Toxicity following concurrent intrathecal and moderate-dose intravenous methotrexate.

To evaluate factors predisposing children with non-Hodgkin's lymphoma to toxicity from moderate dose methotrexate (MTX) (300 mg/m2 per 4 hours), we reviewed the medical records of 15 patients treated at our institution according to two similar protocols. Five patients experienced hyperemesis and/or severe mucositis. In two of these patients, pharmacokinetic analysis demonstrated delayed terminal excretion of methotrexate with a half-life of 3-3.5 days, compared to a previously reported t1/2 of 8-15 hours in subjects with normal clearance. All affected patients were large (body surface area 1.6-1.9 m2), and MTX toxicity was seen only during courses where intravenous MTX was given concurrently with intrathecal MTX. Four patients also received simultaneous prophylactic doses of oral trimethoprim-sulfamethoxazole (trimethoprim 5 mg/kg per day). We recommend that, in protocol design, consideration be given to avoiding concurrent use of intravenous and intrathecal MTX, and possibly trimethoprim-sulfamethoxazole. Where high doses of MTX are given based on large body surface area, urine alkalinization may be indicated.

Candy flavoring as a source of salicylate poisoning.

Methyl salicylate (oil of wintergreen) in the form of candy flavoring was ingested by a 21-month-old male infant who subsequently developed vomiting, lethargy, and hyperpnea. A "swallow" of the solution resulted in a serum salicylate concentration of 81 mg/dL six hours after ingestion. The infant was treated with parenteral fluids and sodium bicarbonate and he recovered rapidly. Hazards associated with salicylate use in this form include lack of parental awareness of the substance's toxic potential, the attractiveness of the candy-like odor, and the availability of the liquid in non-child-resistant packaging containing potentially lethal quantities.

Erythromycin-induced drug interactions. An illustrative case and review of the literature.

The authors report a case of erythromycin-induced carbamazepine toxicity in a 6-year-old child following use of erythromycin ethylsuccinate (50 mg/kg/day). Within 5 days of erythromycin use, vomiting, weakness, lethargy, ataxia, nystagmus, and cogwheeling movements developed. A serum carbamazepine concentration had increased from 11.9 mg/L (measured 1 week prior to antibiotic use) to 25.8 mg/L. Following erythromycin withdrawal, serum concentrations returned toward baseline, and symptoms resolved. Erythromycin has known effects on hepatic enzyme function, with altered cytochrome P-450 function. The dramatic reduction in carbamazepine clearance observed in this patient is similar to that reported when erythromycin is used concurrently with other drugs. A brief review of potentially significant erythromycin drug interactions is presented.

Growth hormone for the treatment of growth failure in children.

The etiology, diagnosis, and clinical features of growth failure in children are presented, with discussion of exogenous growth hormone (GH) replacement, its indications, efficacy, and adverse effects. Causes of growth delay include malnutrition, systemic illness, emotional deprivation, deficiency of endogenous growth hormone, thyroid hormone deficiency, and cortisol excess. Growth hormone (somatotropin) is secreted by the anterior pituitary gland in response to various stimuli, including exercise, hypoglycemia, and arginine. This hormone stimulates growth of skeletal muscle and connective tissue, increases rate of protein synthesis, and decreases rate of glucose use. Diagnosis of GH deficiency usually relies upon detection of adequate GH release in response to two stimuli. However, because patients with adequate endogenous GH release (determined by testing) may also grow when given exogenous GH, other methods are being evaluated for diagnosis of GH-dependent states. In many children, exogenous GH replacement produces increased rates of growth within 6 to 12 months; subsequently, growth rates decline. Distribution of the pituitary-derived GH product somatotropin was halted because of reports of Creutzfeldt-Jakob disease in some patients receiving it. Somatrem, a biosynthetic GH produced by recombinant DNA technology, has shown efficacy similar to somatotropin in clinical studies and is currently available to pediatric endocrinologists. Growth hormone replacement is beneficial in idiopathic and acquired GH deficiency, including partial GH deficiency. Further testing is needed to determine the usefulness and cost-benefit of somatrem therapy in GH-dependent and other types of growth failure.

Diazepam by continuous intravenous infusion for status epilepticus in anticonvulsant hypersensitivity syndrome.

OBJECTIVE: To report a case of status epilepticus in a patient with anticonvulsant hypersensitivity syndrome (AHS) that was controlled successfully using continuous intravenous infusion diazepam. AHS and alternatives for treatment of status epilepticus are also reviewed. DESIGN: Single case report. SETTING: 217-bed children's university hospital. PATIENT: Four-year-old, 20-kg girl, diagnosed with idiopathic tonic-clonic epilepsy, who developed AHS to phenobarbital and phenytoin and status epilepticus unresponsive to lorazepam. RESULTS: Diazepam intravenous infusion at dosages titrated to 8 mg/h was used successfully to control seizures for eight days until signs and symptoms of AHS had resolved and maintenance therapy with valproic acid was started. CONCLUSIONS: Continuous intravenous infusion diazepam is a reasonable therapeutic choice for the management of status epilepticus in a patient with AHS when traditional therapy such as phenytoin and phenobarbital cannot be used.

Phenytoin-induced lymphadenopathy.

Various lymph node abnormalities have been associated with phenytoin therapy. Four distinct categories of lymphadenopathy have been described: lymphoid hyperplasia, pseudolymphoma, pseudo-pseudolymphoma, and lymphoma. These presentations vary from a benign symptom complex, with enlarged lymph nodes, that is reversible upon drug discontinuance to a true malignant lymphoma that is progressive and ultimately fatal. Benign lymph node hyperplasia and pseudolymphoma may result in erroneous diagnosis and treatment of malignant lymphoma if phenytoin-associated lymphadenopathy has not been considered. We describe a patient who developed enlarged inguinal lymph nodes while receiving chronic phenytoin therapy. An initial diagnosis of malignant lymphoma was made, and recurrent hospitalizations and treatment with cytotoxic drugs ensued. Repeat biopsy, as well as reexamination of the removed nodes, later revealed phenytoin-associated hyperplasia. Patients who develop enlarged lymph nodes while receiving phenytoin should be evaluated carefully so that phenytoin-induced lymphadenopathy may be differentiated from true malignant lymphoma and appropriate treatment may be given.

Antibiotic restriction programs and cephalosporin use in pediatrics: a survey of infectious disease specialists.

A survey of 105 pediatric infectious disease specialists was conducted to elicit opinions regarding antibiotic restriction programs and use of individual parenteral cephalosporins in pediatrics. Virtually all respondents favored antibiotic restriction programs, with 68% currently involved in these efforts. Unrestricted availability of cefazolin, cephalothin, cefoxitin, and cefuroxime was recommended by 83%, 72%, 58%, and 49%, respectively, of respondents. Restricted use of third-generation cephalosporins, including cefotaxime, cefoperazone, ceftizoxime, and moxalactam was generally recommended. Over 50% of respondents recommended the use of chloramphenicol plus ampicillin (or a penicillinase-resistant penicillin), while 21.9% advocated the use of cefuroxime as empiric therapy to treat the increasing number of H. influenzae species resistant to ampicillin in infants outside the neonatal period and in young children.

Cardiorespiratory decompensation following methylprednisolone administration.

A 2-year-old white female receiving multidrug chemotherapy for treatment of a primitive neuroectodermal tumor developed acute hypotension, bradycardia, and shock following administration of ondansetron and high-dose methylprednisolone. The subsequent clinical course is described, and cardiovascular reactions to ondansetron and methylprednisolone are reviewed. While the etiology of this severe reaction is uncertain, it is possible that it represents an idiosyncratic reaction to the rapid administration of high-dose adrenal corticosteroids. Patients receiving high-dose corticosteroid therapy should be closely monitored, and slow rates of infusion are recommended.

Digoxin-like immunoreactivity in serum from neonates and infants reduced by centrifugal ultrafiltration and fluorescence polarization immunoassay.

We evaluated the TDx Digoxin II (Abbott) modified procedure for interference from digoxin-like immunoreactive factors (DLIF) in pediatric patients. The effectiveness of centrifugal ultrafiltration as a means of removing DLIF interference from the serum of such patients was assessed. We used sera from 40 patients who had not received digoxin, whom we divided into two age groups: 30 neonates (less than 34 days postpartum) and 10 infants (younger than six months). Digoxin-like immunoreactivity was detected in 34 of 41 (83%) neonatal specimens (range 0.2-1.0 micrograms/L) and 16 of 25 (60%) infants' specimens (range 0.2-1.3 micrograms/L). Centrifugal ultrafiltration of serum specimens from these patients reduced but did not eliminate the DLIF interference in some specimens. A comparison of concentrations of DLIF in serum with various other patients' characteristics demonstrated a strong correlation (r = 0.915; P = 0.0001) between DLIF and serum bilirubin in the infants. Apparent digoxin concentrations from 19 serum and serum ultrafiltrate samples collected from 13 patients (four neonates and nine infants) who were treated with digoxin showed a good correlation (r = 0.97); however, the serum samples showed a positive bias of 0.39 microgram/L. We conclude that the TDx Digoxin II modified procedure is still subject to considerable DLIF interference in these two pediatric populations. This interference can be reduced in some serum specimens, but cannot be eliminated completely as others reported.

Benztropine-induced acute dystonic reaction.

We report an unusual case of benztropine-induced acute dystonia and dyskinesia without findings of acute anticholinergic toxicity in a 20-month-old child. Laboratory analysis of blood, urine, and gastric contents demonstrated the presence of an atropinic compound and diphenhydramine only, suggesting the association of benztropine and acute dystonia. Effects of benztropine on neuronal uptake of dopamine may represent a possible mechanism for this unusual adverse effect.

Metoclopramide as an antiemetic agent in pediatric oncology patients.

Metoclopramide (MCP) was used as an antiemetic agent in 11 pediatric oncology patients during 22 courses of cancer therapy including cisplatin, doxorubicin, and other agents. Initial MCP regimens used 2 mg/kg/dose iv prior to and at 1.5, 3.5, 5.5, and 8.5 hours post-chemotherapy. Subsequent dose reduction to 1 mg/kg and addition of diphenhydramine to all regimens has been made to decrease adverse drug effects. Seven of 11 children reported subjective benefit, defined by comparison with previous antiemetic response, comfort, and willingness to continue MCP therapy. MCP effectively reduced the volume of emesis per 24-hour period as compared with volume of emesis recorded following other antiemetics, an observation that should be confirmed in controlled studies of efficacy. Acute dystonic reactions developed in five children, occurring most frequently in those who received 2 mg/kg/dose regimens or consecutive day dosing. These reactions were rapidly reversible with diphenhydramine, but limited patient acceptance of further MCP use.

Impaired clearance of ceftizoxime and cefotaxime after orthotopic liver transplantation.

The pharmacokinetics of ceftizoxime (CZX) and of cefotaxime (CTX) were studied in five children and five adults after orthotopic liver transplantation (OLT). Delayed clearance of CZX (clearance of 0.21 to 1.26 ml/min per kg [body weight]) and CTX (clearance of 0.40 to 1.49 ml/min per kg) occurred in 7 of the 10 OLT patients. We conclude that abnormal CZX and CTX clearance is common after OLT and may be associated with minimal change in serum creatinine.

Anaphylactoid reactions associated with parenteral cyclosporine use: possible role of Cremophor EL.

Acute anaphylactoid reactions occurred immediately after initiation of intravenous infusions of cyclosporine in three patients post-organ transplantation. Shortness of breath, flushing, tachypnea, chest pain, pruritus, or urticaria were noted; rapid recovery followed cessation of drug infusion. Subsequently, oral cyclosporine has been used in each patient without recurrence of the observed reaction. The presence of Cremophor EL as an emulsifying agent in the parenteral dosage formulation of cyclosporine is a likely etiology for this acute adverse reaction. Slowed rates of drug infusion and antihistamine premedication may permit continued intravenous cyclosporine use in affected patients.

Fatal hepatic necrosis due to pyrimethamine-sulfadoxine (Fansidar).

Pyrimethamine-sulfadoxine has been associated with severe and fatal cutaneous reactions as well as transient liver damage. We report the case of a patient who died of progressive hepatic failure caused by pyrimethamine-sulfadoxine administration. In addition, we summarize reports made to the Food and Drug Administration since 1982 that focus on hepatotoxic reactions to pyrimethamine-sulfadoxine. We suggest that fatal hepatic injury can occur after treatment with pyrimethamine-sulfadoxine and that physicians who prescribe the drug should be aware of this possibility.

Disposition of moracizine (ethmozine) in healthy subjects after oral administration of radiolabelled drug.

Moracizine (ethmozine) is a phenothiazine derivative with demonstrated antiarrhythmic activity. To characterize the pharmacokinetics and material balance relationships in humans, we have given 14C-moracizine X HCl as a single oral dose of 500 mg (50 microCi) to six healthy men. Plasma, urine, and faecal samples were collected for 7 days after administration and the concentrations of total radioactivity and intact moracizine were determined by liquid scintillation counting and HPLC, respectively. Urine and faecal recovery accounted for 95% of the administered radioactivity. Most of this radioactivity was found in the faeces (59%). Only 0.05% of the dose was recovered from urine as intact moracizine. The Cmax and AUC for moracizine equivalents of total radioactivity were 4- and 18-fold higher, respectively, than the corresponding values for intact moracizine. Additionally, both the disappearance of total radioactivity from plasma and its excretion rate into urine were slower in comparison to intact drug. Terminal t1/2 values calculated from plasma concentration-time data were 85.2 and 3.5 h for total radioactivity and intact moracizine, respectively. However, based on urinary excretion rates, the t1/2 for total radioactivity was shorter (29.3 h) while the t1/2 for intact drug was comparable (2.7 h) to the results obtained from the plasma data. The oral plasma clearance of moracizine was relatively large (2.2 l X min-1), suggesting first-pass metabolism. The estimated oral systemic availability of moracizine was 34%.