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At least 1,153 records · Page 64Linked to original sources
PubMed1995

Acid hydrolysis of diazepam. Kinetic study of the reactions of 2-(N-methylamino)-5-chlorobenzophenone, with HCl in MeOH-H2O.

In the acid hydrolysis of diazepam (1), several unusual products, apart from 2-(N-methylamino)-5-chlorobenzophenone (2) and glycine, were isolated. On the assumption that some of those products could arise from further degradation of 2, the reaction of this compound with 0.5-2 M HCl was studied, in 1:1 MeOH-H2O, at 60 and 80 degrees C. Several unexpected products were isolated from the reaction of 2 with HCl, namely, 2-amino-5-chlorobenzophenone (3), 2-(N,N-dimethylamino)-5-chlorobenzophenone (4), 2-(N-methylamino)-3,5-dichlorobenzophenone (5), 2-amino-3,5-dichlorobenzophenone (6), 2,4-dichloro-10-methyl-9,10- acridinone (7), and 2,4-dichloro-9,10-acridinone (8). The methyl transfers, the chlorination, and the cyclization reactions that give rise to products 3-8 are unexpected under the present reaction conditions. The rate of reaction of 2, as well as the rate of formation of compounds 3-6, was measured at several HCl concentrations.

Acids↗
PubMed1999

Acute liver failure associated with prolonged use of bromfenac leading to liver transplantation. The Acute Liver Failure Study Group.

Bromfenac, a nonnarcotic analgesic nonsteroidal anti-inflammatory drug, was associated with reversible, minor elevations in serum aminotransferase levels during clinical trials. The aim of this study is to describe the clinical, laboratory, and histological features of 4 patients with severe bromfenac hepatotoxicity identified at 3 tertiary care centers participating in the US Acute Liver Failure Study Group. Bromfenac was administered for chronic musculoskeletal disorders to 4 women in therapeutic doses of 25 to 100 mg/d for a minimum of 90 days. All patients reported a prodrome of malaise and fatigue and presented with severe, symptomatic hepatocellular injury with associated hypoprothrombinemia. None of the subjects had underlying liver or kidney disease, and there was no evidence of a hypersensitivity reaction. Other identifiable causes of acute liver failure were uniformly excluded. Despite supportive measures, all the subjects developed progressive liver failure over 5 to 37 days, leading to emergency liver transplantation in 3 patients and death in 1 patient while awaiting transplantation. Extensive confluent parenchymal necrosis that appeared to begin in the central zones and was accompanied by a predominantly lymphocytic infiltrate was noted in all the livers examined. Nodular regeneration was seen in the 2 patients with a more protracted clinical course. Administration of therapeutic doses of bromfenac for greater than 90 days was associated with the development of acute liver failure leading to liver transplantation or death in 4 adult women. The poor outcomes observed in this series, coupled with the inability to identify individuals at risk for severe, idiosyncratic bromfenac hepatotoxicity, preclude further use of bromfenac in the medical community.

Adult↗
PubMed2001

Randomized trial of tolcapone versus pergolide as add-on to levodopa therapy in Parkinson's disease patients with motor fluctuations.

In this 12-week, randomized, open-label, blinded-rater, parallel-group trial, the efficacy, safety, and tolerability of tolcapone and pergolide were compared in parkinsonian patients with a fluctuating response to levodopa. Patients received tolcapone 100 mg three times daily (t.i.d.), with a possible increase to 200 mg t.i.d., or pergolide titrated to a maximum dose of 5 mg/day by week 9 (mean final dose 2.2 mg/day). The trial involved 203 patients. Efficacy variables that decreased from baseline to week 12 with tolcapone and pergolide included "off" time (reduced by 2-3 hours/day), daily levodopa intake, sickness impact profile scores, Parkinson's disease questionnaire (PDQ)-39 scores, and Unified Parkinson's Disease Rating Scale (UPDRS) scores. Improvements in efficacy variables were similar with tolcapone and pergolide, with the exception of improvements in quality of life, which were significantly greater with tolcapone; the relative changes in PDQ-39 score at week 12 were -8.7 and -14.2 (P < 0.05) with pergolide and tolcapone, respectively. Improvements in the investigator's global assessment (IGA) of overall efficacy were recorded in 86% of tolcapone-treated patients and in 78% of pergolide-treated patients. The proportion of patients who withdrew because of adverse events was higher in the pergolide group (15%) than in the tolcapone group (5%). Confusion, hypotension, nausea, constipation, abdominal pain, and dyspepsia occurred more frequently with pergolide, whereas diarrhea and urine discoloration occurred more frequently with tolcapone. Tolcapone was better tolerated than pergolide (P < 0.01) according to the IGA of overall tolerability. We conclude that, in this 3-month study, both tolcapone and pergolide provided improvements in motor fluctuations and allowed reductions in levodopa intake when added to levodopa therapy; intent to treat analysis and a less than maximal dose of pergolide may have biased the results in favor of tolcapone. Tolcapone provided greater improvements in quality of fife, was better tolerated, and had a more favorable adverse-event profile than pergolide.

Antiparkinson Agents↗
PubMed2005

Role of COMT inhibitors and dopamine agonists in the treatment of motor fluctuations.

Although levodopa remains the most effective drug for the symptomatic treatment of Parkinson's disease (PD), there are significant limitations to its chronic use. Growing preclinical and clinical evidence suggests that the severity of motor fluctuations is influenced both by PD severity and pulsatile stimulation of striatal dopamine receptors. Current management of motor fluctuations is based primarily on strategies to prolong the effects of dopaminergic stimulation. This prolongation is accomplished either through the use of long-acting dopaminergic drugs or prolonging of the effects of levodopa. During the past decade, the armamentarium of dopamine agonists increased and agents that prolong the plasma half-life of levodopa became available. Furthermore, recent clinical trials provide evidence-based approaches to improve the management of motor fluctuations in patients with advanced and early PD.

Apomorphine↗
PubMed2005

Evidence-based medical review update: pharmacological and surgical treatments of Parkinson's disease: 2001 to 2004.

The objective of this study is to update a previous evidence-based medicine (EBM) review on Parkinson's disease (PD) treatments, adding January 2001 to January 2004 information. The Movement Disorder Society (MDS) Task Force prepared an EBM review of PD treatments covering data up to January 2001. The authors reviewed Level I (randomized clinical trials) reports of pharmacological and surgical interventions for PD, published as full articles in English (January 2001-January 2004). Inclusion criteria and ranking followed the original program and adhered to EBM methodology. For Efficacy Conclusions, treatments were designated Efficacious, Likely Efficacious, Non-Efficacious, or Insufficient Data. Four clinical indications were considered for each intervention: prevention of disease progression; treatment of Parkinsonism, as monotherapy and as adjuncts to levodopa where indicated; prevention of motor complications; treatment of motor complications. Twenty-seven new studies qualified for efficacy review, and others covered new safety issues. Apomorphine, piribedil, unilateral pallidotomy, and subthalamic nucleus stimulation moved upward in efficacy ratings. Rasagiline, was newly rated as Efficacious monotherapy for control of Parkinsonism. New Level I data moved human fetal nigral transplants, as performed to date, from Insufficient Data to Non- efficacious for the treatment of Parkinsonism, motor fluctuations, and dyskinesias. Selegiline was reassigned as Non-efficacious for the prevention of dyskinesias. Other designations did not change. In a field as active in clinical trials as PD, frequent updating of therapy-based reviews is essential. We consider a 3-year period a reasonable time frame for published updates and are working to establish a Web-based mechanism to update the report in an ongoing manner.

Amantadine↗
PubMed2007

Entacapone to tolcapone switch: Multicenter double-blind, randomized, active-controlled trial in advanced Parkinson's disease.

This double-blind study examined the efficacy and safety of replacing entacapone with tolcapone in fluctuating Parkinson's disease (PD) patients. Patients receiving entacapone for > or =15 days were randomly assigned to continue entacapone (n = 75) or switch to tolcapone (n = 75) and were followed up for 3 weeks. Efficacy measures included changes in on time (without disabling dyskinesia) and an investigator's global assessment (IGA). The on time increased by > or =1 hour/day (primary efficacy measure) in 43% of entacapone-treated patients and 53% of tolcapone-treated patients, and by > or =3 hours/day in 13% and 25%, respectively. The IGA indicated moderate/marked improvements in 25% of entacapone patients and 39% receiving tolcapone. Response rates (the proportion of patients with > or =1 hour/day increase in on time and improvements on IGA) were 17% with entacapone and 32% with tolcapone. Dyskinesia was the most common adverse event affecting 29% of entacapone and 31% of tolcapone recipients. One patient in each group had elevated liver enzymes, resulting in treatment withdrawal (levels returned to normal thereafter in both cases). In conclusion, within the limits of the protocol, there was a tendency for tolcapone to offer enhanced efficacy in patients with fluctuating PD, despite optimized entacapone therapy. Tolcapone can be considered, therefore, for patients whose motor fluctuations are inadequately controlled by their existing regimen.

Aged↗
PubMed1995

Effects of tolcapone in Parkinson's patients taking L-dihydroxyphenylalanine/carbidopa and selegiline.

A double-blind, placebo-controlled, crossover trial of tolcapone (RO 40-7592), a potent reversible inhibitor of catechol-O-methyltransferase (COMT), was performed in 10 Parkinson's disease (PD) patients to determine single-dose safety and efficacy. All subjects were chronically treated with stable doses of selegiline and L-dihydroxyphenylalanine (L-DOPA)/carbidopa. Tolcapone was administered in four single ascending doses (50-800 mg) randomly paired with placebo. Motor ratings were performed every 30 min for 6 h. At higher doses (400 mg and 800 mg), tolcapone prolonged the antiparkinson response of L-DOPA. Nausea was the most common adverse effect of the tolcapone-L-DOPA/carbidopa-selegiline combination. Adverse cardiovascular effects were not seen. The acute inhibition of amino acid decarboxylase, monoamine oxidase-B, and COMT is well tolerated and prolongs the L-DOPA response in PD patients. Tolcapone may be a safe and useful adjunct to L-DOPA/carbidopa in PD patients taking selegiline.

Aged↗
PubMed1997

Tolcapone added to levodopa in stable parkinsonian patients: a double-blind placebo-controlled study. Tolcapone in Parkinson's Disease Study Group II (TIPS II).

The primary objective of this study was to assess the effect of tolcapone on levodopa dosage in parkinsonian patients whose "wearing-off" phenomenon has been controlled with more frequent levodopa dosage. After a 1-week placebo run-in, 97 patients were assigned randomly to receive placebo or tolcapone 200 or 400 mg three times daily (t.i.d.). Levodopa dosage was reduced by -35% on day 1 of study and subsequently retitrated as required. After 6 weeks, the tolcapone groups crossed over to receive the other dose for a further 3 weeks for exploratory purposes. Both tolcapone groups had greater reductions in levodopa dosage than the placebo group at week 6 (not statistically different). The 200-mg t.i.d. group showed greatest improvement in estimated mean scores for all efficacy parameters (p < 0.05 versus placebo for change in Unified Parkinson's Disease Rating Scale Subscale II). Fewer dopaminergic and nondopaminergic adverse events were associated with tolcapone 200 mg t.i.d. than with tolcapone 400 mg t.i.d. The most frequently reported dopaminergic adverse events were nausea, cramps, dyskinesia, and dystonia. The most frequently reported unanticipated adverse event was diarrhea. Tolcapone 200 mg t.i.d. may provide additional benefit to patients with moderately advanced Parkinson's disease with treated "wearing-off" phenomenon.

Activities of Daily Living↗
PubMed1998

A pilot evaluation of the tolerability, safety, and efficacy of tolcapone alone and in combination with oral selegiline in untreated Parkinson's disease patients. Tolcapone De Novo Study Group.

Tolcapone is a potent, reversible catechol-O-methyltransferase (COMT) inhibitor with both peripheral and central activity. It has been demonstrated to improve motor function and allow levodopa dose reductions in Parkinson's disease (PD) patients who are experiencing either a stable response or motor fluctuations while on levodopa/dopa decarboxylase inhibitor therapy. Because striatal dopamine is metabolized by COMT and monoamine oxidase (MAO), central COMT inhibition alone or in combination with MAO inhibition might provide symptomatic benefit for patients not receiving levodopa. We conducted a pilot study to evaluate the tolerability, safety, and efficacy of tolcapone alone and in combination with oral selegiline in early untreated PD patients. Patients were randomized to receive 200 mg tolcapone three times a day or placebo for the 8 weeks of the study. Open-label oral selegiline (5 mg in the morning and midday) was administered to all patients during the second 4 weeks of the study. There was no difference between treatment groups according to the investigator's assessment of tolerability at week 4. Ninety-five percent of tolcapone-treated patients and 98% of placebo-treated patients experienced excellent or good tolerability during the first 4 weeks (95% confidence interval [CI]: -10.3, 5.7; p = 0.57). A decrease in tolerability occurred in the tolcapone group during the second 4 weeks of the study following the addition of selegiline. The most commonly reported side effects were diarrhea (31% tolcapone, 7% placebo), nausea (21% tolcapone, 2% placebo), urine discoloration (12% tolcapone, 0% placebo), dizziness (12% tolcapone, 5% placebo), headaches (12% tolcapone, 10% placebo), and abdominal pain (10% tolcapone, 5% placebo). We did not identify symptomatic benefit associated with tolcapone alone or in combination with oral selegiline in this group of otherwise untreated PD patients.

Administration, Oral↗
PubMed2006

A systematic review of NSAIDs withdrawn from the market due to hepatotoxicity: lessons learned from the bromfenac experience.

Drug-induced hepatotoxicity is the leading cause of acute liver failure (ALF) in the US and the most common adverse event causing drug non-approval and drug withdrawal by the U.S. Food and Drug Administration (FDA). Three different nonsteroidal anti-inflammatory drugs (NSAIDs) have been withdrawn in the UK and/or the US due to hepatotoxicity (bromfenac, ibufenac, and benoxaprofen). A systematic review of clinical trials data for these drugs was performed in an effort to identify possible early signals that could have predicted post-marketing serious hepatoxicity. There were very limited published data on benoxaprofen and none on ibufenac or bromfenac. The publicly accessible archives of the FDA provided information on bromfenac. Flu-like symptoms associated with hepatic enzyme elevation and a case of possible drug-related hepatocellular jaundice may in retrospect have been signals for serious hepatotoxicity in the database of 1195 subjects reviewed by the FDA. Following approval, rates of acute liver failure for bromfenac were estimated to be in the range of 1:10 000. In addition, the safety databases of several drugs also accessed through FDA archives have been reviewed (simvastatin, tacrine, troglitazone, and ximelagatran). These data suggest that while ALT elevations alone do not reliably signal serious hepatotoxicity, elevated transaminases in association with symptomatic hepatitis or jaundice may be predictors of an increased risk of ALF. At present, however, pre-approval databases are generally not large enough to rule out low rates of serious hepatotoxicity. Therefore, it remains critical that clinicians report such cases to the FDA through the MEDWATCH system and that active post-marketing monitoring studies be used to identify potential rare cases of hepatotoxicity.

Adverse Drug Reaction Reporting Systems↗
PubMed2004

Photoaffinity scanning in the mapping of the peptide receptor interface of class II G protein-coupled receptors.

The family of G protein-coupled receptors constitutes about 50% of the therapeutic drug targets used in clinical medicine today, although the mechanisms of ligand binding, activation and signal transduction for G protein-coupled receptors are not yet well defined. This review discusses ongoing research using the photoaffinity scanning method to map the bimolecular interface between class II G protein-coupled receptors and their ligands. Furthermore the available computer model of class II peptide ligand docking into the receptor, based on the positional constraints imposed by the photoaffinity scanning analyses, will be discussed briefly. The ultimate goal of these efforts is to understand the molecular basis of receptor binding and therefore to generate a template for rational drug design.

Amino Acid Sequence↗
PubMed2003

The 'apparent' hydrolysis of alkyl esters during electrospray ionization.

Electrospray ionization (ESI) mass spectrometry was employed to obtain both molecular weight confirmation and structural information for a series of novel alkenyldiarylmethane (ADAM) analogs. The mass spectral data were intended for use during the structure elucidation of ester hydrolysis products formed during an in vitro metabolism study of a series of novel ADAM analogs. The data on the precursor molecules show the presence of the molecular ion peak, [M+H](+), as well as a peak consistent with the hydrolysis product of the original ester ([MH-ROH+H(2)O](+)). However, chemical ionization mass spectrometry, elemental analysis and (1)H NMR data indicated the presence of only the intact diester compounds, suggesting that the formation of the hydrolysis product was an instrumental artifact, i.e., in-beam hydrolysis during ESI or a result of longer ion residence times of the ion trap mass analyzer.

Alkylation↗
PubMed2005

The combination of liquid chromatography/tandem mass spectrometry and chip-based infusion for improved screening and characterization of drug metabolites.

An approach has been developed for drug metabolism studies of non-radiolabeled compounds using on-line liquid chromatography/tandem mass spectrometry (LC/MS/MS) combined with chip-based infusion following fraction collection. The potential of this approach, which improves the data quality compared with only LC/MS analysis, has been investigated for the analysis of in vitro metabolites of tolcapone and talinolol, two compounds with well-characterized metabolism. The information-dependent LC/MS/MS analysis enables the characterization of the major metabolites while the chip-based infusion is used to obtain good product ion spectra for lower level metabolites, to generate complementary MS information on potential metabolites detected in the LC/MS trace, or to screen for unexpected metabolites. Fractions from the chromatographic analysis are collected in 20 second steps, into a 96-well plate. The fractions of interest can be re-analyzed with chip-based infusion on a variety of mass spectrometers including triple quadrupole linear ion trap (QqLIT or Q TRAP) and QqTOF systems. Acquiring data for several minutes using multi-channel acquisition (MCA), or signal averaging while infusing the fractions at approximately 200 nL/min, permits about a 50 times gain in sensitivity (signal-to-noise) in MS/MS mode. A 5-10 microL sample fraction can be infused for more than 30 min allowing the time to perform various MS experiments such as MS(n), precursor ion or neutral loss scans and accurate mass measurement, all in either positive or negative mode. Through fraction collection and infusion, a significant gain in data quality is obtained along with a time-saving benefit, because the original sample needs neither to be re-analyzed by re-injection nor to be pre-concentrated. Therefore, a novel hydroxylated talinolol metabolite could be characterized with only one injection.

Animals↗