Response of thalamic pain syndrome to lamotrigine.
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Journal Article↗
Biomedical subjects
R Bruno
Publications and source records attributed to R Bruno.
Population pharmacokinetics/pharmacodynamics of docetaxel in phase II studies in patients with cancer.
PURPOSE: The population pharmacokinetic/pharmacodynamic (PK/PD) approach was prospectively integrated in the clinical development of docetaxel to assess the PK profile in a large population of patients and investigate systemic exposure as a prognostic factor for clinical outcome. PATIENTS AND METHODS: PK analysis was performed at first course in 24 phase II studies of docetaxel monotherapy using four randomized limited-sampling schedules. Bayesian estimates of clearance (CL), area under the concentration-time curve (AUC), and peak and duration of plasma levels greater than threshold levels were used as measures of exposure. PD data included for efficacy, response rate, time to first response, and time to progression (TTP) in breast cancer and non-small-cell lung cancer (NSCLC), and for toxicity, grade 4 neutropenia, and febrile neutropenia at first course and time to onset of fluid retention. PK/PD analysis was conducted using logistic and Cox multivariate regression models. RESULTS: PK protocol implementation was successful. Most of the patients registered (721 of 936, 77%) were sampled and 68% were assessable for PK (640 patients). First-course docetaxel AUC was a significant predictor (P = .0232) of TTP in NSCLC (n = 151). Docetaxel CL was a strong independent predictor (P < .0001) of both grade 4 neutropenia and febrile neutropenia (n = 582). Cumulative dose was the strongest predictor (P < .0001) of the time to onset of fluid retention (n = 631). However, the duration of exposure over 0.20 micromol/L (0.16 microg/mL) at first course was an independent predictor (P = .0029). Few patients (n = 25, 4%) received the recommended dexamethasone premedication. CONCLUSION: First-course docetaxel PK is a predictor of first-course hematologic toxicity, but also of fluid retention, which is cumulative in nature. Patients with elevated hepatic enzymes have a 27% reduction in docetaxel CL and are at a higher risk of toxicity. A starting dose of 75 mg/m2 is currently being evaluated in this population. Prospective implementation of large-scale population PK/PD evaluation is feasible in early drug development and this approach generates clinically relevant findings.
Adult↗
In California, Medi-Cal managed care is superior to Medi-Cal fee-for-service.
This is a comparative analysis of California's "experiment" in Medi-Cal managed care. It compares managed care to fee-for-service in the area of quality. In March 1993, the California State Department of Health Services issued a State Strategic Plan for Medi-Cal Managed Care. The goal: to transfer the delivery of care for the majority of the state's Medi-Cal population from a predominantly fee-for-service payment system to capitated managed care. The state of California has steadily increased its commitment to the large-scale expansion of managed care within the Medi-Cal Program in order to improve beneficiaries' access to quality preventative and primary health care while acting as a prudent purchaser of services. This study examines one Local Initiative--Inland Empire Health Plan--created as a not-for-profit, joint powers, public entity by Riverside and San Bernardino counties, California.
California↗
Pharmacokinetic and pharmacodynamic properties of docetaxel: results of phase I and phase II trials.
The pharmacokinetics of docetaxel as investigated in Phase I and Phase II trials are discussed. Phase I trials have shown that docetaxel exhibits linear pharmacokinetics consistent with a three-compartment model. Population pharmacokinetic and pharmacodynamic analysis of the results of 22 nonrandomized Phase II trials with nonlinear mixed-effects modeling showed that the interpatient variability of docetaxel pharmacokinetics is mainly related to body surface area and hepatic function. The effect of body surface area on clearance does not present a problem, since the dose of docetaxel is adjusted for body size. However, patients with impaired liver function are at increased risk of serious adverse effects (febrile neutropenia, severe infections, severe stomatitis, and toxic death) during treatment with docetaxel 100 mg/ m2. Patients with impaired liver function should receive a reduced dose (75 mg/m2). The presence of liver metastases without impaired liver function had no effect on docetaxel's clearance or safety, suggesting that a dose of 100 mg/m2 is well tolerated in such patients. Docetaxel pharmacokinetics and pharmacodynamics determined in Phase I and Phase II trials indicate a need to adjust the dosage for body surface area and liver function.
Antineoplastic Agents, Phytogenic↗
Simplified determination of combined residues of prochloraz and its metabolites in vegetable, fruit and wheat samples by gas chromatography.
This paper describes a gas chromatographic method for the determination of combined residues of prochloraz and its metabolites in various plant materials, including vegetables, fruits, seeds, grains and roots. The method is much simpler than previous ones as it does not require steam distillation; it consists of preliminary extraction of the sample, hydrolysis with pyridine hydrochloride in a test tube, extraction of the 2,4,6-trichlorophenol without the aid of steam distillation/continuous extraction, derivatization with diazomethane and gas chromatographic determination using electron-capture detection. The method is very rapid and can be done in a test tube; detection limit is from 0.01 to 0.50 mg/kg; recoveries are dependent on concentration of analyte and sample matrix; the determined values were found in the region of 72-102%.
Chromatography, Gas↗
A natural longer glycine-rich region in IKe filamentous phage confers no selective advantage.
Filamentous phage infect bacteria bearing pili. The phage protein involved in the recognition of pili and subsequent penetration of the phage into bacteria is the gene 3 protein (g3p). This is a multi-domain protein with glycine-rich regions separating some of the domains. Here we have found an insertion within the glycine-rich domain of the g3p of IKe, a filamentous phage which infects bacteria bearing N pili. Although this insertion considerably increases the length of the glycine-rich domain it has no selective advantage or disadvantage in infection or production of phage, and can therefore be considered a neutral mutation.
Amino Acid Sequence↗
Population pharmacokinetics of riluzole in patients with amyotrophic lateral sclerosis.
OBJECTIVES: To characterize the population pharmacokinetic of riluzole in patients with amyotrophic lateral sclerosis (ALS). METHODS: One hundred patients with ALS who were participating in a multicenter phase III dose-ranging trial of riluzole were sampled on 179 visits. The sampling strategy (two samples per visit) was varied across patients to define the population kinetic profile (full screen). Riluzole plasma levels were determined by HPLC, and the data were analyzed by nonlinear mixed-effect modeling (NONMEM program) with use of a one-compartment structural model. The model incorporated interoccasion (visit-to visit) variability. RESULTS: In the basic one-compartment pharmacokinetic model, interindividual variability in plasma clearance (51.4%) was higher than intraindividual (visit-to-visit) variability (28.0%), indicating uniform pharmacokinetic behavior during long-term therapy. Riluzole clearance was independent of dosage (25 to 100 mg twice daily), treatment duration (up to 10 months), age, and renal function; gender and smoking were the most important patient covariates, with hepatic function having lesser influence. Typical value of clearance was 51.4 L/hr for a nonsmoking male patient. It was 32% lower in women than in men and 36% lower in nonsmokers than in smokers. Gender- and smoking-related variations in riluzole exposure at the recommended dosage (50 mg twice daily) were within the range of exposures achieved (with no untoward effect) in this dose-ranging study. CONCLUSION: The pharmacokinetics of riluzole has been characterized in patients during long-term therapy. Riluzole clearance is independent of dose and treatment duration. Within-patient variability is low. Gender and smoking status are the main covariates to explain interpatient variability.
Adult↗
G proteins and regulation of pyruvate dehydrogenase activity by insulin in human circulating lymphocytes.
Pertussis toxin (PT) catalyzes ADP-ribosylation of G protein alpha subunits, thus preventing their role as transducers of external signals targeting metabolic pathways. In vitro, in human circulating lymphocytes insulin at physiological concentrations (5 microU/ml) determines sharp activation of pyruvate dehydrogenase (PDH), the rate limiting enzyme in glucose oxidative breakdown. This study evaluates whether the above-described effects of insulin over PDH are mediated through G proteins. Human circulating lymphocytes (six samples from different donors) were exposed to insulin (5 microU/ml), PT (1-2 micrograms/ml) or PT-9K, a mutated PT void of catalytic activity (1-10 micrograms/ml), and to insulin in combination with the two toxins, and then assessed for PDH activity. Plasma membranes from cells incubated with and without PT or PT-9K were subjected to ADP-ribosylation in the presence of [32P] NAD+ and activated PT. In circulating lymphocytes exposed to PT alone, or in combination with insulin, PDH activity falls significantly below basal values (P < 0.001); PT-9K instead has no effect on basal or on insulin-stimulated PDH activity. ADP-ribosylation of a plasma membrane component with apparent molecular mass (42 kDa) comparable to that of the Gi (inhibitory) protein alpha subunit takes place in cells exposed to PT but not in those exposed to PT-9K. In human circulating lymphocytes Gi proteins or Gi protein-like components appear to be involved in preserving basal PDH activity as well as in the mechanism by which insulin exerts its control over PDH.
Adenosine Diphosphate Ribose↗
Insulin resistance in obese subjects and newly diagnosed NIDDM patients and derangements of pyruvate dehydrogenase in their circulating lymphocytes.
BACKGROUND: In circulating lymphocytes of individuals with insulin resistance and overt hyperglycaemia (NIDDM patients), alterations, affecting pyruvate dehydrogenase (PDH), the key enzyme in glucose oxidative breakdown, have been observed. They include below normal enzyme activity and, in vitro, no enzyme response to insulin at low physiological levels (5 microU/ml) as well as activation up to the basal values of controls with insulin at high physiological levels (50 microU/ml), instead of activation and inhibition respectively, as in controls. OBJECTIVE: To investigate whether these alterations characterize circulating lymphocytes of individuals with insulin resistance in whom derangements of glucose homeostasis are absent (obese subjects with normal glucose tolerance), or present but still controllable (nonobese and obese newly diagnosed NIDDM patients on an appropriate diet). SUBJECTS: Thirty obese subjects (BMI 36 +/- 3) responding normally to an oral glucose tolerance (OGT) test; 60 newly diagnosed NIDDM patients (30 nonobese, BMI 22 +/- 4 and 30 obese, BMI 38 +/- 2); 30 nonobese (BMI 21 +/- 5) and nondiabetic subjects, with no family history for NIDDM, served as controls. METHODS: Evaluation of PDH activity in circulating lymphocytes before and after exposure to insulin at 5 and 50 microU/ml, and of clinical parameters before and during an OGT test. RESULTS: 1) in circulating lymphocytes of obese nondiabetic subjects as well as obese and nonobese newly diagnosed NIDDM patients, PDH activity was significantly below normal. In vitro, enzyme response to insulin at 5 microU/ml was reduced in nonobese NIDDM patients with respect to controls, and absent in obese nondiabetic subjects and obese NIDDM patients. Enzyme response to insulin at 50 microU/ml was reversed in all individuals, which allowed enzyme activity to recover up to the basal level of controls. 2) In NIDDM patients and obese nondiabetic subjects, undergoing an OGT test, the area under the glycaemic curve (g-AUC) was as expected; the area under the insulinaemic curve (i-AUC) was increased in both groups with respect to controls, but significantly only in the latter. CONCLUSION: In individuals with insulin resistance PDH activity in their circulating lymphocytes rises up to basal levels of controls, only if these cells are exposed to insulin at high physiological concentrations, and g-AUC is normal only in those subjects who have significantly increased i-AUC. This suggests that with insulin at sufficiently high concentrations both parameters can be corrected. We conclude that the derangements responsible for the alterations of the two parameters share common features and thus the described PDH alterations in circulating lymphocytes reflect systemic insulin resistance whether accompanied by hyperglycaemia or not.
Adult↗
Possible role of transforming growth factor-beta in relapsing-remitting multiple sclerosis.
Cerebrospinal fluid (CSF) and serum levels of transforming growth factor (TGF)-beta and soluble intercellular adhesion molecule-1 (sICAM-1) were evaluated in ten patients with definite multiple sclerosis (MS) of the relapsing-remitting type. CSF TGF-beta levels of MS patients in remission were significantly (p < 0.01) higher than of MS patients in active phase, and there was a significant inverse correlation (p < 0.05) between TGF-beta and slCAM-1 levels in the CSF of patients in both remitting and relapsing type. This is consistent with a possible down-regulation of TGF-beta on ICAM-1 expression and suggests a possible synthesis in the central nervous system of TGF-beta.
Adult↗
Efficacy of a short-term amphotericin B + flucytosine combination therapy followed by itraconazole monotherapy in acute and chronic AIDS-associated cryptococcosis.
The authors report the clinical and microbiological findings of a 6-month follow-up of nine AIDS patients affected with cryptococcosis. Among these, seven patients suffered from meningoencephalitis and two from disseminated infection. The antifungal therapy during acute illness included the administration of amphotericin B at doses of 0.6 mg kg-1 day-1 i.v. plus flucytosine at doses of 100 mg kg-1 day-1 i.v. during the first 15 days followed by itraconazole at doses of 400 mg day-1 p.o. in the following 15 days. The maintenance treatment included itraconazole at doses of 200 mg day-1 p.o. indefinitely. During the 6-month follow-up, one patient died of hepatic failure related to C virus (HCV) hepatitis reactivation and another patient died of polymicrobial pneumonia. In two patients, the presence of multiple nodular lesions in the cerebral computerized tomography (CT) scan, related to cryptococcal granulomas, was associated with the persistance of fungi in the cerebrospinal fluid. In three patients with meningoencephalitis the three-drugs regimen was effective in eradicating the neurological infection, and relapses were not observed during the maintenance therapy with itraconazole during the 6-month follow-up. The two patients with haematogenous cryptococcosis did not relapse after the 6-month follow-up.
AIDS-Related Opportunistic Infections↗
Normative and pathological obsessive-compulsive behavior and ideation in childhood: a question of timing.
This study was designed to test whether obsessive-compulsive behavior declines over development. A cross-sectional design was used on a large community sample of children. Children in grades four, six, and eight (N = 1083), 8 to 14 years of age, were administered the Maudsley Obsessive Compulsive Inventory (MOCI) and the Spielberger State Trait Anxiety Scales. Whereas the mean MOCI score was significantly lower in the eighth grade than in the sixth and fourth, there was an elevation of children with very high MOCI scores in the eighth grade. Obsessive ideas and compulsive behaviors that were common for fourth-grade children were present in only a minority of children in the eighth grade, and were associated with high levels of anxiety. No gender differences were observed for overall obsessive-compulsive behavior, but checking behavior was higher in boys, and cleaning behavior in girls. State anxiety was higher in girls than in boys, and was also higher in older than in younger children.
Age Factors↗
Phase I trial of docetaxel and cisplatin in previously untreated patients with advanced non-small-cell lung cancer.
PURPOSE: To determine the maximum-tolerated doses (MTDs), principal toxicities, and pharmacokinetics of the combination of docetaxel and cisplatin administered every 3 weeks to patients with advanced non-small-cell lung cancer (NSCLC) who have not received prior chemotherapy and to recommend a dose for phase II studies. PATIENTS AND METHODS: Patients with advanced NSCLC and performance status 0 to 2 who had not received prior chemotherapy received docetaxel over 1 hour followed by cisplatin over 1 hour with hydration. Dose levels studied were (docetaxel/cisplatin) 50/75, 75/75, 75/100, and 100/75 mg/m2 repeated every 3 weeks. Colony-stimulating factor (CSF) support was not used. Pharmacokinetics of docetaxel and cisplatin were studied in the first cycle of therapy. Most patients (79%) had metastatic disease or intrathoracic recurrence after prior radiation and/or surgery. RESULTS: Of 24 patients entered, all were assessable for toxicity and 18 for response. The MTD schedules were docetaxel 75 mg/m2 with cisplatin 100 mg/m2 (dose-limiting toxicities [DLTs] in five of six patients), and docetaxel 100 mg/m2 with cisplatin 75 mg/m2 (DLTs in two of two patients, including one fatal toxicity). Limiting toxicities were febrile neutropenia and nonhematologic, principally diarrhea and renal. Two patients had neutropenic enterocolitis. Pharmacokinetics of both drugs were consistent with results from single-agent studies, which suggests no major pharmacokinetic interaction. Neutropenia was related to docetaxel area under the plasma concentration-versus-time curve (AUC). An alternative schedule was investigated, with cisplatin being administered over 3 hours commencing 3 hours after docetaxel, but toxicity did not appear to be less. Independently reviewed responses occurred in eight of 18 patients (44%; 95% confidence interval, 22% to 69%), most following 75 mg/m2 of both drugs. CONCLUSION: Docetaxel 75 mg/m2 over 1 hour followed by cisplatin 75 mg/m2 over 1 hour is recommended for phase II studies. The responses seen in this phase I study suggest a high degree of activity of this combination in previously untreated advanced NSCLC.
Adult↗
Phase I and pharmacologic study of docetaxel and cisplatin in patients with advanced solid tumors.
PURPOSE: This phase I study was performed to assess the feasibility of the combination of docetaxel and cisplatin and to determine the maximum-tolerated dose (MTD) and the side effects with an emphasis on sequence-dependent side effects. MATERIALS AND METHODS: Patients who were not pretreated with taxanes or cisplatin derivatives and who had received no more than one prior combination chemotherapy regimen or two single-agent regimens were entered. Treatment consisted of docetaxel given as a 1-hour infusion followed by cisplatin as a 3-hour infusion (schedule A), or cisplatin followed by docetaxel (schedule B). Docetaxel doses ranged from 55 to 100 mg/m2 and cisplatin doses from 50 to 100 mg/m2. RESULTS: Leukocytopenia and granulocytopenia were common (overall, 90%; grade 3 or 4, 87%), short-lasting, and docetaxel dose-dependent. Infections and neutropenic fever occurred in 10% and 4.5% of courses, respectively. Nonhematologic toxicities were mild to moderate and included alopecia, nausea, vomiting, diarrhea, mucositis, neurotoxicity, fluid retention, and skin and nail toxicity. There were no significant differences in pharmacokinetic parameters between schedules A and B. Tumor responses included one complete response (CR) and nine partial responses (PRs). CONCLUSION: The dose levels docetaxel 100 mg/m2 plus cisplatin 75 mg/m2 and docetaxel 85 mg/m2 plus cisplatin 100 mg/m2 appeared to be manageable. At these dose levels, the median relative dose-intensity was high and 81% and 88% of all cycles, respectively, could be given at full dose. Schedule A is advocated for further treatment.
Adult↗
Hyperamylasemia due to macroamylasemia in adult gluten enteropathy.
We report hyperamylasemia due to macroamylasemia in a 33-year-old-woman with gluten enteropathy. Macroamylasemia was demonstrated by precipitation of 97% of amylase activity with PEG 6000. It was associated with increased serum IgA, with elevated values of specific IgA antibodies against alpha-gliadin and with a high titre of IgA anti-endomysium antibodies. Macroamylasemia disappeared after 2 months of a strict gluten-free diet. These data suggest that the increased IgA concentration in adult gluten enteropathy led to increased macroamylase formation.
Adult↗
CAPD in southern Brazil: an epidemiological study.
There are many studies on the performance of continuous ambulatory peritoneal dialysis (CAPD) in developed countries, but studies in the third world are scarce. The aim of this study is to analyze CAPD experience in the southernmost state of Brazil (Rio Grande do Sul, RS). Records were obtained from the Health Secretary of RS to assemble a cohort of all patients treated with CAPD. Another cohort study followed all patients initiating treatment for uremia in 1993 in the state capital, Porto Alegre, and compared CAPD, hemodialysis, and transplanted patients. In RS, 1316 patients (50.4% male, mean age 45.9 years) were treated in 40 CAPD programs. Despite the initial growth of the CAPD population, it subsequently leveled off. Survival was 78.6% and 40.7% in years 1 and 5, being worse for initial patients of each program, infants, and elders. Technique survival was 57.4% and 10.1% at years 1 and 5. Patients interrupting treatment for any reason had a higher chance of dropout. In Porto Alegre, 294 patients started dialysis during 1993; 21 performed CAPD, 44 had a transplant, and the others were hemodialyzed. Children were treated mostly by CAPD. CAPD patients had less diabetes and ischemic heart disease and received more transplants. Their adjusted actuarial survival (100% year 1; 67% year 3) was no different than hemodialysis. CAPD is not a popular form of renal therapy in RS, and dropout rates are significant.
Adolescent↗
Optimal sampling strategies for bayesian estimation of docetaxel (Taxotere) clearance.
Docetaxel activity has been documented in many solid tumors, including metastatic breast cancer and non-small cell lung cancer. However, as clinical studies in other tumor types are now being conducted, the validation of an optimal sampling strategy would allow the performance of pharmacokinetics/pharmacodynamics studies with minimum inconvenience for the patient. Six optimal sampling strategies with one to six sampling times were computed, based on the D-optimality theory, using population pharmacokinetic parameters estimated from a large pharmacokinetic database of 547 patients treated in previous Phase II studies. Validation of these sampling strategies was performed on a set of 35 patients, from two Phase I studies, who received docetaxel as a 1-h infusion at doses ranging from 50 to 100 mg/m2. Validation consisted of comparing clearance assessed by maximum likelihood estimation obtained using complete plasma concentration-time data (considered as the reference) and clearance determined by Bayesian estimation with an optimal design. For all of the optimal sampling strategies tested, clearance was found to be well estimated when at least two samples were taken. Bayesian estimation with two measured levels (at the end of infusion and at 6 h after the start of infusion) can be selected, because it allows adequate estimation of clearance with a nonsignificant bias of +1.37% and a precision of 12.3%.
Antineoplastic Agents, Phytogenic↗
Affinity purification and characterization of protein gene product 9.5 (PGP9.5) from retina.
Protein gene product 9.5 (PGP9.5) is a cytosolic protein that is highly expressed in vertebrate neurons, which is now included in the ubiquitin C-terminal hydrolase subclass (UCH) on the basis of primary-structure homology and hydrolytic activity on the synthetic substrate ubiquitin ethyl ester (UbOEt). Some UCHs show affinity for immobilized ubiquitin, a property exploited to purify them. In this study we show that this property can also be applied to PGP9.5, since a protein has been purified to homogeneity from bovine retina by affinity chromatography on a ubiquitin-Sepharose column that can be identified with: (a) PGP9.5 with respect to molecular mass, primary structure and immunological reactivity; (b) the known UCHs with respect to some catalytic properties, such as hydrolytic activity on UbOEt, (which also characterizes PGP9.5), Km value and reactivity with cysteine and histidine-specific reagents. However, it differs with respect to other properties, e.g. inhibition by UbOEt and a wider pH range of activity.
Amino Acid Sequence↗