the term neonates at birth. CONCLUSION: The differences in sodium homeostasis between term and preterm babies are modulated via changes in Na(+) K(+)ATPase activity.

Abnormal visual evoked potentials in children with "Alice in Wonderland" syndrome due to infectious mononucleosis.

Visual illusions characterized by distortion of form, size, reciprocal position of objects, movement, or color, labeled as "Alice in Wonderland" syndrome, were discussed in children with infectious mononucleosis, as well as in other clinical conditions, such as migraine, epilepsy, use of certain hallucinogenic drugs, etc. The purpose of our study was to investigate for the first time visual evoked potential results in children with "Alice in Wonderland" syndrome associated with infectious mononucleosis. Five children with "Alice in Wonderland" syndrome associated with infectious mononucleosis underwent visual evoked potential studies during and after their clinical symptoms. Visual evoked potential results during the disease demonstrated statistically significant high amplitudes of P100-N145 in all children compared to the control group. A few weeks later, repeated studies after the resolution of the complaints were normal. Since the same findings can be observed in patients with migraine, we postulate that a common pathophysiologic underlying abnormality, which can cause transient focal decreased cerebral perfusion, could be involved in the disease process of these two conditions.

Hereditary insensitivity to pain with anhidrosis.

Hereditary sensory neuropathy type IV is an autosomal-recessive disorder characterized by congenital insensitivity to pain and anhidrosis and resulting in recurrent hyperpyrexia, self-mutilation, recurrent infections, chronic osteomyelitis, bone and joint deformities, and limb amputations. Described is a child with signs as well as skin and nerve biopsy results compatible with this disease, emphasizing the importance of early diagnosis and appropriate medical and educational care to prevent complications.

Intranasal midazolam as a treatment of autonomic crisis in patients with familial dysautonomia.

To evaluate the efficacy and safety of intranasal midazolam in the treatment of autonomic crises in children with familial dysautonomia, intranasal midazolam was administered at the hospital to six patients during nine episodes of autonomic crisis. Treatment was successful in seven of nine episodes of autonomic crisis in five of six patients, with a mean interval to response of 9.25 +/- 1.25 minutes. The parents of five patients in whom the treatment was successful were instructed to use midazolam at home. At home, 16 additional episodes were treated by the parents, with successful control achieved in 14 (87%). The mean interval to response was 12.8 +/- 2 minutes. No significant side effects were observed at the hospital or at home after intranasal administration of midazolam. Midazolam, given intranasally, is effective and safe in the management of autonomic crises in patients with familial dysautonomia, either in the hospital or at home by the parents after appropriate instruction.

Iron deposition in the anterior pituitary in homozygous beta-thalassemia: MRI evaluation and correlation with gonadal function.

OBJECTIVE: Iron deposition in the anterior pituitary continues to pose a serious problem in older patients with homozygous beta-thalassemia particularly in terms of gonadal function. This study aimed to investigate whether iron loading within the pituitary correlated with endocrine function. PATIENTS: 33 patients above 15 years of age, with transfusion-dependent homozygous beta-thalassemia and iron overload were studied. All had been receiving deferoxamine since 1978. DESIGN AND MEASUREMENTS: The endocrine status of the patients was assessed on clinical examination by an endocrinologist, and by a gonadotropin releasing hormone stimulation test. MRI of the pituitary was carried out for each patient. RESULTS: Anterior pituitary function (GnRH stimulation test) correlated well with MRI results. However, no correlation was found between the MRI measurements, the GnRH stimulation test and the clinical status of the patients, as 28 out of the 33 patients achieved normal puberty. CONCLUSIONS: MRI in conjunction with a GnRH stimulation test may be useful in predicting future impairment of pituitary function; however, further studies are needed to assess the effect of chelation therapy on the iron overload in the gland.

Pharmacokinetics of arginine butyrate in patients with hemoglobinopathy.

Recent reports have demonstrated improvement in the clinical status and hemoglobin levels with use of intravenous arginine butyrate in patients with homozygous ß-thalassemia and sickle cell disease. To allow optimalization of therapy, we conducted pharmacokinetic studies in nine patients, five with sickle cell disease and four with ß-thalassemia, treated with continuous intravenous infusion of arginine butyrate. The disappearance of the drug after discontinuation was characterized by a biphasic elimination with an initial rapid phase followed by a slower phase. Redistribution was noted in five of the patients after 11.2 ± 4.0 min. The short half life was the result of both rapid clearance rate of 93.6 ± 31.9 ml/kg/min and small Vc (0.21 ± 0.26 l/kg) and Vss (0.31 ± 0.37 l/kg). While preliminary results of the effectiveness of arginine butyrate are encouraging with a rise of γ-globin mRNA and F reticulocytes in some patients, the rapid elimination of this agent will probably limit its current use to administration by continuous infusion.

Talismans and amulets in the Pediatric Intensive Care Unit: legendary powers in contemporary medicine.

BACKGROUND: For centuries talismans and amulets have been used in many cultures for their legendary healing powers. METHODS: We asked the parents of every child (Jews and Arabs) admitted to the Pediatric Intensive Care Unit over a 2 month period to complete a questionnaire, which included demographic data on the patient and the family, the use of talismans or other folk medicine practices, and the perception of the effects of these practices on the patient's well-being. A different questionnaire was completed by the ICU staff members on their attitude toward the use of amulets. RESULTS: Thirty percent of the families used amulets and talismans in the ICU, irrespective of the socioeconomic status of the family or the severity of the patient's illness. Amulets and talismans were used significantly more by religious Jews, by families with a higher parental educational level, and where the hospitalized child was very young. The estimated frequency of amulet use by the children's families, as perceived by the staff, was significantly higher than actual use reported by the parents. In Jewish families the actual use of amulets was found to be 30% compared to the 60% rate estimated by the medical staff; while in Moslem families the actual use was zero compared to the staff's estimation of about 36%. Of the 19 staff members, 14 reported that the use of amulets seemed to reduce the parents' anxiety, while 2 claimed that amulet use sometimes interfered with the staff's ability to carry out medical treatment. CONCLUSIONS: The use of talismans in a technologically advanced western society is more frequent than may have been thought. Medical and paramedical personnel dealing with very ill patients should be aware of the emotional and psychological implications of such beliefs and practices on patients and their families.