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Biomedical subjects

A Thibault

Publications and source records attributed to A Thibault.

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

Disposition of phenylbutyrate and its metabolites, phenylacetate and phenylacetylglutamine.

Phenylacetate, an inducer of tumor cytostasis and differentiation, shows promise as a relatively nontoxic antineoplastic agent. Phenylacetate, however, has an unpleasant odor that might limit patient acceptability. Phenylbutyrate, an odorless compound that also has activity in tumor models, is known to undergo rapid conversion to phenylacetate by beta-oxidation in vivo. This phase I study examined the pharmacokinetics of phenylbutyrate and characterized the disposition of the two metabolites, phenylacetate and phenylacetylglutamine. Fourteen patients with cancer (aged 51.8 +/- 13.8 years) received a 30-minute infusion of phenylbutyrate at 3 dose levels (600, 1200, and 2000 mg/m2). Serial blood samples and 24-hour urine collections were obtained. Samples were assayed by high-performance liquid chromatography. A model to simultaneously describe the pharmacokinetics of all three compounds was developed using ADAPT II. Data were modeled as molar equivalents. The model fit the data well as shown by mean (+/- SD) coefficients of determination (r2) for phenylbutyrate, phenylacetate, and phenylacetylglutamine, which were 0.96 +/- 0.07, 0.88 +/- 0.10, and 0.92 +/- 0.06, respectively. The intrapatient coefficient of variation percentage (CV%) around the parameter estimates were small (range 7.2-33.5%). Phenylbutyrate achieved peak concentrations in the range of in vitro tumor activity (500-2000 mumol/L) and exhibited saturable elimination (Km = 34.1 +/- 18.1 micrograms/mL and Vmax = 18.1 +/- 18 mg/h/kg). Metabolism was rapid; the times to maximum concentration for phenylacetate and phenylacetylglutamine were 1 and 2 hours, respectively. The conversion of phenylbutyrate to phenylacetate was extensive (80 +/- 12.6%), but serum concentrations of phenylacetate were low owing to rapid, subsequent conversion to phenylacetylglutamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Acute renal toxicity associated with suramin in the treatment of prostate cancer.

The use of suramin, a polysulfonated naphthylurea, in the treatment of advanced prostate cancer currently is being investigated. A 52-year-old man developed acute renal dysfunction after receiving nine doses of suramin. His suramin therapy was discontinued, but his serum creatinine level continued to rise to 10.8 mg/dl during the next 6 days. The patient was not rechallenged with suramin, and his renal function returned to baseline within the next 3 weeks. Future investigators of this drug should be aware of the possibility of such a reaction with parenteral administration.

Acute Kidney Injury↗
PubMed1994

Growth inhibition, tumor maturation, and extended survival in experimental brain tumors in rats treated with phenylacetate.

Phenylacetate is a naturally occurring plasma component that suppresses the growth of tumor cells and induces differentiation in vitro. To evaluate the in vivo potential and preventive and therapeutic antitumor efficacy of sodium phenylacetate against malignant brain tumors, Fischer 344 rats (n = 50) bearing cerebral 9L gliosarcomas received phenylacetate by continuous s.c. release starting on the day of tumor inoculation (n = 10) using s.c. osmotic minipumps (550 mg/kg/day for 28 days). Rats with established brain tumors (n = 12) received continuous s.c. phenylacetate supplemented with additional daily i.p. dose (300 mg/kg). Control rats (n = 25) were treated in a similar way with saline. Rats were sacrificed during treatment for electron microscopic studies of their tumors, in vivo proliferation assays, and measurement of phenylacetate levels in the serum and cerebrospinal fluid. Treatment with phenylacetate extended survival when started on the day of tumor inoculation (P < 0.01) or 7 days after inoculation (P < 0.03) without any associated adverse effects. In the latter group, phenylacetate levels in pooled serum and cerebrospinal fluid samples after 7 days of treatment were in the therapeutic range as determined in vitro (2.45 mM in serum and 3.1 mM in cerebrospinal fluid). Electron microscopy of treated tumors demonstrated marked hypertrophy and organization of the rough endoplasmic reticulum, indicating cell differentiation, in contrast to the scant and randomly distributed endoplasmic reticulum in tumors from untreated animals. In addition, in vitro studies demonstrated dose-dependent inhibition of the rate of tumor proliferation and restoration of anchorage dependency, a marker of phenotypic reversion. Phenylacetate, used at clinically achievable concentrations, prolongs survival of rats with malignant brain tumors through induction of tumor differentiation. Its role in the treatment of brain tumors and other cancers should be explored further.

Animals↗
PubMed1994

Hypothyroidism associated with aminoglutethimide in patients with prostate cancer.

OBJECTIVE: The administration of aminoglutethimide and hydrocortisone is a second-line hormonal maneuver commonly prescribed for the treatment of metastatic prostate cancer. We determine the incidence of aminoglutethimide-induced primary hypothyroidism in an elderly population who have prostate cancer. DESIGN: Prospective evaluation. PATIENTS: Twenty-nine men with stage D2 prostate cancer who were treated at the National Cancer Institute, Bethesda, Md, in 1992. RESULTS: Clinical and biochemical evidence of hypothyroidism (thyrotropin levels greater than 10 mU/L) was noted in nine of 29 patients treated following the initiation of aminoglutethimide (250 mg four times daily). The elevation in thyrotropin and the clinical symptoms of hypothyroidism were reversed by the administration of levothyroxine (n = 4). CONCLUSION: Hypothyroidism should be included in the differential diagnosis of lethargy in elderly patients who are receiving aminoglutethimide for prostate cancer. Furthermore, patients who are receiving this agent at a dosage of 1000 mg/d or greater should have their serum thyrotropin levels monitored, and replacement therapy with levothyroxine should be initiated when abnormally elevated levels are noted.

Aged↗
PubMed1994

A phase I and pharmacokinetic study of intravenous phenylacetate in patients with cancer.

Phenylacetate has recently been shown to suppress tumor growth and promote differentiation in experimental models. A phase I trial of phenylacetate was conducted in 17 patients with advanced solid tumors. Each patient received a single i.v. bolus dose followed by a 14-day continuous i.v. infusion of the drug. Twenty-one cycles of therapy were administered at four dose levels, achieved by increasing the rate of the continuous i.v. infusion. Phenylacetate displayed nonlinear pharmacokinetics [Km = 105.1 +/- 44.5 (SD) microgram/ml, Vmax = 24.1 +/- 5.2 mg/kg/h and Vd = 19.2 +/- 3.3 L]. There was also evidence for induction of drug clearance. Ninety-nine % of phenylacetate elimination was accounted for by conversion to phenylacetylglutamine, which was excreted in the urine. Continuous i.v. infusion rates resulting in serum phenylacetate concentrations exceeding Km often resulted in rapid drug accumulation and dose-limiting toxicity, which consisted of reversible central nervous system depression, preceded by emesis. Three of nine patients with metastatic, hormone-refractory prostate cancer maintained stable prostatic specific antigen levels for more than 2 months; another had less bone pain. One of six patients with glioblastoma multiforme, whose steroid dosage has remained unchanged for the duration of therapy, has sustained functional improvement for more than 9 months. The use of adaptive control with feedback for the dosing of each patient enabled us to safely maintain stable phenylacetate concentrations up to the range of 200-300 micrograms/ml, which resulted in clinical improvement in some patients with advanced disease.

Adult↗
PubMed1994

Assay of the antiangiogenic compound TNP-470, and one of its metabolites, AGM-1883, by reversed-phase high-performance liquid chromatography in plasma.

This paper describes a reversed-phase, high-performance liquid chromatographic (HPLC) method for the isolation, detection, and quantification of TNP-470 (I) and one of its active metabolites, AGM-1883 (II), from plasma. These compounds are initially extracted from plasma with an organic solvent and then separated from one another on a C18 column. Those fractions eluting from the C18 column and containing either I or II are then derivatized through their epoxide moieties with sodium 8-quinolinethiolate (SQT). This derivatization produces fluorescent species that are isolated and quantified by a second reversed-phase HPLC analysis. The assay yields a lower limit of reliable quantification of 2.5 ng/ml and is linear to a concentration at least as high as 160 ng/ml. The inter-assay percent coefficient of variation is less than 18%.

Acetamides↗
PubMed1994

Surprising activity of flutamide withdrawal, when combined with aminoglutethimide, in treatment of "hormone-refractory" prostate cancer.

BACKGROUND: The best treatment for patients with "hormone-refractory" metastatic prostate cancer is unclear, particularly in patients for whom suramin and hydrocortisone have failed. PURPOSE: We investigated a combination of flutamide withdrawal and aminoglutethimide in suramin- and hydrocortisone-pretreated patients with "hormone-refractory" prostate cancer. METHODS: Twenty-nine patients with metastatic prostate cancer were treated with simultaneous flutamide withdrawal and aminoglutethimide (250 mg given orally four times daily). All patients were taking flutamide at the time of entry, and previous treatments with medical or surgical castration, flutamide, suramin, and hydrocortisone had failed in all of these patients. Because of suramin-induced adrenal insufficiency, all patients had previously received, and continued to receive, physiological doses of hydrocortisone. Treatment of all non-surgically castrated patients had previously failed; however, these patients continued to receive depot leuprolide. RESULTS: In 14 (48%) of 29 patients, the prostate-specific antigen (PSA) decreased by more than 80% for 4 or more weeks. Improvements in anemia, thrombocytopenia, soft-tissue masses, bone scans, and symptoms were also noted. Factors associated with response included prolonged flutamide pretreatment, a markedly elevated pretreatment PSA, and the absence of soft-tissue disease. CONCLUSIONS: Flutamide withdrawal, when combined with the simultaneous administration of aminoglutethimide, is a therapeutically active approach in patients with "hormone-refractory" prostate cancer. IMPLICATIONS: On the basis of these and additional data, we hypothesize that prolonged exposure to flutamide results in the selective proliferation of cancer cells containing a mutant androgen receptor that aberrantly recognizes flutamide metabolites and nonandrogenic steroids as androgenic stimuli.

Aged↗
PubMed1994

In vitro antitumor effect of hydroxyurea on hormone-refractory prostate cancer cells and its potentiation by phenylbutyrate.

Previous clinical trials have suggested that hydroxyurea may possess some activity against prostate cancer. The in vitro antiproliferative activity of hydroxyurea was evaluated in three hormone-refractory prostate cancer cell lines, PC-3, DU-145 and PC-3M. Fifty-percent inhibition of growth in all three cell lines required prolonged (120 h) exposure to hydroxyurea at a concentration of approximately 100 microM. Using pharmacokinetic data obtained during the course of a clinical trial of hydroxyurea, we simulated a dosing regimen that would sustain plasma drug concentrations above 100 microM for 120 h (1 g loading dose, followed by 500 mg every 6 h for 5 days in a 70 kg man). Since this dosing regimen is likely to generate an unacceptable degree of myelosuppression, in vitro combination studies were conducted with hydroxyurea and phenylbutyrate, a new differentiating agent with no myelosuppressive effects. These studies resulted in a reduction of the hydroxyurea concentration necessary for 50% growth inhibition (50 microM of hydroxyurea plus 0.5 mM of phenylbutyrate). A regimen designed to achieve that hydroxyurea concentration (400 mg loading dose, followed by 200 mg every 6 h for 5 days) should be clinically achievable. Based on these results, this combination deserves further evaluation in patients with stage D prostate cancer.

Cell Division↗
PubMed1994

Evaluation of cutaneous and proprioceptive sensation in children: a reliability study.

Forty-three healthy children aged between six and 12 years were tested to determine the intra-rater reliability of four clinical cutaneous and proprioceptive sensory assessment tools: touch pressure, vibration perception, thermal discrimination and kinaesthesis. The tests were carried out bilaterally on proximal and distal upper- and lower- extremity sites. The mean intraclass coefficients represented good to excellent reliability, which suggests that these assessment tools allow objective and reproducible measurements of cutaneous and proprioceptive sensation in children. The results were compared with existing data in the literature: in general, children and adults obtain similar sensory scores, and sex, age and laterality have no significant effect on the results for any test. However, the touch-pressure and vibration scores were significantly influenced by the site tested, the index fingerpad being the most sensitive area in both tests.

Child↗
PubMed1994

Phototherapy for seasonal affective disorder: a blind comparison of three different schedules.

The authors investigated the outcome of an alternating time schedule versus two fixed schedules (either morning or evening) of bright light treatment for seasonal affective disorder. The subjects were 31 patients who met DSM-III-R criteria for major depression with a seasonal pattern. No statistically significant difference was observed among patients in the three groups for response criteria after 1 week of treatment. These results support the use of more flexible phototherapy schedules.

Adolescent↗
PubMed1994

Side effects induced by bright light treatment for seasonal affective disorder.

BACKGROUND: Bright light treatment has become an accepted treatment for seasonal affective disorder (SAD), but there have been few studies about adverse effects from using this treatment. We conducted a study to examine the frequency of adverse effects of bright light treatment for SAD. METHOD: Thirty patients meeting DSM-III-R criteria for major depression, recurrent, with seasonal pattern as determined by the Structured Clinical Interview for DSM-III-R were administered a structured interview, the 42-item Systematic Assessment for Treatment Emergent Events, to assess side effects from bright light treatment. RESULTS: Side effects were limited and mild. They remitted with time or decreased light. No patient discontinued treatment. One patient developed mild hypomania and 3 became agitated. Sleep disturbance occurred in 62% of patients (5 of 8) using evening light. Visual side effects occurred in 26% of patients (8 of 30). CONCLUSION: Except for one case of mild hypomania, no other clinically significant treatment-emergent adverse effects developed. Hypomania is an uncommon, but clinically important side effect. Mild visual complaints were common and remitted promptly. In this group of patients with SAD, bright light treatment was well tolerated and resulted in a limited number of adverse effects, none of which compromised treatment. The absence of a control group limits the specificity of these side effects to bright light treatment.

Adolescent↗
PubMed1992

A comparison of clinical criteria for the diagnosis of veno-occlusive disease of the liver after bone marrow transplantation.

Two major studies have established clinical criteria for the diagnosis of veno-occlusive disease of the liver (VOD) after bone marrow transplantation (BMT). McDonald and co-workers defined VOD as the onset of two of the following occurring before day 30 post-BMT: (a) jaundice (bilirubin > 27 mmol/l), (b) tender hepatomegaly, and (c) ascites or weight gain. In contrast, Jones and co-workers defined VOD as the onset, before day 21 post-BMT, of hyperbilirubinemia (bilirubin > 34 mmol/l) as well as two of the following: (a) hepatomegaly, (b) ascites, and (c) weight gain. We retrospectively reviewed the occurrence of VOD in 101 patients transplanted primarily for hematologic malignancies between 1979 and 1990, applying both sets of criteria. Of the 101 patients, eight (7.9%) fulfilled the Jones criteria whereas 32 (31.7%) had VOD according to the McDonald criteria (p < 0.001). Early mortality (prior to 50 days post-BMT) was 75% (6/8) in patients who fulfilled the Jones criteria but only 28.1% (9/32) in the McDonald group (p < 0.005). Overall, mortality in each group was 75% (6/8) and 65.6% (21/32), respectively. All of the six patients with VOD according to the Jones criteria who died had evidence of hepatic failure. Of the 32 patients who fulfilled the McDonald criteria, eight have also fulfilled the Jones criteria and are described above. Of the remaining 24 patients, 22 had complete resolution of VOD as defined by these criteria within 50 days of BMT, none developed hepatic failure, and 15 died.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Risk factors for the development of Clostridium difficile-associated diarrhea during a hospital outbreak.

OBJECTIVE: To evaluate the risk factors associated with a nosocomial outbreak of Clostridium difficile-associated diarrhea. DESIGN: Case-control study with two control groups. SETTING: University-affiliated urban hospital. PATIENTS: A convenience sample of 26 patients was chosen out of a total of 78 hospitalized patients with C difficile-associated diarrhea, defined as the presence of diarrhea and a positive C difficile cytotoxin assay or stool culture. Twenty-six controls were matched for age, gender, ward, and date of admission; 18 additional controls were matched to surgical patients for date and ward of admission, as well as for the type of surgical procedure performed. RESULTS: Significant risk factors for the development of C difficile-associated diarrhea were gastrointestinal surgery (exposure odds ratio [EOR] = 7.9, p = .004, 95% confidence interval [CI] = 1.9, 35), use of neomycin (EOR = 15.6, p = .012, 95% CI = 1.7, 92), clindamycin (EOR = 15.6, p = .005, 95% CI = 1.7, 92), metronidazole (EOR = 5.7, p = .02, 95% CI = 1.4, 25), and excess antibiotic use (mean number of antibiotics = 4.2 versus 1.4, p less than .00005). The presence of systemic disease and the use of antacids or immunosuppressive drugs were similar in cases and controls. In surgical patients, no specific antibiotic could be linked to C difficile-associated diarrhea because of uniform perioperative antibiotic use. There was a significant difference in the number of antibiotics administered to cases and controls (mean = 3.1 versus 1.9, p less than .005). CONCLUSIONS: The results suggest that control of nosocomial C difficile-associated diarrhea may be attained by minimizing the administration of antibiotics, avoidance of high-risk antibiotics, and having a high index of suspicion of C difficile-associated diarrhea in patients who develop diarrhea after gastrointestinal surgery. Perioperative administration of metronidazole, when given with other antibiotics, failed to protect against the development of C difficile-associated diarrhea.

Anti-Bacterial Agents↗
PubMed1976

Pharmacological aspects of pyrazoline derivatives from 2-hydroxy-butenolides.

A series of pyrazoline derivatives was synthetised and evaluated for toxicological and pharmacological effects; analgesic, hypnotic, anti-inflammatory, antipyretic and cardiovascular properties were screened. Tested compounds were found to have a low toxicity; one of them showed a good analgesic activity without side effects.

Analgesics↗