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Biomedical subjects

M Berkovitch

Publications and source records attributed to M Berkovitch.

At least 55 records · Page 3Linked to original sources
PubMed1996

Hepatotoxicity of 6-mercaptopurine in childhood acute lymphocytic leukemia: pharmacokinetic characteristics.

Treatment with 6-mercaptopurine (6MP) is associated with adverse gastrointestinal (GI) and hepatic effects. Four patients, ages 6.9 +/- 2.6 (mean +/- S.D.) years, with acute lymphocytic leukemia (ALL) on maintenance chemotherapy including 6MP, developed nausea, vomiting, abdominal pain, elevated liver enzymes, and hyperbilirubinemia after 1.4 +/- 1.0 (range 0.5-2) years. Liver biopsy in 1 patient was suggestive of drug-induced intrahepatic cholestatis. Symptoms resolved and liver function returned to normal after discontinuation of 6MP. Pharmacokinetic data of the symptomatic patients were compared with those of 25 ALL patients on the same protocol but without GI symptoms or hepatotoxicity. Levels of 6-thioguanine nucleotides (6-TGN) and the methylated metabolites of 6MP in red blood cells of the patients with hepatotoxicity, were not significantly different when compared to patients without hepatotoxicity, suggesting similar absorption of 6MP in both groups. Time to achieve peak 6MP levels was significantly longer in the symptomatic patients compared to the asymptomatic patients (P = 0.005). Peak levels and standardized concentration versus time curve (AUC) per 1 mg of 6MP per m2 of body surface area were significantly lower in the patients with hepatotoxicity (P = 0.016; P = 0.037, respectively). A significant correlation between peak 6MP levels and standardized AUC (r = 0.729, P < 0.0001) was found. These results suggest accumulation of 6MP and its metabolites in the liver of the patients with GI symptoms, leading to hepatotoxicity.

Antimetabolites, Antineoplastic↗
PubMed1996

Efficacy of deferiprone in the treatment of acute iron intoxication in rats.

BACKGROUND: Deferiprone [(1,2-dimethyl-3-hydroxypyrid-4-one) (L1)], is the first orally active iron chelating agent to reach clinical trials in patients with chronic iron overload. Its efficacy in preventing morbidity and mortality in acute iron poisoning has not been tested. OBJECTIVE: To determine whether deferiprone can reduce the mortality of rats following toxic oral doses of iron. METHODS: Rats were administered 612 mg/kg elemental iron by gavage, corresponding to the LD58. A parallel group received the same oral dose of iron followed by deferiprone intraperitoneally at 400 mg/kg (loading dose), followed by additional intraperitoneal injections of 200 mg/kg, 100 mg/kg and 100 mg/kg of deferiprone at one hour intervals. RESULTS: Coadministering deferiprone with the iron decreased mortality from 58% (11/19) to 15% (3/20) (p = 0.013). The administration of deferiprone was associated with urinary excretion of iron (which did not occur with iron alone) and the production of the red deferiprone-iron complex. On histological examination there appeared to be less iron in the liver and gastrointestinal tract. CONCLUSION: The coadministration of deferiprone can decrease morbidity and mortality caused by acute iron overdose. Deferiprone holds promise for the treatment of iron poisoning but additional study is required.

Animals↗
PubMed1995

Iron-chelation therapy with oral deferiprone in patients with thalassemia major.

BACKGROUND: To determine whether the orally active iron chelator deferiprone (1,2-dimethyl-3-hydroxy-pyridin-4-one) is efficacious in the treatment of iron overload in patients with thalassemia major, we conducted a prospective trial of deferiprone in 21 patients unable or unwilling to use standard chelation therapy with parenteral deferoxamine. METHODS: Hepatic iron stores were determined yearly by chemical analysis of liver-biopsy specimens or magnetic-susceptibility measurements. Detailed clinical and laboratory studies were used to monitor safety and compliance. RESULTS: The patients received deferiprone therapy for a mean (+/-SE) of 3.1 +/- 0.3 years. Ten patients in whom previous chelation therapy with deferoxamine had been ineffective had initial hepatic iron concentrations of at least 80 mumol per gram of liver, wet weight -- values associated with complications of iron overload. Hepatic iron concentrations decreased in all 10 patients, from 125.3 +/- 11.5 to 60.3 +/- 9.6 mumol per gram (P < 0.005), with values that were less than 80 mumol per gram in 8 of the 10 patients (P < 0.005). In all 11 patients in whom deferoxamine therapy had previously been effective, deferiprone maintained hepatic iron concentrations below 80 mumol of iron per gram. CONCLUSIONS: Oral deferiprone induces sustained decreases in body iron to concentrations compatible with the avoidance of complications from iron overload. The risk of agranulocytosis associated with deferiprone may restrict its administration to patients who are unable or unwilling to use deferoxamine.

Administration, Oral↗
PubMed1995

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.

Anesthetics, Local↗
PubMed1995

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.

Adolescent↗
PubMed1995

Assessment of the terminal 40-millisecond QRS vector in children with a history of tricyclic antidepressant ingestion.

Tricyclic antidepressant (TCA) ingestions remain a serious and not uncommon overdose in children. In adults, a terminal 40 millisecond QRS vector (T40-ms) between 120 and 270 degrees has been proposed as a marker for TCA overdose; however, the normal rightward deviation and high incidence of incomplete right bundle branch block noted in the electrocardiograms (ECGs) of young children may limit the usefulness of this criterion in this population. A retrospective chart review of pediatric patients less than 11 years of age admitted to the Hospital for Sick Children with birth dates after 1971 identified by International Classification of Diseases, Ninth Edition, coding for TCA ingestion was undertaken, and data related to complications were collected and reviewed. The ECGs of 35 children presenting with TCA ingestion were examined by two blinded cardiologists and the T40-ms as well as QRS, QTc, and PR intervals were calculated and compared to those of 35 healthy age-matched controls undergoing routine ECGs. In the 35 children (aged 48 +/- 39 months [mean +/- SD]) with a history of TCA ingestion, symptoms were categorized as significant in 18 (51%), mild in 12 (34%), and none in five (14%). Seizures were present in 13 (37%), hypotension in three (9%), and arrhythmias in five (14%). The mean T40-ms axes in the TCA and control groups were 111 +/- 66 degrees and 97 +/- 71 degrees, respectively. A T40-ms between 120 and 270 degrees had a sensitivity of 38% and a specificity of 74%. A marked variability in the T40-ms was noted in both the exposed and control groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Antidepressive Agents, Tricyclic↗
PubMed1995

Evaluation of therapeutic drug monitoring of methotrexate in saliva of children with rheumatic diseases.

Pediatric patients with leukemia, other malignancies, and rheumatological disease receive methotrexate chronically. Because of the documented correlation between methotrexate levels of compliance and clinical outcome, it is conceivable to verify appropriate systemic exposure to the drug. Saliva sampling may be of potential interest, especially in children, in whom blood sampling is ethically limited. Our study shows poor correlation between serum total/free methotrexate concentrations and saliva levels, precluding the clinical use of this test.

Adolescent↗
PubMed1995

BAEP studies in children with attention deficit disorder.

Brainstem auditory evoked potentials (BAEPs) were performed on 114 children with attention deficit disorder (ADD). Prolonged latencies of waves III and V and longer brainstem transmission time interval of waves I-III and I-V were observed in the study group compared with normal controls. A significant asymmetry of wave III latency between the ears was found in children with ADD, but not observed in the control group. The authors conclude that children with ADD have brainstem dysfunction. BAEPs, an objective electrophysiological test, may contribute to the diagnosis of ADD, distinguishing these children from the normal population.

Adolescent↗
PubMed1995

Experience with misoprostol therapy for NSAID gastropathy in children.

OBJECTIVE: To determine the effect of misoprostol, a synthetic prostaglandin E1 analogue, on the gastrointestinal tract (GIT) symptoms associated with non-steroidal anti-inflammatory drug (NSAID) administration and on the haemoglobin value, in children. METHODS: Retrospective chart review of children attending the paediatric rheumatology clinic at a tertiary referral hospital over a three year period, who were receiving NSAIDs and were prescribed misoprostol for treatment of GIT symptoms or anaemia. RESULTS: Twenty five children (mean age 12.0 (SD 2.8) (range 7-17) years were prescribed misoprostol (mean dose 308.4 (76.5) micrograms/m2/day; 9.8 (2.5) micrograms/kg/day) while NSAID therapy was continued. Of the 22 (88%) patients with GIT complaints, 18 (82%) had complete resolution of symptoms and two (9%) had some improvement. Four patients (18%) had a recurrence of symptoms after initial resolution while still receiving misoprostol. Misoprostol therapy was associated with a statistically significant increase in haemoglobin concentration (mean value before misoprostol 115 (18) g/l; after misoprostol 126 (15) g/l (p = 0.02)). The only adverse effect reported was self limited diarrhoea in one child. CONCLUSION: Misoprostol appeared to be effective in the treatment of GIT symptoms in children receiving NSAIDs and to result in significant increase in the haemoglobin concentration. Further prospective studies are needed to evaluate the role of misoprostol therapy for NSAID associated GIT complaints in the paediatric population.

Abdominal Pain↗
PubMed1995

Efficacy of prilocaine-lidocaine cream in the treatment of premature ejaculation.

PURPOSE: We evaluated the efficacy of a new lidocaine-prilocaine cream in preventing premature ejaculation. MATERIALS AND METHODS: An open pilot, unblinded study was done using lidocaine-prilocaine cream in 11 healthy, married men with premature ejaculation without organic or erectile problems. The patients were instructed to apply 2.5 gm. of the cream 30 minutes before sexual contact and to cover the penis with a condom. Patients were asked to grade the effect of the cream on ejaculation after each application. RESULTS: There was a significant improvement in premature ejaculation statistically and clinically. Five patients graded the result as excellent compared to baseline, 4 graded it as better and 2 claimed to have no change compared to ejaculation before use of the cream. No adverse effects were noted. CONCLUSIONS: These promising results should prompt a large double-blind placebo-controlled trial. If confirmed, this therapy may be a breakthrough in the treatment of the most common form of male sexual dysfunction.

Adult↗
PubMed1994

Arthropathy in thalassaemia patients receiving deferiprone.

The iron chelator deferiprone (L1) reduces tissue iron stores in iron-loaded patients. Three of sixteen patients treated with deferiprone developed joint pain and swelling without evidence of systemic lupus erythematosus (SLE). Articular cartilage, synovial hypertrophy and iron deposition, and synovial lining cell proliferation, with no inflammatory or allergic reaction, were observed on synovial exploration and biopsy. Symptoms resolved partly or completely during continued drug administration. We hypothesise that deferiprone-induced shifts of iron to synovium resulted in tissue damage, accelerated by free-radical formation during incomplete complexation of iron and this bidentate chelator. This deferiprone-associated symptom complex is not associated with drug-induced SLE, and does not progress in severity during continued therapy.

Adolescent↗
PubMed1994

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)

Administration, Oral↗
PubMed1994

Pediatric clinical use of the ketoconazole/cyclosporin interaction.

Ketoconazole is known to inhibit the metabolism of cyclosporin through inhibition of cytochrome P-450. This pharmacological interaction was used in an 8-year-old renal transplant patient to successfully achieve therapeutic cyclosporin blood concentrations. The addition of ketoconazole to the cyclosporin regimen should be considered when difficulties are encountered in attaining satisfactory cyclosporin levels.

Child↗
PubMed1994

Acute digoxin overdose in a newborn with renal failure: use of digoxin immune Fab and peritoneal dialysis.

Digitalis intoxication is a common problem, mainly because of the narrow margin of safety of digoxin. These patients may have concomitant renal failure. In patients who have renal failure and who have been treated with digoxin-Fab, the elimination of the digoxin-Fab complex is significantly delayed, and there is a risk of dissociation of the complex with rebound of free digoxin and recurrence of toxicity. The high molecular weight of digoxin and digoxin-Fab complex prevents its elimination by hemodialysis or continuous arteriovenous hemofiltration. A 3-day-old newborn with digoxin overdose and acute renal failure was treated with digoxin immune Fab and peritoneal dialysis. Low levels of total digoxin were measured in the dialyzate, indicating poor elimination of the digoxin-Fab complex through peritoneal dialysis.

Acute Kidney Injury↗
PubMed1994

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.

Abnormalities, Drug-Induced↗
PubMed1994

Recent increases in numbers and risk of fatalities in young children ingesting iron preparations.

Iron preparations are the most frequent cause of pediatric ingestion fatalities. The purpose of this study was to quantify the impression of an increase in iron deaths in young children and to postulate on the reasons. Using the data provided by the American Association of Poison Control Centers, overall annual mortality rate from iron preparations and among children < 6 y was calculated and changes in incidence were recorded. Between 1983 and 1991, there was a 2 to 3-fold increase in the numbers of reported ingestions of iron preparations by toddlers. In the general population the annual mortality rate/100 exposures to iron preparations increased from 0.05 during 1983-1990 to 0.116 in 1991 (p < 0.01). A similar trend was noted in children < 6 y with a rate of 0.004 in 1983-1990 compared with 0.12 in 1991 (p < 0.01). Hence, the increase in mortality was beyond what would be predicted from the increased number of ingestions noted. It is likely that increased awareness of pregnancy-induced anemia results in abundant use of iron pills. These pills have the appearance of candies, which should be changed immediately by legislation. During this period, the volume of iron preparations prescribed increased only marginally (16%), suggesting that over-the-counter use of iron pills increased substantially. In addition to warning labels and child-resistant packaging, an aggressive educational plan directed at the general population and physicians should be instituted immediately.

Child, Preschool↗