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John Earl

Publications and source records attributed to John Earl.

6 recordsLinked to original sources
PubMed2005

Tetrahydrobiopterin-responsive phenylketonuria: the New South Wales experience.

Recent studies have shown that a subgroup of phenylketonuric patients respond to high doses of BH4 (20 mg/kg) by a decrease of plasma phenylalanine. A clinically significant response has been defined as a decrease in phenylalanine by more than 30% within 24 h, after a BH4 challenge. We report our experience with 37 patients diagnosed with hyperphenylalaninemia, mild, moderate, or classical Phenylketonuria (PKU) using a seven day combined BH4 and phenylalanine load. Nine of the 37 patients responded with a 30% decrease in their phenylalanine levels in the first 8 h of treatment. A total of 17 patients (46%) had a decrease of at least 30% during the study period. This study confirms that a significant number of patients with mild to moderate PKU will respond to a BH4 load. Furthermore, it confirms that the seven-day phenylalanine test is more sensitive in detecting BH4 responsive patients.

Adolescent↗
PubMed2004

Increasing the dosage of vincristine: a clinical and pharmacokinetic study of continuous-infusion vincristine in children with central nervous system tumors.

BACKGROUND: Vincristine (VCR) is widely used to treat patients with malignant disease; among the patients treated with VCR are children with brain tumors. In vitro studies have demonstrated that the cytotoxic activity of VCR is related to both extracellular concentration and duration of exposure. The attainment of higher plasma concentrations by injecting larger bolus doses of VCR has been limited by concerns about neurotoxicity. One possible alternative strategy for enhancing the antitumor efficacy of VCR involves prolonging the duration of in vivo exposure. Therefore, the authors explored the neurotoxicity and pharmacokinetics of VCR administered via a 96-hour continuous infusion after administration of a conventional bolus dose in a pediatric population. METHODS: The current study included 16 patients, 11 of whom were males. The median age of the study population was 4.8 years (range, 1.7-15.8 years). The diagnoses included intrinsic pontine glioma (n = 4), ependymoma (n = 5), astrocytoma (n = 3), medulloblastoma/primitive neuroectodermal tumor (PNET; n = 2), ganglioglioma (n = 1), and choroid plexus carcinoma (n = 1). Of the 16 patients, 5 were newly diagnosed, and the remaining 11 had disease recurrences, 8 of which arose after radiotherapy. Treatment included cyclophosphamide 65 mg/kg administered intravenously over 1 hour on Day 1, a bolus of VCR 1.5 mg/m(2) administered intravenously on Day 2, and VCR 0.5 mg/m(2) per 24 hours administered via continuous intravenous infusion on Days 2-5. Thus, a total VCR dose of 3.5 mg/m(2) was administered via infusion over 4 days. Fifteen patients received 2 courses of treatment at 21-28-day intervals, and a total of 31 treatment courses were administered. VCR concentrations in plasma samples were measured using high-performance liquid chromatography. RESULTS: Jaw pain, constipation, mild abdominal pain, and depressed reflexes were common. However, only 1 of 31 courses was associated with Grade III toxicity, and no Grade IV toxicity (e.g., cranial nerve palsy, ileus, inappropriate antidiuretic hormone secretion, seizures, hallucinations, etc.) was noted. The steady-state plasma concentration of VCR during continuous infusion ranged from 1 to 3 microg/L in all patients. Responses after 2 courses were evaluated in 14 of 16 patients. A complete response was noted in one patient (astrocytoma), a partial response in three patients (one each with astrocytoma, ependymoma, and PNET), stable disease in seven patients, and disease progression in three patients. CONCLUSIONS: Continuous infusion of VCR after a conventional bolus dose plus cyclophosphamide for children with tumors of the central nervous system did not result in significant neurotoxicity and appeared to be a safe strategy for achieving increased systemic exposure.

Adolescent↗
PubMed2002

Cerebrospinal fluid concentrations of vincristine after bolus intravenous dosing: a surrogate marker of brain penetration.

BACKGROUND: Vincristine (VCR) is used widely in oncology practice, and regular dosing is commonly associated with the development of sensorimotor or autonomic neuropathies. However, the incidence of VCR-related central nervous system (CNS) toxicity is comparatively low, suggesting that the blood-brain barrier may limit drug penetration into the brain parenchyma. This study determined whether measurable concentrations of VCR could be detected in the cerebrospinal fluid (CSF), as a surrogate marker of brain parenchyma penetration, after bolus intravenous injection in children without primary CNS pathology. METHODS: The authors studied 17 pediatric patients ages 2.5-14.1 years (median, 6.8 years) with acute lymphoblastic leukemia or non-Hodgkin lymphoma without evidence of leptomeningeal disease. Patients received VCR 1.5 mg/m2 by intravenous bolus injection followed at varying intervals by lumbar puncture for scheduled intrathecal methotrexate administration under general anesthesia. Paired VCR concentrations in both plasma and CSF were measured in each patient simultaneously at times ranging from 8 minutes to 146 minutes after the VCR injection. Three patients were studied twice. The paired samples were stored at -40 degrees C until analysis using a high performance liquid chromatography assay with a sensitivity of 0.1 microg/L in CSF and 0.4 microg/L in plasma. RESULTS: Plasma VCR concentrations ranged from 2.2 microg/L to 91.2 microg/L. No measurable VCR concentrations were detected in the CSF samples. CONCLUSIONS: Measurable concentrations of VCR in CSF are not achieved after the administration of standard intravenous bolus doses of VCR. The current observations are consistent with the relative rarity of VCR-related CNS neurotoxicity compared with the commonly observed sensorimotor and autonomic neuropathies. These findings suggest that the penetration of VCR into the brain parenchyma of patients with a relatively intact blood-brain barrier is low and that VCR may have a limited role in the CNS-directed therapy of these patients.

Adolescent↗
PubMed2002

Tyrosine hydroxylase deficiency: clinical manifestations of catecholamine insufficiency in infancy.

Inborn errors of catecholamine biosynthesis are rare but of great interest as they are genetic disorders, and in some, treatment may completely reverse severe neurological abnormalities. They also provide insights into the action of the biogenic amines in the developing brain. We describe the clinical course of an infant with tyrosine hydroxylase (TOH) deficiency over a 30-month period. The parents are consanguineous, and genetic analysis revealed the infant to be homozygous for the common G698A mutation in the TOH gene. TOH deficiency can be seen as a model of pure catecholamine deficiency. Experimental evidence, reports of other disorders of biogenic amines, and our experience with this infant suggest that the symptoms of catecholamine deficiency in infancy can be broadly subdivided. Signs of dopamine deficiency include tremor, hypersensitivity to levadopa (L-dopa) therapy, oculogyric crises, akinesia, rigidity, and dystonia. Manifestations of norepinephrine deficiency include ptosis, miosis, profuse oropharyngeal secretions, and postural hypotension. Hypersensitivity to L-dopa was a particular management problem in this infant.

Consanguinity↗