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Biomedical subjects

A Pujol

Publications and source records attributed to A Pujol.

At least 19 recordsLinked to original sources
PubMed1999

A pharmacokinetic model for alpha interferon administered subcutaneously.

AIMS: To model the pharmacokinetic profiles of alpha interferon (alphaIFN) after a single subcutaneous (s.c.) injection of 3 million units of alpha 2b interferon, to correlate the pharmacokinetic parameters with patient demographic covariates, and to develop a limiting sampling strategy for determining the alphaIFN plasma area under the curve of concentration vs time (AUC). METHODS: The plasma alphaIFN pharmacokinetics were determined in 27 patients with chronic hepatitis C virus infection after the first s.c. injection of the drug. Ten patients had normal renal function and 17 were chronic haemodialysis patients. Plasma samples were assayed by an Elisa method. Concentration-time data was analysed by a population approach using NONMEM. RESULTS: The pharmacokinetic model which better described the concentration vs time data was a one-compartment model with two processes of absorption: a zero-order followed by a first-order process. The mean clearance of dialysis patients represented 37% (with 95% confidence interval: 30% -44%) of the mean value of the patients with normal renal function. The volume of distribution was significantly correlated to the body surface area. Bayesian analysis using NONMEM allowed determination of the individual plasma AUC from three samples within the 24 h period post s.c. injection. CONCLUSIONS: The present pharmacokinetic model will allow one to obtain individual parameters such as, the area under the curve of concentration vs time from a limited-sampling strategy, and to perform pharmacokinetic-pharmacodynamic analysis of combined alphaIFN plasma concentrations and viraemic data.

Adult↗
PubMed1999

Activation of promoter P4 of the autonomous parvovirus minute virus of mice at early S phase is required for productive infection.

Autonomous parvoviruses are tightly dependent on host cell factors for various steps of their life cycle. In particular, DNA replication and gene expression of the prototype strain of the minute virus of mice (MVMp) are closely linked to the onset of host cell DNA replication, pointing to the involvement of an S-phase-specific cellular factor(s) in parvovirus multiplication. The viral nonstructural protein NS-1 is absolutely required for parvovirus DNA replication and is able to transcriptionally regulate parvoviral and heterologous promoters. We previously showed that the promoter P4, which directs the transcription unit encoding the NS proteins, is activated at the onset of S phase. This activation is dependent on an E2F motif in the proximal region of promoter P4. An infectious MVM DNA clone was mutated in the E2F motif of P4. The wild type and the E2F mutant derivative were tested for their ability to produce progeny viruses after transfection of permissive cells. In the context of the whole MVMp genome, the E2F mutation abolished P4 induction in S phase and inactivated the infectious molecular clone, which failed to become amplified and generate progeny particles. The virus could be rescued when NS proteins were supplied in trans, showing that P4 hyperactivity in S is needed to reach a level of NS-1 expression that is sufficient to drive the viral replication cycle. These data show that E2F-mediated P4 activation at the early S phase is a limiting factor for parvovirus production. The primary barrier to parvovirus gene expression in G1 is thought to be promoter formation rather than activation, due to the poor conversion of the parental single-strand genome to a duplex form. The S dependence of P4 activation may therefore be a sign of the virus adaptation to life in the S-phase host cell. If the conversion block in G1 were to be leaky, the S induction of promoter P4 could be envisioned as a safeguard against the production of toxic NS proteins until cells reach the S phase and provide the full machinery for parvovirus replication.

Animals↗
PubMed1998

Evidence from transgenic mice that interferon-beta may be involved in the onset of diabetes mellitus.

A number of cytokines have been shown to alter the function of pancreatic beta-cells and thus might be involved in the development of type 1 diabetes. Interferon-beta (IFN-beta) expression is induced in epithelial cells by several viruses, and it has been detected in islets of type 1 diabetic patients. Here we show that treatment of isolated mouse islets with this cytokine was able to alter insulin secretion in vitro. To study whether IFN-beta alters beta-cell function in vivo and leads to diabetes, we have developed transgenic mice (C57BL6/SJL) expressing IFN-beta in beta-cells. These mice showed functional alterations in islets and impaired glucose-stimulated insulin secretion. Transgenic animals presented mild hyperglycemia, hypoinsulinemia, hypertriglyceridemia, and altered glucose tolerance test, all features of a prediabetic state. However, they developed overt diabetes, with lymphocytic infiltration of the islets, when treated with low doses of streptozotocin, which did not induce diabetes in control mice. In addition, about 9% of the transgenic mice obtained from the N3 back-cross to outbred albino CD-1 mice spontaneously developed severe hyperglycemia and hypoinsulinemia and showed mononuclear infiltration of the islets. These results suggest that IFN-beta may be involved in the onset of type 1 diabetes when combined with either an additional factor or a susceptible genetic background.

Animals↗
PubMed1998

Population pharmacokinetics of total and unbound etoposide.

A population pharmacokinetics study using the NONMEM program was undertaken to determine the effects of different covariates on the pharmacokinetic parameters of etoposide. A total of 1,044 plasma etoposide concentrations were determined by high-performance liquid chromatography (HPLC) in 100 patients (pts; 75 men and 25 women aged 25-85 years) treated for various tumor types with i.v. (57 pts) or oral (43 pts) etoposide. For 67 pts, etoposide plasma protein binding was determined by equilibrium dialysis; the unbound fraction ranged from 4% to 24%. A linear two-compartment model with first-order absorption (for oral dosing) accurately described the concentration versus time data. The central and peripheral volumes of distribution were significantly correlated with the body surface area [Vc (L) = 5.5 x BSA (m2) and Vp = 4.1 x BSA], but even after BSA had been taken into account, the interindividual variability of the two volumes remained high (34% and 57%, respectively). The clearance (CL) was not correlated with the following covariates: age, BSA, sex, height, and levels of serum bilirubin and liver enzymes. The final regression model for CL was CL (ml/min) = 49.8 x (1 - 0.009 x PRO) x WT/Scr + 33.8 x (1 - 0.29 x META) x (1 - 0.012 x ALB), where ALB, PRO, WT, and Scr, respectively, were albuminemia, proteinemia (g/l), weight (kg), and serum creatinine (microM) and META = 1 if the patient had liver metastases (otherwise, META = 0). The interindividual variability in CL (mean value 30 ml/min) decreased only from 32% to 26% when these covariates were taken into account. The mean oral bioavailability was 66%, showing an interindividual variability of 37%. The plasma clearance of the unbound fraction was strongly and negatively correlated with Scr but was not dependent on either PRO or ALB. These data show that modifications in PRO levels do not directly affect plasma exposure to unbound etoposide. This analysis makes possible the rational consideration of modifications of covariates such as Scr in etoposide dosing. This population data base will constitute the prerequisite for adaptative control with feedback dosing for continuous oral administration of etoposide.

Administration, Oral↗
PubMed1998

Co-variables influencing 5-fluorouracil clearance during continuous venous infusion. A NONMEM analysis.

The objective of this study was to attempt to identify patient co-variables which could influence interpatient variability in 5-fluorouracil (5-FU) clearance during a 5-day continuous venous infusion (CVI, cisplatin 100 mg/m2 day 1 then 5-FU 1 g/m2/day days 2-6). The analysis was performed using a NONMEM program according to a linear one-compartment model. A total of 186 cycles (2 samples per day, 8 a.m. and 5 p.m.) were analysed from 104 patients with various cancers (the majority of head and neck and oesophagus). The study co-variables were age, sex, body surface area, hepatic metastases, peripheral mononuclear cell dihydropyrimidine dehydrogenase activity (PMNC-DPD), liver enzymes, clock-time (8 a.m. versus 5 p.m.), elapsed time during CVI. The data showed that 5-FU clearance was significantly reduced by increased age, low PMNC-DPD, high serum alkaline phosphatase and elapsed time during infusion. These data may be useful for improving knowledge of predictive factors which can influence 5-FU exposure and thus predispose to toxic manifestations.

Adult↗
PubMed1998

Intentional overdose and death with 3,4-methylenedioxyethamphetamine (MDEA; "Eve"): case report.

We report a case of suicide following ingestion of a large dose of 3,4-methylenedioxyethamphetamine (MDEA, "Eve") in a 27-year-old woman with a history of depression. Several days before her death, she had attempted suicide with benzodiazepines resulting in a 24-hour hospital admission; at that time, no physiologic abnormalities were detected. Findings on autopsy were nonspecific. Toxicologic analysis showed a high concentration of MDEA and the appearance of benzodiazepines in body fluids. Ethanol and other drugs of abuse were not found. We discuss the clinical manifestations, toxicologic syndromes, and mechanisms of death with amphetamine intoxication. MDEA intoxication in young people may result in sudden death.

3,4-Methylenedioxyamphetamine↗
PubMed1998

Transgenic mice in the analysis of metabolic regulation.

In normal animals, the extracellular concentration of glucose is maintained within a very narrow range by the matching of glucose flux into and out of the extracellular space through the tightly coordinated secretion of insulin and glucagon. Functional alterations in beta-cells, liver, or skeletal muscle and adipose tissue may disrupt glucose homeostasis and lead to the development of non-insulin-dependent diabetes mellitus (type 2 diabetes). This review outlines the contribution of these organs and tissues to the control of glucose homeostasis. We discuss new insights obtained through studies of transgenic mice that overexpress or show decreased expression of putative key genes in the regulation of pancreatic beta-cell function, in the control of hepatic glucose uptake and output, and in the regulation of glucose uptake and utilization by skeletal muscle and adipose tissue.

Adipose Tissue↗
PubMed1998

[Air in the bone? Diagnosis and treatment of a pneumatocyst of the ilium. Apropos of a case].

We present a case of symptomatic pneumatocyst of the ilium observed in a professional scuba diver exposed to pressure variations. Pneumatocysts are rare and except for one case reported in a clavicular localization, are always found in subchondral bone of the iliac or sacral side of the sacroiliac joint. Undoubtedly, air fills an intraosseous node. We report here the first case of efficient treatment achieved by filling the cyst via percutaneous access under scopic control.

Adult↗
PubMed1997

Sequence and analysis of a 36.2 kb fragment from the right arm of yeast chromosome XV reveals 19 open reading frames including SNF2 (5' end), CPA1, SLY41, a putative transport ATPase, a putative ribosomal protein and an SNF2 homologue.

The complete sequence of a 36 196 bp DNA segment located on the right arm of chromosome XV of Saccharomyces cerevisiae has been determined and analysed. The sequence includes the 5' coding region of the SNF2 gene, the CPA1 leader peptide sequence and 17 open reading frames (ORFs) of at least 100 amino acids. Two of these correspond to previously known genes (CPA1, SLY41), whereas 15 correspond to new genes. The putative translation products of three ORFs show significant similarity with known proteins: one is a putative transport ATPase, another appears to be a ribosomal protein, and the third is an Snf2p homologue.

Adenosine Triphosphatases↗
PubMed1997

Inhibition of parvovirus minute virus of mice replication by a peptide involved in the oligomerization of nonstructural protein NS1.

The large nonstructural protein NS1 of the minute virus of mice and other parvoviruses is involved in essential steps of the viral life cycle, such as DNA replication and transcriptional regulation, and is a major contributor to the toxic effect on host cells. Various biochemical functions, such as ATP binding, ATPase, site-specific DNA binding and nicking, and helicase activities, have been assigned to NS1. Homo-oligomerization is a prerequisite for a number of proteins to be fully functional. In particular, helicases generally act as homo-oligomers. Indirect evidence of NS1 self-association has been recently obtained by a nuclear cotransport assay (J. P. Nüesch and P. Tattersall, Virology 196:637-651, 1993). In order to demonstrate the oligomerizing property of NS1 in a direct way and localize the protein region(s) involved, the yeast two-hybrid system was used in combination with deletion mutagenesis across the whole NS1 molecule, followed by high-resolution mapping of the homo-oligomerization domain by a peptide enzyme-linked immunosorbent assay method. This study led to the identification of a distinct NS1 peptide that contains a bipartite domain involved in NS1 oligomerization. Furthermore, this isolated peptide was found to act as a specific competitive inhibitor and suppress NS1 helicase activity in vitro and parvovirus DNA replication in vivo, arguing for the involvement of NS1 oligomerization in these processes. Our results point to drug targeting of oligomerization motifs of viral regulatory proteins as a potentially useful antiviral strategy.

Amino Acid Sequence↗
PubMed1997

[Normalization of cognitive and functional assessment instruments for dementia (NORMACODEM) (I): objectives, content and population].

UNLABELLED: To adequately evaluate patients with 4 neuropsychological deficits a project for norming cognitive and functional instruments that assess dementia (NORMACODEM) was designed. Four hundred fifty-one subjects in three groups: 254 controls, 86 patients with minor memory/cognitive deficits without dementia (DWD) and 111 patients with probable Alzheimer-type dementia (ATD) according to the NINCDS/ADRDA criteria. Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale (ADAS), Abbreviated Barcelona Test (ABT), Global Dementia Staging (GDS), Functional Assessment Staging (FAST), Clinical Dementia Rating (CDR), Rapid Disability Rating Scale-2 (RDRS-2), Blessed Dementia Rating Scale (BDRS), Interview for Deterioration in Daily life in Dementia (IDDD), Geriatric Evaluation by Relatives Rating Instrument (GERRI), Geriatric Depression Scale (GDS), Zung Self-Rating Anxiety Scale (ZSRAS). Descriptive statistics and analysis of variance. The characteristics of the sample were as follows. CONTROLS: 99 men, 155 women. Mean (SD) age: 64.6 (10.9) years. Mean (SD) educational level: 9.1 (4.9) years. DWD: 42 men, 44 women. Mean (SD) age: 65.8 (8.7) years. Men (SD) educational level: 8.4 (4.4) years. ATD: 48 mean, 63 women. Mean (SD) age: 68.3 (8.0) years. Mean (SD) educational level: 6.2 (4.3) years. The ATD patients were significantly older than the controls. Mean educational level was significantly lower in the ATD group than in the other two.

Adult↗
PubMed1997

[Adaptation and normalization of the Alzheimer's disease Assessment Scale for Spain (NORMACODEM) (II)].

UNLABELLED: This report is part of a project for norming cognitive and functional instruments that assess dementia (NORMACODEM). To adapt and norm the Alzheimer's Disease Assessment Scale (ADAS) for use in Spain. Two hundred fifty-four controls, 86 patients with minor memory/cognitive disorders without dementia (deterioration without dementia, DWD), 111 patients with Alzheimer-type dementia (ATD). Statistical description. Multivariate linear regression. Crossed validation. Internal consistency and test-retest (n = 48). The mean scores (SD) obtained were as follows. CONTROLS: ADAS-Cog = 8.0 (3.4), ADAS-Noncog = 2.9 (2.9), ADAS-Tot = 10.9 (4.6). DWD: ADAS-Cog = 11.37 (5.1), ADAS-Noncog = 4.9 (4.3), ADAS-Tot = 16.2 (7.0). ATD: ADAS-Cog = 31.8 (5.1), ADAS-Noncog = 10.3 (4.3), ADAS-Tot = 42.2 (20.7). Multiple regression analysis revealed that educational level and age were significantly associated with the ADAS-Cog score. The internal consistency of the ADAS-Cog was 0.963. The test-retest procedure yielded linear correlation, coefficients of 0.93 for the ADAS-Cog, 0.86 for the ADAS-Noncog and 0.95 for the ADAS-Tot. Age and educational level/schooling are associated to the earned on the ADAS-Cog instrument. The present Spanish version of the ADAS has high internal consistency and reproducibility. The instruments can be use for assessment in Spanish populations.

Adult↗
PubMed1996

Correction of diabetic alterations by glucokinase.

Hyperglycemia is a common feature of diabetes mellitus. It results from a decrease in glucose utilization by the liver and peripheral tissues and an increase in hepatic glucose production. Glucose phosphorylation by glucokinase is an initial event in glucose metabolism by the liver. However, glucokinase gene expression is very low in diabetic animals. Transgenic mice expressing the P-enolpyruvate carboxykinase/glucokinase chimeric gene were generated to study whether the return of the expression of glucokinase in the liver of diabetic mice might prevent metabolic alterations. In contrast to nontransgenic mice treated with streptozotocin, mice with the transgene previously treated with streptozotocin showed high levels of both glucokinase mRNA and its enzyme activity in the liver, which were associated with an increase in intracellular levels of glucose 6-phosphate and glycogen. The liver of these mice also showed an increase in pyruvate kinase activity and lactate production. Furthermore, normalization of both the expression of genes involved in gluconeogenesis and ketogenesis in the liver and the production of glucose and ketone body by hepatocytes in primary culture were observed in streptozotocin-treated transgenic mice. Thus, glycolysis was induced while gluconeogenesis and ketogenesis were blocked in the liver of diabetic mice expressing glucokinase. This was associated with normalization of blood glucose, ketone bodies, triglycerides, and free fatty acids even in the absence of insulin. These results suggest that the expression of glucokinase during diabetes might be a new approach to the normalization of hyperglycemia.

Animals↗