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Biomedical subjects

M Woo

Publications and source records attributed to M Woo.

At least 19 recordsLinked to original sources
PubMed1997

Pharmacokinetics of pamidronate disodium in patients with cancer with normal or impaired renal function.

Pamidronate is a second-generation bisphosphonate that undergoes negligible biodegradation and is eliminated exclusively by renal excretions. Nineteen cancer patients were stratified according to baseline creatinine clearance (Clcr): group I, Clcr > 90 mL/min (n = 6); group II, Clcr 61 mL/min to 90 mL/min (n = 6); group III, Clcr 30 mL/min to 60 mL/min (n = 3); group IV, Clcr < 30 mL/min (n = 4). All patients received a single, 90-mg dose of pamidronate disodium administered in a 4-hour intravenous infusion. Plasma and urine samples were collected at intervals up to 36 and 120 hours, respectively, after the start of infusion and were assayed for pamidronate, using validated high-performance liquid chromatography. Pamidronate's pharmacokinetics were characterized by a short distribution phase (2-3 hours) followed by rapid elimination of the drug in urine. Elimination of pamidronate was slower in patients in group IV with a mean +/- standard deviation area under the plasma concentration-time curve (AUC0-36) of 19.0 +/- 4.60 micrograms.hr/mL compared with 8.1 +/- 3.13 micrograms.hr/mL in patients in group I. A linear relationship in Clcr was observed for AUC0-36 (r = 0.67), urinary excretion (r = 0.69), and renal clearance (r = 0.81). Renal clearance was proportional to Clcr for patients in all four renal-function groups. In the treatment of bone metastases of malignancy, successive doses of pamidronate are generally separated by weeks; thus, plasma accumulation in patients with renal impairment is not expected to be clinically relevant. A reduction in dose of pamidronate disodium should not be necessary in cancer patients with renal impairment.

Aged↗
PubMed1996

Tacrolimus and minidose methotrexate for prevention of acute graft-versus-host disease after matched unrelated donor marrow transplantation.

Thirty adults with leukemia or lymphoma undergoing marrow transplantation from HLA-compatible unrelated donors received tacrolimus (FK506), a new immunosuppressive macrolide lactone, and minidose methotrexate to prevent acute graft-versus-host disease (GVHD). The group had a median age of 36 years (range 21 to 49 years). Twenty-four patients had advanced disease, and 11 were resistant to conventional therapy. Tacrolimus was administered at 0.03 mg/kg/d intravenously (i.v.) by continuous infusion from day -2, converted to oral at four times the i.v. dose following engraftment, and continued through day 180 posttransplant. Methotrexate 5 mg/m2 was given i.v. on days 1, 3, 6, and 11. All patients engrafted. Grades 2-4 GVHD occurred in 34% (95% CI, 17% to 52%), and grades 3-4 GVHD in 17% (95% CI, 3% to 31%). Mild renal toxicity was common before day 100; 63% of patients had a doubling of creatinine, and 52% had a peak creatinine greater than 2 mg/dL, but only one patient was dialyzed. The median last i.v. dose of tacrolimus was 53% of the scheduled dose, and the median oral dose on day 100 was 41% of that scheduled. Overall survival at 1 year was 47% (95% CI, 27% to 66%). We conclude that tacrolimus can be combined safely with minidose methotrexate, and the combination has substantial activity in preventing acute GVHD after unrelated donor marrow transplantation.

Actuarial Analysis↗
PubMed1996

The tumor suppressor gene Brca1 is required for embryonic cellular proliferation in the mouse.

Mutations of the BRCA1 gone in humans are associated with predisposition to breast and ovarian cancers. We show here that Brca1+/- mice are normal and fertile and lack tumors by age eleven months. Homozygous Brca1(5-6) mutant mice die before day 7.5 of embryogenesis. Mutant embryos are poorly developed, with no evidence of mesoderm formation. The extraembryonic region is abnormal, but aggregation with wild-type tetraploid embryos does not rescue the lethality. In vivo, mutant embryos do not exhibit increased apoptosis but show reduced cell proliferation accompanied by decreased expression of cyclin E and mdm-2, a regulator of p53 activity. The expression of cyclin-dependent kinase inhibitor p21 is dramatically increased in the mutant embryos. Buttressing these in vivo observations is the fact that mutant blastocyst growth is grossly impaired in vitro. Thus, the death of Brca1(5-6) mutant embryos prior to gastrulation may be due to a failure of the proliferative burst required for the development of the different germ layers.

Alternative Splicing↗
PubMed1996

Metabolite profiles in patients on high-dose valproate monotherapy.

To investigate the mechanism of valproate (VPA)-induced hepatotoxicity, we measured the serum and urine metabolites of VPA in high-dose VPA monotherapy by GC/MS/SIM and discussed the relationship between liver function and beta-oxidation, omega-, (omega-1)-oxidation metabolites and 4-en-VPA. In high-dose VPA monotherapy, the concentrations of beta-oxidation metabolites were not increased except for 2-en-VPA, but the concentrations of {omega + (omega-1)}-oxidation metabolites and of 4-en-VPA were increased about 4-5 times compared to those of standard dose VPA monotherapy. Serum GOT was not significantly correlated to 4-en-VPA and the ratio of beta-oxidation/{omega + (omega-1)} oxidation metabolites of VPA in serum. In high-dose VPA monotherapy, it is speculated that the beta-oxidation of VPA in the mitochondria reached the saturation point. However, instead of the beta-oxidation, the {omega + (omega-1)}-oxidation in microsomes was increased. We could not find significant relationship between the formation of toxic metabolites of VPA and liver dysfunction. Our data in VPA monotherapy suggest that the mechanisms of VPA-induced fatal hepatotoxicity cannot be explained by decreased beta-oxidation, increased omega-oxidation and increased 4-en-VPA level.

Adolescent↗
PubMed1996

Valproate metabolites in high-dose valproate plus phenytoin therapy.

PURPOSE: We wished to determine the relation between liver function, beta-, and omega-, and omega-1-oxidation metabolites and 4-en-valproate (VPA). METHODS: We measured the serum levels of VPA and its metabolites in children and adolescent receiving high-dose VPA plus phenytoin (PHT) therapy using gas chromatography-mass spectrometry with selected ion monitoring (GC/MS/ SIM). RESULTS: In high-dose VPA plus PHT polytherapy, the total VPA serum concentration was distinctly low, the concentrations of total beta-oxidation metabolites were decreased, the percentage values of VPA (percent of VPA) of total beta-oxidation metabolites were increased, and the E-2-en-VPA/3-keto-VPA ratios were decreased, as compared with those in high-dose VPA monotherapy. In high-dose VPA plus PHT polytherapy, 4-en-VPA (microM) was decreased and the concentrations of [omega + (omega-1)]-oxidation metabolites (microM) were decreased as compared with those in high-dose VPA monotherapy. In high-dose VPA plus PHT, serum glutamic-oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT) and lactic dehydrogenase (LDH) did not correlate significantly with the ¿beta/omega + (omega-1)¿ metabolites ratio and 4-en-VPA levels, but serum GOT, GPT, and LDH were increased as compared with those in high-dose VPA therapy. We were not able to establish a significant relation between the formation of metabolites of VPA metabolites and liver dysfunction in patients receiving high-dose VPA and PHT concurrently. CONCLUSIONS: Metabolic levels do not appear to be a reliable predictor of hepatotoxicity in children receiving pharmacological antiepileptic drug (AED) therapy.

Adolescent↗
PubMed1996

Effect of L-carnitine supplementation on acute valproate intoxication.

We analyzed urinary valproate (VPA) metabolites and carnitine concentrations in a child who accidentally ingested 400 mg/kg VPA. The concentration of 4-en VPA, the presumed major factor in VPA-induced hepatotoxicity, was markedly increased, without liver dysfunction or hyperammonemia. The other major abnormality was decreased beta-oxidation and markedly increased omega-oxidation. After L-carnitine supplementation, VPA metabolism returned to normal. The level of valproylcarnitine was not increased and therefore was not affected by L-carnitine. L-Carnitine may be useful in treating patients with coma after VPA overdose.

Ammonia↗
PubMed1996

[Benign infantile mitochondrial myopathy caused by reversible cytochrome c oxidase deficiency].

A 2-month-old girl had generalized weakness, profound muscular hypotonia, hepatomegaly and severe lactic acidosis. She needed ventilatory support. Muscle specimen taken at 2 months showed ragged-red fibers, abnormal mitochondria, and reduced cytochrome c oxidase (CCO) staining Biochemical analysis showed CCO activity to be reduced to about 16% of the normal mean. She received carnitine and coenzyme Q10 supplementation from the age of 3 months and abnormal blood lactate values declined to near normal values during the first three weeks. Gradually her condition started to improved: she held her head at 9 months, and walked alone at 15 months. The second biopsy specimen at 3 years and 8 months showed almost normal CCO staining and she was free of clinical signs. This case is an example of a rare benign infantile mitochondrial myopathy caused by CCO deficiency. Early diagnosis is crucial to provide intensive treatment until spontaneous clinical improvement appears. We concluded that carnitine and coenzyme Q10 supplementation was a useful treatment for clinical improvement in patients with a benign infantile mitochondrial myopathy caused by CCO deficiency.

Carnitine↗
PubMed1995

Target heart failure populations for newer therapies.

BACKGROUND: The scarcity of donor hearts has created a large population of heart failure patients who are unlikely to undergo transplantation. Newer surgical therapies that might sustain such patients at home previously have been applied in critical situations in which early outcome is jeopardized by multiorgan failure. The optimal population for studies of extended support would be ambulatory patients with low operative risk but high risk of later unfavorable outcome. METHODS AND RESULTS: Baseline clinical, echocardiographic, and hemodynamic data were collected prospectively between 1988 and 1993 in 500 patients who were discharged on tailored medical therapy after evaluation for transplantation. Specific criteria were examined to identify high risk of death or need for urgent transplantation during the next 2 years. In 265 patients with ejection fraction < or = 25% and initial New York Heart Association class IV symptoms, survival at 2 years was 55% (without urgent transplantation, 45%). Lower cardiac index or higher filling pressures at the time of referral did not confer higher risk, which was predicted by persistence of higher pressures after therapy. Serum sodium below 133 was associated with 34% 2-year survival without urgent transplantation, and ventricular dimension > 80 mm with a rate of 25%. Patients with initial peak oxygen consumption > 10 mL/kg per minute had a 2-year event-free rate of 72% compared with 48% for those with < 10 mL/kg per minute and 32% for those unable to exercise at referral. Demonstration of a 30% decrease in mortality with a controlled trial of new therapy in patients with ejection fraction < or = 25% would require 600 patients with class III symptoms or almost 300 patients with class IV symptoms unless another criterion were added. CONCLUSIONS: Ambulatory populations with high predicted event rates can be identified at initial evaluation, when hemodynamic criteria may be less useful than ventricular dimension, serum sodium, and ability to exercise. The use of outcome data from previous eras may lead to overestimation of benefits from newer therapies and underestimation of the sample size required in a prospective trials.

Cardiac Output, Low↗
PubMed1995

Determination of urinary valproylcarnitine by gas chromatography-mass spectrometry with selected-ion monitoring.

A modified method for the determination of valproylcarnitine in urine samples of patients receiving sodium valproate by gas chromatography-mass spectrometry with selected-ion monitoring is described. The chemically analogous internal standard 2-ethylpentanoylcarnitine was added to the urine samples. Valproic acid and its metabolites were removed by extraction with chloroform at pH 5.0. The samples were then applied onto a C18 Sep-Pak column. Inorganic and water soluble compounds were washed out with water. Valproylcarnitine and internal standard were eluted with methanol and were derivatized to the corresponding acyl-containing lactones by heating at 100 degrees C for 60 min in dimethylformamide. Urinary valproylcarnitine levels of epileptic patients receiving valproate were determined according to the present method. The data obtained might be useful for diagnosis of carnitine deficiency.

Calibration↗
PubMed1995

When do brain abnormalities in cerebral palsy occur? An MRI study.

The authors used MRI to analyse retrospectively the brain images of patients with cerebral palsy (CP) to evaluate its the role in the assessment of brain abnormalities and injury, and the relationship of pre-, peri- and postnatal events to CP. 70 patients with CP aged two to 16 years who underwent MRI were divided into four groups: group 1 (26 patients) comprised subjects whose CP was considered to have been caused by neuronal migration disorders in the embryonal stage; group 2 (30 patients) contained subjects whose cause was vascular disorders; in group 3 patients (five) the cause was intra-uterine infection; and CP clearly attributable to birth asphyxia (group 4) was noted in only nine patients. The results indicate that CP of term infants is often the result of prenatal factors, and their MRI findings indicated migration and cerebral infarction. Brain MRI is an essential examination in identifying the factors causing brain damage in CP.

Adolescent↗
PubMed1993

Predicting death from progressive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy.

Data were retrospectively reviewed on 528 consecutive patients hospitalized for treatment of advanced heart failure (left ventricular ejection fraction 0.2 +/- 0.07) and cardiac transplant evaluation, who were stabilized with medical therapy and discharged home. Predictors of heart failure death or rehospitalization for urgent transplantation were identified using the Cox proportional-hazards model. Within 1 year, 59 patients (11%) died suddenly and 70 (13%) died of heart failure or required urgent transplantation. A serum sodium < or = 134 mEq/liter, pulmonary arterial diastolic pressure > 19 mm Hg, left ventricular diastolic dimension index > 44 mm/m2, peak oxygen consumption during exercise testing < 11 ml/kg/min and the presence of a permanent pacemaker were independent predictors of hemodynamic deterioration. In the absence of these risk factors the risk of hemodynamic deterioration within 1 year from this study was only 2%. This risk increased to > 50% in the presence of hyponatremia and any 2 additional risk factors. Thus, patients with advanced heart failure at highest risk for progressive hemodynamic deterioration can be identified from clinical variables that could aid in triaging such patients to earlier cardiac transplantation.

Actuarial Analysis↗
PubMed1993

MRI of the head in the evaluation of microcephaly.

Fifty-five patients with microcephaly (head circumference < -2SD) were identified. The 55 patients were divided into two groups, consisting of group 1 (34 cases) in which genetic causes were considered primary, and group 2 (21 cases) in which intrauterine and/or postnatal acquired factors were thought to be responsible. MRI abnormalities were present in 80% of the total series: 68 and 100% in groups 1 and 2, respectively. In group 1, migration abnormalities were the most prominent and mental retardation was the major neurological handicap, while in group 2, hydranencephaly and infarction secondary to brain circulatory derangements were the most frequently observed abnormalities, with severe multiple handicaps such as cerebral palsy, epilepsy and mental retardation seen. Head MRI was considered indispensable in the investigation of the causes of microcephaly and in determining the neurological prognosis of affected patients.

Agenesis of Corpus Callosum↗
PubMed1993

Preoxygenation techniques: the value of nitrous oxide.

Changes in arterial oxygen saturation during induction of anaesthesia and intubation were studied using the pulse oximeter. Seventy-five young ASA I patients undergoing elective uncomplicated surgery were divided equally into three groups. The patients were preoxygenated with 100% oxygen, 50% oxygen: 50% nitrous oxide or 30% oxygen: 70% nitrous oxide for 1 min. All were then induced with thiopentone, paralysed with suxamethonium and orally intubated. Arterial oxygen saturations were continuously recorded by a separate investigator. All groups showed similar arterial desaturation during suxamethonium-induced apnoea and intubation, but the degree of desaturation was not clinically significant and no patient showed clinical signs of hypoxaemia. Preoxygenation with mixtures of oxygen and nitrous oxide can hasten the build-up of alveolar nitrous oxide concentration and help to smooth induction without compromising oxygenation of patients.

Adolescent↗
PubMed1993

A mild case of nesidioblastosis with diagnostic and therapeutic difficulty.

A female infant with nesidioblastosis who showed mild clinical symptoms is reported. In this patient, insulin levels and insulin to glucose ratios (IRI/G) were often normal. Regular milk feedings supplemented with continuous glucose infusion (0.7-2 mg/kg per min) or oral glucose feedings (4.5 mg/kg per min) prevented hypoglycemia. As leucine-sensitivity was diagnosed at 2 months of age, she was started on diazoxide. This was, however, ineffective, and adverse effects appeared. Subtotal pancreatectomy (95%) was therefore attempted at 5 months of age, and persistent normoglycemia as well as normal growth and development followed up to 3 years after the operation. The pancreas showed characteristic signs of nesidioblastosis. The above clinical observation suggests that a patient with nesidioblastosis whose blood glucose level is easily controllable may develop an unexpected episode of hypoglycemia in the presence of a leucine sensitivity. In such a patient, diazoxide or, when it is of no avail, surgical intervention should promptly be instituted to prevent possible neurologic sequelae induced by hypoglycemia.

Combined Modality Therapy↗