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Biomedical subjects

A Metz

Publications and source records attributed to A Metz.

At least 19 recordsLinked to original sources
PubMed2002

Introduction of a ketogenic diet in young infants.

The ketogenic diet is a rational treatment for pyruvate dehydrogenase complex deficiency (McKusick 312170) and GLUT1 deficiency syndrome (McKusick 138140). An increasing number of patients are diagnosed in early infancy, but few data are available on the introduction of a ketogenic diet in this age group. GLUT1 deficiency syndrome was suspected in four infants presenting with seizures and unexplained hypoglycorrhachia. A ketogenic diet was introduced at 6-28 weeks of age. Ketosis was initiated by fasting, monitored by bedside blood glucose and 3-hydroxybutyrate determinations, and was maintained successfully using supplemented carbohydrate-free infant formula and emulgated triglycerides. All patients developed ketosis within 24 h. 3-Hydroxybutyrate concentrations available at the bedside correlated inversely with the base excess. At glucose levels < or = 40 mg/dl patients remained asymptomatic in the presence of ketones. The ketogenic formula was tolerated well, parental compliance was good, and all patients remained seizure-free on the diet. GLUT1 deficiency was confirmed in two patients; the diet was discontinued in the other two patients. In one infant, failure to thrive on medium-chain triglycerides was effectively reversed using long-chain triglycerides. Urine dipstick analyses failed to detect ketosis in another infant. Adverse effects of the diet were limited to renal stones in one patient. The ketogenic diet can be introduced and maintained successfully in young infants using long-chain fat emulsion. Monitoring 3-hydroxybutyrate at the bedside was useful for metabolic control and superior to urine dipstick analysis. Seizure control was effective and adverse effects were limited, but evaluation of the long-term effects of the ketogenic diet in this age group must await ongoing studies.

Blood Glucose↗
PubMed2001

Effect of encapsulation on absorption of sumatriptan tablets: data from healthy volunteers and patients during a migraine.

BACKGROUND: Some comparative trials of selective serotonin 1B/ID-agonists in migraine have reported -15% lower efficacy for sumatriptan tablets than that reported in placebo-controlled trials. OBJECTIVE: This study was designed to test the hypothesis that the encapsulation methods used to mask active drug may delay absorption of sumatriptan from dosing to 2 hours after dosing (the traditional end point in clinical trials of migraine treatment), an effect that may be enhanced by migraine-associated gastric stasis. METHODS: Two randomized, open-label, 2-way crossover trials were conducted to evaluate the absorption and bioequivalence of conventional 50-mg sumatriptan tablets and encapsulated 50-mg sumatriptan tablets in supine, fasted, healthy volunteers (Glaxo Wellcome protocol SUM40270) and supine patients experiencing a migraine (Glaxo Wellcome protocol SUM40268). Absorption was assessed by calculating the area under the plasma concentration-time curve from dosing to 2 hours after dosing (AUC2) and the times to first measurable plasma concentration, 10 ng/mL, 20 ng/mL, and maximum plasma concentration. Data for the AUC from time zero to infinity and maximum plasma concentration were used to assess standard bioequivalence, which is considered to occur when the 90% CIs for the geometric mean treatment ratios (test/reference) fall between 0.8 and 1.25. RESULTS: Study 1 included 26 healthy subjects (73% men, 27% women; mean age, 39.1 years), and study 2 included 30 patients with migraine (67% women, 33% men; mean age, 42.7 years). Sumatriptan absorption was delayed with the encapsulated tablet compared with the conventional tablet 0 to 2 hours after dosing, particularly during a migraine. AUC2 values with encapsulated sumatriptan compared with the conventional tablet were 21% lower in healthy volunteers (ratio of capsule/tablet, 0.79; 90% CI, 0.588-1.050) and 27% lower in patients experiencing a migraine (ratio of capsule/tablet, 0.73; 90% CI, 0.519-1.023). Standard bioequivalence was demonstrated in both healthy volunteers and patients experiencing a migraine. CONCLUSIONS: Encapsulation delayed absorption of sumatriptan 0 to 2 hours after dosing, particularly during a migraine. This delay in absorption of the encapsulated form may account for the lower efficacy of sumatriptan in some comparative studies.

Adult↗
PubMed2001

A placebo-controlled comparison of the effects on sexual functioning of bupropion sustained release and fluoxetine.

BACKGROUND: Many antidepressants are associated with sexual dysfunction, a side effect that may lead to patients' dissatisfaction and noncompliance with treatment. OBJECTIVE: This study compared the efficacy, tolerability, and effects on sexual functioning of bupropion sustained release (bupropion SR) and the selective serotonin reuptake inhibitor fluoxetine. METHODS: In this multicenter, randomized, double-blind, double-dummy, parallel-group study, patients with recurrent major depression were treated with bupropion SR 150 to 400 mg/d, fluoxetine 20 to 60 mg/d, or placebo for up to 8 weeks. Depression and sexual-functioning status were assessed by site-specific trained investigators at weekly clinic visits; tolerability was assessed primarily by monitoring adverse events. RESULTS: Four hundred fifty-six patients participated in the study, 150 receiving bupropion SR, 154 fluoxetine, and 152 placebo. The majority of patients in each group completed the study (63% each, bupropion SR [n = 94] and fluoxetine [n = 97]; 67%, placebo [n = 102]). Bupropion SR and fluoxetine were similarly effective in the treatment of depressive symptoms. Beginning at week 2 and continuing throughout the study, significantly more fluoxetine-treated patients experienced orgasm dysfunction than did patients receiving bupropion SR or placebo (P < 0.001); similar results were seen in patients defined as clinical responders (> or =50% decrease from baseline in 21-item Hamilton Rating Scale for Depression [HAM-D] total score) (P < 0.001) and in those experiencing remission of depression (HAM-D total score <8) (P < 0.05). At various time points, worsened sexual functioning, sexual desire disorder, sexual arousal disorder, and dissatisfaction with sexual functioning in those satistied at baseline were more frequently associated with fluoxetine treatment than with bupropion SR or placebo. Both active treatments were well tolerated. CONCLUSIONS: Bupropion SR and fluoxetine were similarly effective and well tolerated in the treatment of depression. Fluoxetine, however, was more frequently associated with sexual dysfunction compared with bupropion SR. Bupropion SR may be an appropriate initial choice for the treatment of depression in patients concerned about sexual functioning.

Adult↗
PubMed2001

Does pretreatment anxiety predict response to either bupropion SR or sertraline?

BACKGROUND: A common clinical belief is that more sedating and/or serotonin-selective antidepressants are preferred for depressed patients with symptoms of anxiety compared with more activating and/or catecholamine-selective antidepressants. The purpose of this study was to determine whether higher baseline anxiety is associated with different antidepressant responses to bupropion sustained release (SR) or sertraline. METHODS: A retrospective data analysis was conducted using pooled data from two identical 8-week, randomized, double-blind, placebo-controlled multicenter studies of bupropion SR (n=234), sertraline (n=225), and placebo (n=233) in adult outpatients with recurrent, major depressive disorder. Anxiety symptoms were measured using the 14-item Hamilton Anxiety Rating Scale scores. RESULTS: Baseline anxiety levels were not related to antidepressant response to treatment with either bupropion SR or sertraline, nor did they differentiate between responders to bupropion SR and responders to sertraline. CONCLUSIONS: Baseline anxiety levels do not appear to be a basis for selecting between bupropion SR and sertraline in the treatment of outpatients with major depressive disorder.

Antidepressive Agents↗
PubMed2001

Response in relation to baseline anxiety levels in major depressive disorder treated with bupropion sustained release or sertraline.

Our objective was to determine if pretreatment anxiety levels were associated with preferential response to bupropion sustained release (n = 122) or sertraline (n = 126) during a 16-week randomized acute phase treatment study. Both agents had comparable antidepressant activity, and comparable anxiolytic effects using the intent-to-treat sample. Baseline anxiety levels were not related to antidepressant efficacy, and they did not differentiate responders to each agent. Time to clinically significant anxiolysis did not differentiate between treatment groups or between responders to each agent. These results contradict the commonly held, but unsubstantiated, belief that in clinically depressed anxious patients, serotonergic antidepressants are especially anxiolytic and that such patients preferentially benefit from the antidepressant or anxiolytic effects of selective serotonin reuptake inhibitors. Thus, the clinical decision to select between these two agents when treating depressed outpatients cannot rest on either levels of pretreatment anxiety or on anticipation of more rapid or more complete anxiolysis.

Adult↗
PubMed2001

Long-term nonsurgical management of Barrett's esophagus with high-grade dysplasia.

BACKGROUND & AIMS: Surgical resection of the esophagus is frequently recommended for Barrett's high-grade dysplasia (HGD) without cancer. METHODS: During a 20-year period, patients were diagnosed and observed through an organized surveillance program at the Hines Veterans Affairs Hospital. The program was supported by Hines VA and organized and managed by 2 endoscopists using preestablished endoscopic criteria. RESULTS: Barrett's esophagus was diagnosed in 1099 patients, and 36,251 esophageal mucosal specimens were reviewed. Seventy-nine of 1099 patients (7.2%) initially had HGD (34 prevalent) or subsequently developed HGD (45 incident) without evidence of cancer. Of the 75 HGD patients who remained without detectable cancer after the 1 year of intensive searching, 12 developed cancer (16%) during a mean 7.3-year surveillance period: 11 of the 12 who were compliant were considered cured with surgical or ablation therapy. Cancer did not develop in the remaining 63 HGD patients during the surveillance period. CONCLUSIONS: HGD without cancer in Barrett's esophagus follows a relatively benign course in the majority of patients. In the patients who eventually progress to cancer during regular surveillance, surgical resection is curative. Surveillance endoscopies with biopsy is a valid and safe follow-up strategy for Barrett's patients who have HGD without cancer.

Adenocarcinoma↗
PubMed2001

Bupropion SR as an aid to smoking cessation in smokers treated previously with bupropion: a randomized placebo-controlled study.

BACKGROUND: Many persons who attempt to quit smoking have made previous unsuccessful attempts to quit with pharmacologic aids. An understanding of the impact of these previous attempts to quit is vital for selecting medications that may be more successful in a future attempt to quit. In particular, the effect of repeated use of bupropion SR (Zyban; INN, amfebutamone) on abstinence rates has not been studied previously. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study in 450 smokers who had previously used bupropion in a smoking cessation attempt. The study consisted of a screening phase, a 12-week treatment phase, and a follow-up at month 6. Participants made regular clinic visits throughout the treatment phase during which they received brief counseling sessions to encourage abstinence from smoking. The primary end point was continuous abstinence from smoking from weeks 4 through 7. Secondary efficacy end points were examined throughout the treatment phase and at follow-up after 6 months. RESULTS: In participants receiving bupropion SR, 27% (61 of 226) remained abstinent throughout the period from weeks 4 through 7 compared with 5% (11 of 224) of participants receiving placebo (P <.001). Significantly (P <.001) more participants who received bupropion SR during the treatment phase remained continuously abstinent from the start of week 4 through month 6 (27 of 226; 12%) compared with participants who received placebo (5 of 224; 2%). Eleven participants receiving placebo (5%) and 19 participants receiving bupropion SR (8%) stopped taking the study medication because of an adverse event. CONCLUSIONS: Bupropion SR is an effective medication for retreatment of smokers who have used bupropion SR previously.

Adult↗
PubMed2001

Do bupropion SR and sertraline differ in their effects on anxiety in depressed patients?

OBJECTIVE: To examine the effects of bupropion sustained release (SR) and sertraline on anxiety in outpatients with recurrent DSM-IV-defined major depressive disorder. METHOD: This retrospective analysis was conducted using pooled data from 2 identical, 8-week, acute-phase, double-blind, placebo-controlled, parallel-group studies of bupropion SR (N = 234), sertraline (N = 225), and placebo (N = 233). Symptoms of anxiety and depression were measured using the 14-item Hamilton Rating Scale for Anxiety (HAM-A) and the 21-item Hamilton Rating Scale for Depression (HAM-D-21), respectively. Percentage reduction in baseline HAM-A total score for each treatment week was calculated to determine whether the time to onset of anxiolytic activity differed among antidepressant responders to each agent. Central nervous system (CNS) adverse events were tabulated. RESULTS: Bupropion SR and sertraline were comparably effective, both were superior to placebo in reducing depressive symptoms. and they did not differ in their effect on anxiety symptoms. Antidepressant responders (> 50% reduction in baseline HAM-D-21 score) in both groups showed marked and comparable reductions in HAM-A scores (baseline to exit). There were no differences between bupropion SR and sertraline in the median time (4 weeks) to reach a clinically significant anxiolytic effect (> or = 50% reduction in baseline HAM-A score). CNS adverse events were comparable for bupropion SR and sertraline, except for somnolence, which was more common in sertraline-treated patients. CONCLUSION: Bupropion SR and sertraline had comparable antidepressant and anxiolytic effects and an equally rapid onset of clinically significant anxiolytic activity. There was no difference in the activating effects between the 2 antidepressants. Selection between these 2 agents cannot be based on either anticipation of differential anxiolytic activity or differential CNS side effect profiles.

Adult↗
PubMed2000

Measurement of the spin asymmetry in the photoproduction of pairs of high- p(T) hadrons at HERMES

We present a measurement of the longitudinal spin asymmetry A(||) in photoproduction of pairs of hadrons with high transverse momentum p(T). Data were accumulated by the HERMES experiment using a 27.5 GeV polarized positron beam and a polarized hydrogen target internal to the HERA storage ring. For h(+)h(-) pairs with p(h(1))(T)>1.5 GeV/c and p(h(2))(T)>1.0 GeV/c, the measured asymmetry is A(||) = -0. 28+/-0.12(stat)+/-0.02(syst). This negative value is in contrast to the positive asymmetries typically measured in deep inelastic scattering from protons, and is interpreted to arise from a positive gluon polarization.

Journal Article↗
PubMed2000

Effect of early intervention with sumatriptan on migraine pain: retrospective analyses of data from three clinical trials.

OBJECTIVE: This study assessed the efficacy of sumatriptan 50- and 100-mg tablets in the treatment of migraine attacks while the pain is mild rather than moderate/severe. BACKGROUND: Results from The Spectrum Study suggested that early treatment of migraine attacks with sumatriptan 50-mg tablets while the pain is mild might enhance pain-free response and reduce headache recurrence. METHODS: Retrospective analyses of headaches treated during mild pain were performed using data from 3 studies of sumatriptan tablets (protocols S2CM09, S2BT25, and S2BT26). Our primary interest was pain-free response 2 and 4 hours after dosing; secondary interests were use of a second dose of medication, clinical disability (as measured on a 4-point disability scale), migraine-associated symptoms, meaningful pain relief (patient defined), time to meaningful relief, sustained pain-free response, and proportion of attacks in which pain had worsened 2 and 4 hours after dosing, all of which were compared in headaches treated during mild versus moderate/severe pain. RESULTS: In S2CM09, 92 patients treated 118 headaches during mild pain. Rates of pain-free response were higher 2 hours after dosing with sumatriptan 50 mg (51%) or 100 mg (67%; P < 0.05) compared with placebo (28%), and were higher with early treatment of mild pain compared with treatment of moderate/severe pain at 2 hours (sumatriptan 50 mg: mild pain, 51%; moderate/severe pain, 31%; P < 0.05; sumatriptan 100 mg: mild pain, 67%; moderate/severe pain, 36%) and 4 hours (50 mg: 75% vs 56%; 100 mg: 90% vs 61%; P < 0.05). Early intervention also resulted in less redosing than when moderate/severe pain was treated (50 mg: 21% vs 32%; 100 mg: 20% vs 29%). More attacks treated early with sumatriptan 50 or 100 mg were associated with normal function 4 hours after dosing compared with placebo (70% and 93% vs 46%, respectively). Sustained pain-free response rates 2 to 24 hours after early dosing with sumatriptan 50 or 100 mg were also higher (34% and 53%, respectively) compared with treatment of moderate/severe pain (19% and 24%, respectively). Early treatment with sumatriptan 100 mg produced significantly higher pain-free rates at 2 hours after dosing (P < 0.001) than did ergotamine plus caffeine (S2BT25: 69% vs 34%, respectively) or aspirin plus metoclopramide (S2BT26: 73% vs 25%, respectively). CONCLUSIONS: Sumatriptan 50- and 100-mg tablets are effective whether pain is mild or moderate/severe. However, treatment with sumatriptan while pain is mild provides high pain-free response rates while reducing the need for redosing, benefits not seen with ergotamine plus caffeine or aspirin plus metoclopramide.

Dose-Response Relationship, Drug↗
PubMed1998

Structural and functional analysis of the BMP-4 promoter in early embryos of Xenopus laevis.

The Xenopus laevis BMP-4 gene shows an evolutionary conserved structure containing two coding exons and a leader exon. The transcripts which are detected after zygotic activation of the gene in ventral mesoderm of late blastula stage embryos do either contain the leader exon or begin within the first intron. Luciferase reporter/promoter studies revealed multiple elements being required for the activation and for the spatial control of transcription. These elements are located within the upstream region and within the second intron and they interact with a most proximal located basal promoter being indispensable for transcriptional activation. The auto-activatory capacity of BMP-4 is mediated by several enhancer elements being responsive not only to BMP-4 but also to BMP-2 signaling. BMP-2 might thus function as a natural activator of the BMP-4 gene in the early embryo. Since reporter activity obtained with distinct BMP-2/4 responsive promoter deletion mutants is simultaneously inhibited by the dominant negative BMP receptor as well as by chordin, we suggest that down-regulation of the BMP-4 gene by chordin results from an interference with the auto-regulatory loop at the level of protein-protein interactions.

Amino Acid Sequence↗
PubMed1996

Antagonistic actions of activin A and BMP-2/4 control dorsal lip-specific activation of the early response gene XFD-1' in Xenopus laevis embryos.

Transcription of the early response gene XFD-1' (XFKH1) in the dorsal lip (Spemann organizer) of Xenopus embryos is activated by dorsal mesoderm inducing factors. Promoter studies revealed the presence of an activin A response element (ARE) which is both necessary and sufficient for transcriptional activation of reporter genes in animal cap explants incubated with activin A. Surprisingly, this ARE is also active within vegetal explants in the absence of exogenously added inducers, but an additional inhibitory response element prevents transcription of the XFD-1' gene in the ventral/vegetal region of the embryo in vivo. This element is located upstream of the ARE, it responds to bone morphogenic proteins 2 and 4 (BMP-2/4) triggered signals and it overrides the activating properties of the ARE. Expression patterns of BMP-2 and BMP-4 in the late blastula stage embryo and, especially, their absence from the dorsal blastopore lip may thus control the spatial transcription of the XFD-1' gene. Accordingly, the temporal activation and the spatial restriction of XFD-1' gene activity to the Spemann organizer is regulated by antagonistic actions of two distinct members of the TGF-beta family (activin and BMP) which act on different promoter elements.

Activins↗
PubMed1996

Quinolone arthropathy in immature rabbits treated with the fluoroquinolone, PD 117596.

To study the potential of the fluorquinolone, PD 117596 to cause arthropathy in experimental animals, immature rabbits were orally administered the drug for five days at 0, 100, 350, 500 and 750 mg/kg. Characterization of changes induced in major synovial joints was based on: macroscopic and histopathologic observations, transmission electron microscopic examinations and magnetic resonance imaging. Preferentially targeting the knee, PD 117596 produced vesicles and erosions in articular cartilage which resembled, morphologically, those described in other laboratory species. Lesion incidence was not clearly dose-related. In the perivesicular region, degenerate chondrocytes were intermixed with hypertrophic cartilage cells and chondrocyte clusters. Ultrastructurally, hypertrophic chondrocytes were the consequence of karyomegaly and RER proliferation. Matrix density was reduced due to collagen and proteoglycan loss. Joint structures were readily visualized by magnetic resonance imaging which identified thickened articular cartilage, surface irregularities consistent with ruptured vesicles and separation of opposing articular surfaces secondary to synovival effusions. The immature rabbit, although less sensitive than the juvenile dog to the arthropathic effects of quinolones, was nonetheless a good model to study this experimental osteoarticular disease.

Animals↗
PubMed1995

Effect of alosetron (a new 5-HT3 receptor antagonist) on the pharmacokinetics of haloperidol in schizophrenic patients.

Alosetron is under clinical development for the treatment of schizophrenia. This study evaluated the effect of oral alosetron dosing on the pharmacokinetics of haloperidol, the latter being administered daily to 13 schizophrenic patients for 56 days. Alosetron 1 mg daily or placebo was given by random assignment for 2 weeks. After a two-week alosetron washout period (during which patients received placebo), patients received the alternate treatment for another two weeks. Serial blood samples were collected for high-performance liquid chromatography determination of plasma haloperidol, reduced haloperidol, and alosetron at selected times for 24 hours after administration of haloperidol and alosetron on study days 21 and 49. Mean pharmacokinetic parameters of haloperidol in the presence of alosetron and placebo treatments were not significantly (P > .05) different: dose-normalized Cmax (6.40 versus 5.75 ng/mL), dose-normalized Cmin (2.00 versus 1.90 ng/mL), dose-normalized AUC (85.97 versus 68.48 ng.hr/mL), and CL/f (78.23 versus 104.7 L/hr). A two-compartment model was used to assess the concentration- and time-independent pharmacokinetics of haloperidol after multiple dosing. The model confirmed that there was no change in the pharmacokinetics of haloperidol when alosetron was administered concomitantly. Mean AUC ratios of reduced haloperidol to haloperidol (0.18) in the presence of alosetron were similar to values obtained in the absence of alosetron, indicating that alosetron had no influence on the metabolism of haloperidol. Mean pharmacokinetic parameters of alosetron were similar to those in previous studies in healthy subjects.

Adult↗