Matitiahu Berkovitch

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.

Medications and glucose-6-phosphate dehydrogenase deficiency: an evidence-based review.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzyme defect and one of the most common genetic disorders worldwide, with an estimated 400 million people worldwide carrying a mutation in the G6PD gene that causes deficiency of the enzyme. Although drug-induced haemolysis is considered the most common adverse clinical consequence of G6PD deficiency, significant confusion exists regarding which drugs can cause haemolytic anaemia in patients with G6PD deficiency. In the absence of consensus among physicians, patients are subject to conflicting advice, causing uncertainty and distress. In the current review we aimed, by thorough search of the medical literature, to collect evidence on which to base decisions either to prohibit or allow the use of various medications in patients with G6PD deficiency. A literature search was conducted during May 2009 for studies and case reports on medication use and G6PD deficiency using the following sources: MEDLINE (1966–May 2009), PubMed (1950–May 2009), the Cochrane database of systematic reviews (2009), and major pharmacology, internal medicine, haematology and paediatric textbooks. After assessing the literature, we divided medications into one of three groups: medications that should be avoided in individuals with G6PD deficiency, medications that were considered unsafe by at least one source, but according to our review can probably be given safely in normal therapeutic dosages to individuals with G6PD deficiency as evidence does not contravene their use, and medications where no evidence at all was found to contravene their use in G6PD-deficient patients. It is reasonable to conclude that, over time, many compounds have been wrongly cited as causing haemolysis because they were administered to patients experiencing an infection-related haemolytic episode. We found solid evidence to prohibit only seven currently used medications: dapsone, methylthioninium chloride (methylene blue), nitrofurantoin, phenazopyridine, primaquine, rasburicase and tolonium chloride (toluidine blue). Regarding all other medications, our review found no evidence to contravene their use in normal therapeutic doses to G6PD-deficient patients.There is a need for evidence-based global consensus regarding medication use in G6PD-deficient patients.

Use of antibiotic and analgesic drugs during lactation.

During lactation, multiple situations can arise that require maternal pharmacological treatment. Because of the many health advantages of human milk to infants, breast feeding should be interrupted only when the needed drug might be harmful to the nursing child and exposure via the breast milk will be sufficient to pose a risk. Since the majority of drugs have not been shown to cause adverse effects when used during lactation, and even temporary interruption of breast feeding can be difficult for the nursing dyad, decisions regarding maternal medication use during breast feeding should be based on accurate and up-to-date information. This article reviews available data on the most commonly used antibiotics and analgesics.The use of most antibiotics is considered compatible with breast feeding. Penicillins, aminopenicillins, clavulanic acid, cephalosporins, macrolides and metronidazole at dosages at the low end of the recommended dosage range are considered appropriate for use for lactating women. Fluoroquinolones should not be administered as first-line treatment, but if they are indicated, breast feeding should not be interrupted because the risk of adverse effects is low and the risks are justified.Paracetamol (acetaminophen), low-dose aspirin (acetylsalicylic acid) [up to 100 mg/day] and short-term treatment with NSAIDs, codeine, morphine and propoxyphene are considered compatible with breast feeding.Safer alternatives should be considered instead of dipyrone, aspirin at a dosage >100 mg/day and pethidine (meperidine).In the light of the many safe alternatives for pain control, breast-feeding mothers should not be allowed to experience pain or be made to feel that they must choose between analgesia and breast feeding.

Pemoline‐associated fulminant liver failure: Testing the evidence for causation

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.

Pregnancy outcome after in utero exposure to colchicine

OBJECTIVE We sought to examine the fetal safety of colchicine. STUDY DESIGN This was a prospective observational comparative cohort study regarding colchicine exposure during pregnancy including contacts to 2 Teratology Information Services in Israel from 1994 through 2006. RESULTS In all, 238 colchicine-exposed pregnancies (97.0% first trimester) and 964 pregnancies with nonteratogenic exposure were followed up. Treatment indications were: familial Mediterranean fever (87.3%), Behçet disease (7.5%), or other (5.2%). The rate of major congenital anomalies was comparable between the groups (10/221 [4.5%] vs 35/908 [3.9%]; P = .648). There were no cytogenetic anomalies in the colchicine group. The median gestational age at delivery was earlier (39 [38-40] vs 40 [38-41] weeks; P < .001), the rate of preterm deliveries was higher (32/214 [15.0%] vs 51/867 [5.9%]; P < .001), and the median birthweight was lower (3000 [2688-3300] vs 3300 [2900-3600] g; P < .001) in the colchicine group. CONCLUSION The present study suggests that colchicine does not appear to be a major human teratogen, and, probably, has no cytogenetic effect.

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 l‐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.

The stethoscope as a vector of infectious diseases in the paediatric division

Aim: Nosocomial infections are of great concern in hospital settings, and even more so in the paediatric ward. Health professionals and their medical equipment have long been known to act as vectors of infectious diseases. This study aimed at evaluating the presence of bacterial pathogens on the stethoscopes of medical personnel in the paediatric division.

Early and late effects of low-dose aspirin on renal function in elderly patients

BACKGROUND Although low-dose aspirin is used by many elderly patients, monitoring of renal function is currently not recommended. We recently reported transient retention of uric acid and creatinine caused by aspirin in doses of 75 to 325 mg/d. We therefore evaluated the renal effects of aspirin (100 mg/d), including post-treatment effects. METHODS We studied 83 stable geriatric patients in long-term care (aged 56 to 98 years) who were treated with low-dose aspirin (100 mg/d) for 2 weeks and 40 control patients. Other medications and diet were kept constant. Biochemical monitoring including blood samples and 24-hour urinary collections for creatinine and uric acid at baseline and weekly for a total of 5 weeks. RESULTS After 2 weeks on aspirin, urinary excretion of creatinine decreased in 60 (72%) and excretion of uric acid decreased in 54 (65%) of the 83 patients, and their mean clearances decreased; during the same period, serum blood urea nitrogen, creatinine, and uric acid levels increased (P <0.05 for all). Deterioration from baseline levels was significantly greater (and more prevalent) in the aspirin-treated group than in the 40 control patients (P = 0.001 to 0.09). After withdrawal of aspirin these parameters improved. However, 3 weeks after stopping aspirin, 48% (35 of the 73 in whom this measurement was available) had a persistent decline in creatinine clearance from baseline, as compared with only 8% (3/36) controls (P <0.001). CONCLUSION Short-term low-dose aspirin treatment may affect renal function in elderly patients. These effects persist 3 weeks after cessation of the drug in some of these patients.

Neutropenia as a complication of intravenous immunoglobulin (IVIG) therapy in children with immune thrombocytopenic purpura: common and non-alarming

UNLABELLED Following reports on adult patients with neutropenia as a result of administration of intravenous immunoglobulin (IVIG) we have investigated the incidence and consequences of neutropenia following IVIG treatment in children with immune thrombocytopenic purpura (ITP). The medical records of 14 children with ITP who received IVIG as inpatients were reviewed. Past and present history, age, previous medications, complete blood count and differential before and after treatment with IVIG were recorded for each patient. The patients, aged 5.5 +/- 3.5 (0.5-11.5) years [mean +/- SD; range] received one or more courses of IVIG. Neutropenia (total neutrophils < 2000/mm3) was observed within 24 h after the first course of IVIG in five children (36%). The pretreatment neutrophil count in this group was not significantly different from that observed in the patients without IVIG-induced neutropenia (p = 0.98). The condition resolved spontaneously and without complications in all patients within 48 h. In a preliminary experiment in which bone marrow derived mononuclear cells were assayed for the clonogenicity in methylcellulose, there was no suppressive effect of IVIG on the number of CFU-GM colonies. CONCLUSIONS Since IVIG is currently administered in a vast number of medical indications, neutropenia following IVIG administration may not be an uncommon finding. It seems to be transient and self limited.

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.