Modifying Effect of Folinic Acid on Methotrexate-induced Embryotoxicity in Rats

Abstract Embryotoxicity of methotrexate (MTX) and modification of its effect by folinic acid (FA) were evaluated in rats. MTX was administered intraperitoneally to pregnant rats on day 9 of gestation (vaginal plug = day 0), and was followed by an intraperitoneal injection of FA after various time intervals (0-8 hours). Two dose combinations were used; 0.3 mg/kg of MTX and 1.0 mg/kg of FA, and 3.0 mg/kg of MTX and 10.0 mg/kg of FA. The dams were sacrificed on day 20 of gestation, and the fetuses were examined for visceral and skeletal development. The results are as follows: 1) A single dose of 0.3 mg/kg of MTX resulted in high embryolethality and growth retardation in all live fetuses and a single dose of 3.0 mg/kg of MTX showed 100% embryolethality. 2) A single dose of 1.0 or 10.0 mg/kg of FA showed no embryotoxicity. 3) The mitigating effect of FA on MTX-induced embryotoxicity was observed when FA was administered simultaneously with MTX, but was rapidly decreased as the time interval between MTX and FA dosings became longer. 4) Some live fetuses which escaped from MTX embryolethality showed growth retardation and dilation of the cerebral ventricles. The dilation of the cerebral ventricles was found even in the simultaneously treated groups, though the incidences were much lower than the belatedly treated groups.     

Plasma methotrexate, red blood cell methotrexate, and red blood cell folate values and outcome in children with precursor B-acute lymphoblastic leukemia: a report from the Children's Oncology Group

Plasma steady state methotrexate (MTX) level and red blood cell (RBC) MTX and folate concentrations were evaluated in 1124 children with newly diagnosed acute lymphoblastic leukemia enrolled in the Pediatric Oncology Group studies 9005 (lower risk; Regimens A and C) and 9006 (higher risk; Regimen A). These regimens included intermediate-dose MTX (1 g/m) given as a 24 hours infusion every other week for 12 doses during intensification. Plasma MTX level was evaluated at the end of MTX infusions. RBC MTX and folate concentrations were measured at the end of intensification. The 5 year continuous complete remission was 76±1.4% versus 85±3.0% for those patients with steady state MTX levels less than or equal to and greater than 14 μM, respectively (P=0.0125). Hispanic children had significantly reduced median steady state MTX levels, 8.7 μM, compared with non-Hispanic children, 9.95 μM (P=0.0015), but this did not correlate with a difference in outcome. Neither RBC MTX, RBC folate, nor the RBC MTX:folate ratio identified children at increased risk of failure.     

孕鼠叶酸缺乏对子鼠胰岛素样生长因子系统甲基化的影响

目的观察孕期叶酸缺乏对胎鼠生长发育及胰岛素样生长因子(IGF)系统甲基化的影响。方法将22只Sprague-Dawley雌鼠随机分为叶酸缺乏组(n=12)和正常对照组(n=10),分别喂养叶酸缺乏饲料和普通饲料,2周后与雄鼠交配,两组各8只雌鼠成功受孕,于怀孕第20天对孕鼠剖腹取胎,每组取32只胎鼠测量其头尾长、体重。两组分别另取8只胎鼠,采用ELISA法对其脑、肝脏组织中的叶酸、IGF-1、胰岛素样生长因子结合蛋白(IGFBP)-3水平进行检测。两组分别另取3只胎鼠,使用全基因组甲基化测序方法检测其脑、肝脏组织IGF系统的甲基化情况。同时采用ELISA法对两组孕鼠血清IGF-1、IGFBP-3水平进行检测。结果叶酸缺乏组胎鼠头尾长、体重较正常对照组降低(P0.05);叶酸缺乏组孕鼠血清IGF-1、IGFBP-3与胎鼠脑、肝脏组织中的叶酸、IGFBP-3水平均低于正常对照组(P0.05);叶酸缺乏组胎鼠脑组织中IGF-1R、IGF-2R、IGFBP-2、IGFBP-5、IGFBP-6、IGFBP-7的甲基化水平均高于正常对照组(P0.05);而在肝脏组织中,相比于正常对照组,叶酸缺乏组胎鼠IGF-1R、IGF-2R、IGFBP-3、IGFBP-5甲基化水平增加,IGF-2甲基化水平则下降(P0.05)。结论孕鼠叶酸缺乏会影响胎鼠宫内的生长发育,其机制可能与胰岛素生长因子系统的甲基化异常有关。     

Successful treatment of intrathecal methotrexate overdose with folinic acid rescue: a case report

A 7-y-old boy with acute lymphoblastic leukaemia (ALL) received 600 mg of i.v. methotrexate (MTX) over 2 h, followed by triple intrathecal therapy (TIT) with cytosine arabinoside 30 mg, methylprednisolone 10 mg and MTX 300 mg (instead of the prescribed 12 mg). Ninety minutes later the patient developed headache, loss of consciousness and generalized hypertonia. He was transferred to the Intensive Care Unit, intubated and treated with phenobarbital. Three hours after the TIT, the levogyrus form of folinic acid (equivalent to double doses of the racemic product) was started i.v. at a dose of 100 mg every 3 h for 24 h, and every 6 h in the following 24 h. Cerebrospinal fluid was examined and was found normal. The patient subsequently remained in normal neurological status. The favourable outcome in our case suggests that folinic acid rescue may be adequate to prevent sequelae in patients who undergo intrathecal MTX overdoses up to 300 mg.     

叶酸缺乏的离乳大鼠模型建立和评价

初次探讨在国内尝试用RHAA配方建立离乳大鼠的FD模型 ,并对该模型进行评价 ,以期今后对叶酸缺乏 (FolatesDeficiency ,FD)影响离乳大鼠学习记忆的观察和可能机制的分析有一更可信的基础。选择 5 4只刚离乳的健康雄性SD大鼠 ,随机分成实验组、对饲组和对照组三组。实验组饲以去叶酸的RHAA配方饲料 ,另二组饲以添加了 8mg叶酸 /kg膳食的RHAA饲料 ,对饲组按实验组的进食量加以控制 ,对照组不控制进食。每周记录体重和摄食量两次。分别于饲养第 2和第 6周末测定血清叶酸浓度。结果 :实验第 2周除实验组血清叶酸浓度降低外 (P <0 .0 1) ,其余各指标在三组间无明显差异 (P >0 .0 5 )。实验组从第 3周、对饲组从第 4周开始摄食量减少 ,生长速度减慢 (P <0 .0 5 )。第 6周实验组的平均体重、血清叶酸浓度明显低于对照组和对饲组 (P <0 .0 1)。结论显示 :用RHAA配方饲料饲养 6周可建成较重的离乳大鼠的叶酸缺乏模型 ,并最大限度地促进其生长 ,是短期内建立离乳大鼠叶酸缺乏模型较理想的配方     

Folic acid supplements in vitamin tablets: a determinant of hematological drug tolerance in maintenance therapy of childhood acute lymphoblastic leukemia

Methotrexate (MTX) is an antifolate that inhibits cell division by reducing intracellular amounts of reduced tetrahydrofolates. Of 53 children with acute lymphoblastic leukemia (ALL) in maintenance treatment with MTX and 6-mercaptopurine (6-MP), 25 had received daily folic acid supplements in vitamin tablets containing 75-200 micrograms folic acid for at least the preceding 3-month period. Experimental data have shown that increased folate concentrations intracellularly inhibit MTX metabolism and toxicity. Therefore we found it relevant to investigate the extent to which folic acid supplements affect hematological tolerance to MTX and 6-MP in children during maintenance therapy for ALL. The erythrocyte folate (ery-folate) concentration was significantly higher in children who received extra folic acid than in those who did not (p less than 0.001). The ery-folate in MTX-treated children was only marginally reduced compared with the controls. The erythrocyte methotrexate (ery-MTX) concentration correlated with the weekly dose of MTX but not with any of the investigated hematological parameters. Children who received vitamin tablets containing folic acid had higher thrombocyte counts (p = 0.0056), higher leukocyte counts (p = 0.06), higher neutrophil counts (p = 0.05), and lower erythrocyte mean cell volumes (p = 0.05) than children who received no folic acid. We conclude that folic acid supplements of 75-200 micrograms/day affect the proliferative capacity of the bone marrow. Since none of the children was folate deficient as judged by the ery-folate, we recommend that vitamins given to children in maintenance treatment with MTX and 6-MP for ALL should not contain folic acid.(ABSTRACT TRUNCATED AT 250 WORDS)     

High-dose methotrexate causes short-term suppression of growth in rabbits

Bone growth in rabbits was measured using roentgen stereophotogrammetric analysis (RSA), a method for accurate measurement of the distance between metallic markers inserted into long bones. Injections of methotrexate (Mtx) were given to five rabbits and tibial growth was measured daily for 5 days. Im injections of Mtx lOOmg/kg body weight, followed by folinic acid "rescue" 48 h later, had no influence on growth. Intraperitoneal injection of Mtx 1000 mg/kg body weight resulted in a clear reduction in daily growth during the study period. The rabbits were given folinic acid "rescue" 24, 36 and 48 h after Mtx injection and showed no symptoms or signs of Mtx toxicity. Serum levels of Mtx, 3 days after the high-dose injection, declined successively but were still measurable after 72 h. Using RSA, the short-term influence of cytostatic drugs can be evaluated in an experimental setting. The effect of Mtx on growth in rabbits was discernible only at very high doses. Suppression of growth was moderate, appeared soon after injection of Mtx and was of moderate duration.     

How long can folinic acid rescue be delayed after high‐dose methotrexate without toxicity?

To determine the optimal time of folinic acid rescue after methotrexate (MTX) treatment in patients with ALL, we selected and evaluated relevant studies that included doses, rescue delay, and side effects. Rescue at 42–48 hours resulted in considerable toxicity, except when low doses of MTX were used (1 g/m²) or serum MTX levels remained consistently low at 24, 30, and 36 hours. Rescue started at 30–36 hours was safe. In the absence of evidence that later rescue improves prognosis, we suggest that folinic acid rescue (105 mg/m²) be started no later than 36 hours from the start of MTX (5–6 g/m²). Pediatr Blood Cancer 2014;61:7–10. © 2013 Wiley Periodicals, Inc.     

Potentiated Embryotoxicity of Pyrimethamine by Folic Acid in Mice

ABSTRACT Effects of folic acid (FA) and folinic acid (FNA) on the embryotoxicity of pyrimethamine (PYR), an antifolate drug, were examined in mice. PYR and FA were administered orally, and FNA was injected intraperitonially for 7 days from day 9 to 15 of pregnancy. The incidence of embryotoxicity including intrauterine deaths and malformations, was 33.5 % in the PYR 50 mg/kg/day group. However, all the fetuses were resorbed in the PYR 50 + FA 50 mg/kg/day group, and FA potentiated the embryotoxicity of PYR. On the contrary, FNA reduced the embryotoxicity of PYR (PYR 50 + FNA 10mg/kg/day; 8.5%). Plasma concentrations of PYR and 5-methyltetrahydrofolic acid (5MF), a principal form of folate in plasma, were determined after single oral administration of PYR 50 mg/kg with or without FA 50 mg/kg to non-pregnant mice. Plasma 5MF concentration decreased drastically in the group receiving PYR with FA, compared with the PYR alone group. The pharmacokinetics of PYR were not affected by co-administration of FA. Therefore, we consider that the potentiated embryotoxicity of PYR by oral FA results from a decrease of plasma 5MF concentration in dams.     

Effects of oral administration of insulin-like growth factor-I on circulating concentration of insulin-like growth factor-I and growth of internal organs in weanling mice

Insulin-like growth factor (IGF)-I is a polypeptide that mediates the growth-promoting action of growth hormone in postnatal animals. The present study was conducted to examine whether orally administered IGF-I would be absorbed into the general circulation and also whether ingested IGF-I would enhance the growth of whole body as well as internal organs, and tissues in 3-week-old ICR-strain female weanling mice. In experiment (Exp) 1, a total of 70 mice received IGF-I orally at 1 microg.g-1 in 0.2-ml PBS or the vehicle alone. Concentrations of IGF-I and glucose in heart blood were measured after killing 5 animals in each group every fourth hour during a 24-hour period. In Exp 2, a total of 40 mice received oral IGF-I administration at 1 microg.g-1 or vehicle every third day beginning from day 0 for a 13-day period. Half the animals were killed at day 7 and the other half at day 13. Weights of whole body and organs/tissues (small intestine, liver, thigh muscle, and brain) were measured every day and at slaughter, respectively. In Exp 1, following the oral IGF-I administration, serum IGF-I concentration increased at hour 4 (p<0.01) and returned to the hour 0 level by hour 8, whereas glucose concentration was lowest at hour 4 and returned to the hour 0 level by hour 16. In the PBS-fed group, neither IGF-I nor glucose concentration changed during the 24-hour period. In Exp 2, weight of small intestine increased (p<0.05) in response to the oral IGF-I, whereas weights of liver and thigh muscle of the IGF-I-fed group were greater (p<0.01) and tended to be greater (p=0.06), respectively, than those of the PBS-fed only at day 13. However, brain weight and serum concentrations of IGF-I and IGF-II were not affected by oral IGF-I administration. Results suggest that although orally administered IGF-I mainly acts at the intestine, a portion of ingested IGF-I is absorbed into the general circulation to enhance the growth of selective organs/tissues in weanling mice.     

Amelioration of sodium valproate-induced neural tube defects in mouse fetuses by maternal folic acid supplementation during gestation

Infants of epileptic women treated with valproic acid (VPA) during pregnancy have a higher risk of developing spina bifida than those of the general population. VPA induces exencephaly in experimental animal embryos. But the pathogenetic mechanism remains rather elusive. Antiepileptic drugs (AED) in general accentuate pregnancy-imposed fall in maternal folate levels. Periconceptional folic acid supplementation is reported to protect embryos from developing neural tube defects (NTD). Conflicting results have been reported by experimental studies that attempted to alleviate VPA-induced NTD by folic acid. Our objectives were to determine the critical developmental stages and an effective dose of folic acid for the prevention of VPA-induced exencephaly in mouse fetuses. A single teratogenic dose of 400 mg/kg of VPA was administered to TO mice on gestation day (GD) 7 or 8. It was followed by (1) a single dose of 12 mg/kg of FA (folinic acid) or (2) 3 doses of FA 4 mg/kg each. In experiment (3), FA (4 mg/kg) was administered thrice daily starting on GD 5 and continued through GD 10. These animals received VPA on GD 7 or 8. VPA and B12 concentrations were determined by radioimmunoassay. The single heavy dose of FA had no rescue effect on NTD. Three divided doses of FA on GD 7 and continuous dosing of FA from GD 5 through GD 10 substantially reduced the VPA-induced exencephaly in the fetuses. In the later experiments, the neural folds elevated faster than the non-supplemented group. VPA considerably reduced maternal plasma folate and B12 concentrations. The heavy dose of FA only moderately improved vitamin levels. Three divided doses of FA elevated the vitamin levels slightly better but it was the prolonged dosing of FA that was associated with sustained elevation of plasma levels higher than the control levels and acceleration of neural tube closure thus accounting for the pronounced protection against VPA-induced NTD development. These data suggest that plasma levels of FA and B12 have to be kept substantially elevated and maintained high throughout organogenesis period to protect embryos against VPA-induced NTD in this mouse model.     

Successful Carboxypeptidase G2 Rescue in Delayed Methotrexate Elimination Due to Renal Failure

We report on an 18.5-year-old woman with osteosarcoma and delayed methotrexate (MTX) elimination due to renal failure after high-dose MTX, in whom rescue with high doses of folinic acid caused intolerable side effects. In this life-threatening clinical situation, the patient was rescued by the administration of recombinant carboxypeptidase G₂, a bacterial enzyme that rapidly hydrolyzes MTX into inactive metabolites. This is the first report on the successful clinical use of this alternative catabolic route for the elimination of MTX.     

A Rare Complication of Intrathecal Methotrexate in a Child with Acute Lymphoblastic Leukemia

Methotrexate (MTX) is an essential component of chemotherapy for childhood acute lymphoblastic leukemia (ALL). Both intravenous and most commonly intrathecal routes of MTX have been implicated in acute, subacute, and chronic neurotoxicity syndromes. Subacute MTX neurotoxicity occurs within days to weeks after the intravenous or intrathecal therapy and characterized by a distinct presentation with remarkable clinical resemblance to stroke, including hemiparesis, hemisensory deficits, aphasia, dysarthria, dysphagia, and diplopia. Herein the authors describe the clinical and typical neuroimaging features of a female patient with ALL who presented with subacute MTX neurotoxicity that rapidly progressed to a severe clinical condition in a few hours but eventually resolved completely with dexamethasone and folinic acid. Subacute MTX neurotoxicity is a transient neurological dysfunction that should be considered in patients presenting with stroke-like and various neurological symptoms 10 to 14 days after intrathecal therapy and diffusion-weighted magnetic resonance imaging should be undertaken for the correct diagnosis and exclusion of possible ischemic infarct. Discontinuation of subsequent intrathecal MTX therapies should be considered in severe cases and treatment with dexamethasone and folinic acid may help to resolve the symptoms.     

A rare complication of intrathecal methotrexate in a child with acute lymphoblastic leukemia

Methotrexate (MTX) is an essential component of chemotherapy for childhood acute lymphoblastic leukemia (ALL). Both intravenous and most commonly intrathecal routes of MTX have been implicated in acute, subacute, and chronic neurotoxicity syndromes. Subacute MTX neurotoxicity occurs within days to weeks after the intravenous or intrathecal therapy and characterized by a distinct presentation with remarkable clinical resemblance to stroke, including hemiparesis, hemisensory deficits, aphasia, dysarthria, dysphagia, and diplopia. Herein the authors describe the clinical and typical neuroimaging features of a female patient with ALL who presented with subacute MTX neurotoxicity that rapidly progressed to a severe clinical condition in a few hours but eventually resolved completely with dexamethasone and folinic acid. Subacute MTX neurotoxicity is a transient neurological dysfunction that should be considered in patients presenting with stroke-like and various neurological symptoms 10 to 14 days after intrathecal therapy and diffusion-weighted magnetic resonance imaging should be undertaken for the correct diagnosis and exclusion of possible ischemic infarct. Discontinuation of subsequent intrathecal MTX therapies should be considered in severe cases and treatment with dexamethasone and folinic acid may help to resolve the symptoms.     

Megaloblastic Anemia and Immune Abnormalities in a Patient with Methionine Synthase Deficiency

ABSTRACT. We report a case of methionine synthase deficiency associated with cellular immune deficiency discovered in a 14-year-old boy. Principal findings were: developmental delay, recurrent upper and lower respiratory tract infections, megaloblastic anemia, discovered at 3 months of age, unresponsive to cyanocobalamin and poorly responsive to folinic acid. Biochemical studies showed: an abnormal deoxyuridine suppression test despite normal serum folate, cobalamin and transcobalamin levels; a normal intracellular uptake of these two coenzymes; and an absolute requirement of methionine for fibroblast growth, suggestive of defective methionine synthesis. An absence of methionine synthase activity in the patient's bone marrow and a profound depression of this activity in lymphocytes and liver were found. Hypergammaglobulinemia with variable lymphopenia, depressed lymphocyte transformation after lectin or recall-antigen stimulation, defective delayed-type hypersensitivity and decreased natural killer activity were noted as well. The patient died at the age of 14.     

Megaloblastic anemia and immune abnormalities in a patient with methionine synthase deficiency

We report a case of methionine synthase deficiency associated with cellular immune deficiency discovered in a 14-year-old boy. Principal findings were: developmental delay, recurrent upper and lower respiratory tract infections, megaloblastic anemia, discovered at 3 months of age, unresponsive to cyanocobalamin and poorly responsive to folinic acid. Biochemical studies showed: an abnormal deoxyuridine suppression test despite normal serum folate, cobalamin and transcobalamin levels; a normal intracellular uptake of these two coenzymes; and an absolute requirement of methionine for fibroblast growth, suggestive of defective methionine synthesis. An absence of methionine synthase activity in the patient's bone marrow and a profound depression of this activity in lymphocytes and liver were found. Hypergammaglobulinemia with variable lymphopenia, depressed lymphocyte transformation after lectin or recall-antigen stimulation, defective delayed-type hypersensitivity and decreased natural killer activity were noted as well. The patient died at the age of 14.     

Growth hormone treatment in children with rheumatic disease, corticosteroid induced growth retardation, and osteopenia

Background

In children with severe rheumatic disease (RD), treatment with corticosteroids (CS) is frequently needed and growth retardation and osteopenia may develop. A beneficial effect of human growth hormone (hGH) has been reported but mostly in trials without a control group.

Aims

To study the effect of hGH on growth, bone mineral density (BMD), and body composition, taking the disease activity and CS use into account.

Methods

Randomised controlled trial on 17 prepubertal RD patients with growth retardation and/or decreased BMD. The hGH group (n = 10) received treatment with hGH 4 IU/m²/day (∼0.045 mg/kg/day) during two years. The controls (n = 7) received no GH treatment.

Results

During the two year study period the disease activity, and use of CS and methotrexate (MTX) did not differ between the groups. There was a significant mean increase in height standard deviation score (HSDS) in the hGH group (0.42±0.16 SDS) and a non‐significant decrease in the controls (−0.18±0.11 SDS). Change in BMD did not differ significantly between the groups, although the increase in BMD for lumbar spine within the hGH group was significant. Lean body mass improved significantly in the hGH group compared to controls (0.64±0.19 SDS versus −0.20±0.17 SDS), while the decrease in percentage fat was not significant.

Conclusions

There was a significant effect of hGH on growth and lean body mass, but a longer duration of treatment might be necessary to evaluate the effect of hGH on BMD.     

The effects of surgery on the nitrogen metabolism of parenterally fed human neonates

Nitrogen retention and rates of whole body amino nitrogen flux, protein synthesis, and breakdown were measured in 18 neonates during the 72 h immediately postsurgery. The infants were all intravenously fed with a crystalline amino acid source (Vamin), glucose, and Intralipid The infants were divided into two groups based on amino acid intake: either 2.3 SD 0.4 g or 3.9 SD 0.5 g/kg/day. Nonprotein energy intakes were similar and averaged 81 kcal/kg/day. Group A (n = 11) retained 145 SD 110 mg N/kg/day, whilst group B (n = 7) retained 315 SD 93 mg N/kg/day (p less than 0.001). There were no differences seen in flux, synthesis or breakdown. However, group B had significantly higher net protein synthesis rates (synthesis-breakdown) (p less than 0.01). The improved nitrogen utilization in group B was achieved principally by a reduction in endogenous protein breakdown. There were no differences between the two groups in urinary creatinine or 3-methylhistidine excretion. Since these two parameters reflect skeletal muscle turnover the differences between groups in nitrogen retention and turnover appear to be mediated through visceral protein.     

广州和佛山地区早产低出生体重儿出院时宫外生长迟缓发生情况调查

目的评价早产低出生体重儿出生时宫内生长受限(IUGR)和出院时宫外生长迟缓(EUGR)的发生情况。方法广州市、佛山市10家医院新生儿科出院的早产低出生体重儿(胎龄<37周,体重<2500g),分别以出生时、出院时生长发育指标在相应宫内生长速率期望值的第10百分位水平以下定义为IUGR、EUGR,分别计算各胎龄组、各体重组IUGR、EUGR发生率及总的发生率,并计算各胎龄组、各体重组EUGR发生率比IUGR发生率增加的比例。结果共595例早产低出生体重儿,出生时以体重、身长、头围为指标的IUGR发生率分别为20.2%、16.5%和24.4%,出院时以体重、身长、头围为指标的EUGR发生率分别为42.2%、28.1%和34.3%。不同出生胎龄(<31周、31～32周、33～34周、≥35周)出院时EUGR发生率较出生时IUGR发生率变化的情况:以体重为指标,EURG发生率各组分别增加36.8%、24.8%、19.1%、18.3%;以身长为指标,EUGR发生率各组分别增加26.5%、17.4%、8.2%、6.5%;以头围为指标,各组分别增加26.5%、14.0%、8.2%、3.2%,胎龄越小,增加率越高,组间比较差异有统计学意义(P<0.05)。不同出生体重(<1500g、1500～1999g、≥2000g)出院时EUGR发生率较出生时IUGR发生率变化的情况:以体重为指标,EUGR发生率分别增加45.3%、21.2%、17.4%;以身长为指标,EUGR发生率分别增加29.7%、14.8%、4.6%;以头围为指标,EUGR发生率分别增加26.6%、12.0%、4.3%,体重越低,增加率越高,组间比较差异有统计学意义(P<0.05)。结论早产低出生体重儿IUGR发生率较高,出院时EUGR发生率较IUGR发生率增高,且出院时EUGR发生率较出生时IUGR发生率的增加随出生胎龄和出生体重的降低而升高。     

Early and Late Neutropenia in Children Treated with Cotrimoxazole (Trimethoprim-Sulfamethoxazole)

ABSTRACT. The incidence of hematologic abnormalities was evaluated in 120 children with otitis media treated respectively with cotrimoxazole (trimethoprim-sulfamethoxazole) (group 1), cotrimoxazole plus folinic acid (group 2) and amoxicillin (group 3) in therapeutic doses for ten days. Only eosinophilia (an absolute count ≥0.5×10⁹/l) (group 1 = 10%, 2=5%, 3=7.5%) and neutropenia (polymorphonuclear neutrophilic leucocyte count ≤1.5×10⁹/l) (group 1=35%, 2=17.5%, 3=13.3%) were noted. Early neutropenia (evident on the 5th day of therapy) occurred in all the treatment groups, thus it is not related to cotrimoxazole administration and in most cases neutrophil count reversed to normal in few days without drug discontinuation. Late neutropenia (evident after 10 days of treatment) appeared only in cotrimoxazole treated children ( p <0.05). No superimposed bacterial infection was demonstrated in any case. Late neutropenia seems to be strictly related to the sequential blockage of folinic acid metabolism and can be prevented by the concomitant administration of folinic acid.