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Biomedical subjects

L Price

Publications and source records attributed to L Price.

At least 37 records · Page 2Linked to original sources
PubMed1995

Cyclophosphamide metabolism in children.

The alkylating agent cyclophosphamide is a prodrug which is metabolized in vivo to produce both therapeutic and toxic effects. Cyclophosphamide metabolism was investigated in 36 children with various malignancies. Concentrations of cyclophosphamide and its principal metabolites were measured in plasma and urine using a quantitative high-performance TLC method. The results indicated a high degree of inter-patient variation in metabolism. In contrast to previous adult studies on urinary metabolites, plasma carboxyphosphamide concentrations did not support the existence of polymorphic metabolism. Plasma concentrations of dechlorethylcyclophosphamide and carboxyphosphamide were correlated in individual patients, suggesting that the activity of both aldehyde dehydrogenase and cytochrome P450 enzyme(s) determine carboxyphosphamide production in vivo. The presence of ketocyclophosphamide in plasma was strongly associated with dexamethasone pretreatment and was also accompanied by a high clearance of the parent drug. Interpatient differences in metabolism reflect individual levels of enzyme expression and may contribute to variation in clinical effect.

Adolescent↗
PubMed1995

Granisetron as antiemetic therapy in children with cancer.

The safety and efficacy of the new 5HT-3 antagonist granisetron as an antiemetic in children with cancer was evaluated in 40 children at a single dose of 40 micrograms/kg. No adverse affects attributable to the granisetron were noted. The overall major and complete response rate was 82.5% and this was highest in the younger children. Only 2 patients showed no response. Pharmacokinetic studies showed associations between some pharmacokinetic parameters and age which were no longer apparent after normalisation for body weight. Granisetron is an effective and very well-tolerated antiemetic and appears to be an important addition to the supportive care available for children with cancer.

Adolescent↗
PubMed1995

Comparison of continuous infusion and bolus administration of ifosfamide in children.

The pharmacological effects of ifosfamide (IFO) are dependent on its metabolism which may vary between different modes of administration. This was studied in 17 patients who received both a continuous infusion (9 g/m2 over 72 h) and repeated bolus administration (3 g/m2 every 24 h for 3 days). Concentrations of IFO and its metabolites were determined in plasma and urine. There was up to 70% less of the dechloroethylated metabolites in plasma following bolus administration compared to continuous infusion. Since dechloroethylation results in the formation of the toxic metabolite chloroacetaldehyde, this difference in metabolism may have an impact on the toxicity of IFO. There were no other consistent differences between the two modes of administration. Auto-induction of IFO metabolism, with an increase in dechloroethylated metabolites, was observed for both modes of administration. In conclusion, apart from dechloroethylation, there is little difference between these two modes of administration. However, during multiple cycles of IFO therapy such differences could have a significant effect.

Adolescent↗
PubMed1995

Recognition and management of teething diarrhea among Florida pediatricians.

According to current medical opinion, teething diarrhea (TD) is a myth; yet cross-cultural data document a worldwide distribution of popular belief in the association of frequent, loose stools with tooth eruption. A mail survey in 1990 of 215 pediatricians practicing in Florida investigated beliefs and practices related to TD. Thirty-five percent of respondents believed there is a real association between diarrhea and tooth eruption. When compared with pediatricians who do not believe in TD, these respondents were more likely to be more recent graduates of medical school, to be in general pediatric practice, to be female, to see more patients per week, and to practice in metropolitan areas. The most common explanations for the link between dentition and diarrhea were changes in eating habits, increased salivation, and stress. Respondents reported that both they and the parents of their patients tended to view TD as less serious than other types of diarrhea, and both managed it accordingly. When compared with earlier studies, our findings indicate that belief in TD among pediatricians may have increased since the 1970s. The results suggest a need for more empirical research on the effects of tooth eruption on bowel function.

Diagnosis, Differential↗
PubMed1994

Exaggerated epinephrine response to hypoglycemia in a physically fit, well-controlled IDDM subject.

Metabolically well controlled insulin-dependent diabetic subjects (IDDM) have deficient autonomic adrenomedullary responses to hypoglycemia. This defect, coupled with the characteristic deficient glucagon response to hypoglycemia, predisposes well-controlled IDDM subjects to an increased incidence of severe hypoglycemic episodes. In this report we describe a physically trained subject with long-duration IDDM (9 years) who was rigorously well-controlled (normal HBA1c), yet had exaggerated epinephrine responses to hypoglycemia compared with normal controls. Steady state epinephrine levels during a low-dose insulin (9 pM/kg/min) hypoglycemic clamp (2.9 +/- 0.1 mM) were approximately 2-fold higher compared with normal controls (10.6 vs. 5.5 +/- 0.7 nM). Epinephrine levels during a high-dose insulin (30 pM/kg/min) hypoglycemic clamp (2.8 +/- 0.1 mM) were also increased compared with normal controls (13.1 vs. 8.8 +/- 0.6 nM). We conclude that physical training in this metabolically well-controlled IDDM subject was associated with an augmented autonomic adrenomedullary response to hypoglycemia.

3-Hydroxybutyric Acid↗
PubMed1994

Implantable cardioverter defibrillator patch erosion presenting as hemoptysis.

Although the internal cardioverter defibrillator has prevented many premature deaths from lethal ventricular arrhythmias, some complications have occurred with its use. We present a patient who developed a fistula between the left ventricle and a bronchus, caused by erosion of the ventricular patch. The patient's presenting symptom was hemoptysis. Physicians caring for patients with these devices should be aware of this potential problem.

Animals↗
PubMed1994

Inaccuracy of glomerular filtration rate estimation from height/plasma creatinine ratio.

Use of a height/plasma creatinine formula to estimate glomerular filtration rate (GFR) is simpler and less invasive than renal or plasma clearance methods. The aim of this study was to determine whether these formulas enabled accurate prediction of GFR measured from the plasma clearance of 51Cr labelled ethylenediaminetetra-acetic acid (51Cr-EDTA). Thirty nine patients underwent GFR measurement at least six months after potentially nephrotoxic chemotherapy. Altman-Bland analysis was performed on the measured GFR and that estimated simultaneously using the original and a modified Counahan-Barratt formula and the Schwartz formula. The limits of agreement of the estimated GFR with the measured GFR were unacceptably wide in each case, despite highly significant correlation coefficients. The bias was smallest for the modified Counahan-Barratt formula. Use of these formulas to estimate GFR in children is insufficiently accurate for research purposes and has limitations in clinical practice. Furthermore, use of correlation coefficients to evaluate different methods of measuring GFR is inappropriate.

Adolescent↗
PubMed1994

Effects of physiological hyperinsulinemia on counterregulatory response to prolonged hypoglycemia in normal humans.

To test the hypothesis that differing physiological insulin levels can modify the counter-regulatory response to prolonged hypoglycemia, experiments were carried out in 10 healthy male subjects. Insulin was infused subcutaneously for 8 h in two separate randomized protocols, so that steady-state levels of 132 +/- 6 pM (low) and 402 +/- 18 pM (high) were obtained. The fall in plasma glucose was controlled by the glucose-clamp technique. Plasma glucose fell slowly and similarly in both groups, reaching an identical steady-state (final 120 min of each study) level of 3.4 +/- 0.1 mM. Steady-state plasma epinephrine (2.5 +/- 0.4 vs. 1.5 +/- 0.2 nM) and norepinephrine (1.5 +/- 0.2 vs. 1.1 +/- 0.1 nM) were significantly (P < 0.05) greater during high- compared with low-dose insulin infusions. Plasma glucagon was reduced during high compared with low infusions (104 +/- 9 vs. 150 +/- 19 ng/l, P < 0.05). Growth hormone, cortisol, and pancreatic polypeptide increased significantly but were not different during the two insulin infusions. Hepatic glucose production (HGP) was equal during the steady-state period (8.4 +/- 1.0 mumol.kg-1.min-1) of each infusion. Blood lactate levels (1,255 +/- 73 vs. 788 +/- 69 mumol/l, P < 0.02) were increased in high compared with low, but nonesterified fatty acid (205 +/- 43 vs. 579 +/- 65 mumol/l) and 3-hydroxybutyrate (40 +/- 36 vs. 159 +/- 51 mumol/l) were reduced (P < 0.002) during the high-compared with low-dose infusions.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Pharmacokinetics and metabolism of ifosfamide administered as a continuous infusion in children.

The pharmacokinetics and metabolism of ifosfamide was investigated in a group of 16 pediatric patients (5 girls) aged 1-17 years. Each received a dose of 3 g/m2/day for up to 3 days by continuous infusion. Plasma and urine were collected, and concentrations of ifosfamide and its principal metabolites were determined by a quantitative high-performance thin layer chromatography method. During 3 days of continuous infusion, the plasma concentrations of parent drug decreased. This was accompanied by a continuous increase in dechloroethylated products in plasma but not in urine. Estimated pharmacokinetic parameters (clearance, volume of distribution, and half-life) were dependent on body size and age but not any other patient variable. Renal clearance was a relatively minor route of elimination for parent drug and corresponded to < 25% of glomerular filtration rate. Metabolite data from plasma and urine indicated a high degree of interindividual variation in metabolism. Comparison of metabolite recoveries in urine indicated a positive correlation between activation and inactivation routes of metabolism. Prior exposure to ifosfamide was associated with a higher recovery in urine of dechloroethylated metabolites. The severity of hematological toxicity was inversely correlated with glomerular filtration rate but not to parameters of ifosfamide metabolism. There was marked variation in levels of the carboxy metabolite, which could not be detected in the plasma of 5 subjects. However, evidence for a polymorphism in metabolism to this metabolite was weaker than that seen with the isomeric oxazaphosphorine cyclophosphamide. There appeared to be a higher clearance of ifosfamide in pediatric patients compared to adults. The significance of this, and of the variation in metabolism of ifosfamide, for clinical outcome remains to be established, but the increase in the dechloroethylation route of metabolism may be associated with an increased risk of toxicity.

Adolescent↗
PubMed1993

Mutations in U1 snRNA bypass the requirement for a cell type-specific RNA splicing factor.

Previous studies have demonstrated that efficient splicing of the primary transcript of the yeast MER2 gene requires the MER1 protein, which is produced only in meiotic cells. A genetic selection was devised to recover second-site mutations that bypass the requirement for MER1 in MER2 RNA-splicing. This selection identified a mutation in SNR19, the gene for U1 snRNA. The suppressor mutation affects the first residue in U1 snRNA, allowing this nucleotide to base pair with the eighth nucleotide in the MER2 intron. This base in MER2 lies outside the conserved hexanucleotide that defines the 5' splice site in yeast. The MER2 5' splice site (GUUCGU) differs from the consensus in yeast (GUAYGU) at the third position. When this nucleotide is mutated to restore the consensus, base pairing with U1 snRNA is increased and the requirement for MER1 is alleviated.

Base Sequence↗
PubMed1993

Effects of insulin on the counterregulatory response to equivalent hypoglycemia in normal females.

The aim of this study was to determine if insulin could augment the counterregulatory response to equivalent hypoglycemia in normal females similarly to males. Experiments were carried out in nine normal lean overnight-fasted female subjects. Insulin was infused in two separate randomized protocols so that steady-state levels of 794 +/- 62 (low) and 3,620 +/- 476 pM (high) were obtained. Despite an identical plasma glucose level (2.8 +/- 0.1 mM), epinephrine (5.7 +/- 0.9 vs. 3.9 +/- 0.6 nM), norepinephrine (2.7 +/- 0.4 vs. 1.8 +/- 0.3 nM), cortisol (918 +/- 55 vs. 826 nM), and growth hormone (35.8 +/- 3.7 vs. 28.4 +/- 2.7 micrograms/l) were increased (P < 0.05) during high compared with low insulin infusion, respectively. Glucagon and pancreatic polypeptide levels increased significantly but were not different during the two insulin infusions. Hepatic glucose production was increased during the high-compared with low-dose infusions (9.5 +/- 1.1 vs. 5.1 +/- 2.2 mumol.kg-1 x min-1; P < 0.05). Lipolysis, as indicated by the blood glycerol level, increased significantly during high- compared with low-dose insulin infusions (121 +/- 29 vs. 65 +/- 13 microM; P < 0.05). The hormonal and metabolic responses to hypoglycemia were significantly different in females compared with previous results in males.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Carboplatin pharmacokinetics in children: the development of a pediatric dosing formula. The United Kingdom Children's Cancer Study Group.

PURPOSE: The aim of this study was to define the pharmacokinetics of carboplatin in children and use the data to develop a pediatric dose formula. It was anticipated that renal function would be a major determinant of carboplatin disposition and the relationship between carboplatin clearance and glomerular filtration rate (GFR) was examined in detail. PATIENTS AND METHODS: Plasma carboplatin pharmacokinetics were measured as ultrafiltrable platinum in 22 patients (5 to 63 kg) following 200 to 1,000 mg/m2 of carboplatin. GFR was measured by the plasma clearance of chromium 51-edathamil (51Cr-EDTA). RESULTS: Carboplatin pharmacokinetics in children were best described in most patients (16 of 22) by a two-compartment model. The dose-normalized area under the plasma carboplatin concentration versus time curve (AUC) ranged from 3.1 to 9.6 mg/mL.min/400 mg/m2 and there was only a weak linear relationship between carboplatin dose and AUC (R2 = .31). There was a significant relationship between absolute carboplatin and 51Cr-EDTA clearances (R2 = .56), but the relationship was weaker (R2 = .28) when both clearances were normalized for body surface area. Carboplatin plasma clearance was predicted by the equation: clearance = GFR (mL/min) + 0.36 x body weight (BW; kg), and a modified form of the adult carboplatin dose formula is proposed: dose (mg) = target AUC x (GFR [mL/min] + [0.36 x BW(kg)]). Two further equations were developed that use the 51Cr-EDTA half-life (t1/2) to calculate the GFR and these may reduce errors resulting from inaccurate measurement of the volume of distribution for 51Cr-EDTA. In patients treated with single-agent carboplatin or carboplatin plus vincristine, there was a significant sigmoidal relationship between AUC and thrombocytopenia (R2 = .56). CONCLUSION: GFR-based carboplatin dosing in children should be feasible and will be evaluated prospectively.

Adolescent↗
PubMed1993

The effects of insulin on the counterregulatory response to equivalent hypoglycemia in patients with insulin-dependent diabetes mellitus.

We previously demonstrated that hyperinsulinemia can amplify the counterregulatory response to hypoglycemia in normal subjects. The aim of the present study was to determine if differing concentrations of insulin can modify the counterregulatory response to equivalent fixed hypoglycemia in insulin-dependent-diabetic subjects (IDDM). Experiments were carried out in seven lean, overnight-fasted, moderately controlled (hemoglobin A1c, 10.9%; normal range, 5-9) IDDM subjects with a disease duration of 13 +/- 3 yr. All were maintained normoglycemic overnight so that basal plasma glucose (5.6 +/- 0.2 and 5.4 +/- 0.2 mmol/L) and insulinemia (63 +/- 18 and 48 +/- 10 pmol/L) were similar at the start of each study. Insulin was infused for 120 min in two separate randomized protocols, so that steady state levels (mean +/- SE) of 742 +/- 212 pmol/L (low) and 3360 +/- 710 pmol/L (high) were obtained. Glucose was infused during both protocols to ensure that the rate of fall of plasma glucose (0.09 mmol/L.min) and the hypoglycemic plateau (2.8 +/- 0.1 mmol/L) were similar. In response to hypoglycemia, plasma levels of epinephrine, norepinephrine, cortisol, GH, and pancreatic polypeptide increased similarly during both insulin infusions. During the final 30 min, despite similar levels of counterregulatory hormones, hepatic glucose production was significantly reduced in the presence of high compared to low insulin levels (1.7 +/- 2.8 vs. 8.3 +/- 1.7 mumol/kg.min; P < 0.05). Similarly, plasma nonesterified fatty acids (472 +/- 94 vs. 787 +/- 105 mumol/L) and blood 3-hydroxybutyrate levels (30 +/- 12 vs. 106 +/- 29 mumol/L) were significantly reduced (P < 0.05) during high compared to low dose infusions. Cardiovascular parameters (heart rate and systolic, diastolic, and mean arterial pressures) responded similarly during both infusions. We conclude that 1) insulin per se does not amplify the counterregulatory response to equivalent hypoglycemia in individuals with moderately controlled, long duration IDDM; and 2) there may be a relative autonomic adrenomedullary deficit in some IDDM subjects that prevents the amplified epinephrine response to hyperinsulinemia during hypoglycemia.

Adult↗
PubMed1993

The effects of differing insulin levels on the hormonal and metabolic response to equivalent hypoglycemia in normal humans.

The aim of this study was to determine if differing concentrations of insulin can modify the counterregulatory response to equivalent hypoglycemia in normal humans. Experiments were conducted in 9 normal, lean men, who had fasted overnight. Insulin was infused in two separate, randomized protocols so that steady-state levels of 486 +/- 33 (low) and 3056 +/- 236 pM (high) were obtained. Glucose was infused during both protocols to ensure that the rate of fall of plasma glucose (0.07 mM/min) and hypoglycemic plateau (2.8 +/- 0.1 mM) were similar. Despite similar plasma glucose levels, EPI (8.7 +/- 0.7 vs. 5.5 +/- 0.7 nM), NE (3.3 +/- 0.3 vs. 2.3 +/- 0.2 nM), and cortisol (811 +/- 36 vs. 611 +/- 72 nM) significantly increased during high compared with low insulin infusion, respectively (P < 0.05). Glucagon, growth hormone, and pancreatic polypeptide levels increased briskly and significantly but were not different during the two insulin infusions. HGP rose significantly from 12.1 +/- 0.3 to 18.1 +/- 1.1 mumol.kg-1 x min-1 in response to the high insulin level (P < 0.05) but remained unchanged (12.1 +/- 0.4 and 11.7 +/- 1.4 mumol.kg-1 x min-1) in the presence of th low insulin level. GRa increased significantly during high insulin levels (3.4 +/- 0.3 to 4.8 +/- 0.7 mumol.kg-1 x min-1, P < 0.05) but remained at a basal rate (3.0 +/- 0.3 to 2.7 +/- 0.6 mumol.kg-1 x min-1) in the presence of low insulin levels. sBP and heart rate increased more during high insulin infusion (18 +/- 5 vs. 6 +/- 5 mmHg and 18 +/- 4 vs. 7 +/- 2 beats/min, respectively, P < 0.05). In summary, the 6-fold higher insulin level resulted in significantly greater increases in catecholamine and cortisol secretion, HGP, lipolysis, heart rate, and sBP despite equivalent hypoglycemia. We conclude that at moderate hypoglycemia, high doses of insulin can augment certain aspects of the counterregulatory response in normal humans.

Adult↗