Denise L. Howrie

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.

The addition of sirolimus to tacrolimus/methotrexate GVHD prophylaxis in children with ALL: A phase 3 children's oncology group/pediatric blood and marrow transplant consortium trial

Sirolimus has activity against acute lymphoblastic leukemia (ALL) in xenograft models and efficacy in preventing acute graft-versus-host disease (aGVHD). We tested whether addition of sirolimus to GVHD prophylaxis of children with ALL would decrease aGVHD and relapse. Patients were randomized to tacrolimus/methotrexate (standard) or tacrolimus/methotrexate/sirolimus (experimental). The study met futility rules for survival after enrolling 146 of 259 patients. Rate of Grade 2-4 aGVHD was 31% vs 18% (standard vs experimental, P = .04), however, grade 3-4 aGVHD was not different (13% vs 10%, P = .28). Rates of veno-occlusive disease (VOD) and thrombotic microangiopathy (TMA) were lower in the nonsirolimus arm (9% vs 21% VOD, P = .05; 1% vs 10% TMA, P = .06). At 2 years, event free survival (EFS) and overall survival (OS) were 56% vs 46%, and 65% vs 55% (standard vs experimental), respectively (P = .28 and .23). Multivariate analysis showed increased relapse risk in children with ≥0.1% minimal residual disease (MRD) pretransplant, and decreased risk in patients with grades 1-3 aGVHD (P = .04). Grades 1-3 aGVHD were associated with improved EFS (P = .02), whereas grade 4 aGVHD and extramedullary disease at diagnosis led to inferior OS. Although addition of sirolimus decreased aGVHD, survival was not improved. This study is registered with ClinicalTrials.gov as #NCT00382109.

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.

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.

Phenytoin-induced Movement Disorder Associated with Intravenous Administration for Status Epilepticus:

Altered behavior, confusion, and deteriorating seizure control have been reported in epileptic patients with levels above 100 megf rnl.3 Our patient, a nonepileptic, illustrated confusion at a level of 39.6 mcg/ml. Although there are reports in the literature of valproic acid-induced confusion states at therapeutic concentrations, these have occurred in patients who are epileptic and on other anticonvulsants.4 Because the patient had had spontaneous emesis, neither ipecac-induced emesis nor gastric lavage was attempted. The subsequent increase in serum concentration of valproic acid suggests that these might have been useful. Further, only a single dose of activated charcoal and cathartics was administered, and no bowel movements occurred during the 4-day hospitalization. Only 3 to 7 percent of valproic acid is excreted unchanged in the urine, and since levels were sustained and high, it may be postulated that either continued absorption occurred or that valproic acid metabolism demonstrated saturable kinetics. Be-

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.

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.

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 childrens 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.

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

SummaryMoracizine (ethmozine) is a phenothiazine derivative with demonstrated antiarrhythmic activity. To characterize the pharmacokinetics and material balance relationships in humans, we have given14C-moracizine·HCl as a single oral dose of 500 mg (50 μCi) 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 (2.2l·min−1), suggesting first-pass metabolism. The estimated oral systemic availability of moracizine was 34%.

Phototoxic dermatoses in pediatric BMT patients receiving voriconazole

We investigated the incidence of phototoxic skin reactions in pediatric BMT recipients treated with voriconazole. Nine out of 40 patients (22.5%), all Caucasian, developed skin lesions in sun‐exposed distributions. Dermatologic findings included sunburn‐like erythema, pseudo‐porphyria, linear papulovesicular lesions, severe erosive cheilitis, dermatoheliosis and lentigines. Patients were treated with sun avoidance, high‐potency sunscreens, and topical steroids with significant improvement in all cases. Prolonged voriconazole use requires close monitoring for chronic skin toxicities. Long‐term risks including the risk of skin cancer need to be investigated. Pediatr Blood Cancer 2014;61:1325–1328.