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Biomedical subjects

J Laurin

Publications and source records attributed to J Laurin.

At least 19 recordsLinked to original sources
PubMed2006

A Phase II study targeting amyloid-beta with 3APS in mild-to-moderate Alzheimer disease.

BACKGROUND: As a potential disease-modifying treatment for Alzheimer disease (AD), 3-amino-1-propanesulfonic acid (3APS) is a compound that binds to amyloid beta (Abeta), a toxic protein known to aggregate, leading to amyloid plaque deposition in the brain. METHODS: We assessed the safety, tolerability, and pharmacokinetic/pharmacodynamic effect of 3APS in a randomized, double-blind, placebo-controlled Phase II study in which 58 subjects with mild-to-moderate AD were randomly assigned to receive placebo or 3APS 50, 100, or 150 mg BID for 3 months. At the end of the double-blind phase, 42 of these subjects entered an open-label phase in which they received 3APS 150 mg BID for 17 months. Assessments included plasma and CSF 3APS concentrations, CSF levels of Abeta (Abeta(40) and Abeta(42)), and total tau, as well as cognitive (Alzheimer's Disease Assessment Scale-cognitive subscale, Mini-Mental State Examination) and clinical (Clinical Dementia Rating scale-Sum of Boxes) measures. RESULTS: 3APS had no significant impact on vital signs or laboratory test values. The most frequent side effects were nausea, vomiting, and diarrhea, which were intermittent and mild to moderate in severity. Seven 3APS-treated subjects discontinued because of side effects (all causalities) over the course of the study, and there were no 3APS-related serious adverse events. 3APS crossed the blood-brain barrier, and dose-dependently reduced CSF Abeta(42) levels after 3 months of treatment. There were no psychometric score differences between groups over the 3-month double-blind period. CONCLUSION: Long-term administration of 3-amino-1-propanesulfonic acid is safe, tolerated and reduces CSF Abeta(42) levels in patients with mild-to-moderate Alzheimer disease.

Aged↗
PubMed2002

A prospective study of the incidence and open-label treatment of interferon-induced major depressive disorder in patients with hepatitis C.

Interferon (IFN) therapy has been associated with the development of Major Depressive Disorder (MDD) when given to patients with hepatitis C (HCV). The incidence, time course, risk factors, and treatment of IFN-induced MDD are poorly understood. The objectives of the present study were to determine the incidence of IFN-induced MDD, as well as to determine the efficacy of open-label antidepressant treatment, in particular selective serotonin reuptake inhibitors (SSRIs) for IFN-induced MDD. Thirty-nine HCV patients on IFN therapy were monitored weekly using the Beck Depression Inventory (BDI). Those who became depressed were treated with citalopram, a SSRI antidepressant. Main outcome measures included the incidence of IFN-induced MDD, as well as response rates to antidepressants in those patients who developed IFN-induced MDD. Our results showed that 13 of 39 patients (33%) developed IFN-induced MDD. There were no differences in age, gender, past history of MDD, or substance use between those who became depressed and those who did not. However, there were significantly fewer African American patients in the depressed group. Patients who developed IFN-induced MDD were on IFN therapy for an average of 12.1 weeks prior to the development of MDD. Eleven of 13 patients (85%) were responsive to antidepressant treatment. We conclude that IFN-induced MDD is common in HCV patients. Health care providers should follow IFN-treated HCV patients for the development of MDD, particularly between the 2nd and 5th months of IFN therapy. SSRIs, in particular citalopram, are an effective treatment for IFN-induced depression in HCV patients.

Adult↗
PubMed2002

Stereoselective in vitro degradation pattern of mivacurium in human plasma.

BACKGROUND: Mivacurium is a mixture of three isomers, two of which are rapidly broken down in vivo by plasma cholinesterases. This study investigates the stereospecificity of mivacurium in vitro degradation to determine if it accounts for its in vivo behaviour. METHODS: The in vitro rate of degradation of each isomer of mivacurium and the in vitro rate of formation of their primary (monoesters and alcohols) and secondary (alcohols) metabolites were examined using human plasma from six healthy volunteers. The in vitro rate of degradation of the monoester metabolites was also assessed. All these determinations were made using a stereospecific high-performance liquid chromatography assay. RESULTS: The in vitro rate of disappearance of the two active isomers of mivacurium was very rapid, with mean values for the trans trans and cis trans isomers of 0.803 and 0.921 min(-1) respectively. These values are twofold faster than published in vivo data. The in vitro rate of disappearance was much slower for the cis cis isomer, with a mean value of 0.0106 min(-1). The cis trans isomer was converted exclusively to cis monoester and trans alcohol, while only metabolites in the trans and cis configuration were found for the trans trans and cis cis isomers respectively. Mean in vitro rates of disappearance for the trans and cis monoester were 0.00750 and 0.000633 min(-1) respectively. CONCLUSIONS: The in vitro rates of hydrolysis of the active isomers of mivacurium confirm that plasma cholinesterases play a major role in their in vivo degradation, but that in vivo elimination is slowed by extravascular distribution. Mivacurium hydrolysis is stereoselective, the ester group in the trans configuration being more accessible to enzymatic attack. This stereoselective pattern, along with the relatively slow breakdown of the cis cis isomer, sheds light on the in vivo disposition of the cis alcohol metabolite.

Adult↗
PubMed2001

Peripheral link model as an alternative for pharmacokinetic-pharmacodynamic modeling of drugs having a very short elimination half-life.

Attempts to obtain estimates of pharmacokinetic-pharmacodynamic (PK-PD) parameters for mivacurium with traditional central link models were unsuccessful in many patients. We hypothesized that a link model with the peripheral compartment would be more appropriate for mivacurium in view of its extremely rapid plasma clearance and its potential elimination by tissue pseudocholinesterases. For validation purposes, the peripheral link model was applied to other neuromuscular blocking agents (NMBA), i.e., atracurium and doxacurium which have respectively an intermediate and a long elimination half-life. Assuming peripheral elimination in PK-PD modeling was investigated but found to have no impact on the estimation of PK-PD parameters. Our results indicate that, for drugs having intermediate and long elimination half-lives, EC50 values are similar with either the central or peripheral link model. For mivacurium, a peripheral link model enables PK-PD modeling in all subjects, with more precision in the PK-PD parameter estimates and a better fitting of the effect data when compared to the central link model. For these reasons, a peripheral link model should be preferred for mivacurium.

Adolescent↗
PubMed2001

Glycosaminoglycan mimetics: a therapeutic approach to cerebral amyloid angiopathy.

Amyloid deposits characteristic of cerebral amyloid angiopathy lead to vessel rupture and intracerebral hemorrhage. Proteoglycans associate with the amyloid fibril deposits and are thought to play a role in the polymerization of amyloid proteins and the propagation of the deposition process. A series of low molecular weight anionic compounds was developed to mimic the glycosaminoglycan moieties of these proteoglycans. These compounds were tested in different in vitro systems to determine their anti-Abeta amyloid activity. Specific compounds were identified as being anti-fibrillogenic and protective against Abeta-induced cvtotoxicity. Such compounds also did not show intrinsic cellular toxicity could cross the blood-brain barrier (BBB) in vivo, and showed a good safety profile following chronic' exposure. Molecules showing an anti-amyloid profile combined with the ability to cross the BBB represent promising therapeutics for CAA.

Amyloid beta-Peptides↗
PubMed2000

Unsedated esophagoscopy for the diagnosis of esophageal varices in patients with cirrhosis.

BACKGROUND AND STUDY AIMS: Unsedated endoscopy with ultrathin endoscopes has been shown to be an alternative to conventional endoscopy. This technique would appear to be an ideal way to screen for varices, but there is scant data for unsedated endoscopy in patients with cirrhosis. The aims of this pilot study were to evaluate whether unsedated endoscopy can be used to screen for varices and to determine how well it is tolerated in patients with hepatic dysfunction. PATIENTS AND METHODS: We prospectively evaluated unsedated esophagoscopy in 15 patients with cirrhosis who were candidates for beta-adrenergic-antagonist therapy. Patients with cirrhosis without gastrointestinal bleeding or contraindications to beta-adrenergic-antagonist therapy gave consent to the procedure. The presence and size of varices and the procedure time were recorded. After the procedure, patient tolerance, as gauged by questionnaire and willingness to repeat, was assessed. RESULTS: All patients tolerated the procedure without significant discomfort. The mean time of the procedure was 2 minutes. Esophageal varices were found in nine of 15 patients. Of these, one patient with Child-Pugh class C cirrhosis had large varices and was started on propranolol. CONCLUSIONS: Unsedated esophagoscopy in patients with cirrhosis appears to be well tolerated. Given both potential safety and cost benefits over conventional endoscopy, this could be a useful method for screening for varices. A randomized trial comparing this method with standard endoscopy is warranted.

Procedural Sedation↗
PubMed2000

Abnormal fetal aortic velocity waveform and postnatal growth.

Postnatal growth from birth up to 7 y of age was evaluated in 151 children with varying degrees of intrauterine growth retardation who were previously examined in their intrauterine life with Doppler velocimetry of the thoracic descending aorta. The children with abnormal fetal aortic blood flow class (BFC), of which 39/46 (85%) had a birthweight > or = 2 SD below the mean of the population, were lean at birth and had a high rate of catch-up growth in weight and length during the first 3 and 6 mo, respectively. After the initial phases of rapid catch-up in weight and length, mean values of SD scores for weight and height remained relatively unchanged up until 2 y of age, thereafter increasing gradually up to 7 y of age, leaving 4/46 (8%) and 4/46 (8%) below -2 SD for weight and height, respectively. The pattern of changes in length/height and weight over time did not differ between those infants with abnormal BFC and those with normal BFC. The abnormal fetal aortic waveform was not related to rate of early catch-up growth or to height or weight at 7 y of age after adjustment for deviation in growth at birth. The magnitude of deficit in weight and length at birth was more predictive of subsequent growth.

Age Factors↗
PubMed1999

Assuming peripheral elimination: its impact on the estimation of pharmacokinetic parameters of muscle relaxants.

For anesthetic drugs undergoing nonorgan-based elimination, there is a definite trend towards using pharmacokinetic (PK) models in which elimination can occur from both central (k10) and peripheral compartments (k20). As the latter cannot be assessed directly, assumptions have to be made regarding its value. The primary purpose of this paper is to evaluate the impact of assuming various degrees of peripheral elimination on the estimation of PK parameters. For doing so, an explanatory model is presented where previously published data from our laboratory on three muscle relaxants, i.e., atracurium, doxacurium, and mivacurium, are used for simulations. The mathematical aspects for this explanatory model as well as for two specific applications are detailed. Our simulations show that muscle relaxants having a short elimination half-life are more affected by the presence of peripheral elimination as their distribution phase occupies the major proportion of their total area under the curve. Changes in the exit site dependent PK parameters (Vdss) are also mostly significant when k20 is smaller than k10. Although the physiological processes that determine drug distribution and those affecting peripheral elimination are independent, the two are mathematically tied together in the two-compartment model with both central and peripheral elimination. It follows that, as greater importance is given to k20, the rate of transfer from the central compartment (k12) increases. However, as a result of a proportional increase in the volume of the peripheral compartment, peripheral concentrations remain unchanged whether or not peripheral elimination is assumed. These findings point out the limitations of compartmental analysis when peripheral elimination cannot be measured directly.

Adolescent↗
PubMed1998

Successful use of chronic epoprostenol as a bridge to liver transplantation in severe portopulmonary hypertension.

BACKGROUND: Portopulmonary hypertension, defined as mean pulmonary artery pressure >25 mmHg in the presence of a normal pulmonary capillary wedge pressure and portal hypertension, is a known complication of end-stage liver disease that has been associated with high morbidity and mortality at the time of liver transplantation. We have recently reported the successful treatment of portopulmonary hypertension with chronic intravenous epoprostenol and now report the first patient with severe portopulmonary hypertension successfully treated with epoprostenol who subsequently underwent successful liver transplantation. METHODS: A patient with severe portopulmonary hypertension was treated with intravenous epoprostenol, 23 ng/kg/min, for a 4-month period, after which the portopulmonary hypertension resolved and the patient underwent successful liver transplantation. RESULTS: The patient was discharged, continues to do well, and at 3 months is off epoprostenol with near normal pulmonary artery pressures. CONCLUSIONS: Chronic epoprostenol, in conjunction with a multidisciplinary, well-planned perioperative evaluation and treatment plan, may be the answer to a heretofore untreatable disease.

Antihypertensive Agents↗
PubMed1998

Primary hepatic low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) associated with primary biliary cirrhosis.

We describe a case of low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) arising in the liver of a patient with early-stage primary biliary cirrhosis (PBC). The patient, a 62-year old woman, presented with abnormal liver function tests, a positive antimitochondrial antibody titer (1:160), and a liver mass. The resected mass, 6.0 x 5.0 x 4.0 cm, had the features of MALT-type lymphoma. The neoplastic cells were small lymphoid cells of B-cell lineage that surrounded reactive lymphoid follicles and infiltrated bile ductules to form lymphoepithelial lesions. The uninvolved liver had histologic evidence of early stage PBC, characterized by segmental duct destruction with granulomata and an inflammatory infiltrate in the portal triads composed of lymphocytes, plasma cells, and occasional eosinophils. A periportal lymph node showed histologic features of the hyaline-vascular type of Castleman's disease, without evidence of malignant lymphoma. Low-grade B-cell lymphomas of the MALT type rarely arise in the liver and, to our knowledge, have not been reported previously in association with PBC. The association in this case suggests that chronic antigenic stimulation as a result of PBC induced the accumulation of acquired MALT, which subsequently transformed to low-grade B-cell lymphoma.

Female↗
PubMed1996

Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study.

Non-alcohol-induced steatohepatitis (NASH) is characterized by elevated serum aminotransferase activities with hepatic steatosis, inflammation, and occasionally fibrosis that may progress to cirrhosis. No established treatment exists for this potentially serious disorder. Our aim was to conduct a pilot study to evaluate the safety and estimate the efficacy of ursodeoxycholic acid (UDCA) and clofibrate in the treatment of NASH. Forty patients were diagnosed with NASH based on a compatible liver biopsy with other causes of liver disease, including alcohol abuse, excluded by history, serum tests, and use of ultrasound. Twenty-four patients received 13 to 15 mg/kg/d of UDCA for 12 months. Sixteen patients with hypertriglyceridemia were placed on clofibrate, 2 g/day for 12 months. Twenty-five women and 15 men entered the study. Six of 40 patients (15%) withdrew because of side effects. Four additional patients were withdrawn because of noncompliance; one of them later required liver transplantation. In the UDCA group, the decreases in mean serum levels of alkaline phosphatase, alanine transaminase (ALT), and gamma-glutamyl transpeptidase (GGT) as well as histological grade of steatosis were significant. Among the patients treated with clofibrate, no change from baseline was found in mean ALT, aspartate transaminase (AST), GGT, bilirubin, triglycerides, and cholesterol, or in histological grade of steatosis, inflammation, or fibrosis after 12 months of treatment as compared with entry. Alkaline phosphatase activities decreased significantly from baseline. Despite the known lipid-lowering effects of clofibrate, it did not appear to be of clinical benefit in the treatment of NASH in this 1-year pilot study. However, treatment of NASH with UDCA for 12 months resulted in significant improvement in alkaline phosphatase, ALT, GGT, and hepatic steatosis. The possible benefit of UDCA therapy should be further investigated in the context of a randomized, controlled trial.

Alanine Transaminase↗
PubMed1996

Is the role of transjugular intrahepatic portosystemic shunts limited in the management of patients with end-stage liver disease?

BACKGROUND: Transjugular intrahepatic portosystemic shunts (TIPS) are an established method for the treatment of the complications of portal hypertension. Recent reports have suggested that TIPS require frequent follow-up and may interfere with orthotopic liver transplantation (OLT). METHODS: Retrospective chart review was performed of ultrasound studies, angiographic studies, and complications of the first 100 patients treated consecutively with TIPS from February 1992 through October 1995. RESULTS: Ninety-seven patients had functional TIPS. Thirty-one percent of patients treated emergently survived, significantly less than the 96% survival of elective patients. Fifty percent of the shunts were found to require angioplasty by 5 months. Seventeen patients treated with OLT did well, without intraoperative bleeding problems, and are alive. CONCLUSIONS: The TIPS method treats successfully the complications of portal hypertension but requires careful follow-up. The technique may be used prior to OLT. For non-OLT candidates, the cost effectiveness of TIPS versus surgical shunting remains in question.

Adolescent↗
PubMed1996

Abnormal fetal aortic velocity waveform and minor neurological dysfunction at 7 years of age.

Measurements of fetal aortic blood flow velocity and fetal growth were performed in 178 pregnancies. In 87 cases, the estimated fetal weight was > or = 2 SD below the gestational age-related mean of the population. Three fetuses died in utero. In 149 children (85%), a neurological examination was performed at 7 years of age with special emphasis on minor neurological dysfunction. The frequency of the more severe form of minor neurological dysfunction, MND-2, was higher in the group with blood flow class (BFC) III (absent or reversed end-diastolic flow velocity (8/21) than in the group with BFC 0 (normal velocity waveform) (14/105). Logistic regression analysis revealed that abnormal blood flow class, both independently and in combination with other factors, was the most significant predictor of MND-2. The association found between abnormal fetal aortic velocity waveforms and adverse outcome in terms of minor neurological dysfunction suggests that hemodynamic evaluation of the fetus has a predictive value regarding postnatal neurological development.

Analysis of Variance↗
PubMed1996

Abnormal fetal aortic velocity waveform and intellectual function at 7 years of age.

Measurements of fetal aortic blood flow velocity and fetal growth were performed in 178 pregnancies. In 87 cases, the estimated fetal weight was > 2 SD below the gestational age-related mean of the population. Three fetuses died in utero. In 148 children (84%) an assessment of overall intellectual ability was performed at 6.5 years of age. Verbal and global IQ was lower in the group with an abnormal fetal aortic blood flow velocity waveform (mean +/- SD 96.0 +/- 17.7 and 95.9 +/- 15.7, respectively; n = 41) compared to the group with a normal waveform (102.1 +/- 12.2 and 102.9 +/- 13.2, respectively; n = 105; p < 0.05). Logistic regression analysis revealed that abnormal fetal aortic velocity waveform, both independently and in combination with other factors, was a significant predictor of impaired intellectual outcome. The association found between abnormal fetal aortic velocity waveform and impaired intellectual outcome suggests that hemodynamic evaluation of the fetus has a predictive value regarding postnatal intellectual development.

Analysis of Variance↗
PubMed1995

Liver transplantation in a patient with sickle cell anemia.

Orthotopic liver transplantation in a patient with sickle cell disease presents many new challenges to the transplant team. We describe the case of a 47-year-old patient with sickle cell disease and hepatitis C virus-induced cirrhosis who required liver transplantation.

Anemia, Sickle Cell↗
PubMed1994

Placental histology and fetal blood flow in intrauterine growth retardation.

OBJECTIVE: To define the histological lesions in the placenta associated with abnormal blood flow findings and to evaluate their possible clinical significance. DESIGN: A prospective blind study. SETTING: A clinical study at a teaching hospital, Malmö General Hospital, University of Lund, Sweden, morphological studies of placentas being performed at the Institute of Pathology, University of Lausanne, Switzerland. MATERIAL: Thirty-seven pregnancies where intrauterine growth retardation (IUGR) was suspected. METHODS: Blood velocimetry of the fetal descending aorta, umbilical artery and vein, and the maternal arcuate artery, using 2.5 MHz pulsed wave Doppler ultrasound. Histological examination of at least five random samples from each placenta. MAIN OUTCOME MEASURES: Frequency of small-for-gestational age (SGA) newborns (birth weight < or = mean -2 s.d.) and of operative delivery for fatal distress. RESULTS: Only the presence of placental infarction was significantly associated with IUGR and with intrauterine findings of abnormal blood velocity in the fetal descending aorta and umbilical artery. CONCLUSION: Placental infarction would seem to be a valuable morphological marker of uteroplacental vascular disease related to IUGR and impaired fetal and umbilical blood flow.

Adolescent↗
PubMed1993

p53 point mutations in dysplastic and cancerous ulcerative colitis lesions.

BACKGROUND: The molecular basis of colorectal dysplasia and carcinoma arising in ulcerative colitis is poorly understood. Loss of heterozygosity involving the tumor suppressor gene p53 occurs frequently in neoplastic ulcerative colitis lesions. Point mutation affecting p53 is associated with loss of heterozygosity in other cancers. Therefore, it was determined whether p53 point mutation occurs in ulcerative colitis-associated neoplasia. METHODS: Single-strand conformation polymorphism analysis, DNA sequencing, and loss of heterozygosity studies were performed on 45 patients with ulcerative colitis-associated dysplasia and carcinoma. RESULTS: Point mutations were detected in 26 lesions from 20 patients, including 18 carcinomas, 6 dysplasia-associated masses, 1 flat dysplasia, and 1 lymph node metastasis. In two cases, identical p53 mutations were observed in both carcinoma and adjacent dysplasia. Missense mutations causing amino acid substitutions as well as nonsense mutations resulting in premature stop codons were seen. Tandem mutations, in which more than 1 sequence alteration occurred on the same allele of p53, were also detected. Point mutation was accompanied by loss of the other p53 allele in 8 of 10 patients informative for both loss of heterozygosity and mutation assays. CONCLUSIONS: These findings suggest that inactivation of p53 by mutation and loss of heterozygosity is a common mechanism of malignant transformation in ulcerative colitis. They also imply that in contrast to sporadic colorectal carcinoma, ulcerative colitis-associated neoplastic progression may involve p53 inactivation at relatively early, noninvasive stages.

Chromosome Deletion↗