23 results on '"Hutzelmann, J"'
Search Results
2. 0488 Pilot Evaluation of an Actigraphy Watch Compared to Polysomnography in a Clinical Trial of Suvorexant for Treating Insomnia in Patients with Alzheimer’s Disease
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Svetnik, V, primary, Wang, T, primary, Ceesay, P, primary, Snyder, E, primary, Ceren, O, primary, Bliwise, D, primary, Budd, K, primary, Hutzelmann, J, primary, Stevens, J, primary, Lines, C, primary, Michelson, D, primary, and Herring, W, primary
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- 2020
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3. 0487 Effects of Suvorexant on Sleep Architecture in Patients with Alzheimer’s Disease and Insomnia
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Svetnik, V, primary, Wang, T, primary, Ceesay, P, primary, Ceren, O, primary, Snyder, E, primary, Bliwise, D, primary, Budd, K, primary, Hutzelmann, J, primary, Stevens, J, primary, Lines, C, primary, Michelson, D, primary, and Herring, W, primary
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- 2020
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4. A randomized controlled trial of suvorexant for treating insomnia in patients with Alzheimer's disease: effects on objective sleep measures
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Herring, W.J., primary, Ceesay, P., additional, Snyder, E., additional, Bliwise, D., additional, Budd, K., additional, Hutzelmann, J., additional, Stevens, J., additional, and Michelson, D., additional
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- 2019
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5. Design of a clinical trial for assessing the orexin receptor antagonist suvorexant in treating insomnia in patients with Alzheimer's disease
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Herring, W.J., primary, Snyder, E., additional, Bliwise, D., additional, Ancoli-Israel, S., additional, Budd, K., additional, Hutzelmann, J., additional, Dam, T., additional, Michelson, D., additional, and Swartz, J., additional
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- 2017
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6. Central corneal thickness in the European Glaucoma Prevention Study
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Pfeiffer, N, Torri, V, Miglior, S, Zeyen, T, Adamsons, I, Cunha-Vaz, J, Linsen, Mc, Pellicci, L, Janssens, A, van der Veken, A, Nerinckx, F, Boeyden, V, Kestelijn, P, Van den Abeele, K, Jacobs, K, Decock, C, Goethals, M, Pourjavan, S, Maris, K, Kersten, I, Vogel, A, Herkel, U, Schwenn, O, Maser-Wahle, M, Funk, J, Schmidt, B, Akbariyeh, N, Burk, R, Thomsen, A, Grehn, F, Marquardt, D, Orzalesi, N, Rossetti, L, Ferrante, M, Mandelli, L, Bertoni, G, Blini, M, De Molfetta, M, Bonomi, L, Morbio, R, Marraffa, M, Maraini, G, Gandolfi, S, Williams, S, Cimino, L, Dondi, P, Lumbroso, B, Marini, G, Centofanti, M, Cocco, F, Glorialanza, G, Villani, Cm, Pocobelli, A, Cesareo, M, Cupo, G, Neuschuler, R, Pernini, C, Catalani, R, Ribeiro, L, Faria, I, Pereira, Jm, Chingui, S, Duarte, L, Carvalheira, F, Baltar, A, Simao, A, Arede, J, Magalhaes, A, Abrantes, P, Reina, M, Silva, Jp, Romano, G, Silva, S, Floriani, I, Poli, D, Tinazzi, A, Caprioli, J, Wormald, R, Hejil, A, Airaksinen, J, Michaelis, J, Mandelli, La, Bagno, S, Shedden, A, Gottfried, E, Hutzelmann, J, Rusk, C, Reines, S, Spector, R, Hombrey, J, Snyder, H, Gacos, J, Snapinn, S, Getson, A, Amos, J, Serruys, K, Malbecq, W, John, E, Chapman, J, Beck, J, Tessi, C, Rao, N, Bottari, Fp, D'Achille, R, Wilkins, A, Magerl, K, Bauer, C, Derouwaux, C, Cunha, M, Santana, R, Andrade, Lg, Bule, S, Melo, R, Baumont, H, Bonaventura, I, Pfeiffer, N, Torri, V, Miglior, S, and The European Glaucoma Prevention Study, G
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Adult ,Male ,Intraocular pressure ,medicine.medical_specialty ,genetic structures ,Settore MED/06 - Oncologia Medica ,Glaucoma, ocular hypertension, central corneal thickness ,Ocular hypertension ,Glaucoma ,Thiophenes ,Placebo ,law.invention ,Cornea ,Diabetes Complications ,Sex Factors ,Double-Blind Method ,Randomized controlled trial ,Dorzolamide ,law ,Diabetes mellitus ,Ophthalmology ,medicine ,Humans ,Intraocular Pressure ,Aged ,Ultrasonography ,Sulfonamides ,business.industry ,Age Factors ,Middle Aged ,medicine.disease ,eye diseases ,Surgery ,medicine.anatomical_structure ,Female ,Ocular Hypertension ,sense organs ,business ,medicine.drug - Abstract
Purpose: To measure central corneal thickness (CCT) within the participants of the European Glaucoma Prevention Study (EGPS). This study was designed to test if lowering intraocular pressure (IOP) by means of dorzolamide is able to prevent or delay conversion from ocular hypertension to glaucoma. Design: Randomized, double-masked, controlled, observational clinical trial. Participants: Eight hundred fifty-four of 1077 ocular hypertensive participants within the EGPS were investigated. Four hundred twenty-nine patients were treated with dorzolamide and 425 patients received placebo. Intervention: Treatment with dorzolamide or placebo (the vehicle of dorzolamide) in 1 or both eyes. Main Outcome Measures: Central corneal thickness as measured by ultrasound pachymetry (DGH-500 Pachette; DGH Technologies, Exton, PA). The CCT measurements were obtained in the morning before measuring IOP. Five measurements were taken from each eye of each patient within 5 minutes of application of anesthetic eye drops. Results: Mean CCT was 572.6±37.4 μm (range, 458.5-695.6 μm). The CCT was higher in younger patients, male patients, and diabetic patients. Mean CCTs for the 429 patients receiving dorzolamide were 574.2±38.48 μm (range, 458.5-695.6 μm) and 571.0±36.21 μm (469.7-690.1 μm) for the 425 patients receiving placebo (P = 0.205). Central corneal thickness did not correlate with refraction, baseline IOP, or systemic hypertension. Conclusion: Central corneal thickness measurements within the EGPS were greater than those reported in other studies of normal eyes without ocular hypertension. Larger CCT measurements correlated with male gender, younger age, and diabetes. © 2007 American Academy of Ophthalmology.
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- 2007
7. Reproducibility of evaluation of optic disc change for glaucoma with stereo optic disc photographs
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Miglior, S, Zeyen, T, Pfeiffer, N, Cunha-Vaz, J, Linsen, Mc, Pellicci, L, Janssens, A, van der Veken, A, Nerinckx, F, Boeyden, V, Czupper, M, Wendrix, G, Detry-Morel, M, Kestelyn, P, Van den Abeele, K, Jacobs, K, Decock, C, Goethals, M, Pourjavan, S, Maris, K, Deghislage, C, Kersten, I, Vogel, A, Herkel, U, Schwenn, O, Maser-Wahle, M, Funk, J, Schmidt, B, Akbariyeh, N, Burk, R, Thomsen, A, Grehn, F, Marquardt, D, Orzalesi, N, Rossetti, L, Ferrante, M, Mandelli, L, Marini, S, Bertoni, G, Blini, M, De Molfetta, M, Bonomi, L, Morbio, R, Marraffa, M, Maraini, G, Gandolfi, S, Williams, S, Cimino, L, Dondi, P, Lumbroso, B, Manni, G, Cocco, F, Glorialanza, G, Villani, Cm, Pocobelli, A, Cesareo, M, Cupo, G, Neuschuler, R, Pernini, C, Catalani, R, Ribeiro, L, Faria, I, Pereira, Jm, Chingui, S, Duarte, L, Carvalheira, F, Baltar, A, Simao, A, Arede, J, Magalhaes, A, Abrantes, P, Reina, M, Silva, Jp, Romano, G, Silva, S, Torri, V, Poli, D, Nerviani, C, Tinazzi, A, Floriani, I, Adamsons, I, Caprioli, J, Wormald, R, Heijl, A, Airaksinen, J, Michaelis, J, Shedden, A, Gottfried, E, Hutzelmann, J, Rusk, C, Reines, S, Spector, R, Hombrey, J, Snyder, H, Gacos, J, Snapinn, S, Getson, A, Amos, J, Serruys, K, Malbecq, W, John, E, Chapman, J, Beck, J, Tessi, C, Rao, N, Bottari, Fp, D'Achille, R, Wilkins, A, Bauer, C, Derouwaux, C, Van der Straeten, A, Cunha, M, Santana, R, Andrade, Lg, Bule, S, Melo, R, Baumont, H, and Bonaventura, I
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medicine.medical_specialty ,genetic structures ,Optic Disk ,Optic disk ,Glaucoma ,Interobserver reproducibility ,Cohen's kappa ,Double-Blind Method ,Ophthalmology ,Optic Nerve Diseases ,medicine ,Photography ,Humans ,Observer Variation ,Reproducibility ,business.industry ,Outcome measures ,Reproducibility of Results ,medicine.disease ,eye diseases ,Confidence interval ,medicine.anatomical_structure ,sense organs ,business ,Optic disc - Abstract
PURPOSE To determine the reproducibility of the assessment for glaucomatous change in serial optic disc stereo-slides. DESIGN Masked interobserver variability study. PARTICIPANTS Serial optic disc stereo-slides from 40 patients. METHODS Three independent ophthalmologists evaluated for change a set of two serial 20 degrees optic disc color stereo-slides of 40 patients. This test set was not from European Glaucoma Prevention Study (EGPS) patients. Each observer performed two evaluations at least 30 days apart and was masked from the temporal sequence of the slides and his or her previous evaluation. Each patient was graded as changed or stable by two-out-of-three agreement. A kappa statistic was used to calculate the intra- and interobserver reproducibility as well as the assignment reproducibility (first consensus versus second consensus). The same procedure was followed to test the reproducibility when another experienced ophthalmologist was added to one of the three reading centers. MAIN OUTCOME MEASURES Reproducibility in evaluating glaucomatous optic disc change. RESULTS The intraobserver reproducibility (95% confidence interval [CI]) in the evaluation of change ranged between 0.79 (0.45-1.14) and 1.00 (0.69-1.31). The interobserver reproducibility (95% CI) in the evaluation of change ranged between 0.45 (0.15-0.75) and 0.75 (0.44-1.06). The assignment reproducibility (first consensus versus second consensus in the evaluation of change) between the senior EGPS readers was 0.94 (0.63-1.25). The assignment reproducibility when another experienced ophthalmologist replaced one of the readers was 0.94 (0.63-1.25). CONCLUSIONS The assignment reproducibility of three expert readers looking for glaucomatous change in serial optic disc stereo-slides was excellent. It remained so when one of the three experts was replaced by another experienced reader.
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- 2003
8. The European glaucoma prevention study design and baseline description of the participants
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Miglior, S, Zeyen, T, Pfeiffer, N, Cunha-Vaz, J, Linsen, Mc, Pellicci, L, Janssens, A, van der Veken, A, Nerinckx, F, Boeyden, V, Detry-Morel, M, Kestelijn, P, Van den Abeele, K, Jacobs, K, Decock, C, Goethals, M, Pourjavan, S, Maris, K, Kersten, I, Vogel, A, Herkel, U, Schwenn, O, Maser-Wahle, M, Funk, J, Schmidt, B, Akbariyeh, N, Burk, R, Thomsen, A, Grehn, F, Marquardt, D, Orzalesi, N, Rossetti, L, Ferrante, M, Mandelli, L, Marini, S, Bagno, S, Bertoni, G, Blini, M, De Molfetta, M, Bonomi, L, Morbio, R, Marraffa, M, Maraini, G, Gandolfi, S, Williams, S, Cimino, L, Dondi, P, Lumbroso, B, Manni, G, Cocco, F, Glorialanza, G, Villani, Cm, Pocobelli, A, Cesareo, M, Cupo, G, Neuschuler, R, Pernini, C, Catalani, R, Ribeiro, L, Faria, I, Pereira, Jm, Chingui, S, Duarte, L, Carvalheira, F, Baltar, A, Simao, A, Arede, J, Magalhaes, A, Abrantes, P, Reina, M, Silva, Jp, Romano, G, Silva, S, Torri, V, Poli, D, Nerviani, C, Tinazzi, A, Adamsons, I, Caprioli, J, Wormald, R, Hejil, A, Airaksinen, J, Michaelis, J, Floriani, I, Shedden, A, Gottfried, E, Hutzelmann, J, Rusk, C, Reines, S, Spector, R, Hombrey, J, Snyder, H, Gacos, J, Snapinn, S, Getson, A, Amos, J, Serruys, K, Malbecq, W, John, E, Chapman, J, Beck, J, Tessi, C, Rao, N, Bottari, Fp, D'Achille, R, Wilkins, A, Magerl, K, Bauer, C, Derouwaux, C, Cunha, M, Santana, R, Andrade, Lg, Bule, S, Melo, R, Baumont, H, Bonaventura, I, Miglior, S, Zeyen, T, Pfeiffer, N, Cunha Vaz, J, Torri, V, and Adamsons, I
- Subjects
Adult ,Male ,medicine.medical_specialty ,Intraocular pressure ,Visual acuity ,genetic structures ,Visual Acuity ,Glaucoma ,Ocular hypertension ,Thiophenes ,Sulfonamide ,law.invention ,Visual Field Test ,Randomized controlled trial ,Dorzolamide ,Double-Blind Method ,Thiophene ,law ,Ophthalmology ,medicine ,Humans ,Dioptre ,Antihypertensive Agents ,Intraocular Pressure ,Aged ,Aged, 80 and over ,Sulfonamides ,business.industry ,Middle Aged ,medicine.disease ,eye diseases ,Europe ,Antihypertensive Agent ,medicine.anatomical_structure ,Research Design ,Visual Field Tests ,Female ,Ocular Hypertension ,sense organs ,medicine.symptom ,Safety ,Visual Fields ,business ,Glaucoma, Open-Angle ,Human ,Optic disc ,medicine.drug - Abstract
Objectives The European Glaucoma Prevention Study seeks to evaluate the efficacy of reducing intraocular pressure (IOP), with dorzolamide to prevent or delay patients affected by ocular hypertension from developing primary open-angle glaucoma. Design Randomized, double-blinded, controlled clinical trial. Participants Patients (age > or =30 years) were enrolled from 18 European centers. The patients fulfilled a series of inclusion criteria including the measurements of IOP (22-29 mmHg), two normal and reliable visual fields (VFs) (on the basis of mean defect and corrected pattern standard deviation/corrected loss of variance of standard 30/II Humphrey or Octopus perimetry), and normal optic disc as determined by the Optic Disc Reading Center (vertical and horizontal cup-to-disc ratios; asymmetry between the two eyes Intervention Patients were randomized to the treatment with dorzolamide or a placebo. Main outcome measures End points are VF and/or optic disc changes. A VF change during the follow-up must be confirmed by two further positive tests. Optic disc change is defined by the agreement of two out of three independent observers evaluating optic disc stereo-slides. Results One thousand seventy-seven subjects were randomized between January 1, 1997 and May 31, 1999. The mean age was 57.03 +/- 10.3 years; 54.41% were women and 99.9% were Caucasian. Mean IOP was 23.6 +/- 1.6 mmHg in both eyes. Mean visual acuity was 0.97 +/- 0.11 in both eyes; mean refraction was 0.23 +/- 1.76 diopters in the right eye and 0.18 +/- 1.79 diopters in the left eye. Previous use of medication for ocular hypertension was reported by 38.4% of the patients, systemic hypertension by 28.1%, cardiovascular diseases by 12.9%, and diabetes mellitus by 4.7%. The qualifying VFs were normal and reliable according to protocol criteria. Conclusions The mean IOP of the patients enrolled in the European Glaucoma Prevention Study is consistent with the estimated mean IOP (within the range of 22-29 mmHg) found in a large sample of the European population. The European Glaucoma Prevention Study should be able to better address the clinical question of whether pharmacological reduction of IOP (by means of dorzolamide) in ocular hypertension patients at moderate risk for developing primary open-angle glaucoma effectively lowers the incidence of primary open-angle glaucoma.
- Published
- 2002
9. Orexin receptor antagonism for treatment of insomnia: A randomized clinical trial of suvorexant
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Herring, W. J., primary, Snyder, E., additional, Budd, K., additional, Hutzelmann, J., additional, Snavely, D., additional, Liu, K., additional, Lines, C., additional, Roth, T., additional, and Michelson, D., additional
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- 2012
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10. Plasminogen activator inhibitor-1 suppresses endogenous fibrinolysis in a canine model of pulmonary embolism.
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Reilly, C F, primary, Fujita, T, additional, Hutzelmann, J E, additional, Mayer, E J, additional, and Shebuski, R J, additional
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- 1991
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11. Comparison of the safety and efficacy of the fixed combination of dorzolamide/timolol and the concomitant administration of dorzolamide and timolol: a clinical equivalence study
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Hutzelmann, J., Owens, S., Shedden, A., Adamsons, I., and Vargas, E.
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Aims To compare the tolerability and efficacy of a fixed combination solution of dorzolamide/timolol (Cosopt), administered twice daily with the concomitant administration of its components, dorzolamide (Trusopt) twice daily and timolol (Timoptic) twice daily. Methods After a 2 week timolol run in, patients with open angle glaucoma or ocular hypertension were randomised (1:1) to receive treatment with either the dorzolamide/timolol combination solution twice daily (combination) or the dorzolamide solution twice daily plus timolol maleate solution twice daily (concomitant) for 3 months. Results299 patients were entered and 290 patients completed the study. Compared with the timolol baseline, additional IOP lowering of 16% was observed at trough (hour 0) and 22% at peak (hour 2) at month 3 in both the concomitant and combination groups. The IOP lowering effects of the two treatment groups were clinically and statistically equivalent as demonstrated by the extremely small point differences (concomitant - combination) observed in this study-0.01 mm Hg at trough and 0.08 mm Hg at peak. The safety variables of the concomitant and combination groups were very similar. Both combination and concomitant therapy were well tolerated and few patients discontinued due to adverse effects. Conclusions The dorzolamide/timolol combination solution administered twice daily is equivalent in efficacy and has a similar safety profile to the concomitant administration of the components administered twice daily.
- Published
- 1998
12. Pilot evaluation of a consumer wearable device to assess sleep in a clinical polysomnography trial of suvorexant for treating insomnia in patients with Alzheimer's disease.
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Svetnik V, Wang TC, Ceesay P, Snyder E, Ceren O, Bliwise D, Budd K, Hutzelmann J, Stevens J, Lines C, Michelson D, and Herring WJ
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- Azepines, Humans, Pilot Projects, Polysomnography, Sleep, Triazoles, Alzheimer Disease complications, Alzheimer Disease drug therapy, Sleep Initiation and Maintenance Disorders drug therapy, Sleep Initiation and Maintenance Disorders etiology, Wearable Electronic Devices
- Abstract
The orexin receptor antagonist suvorexant was previously reported to significantly improve total sleep time (TST), by 28 min per night versus placebo after 4 weeks, in a sleep laboratory polysomnography (PSG) study of patients with Alzheimer's disease and insomnia. The study included an exploratory evaluation of a consumer-grade wearable "watch" device for assessing sleep that we report on here. Participants who met diagnostic criteria for both probable Alzheimer's disease dementia and insomnia were randomized to suvorexant 10-20 mg (N = 142) or placebo (N = 143) in a double-blind, 4-week trial. Patients were provided with a consumer-grade wearable watch device (Garmin vívosmart
® HR) to be worn continuously. Overnight sleep laboratory PSG was performed on three nights: screening, baseline and Night 29 (last dose). Watch treatment effects were assessed by change-from-baseline in watch TST at Week 4 (average TST per night). We also analysed Night 29 data only, with watch data restricted to the PSG recording time. In the 193 participants included in the Week 4 watch analysis (suvorexant = 97, placebo = 96), the suvorexant-placebo difference in watch TST was 4 min (p = .622). In patients with usable data for both assessments at the baseline and Night 29 PSG (suvorexant = 57, placebo = 50), the watch overestimated TST compared to PSG (e.g., placebo baseline = 412 min for watch and 265 min for PSG) and underestimated change-from-baseline treatment effects: the suvorexant-placebo difference was 20 min for watch TST (p = .405) and 35 min for PSG TST (p = .057). These findings show that the watch was less sensitive than PSG for evaluating treatment effects on TST., (© 2021 European Sleep Research Society.)- Published
- 2021
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13. Polysomnographic assessment of suvorexant in patients with probable Alzheimer's disease dementia and insomnia: a randomized trial.
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Herring WJ, Ceesay P, Snyder E, Bliwise D, Budd K, Hutzelmann J, Stevens J, Lines C, and Michelson D
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- Aged, Female, Humans, Male, Alzheimer Disease psychology, Azepines administration & dosage, Polysomnography, Sleep drug effects, Sleep Aids, Pharmaceutical administration & dosage, Sleep Initiation and Maintenance Disorders drug therapy, Triazoles administration & dosage
- Abstract
Introduction: We evaluated the clinical profile of the orexin receptor antagonist suvorexant for treating insomnia in patients with mild-to-moderate probable Alzheimer's disease (AD) dementia., Methods: Randomized, double-blind, 4-week trial of suvorexant 10 mg (could be increased to 20 mg based on clinical response) or placebo in patients who met clinical diagnostic criteria for both probable AD dementia and insomnia. Sleep was assessed by overnight polysomnography in a sleep laboratory. The primary endpoint was change-from-baseline in polysomnography-derived total sleep time (TST) at week 4., Results: Of 285 participants randomized (suvorexant, N = 142; placebo, N = 143), 277 (97%) completed the trial (suvorexant, N = 136; placebo, N = 141). At week 4, the model-based least squares mean improvement-from-baseline in TST was 73 minutes for suvorexant and 45 minutes for placebo; (difference = 28 minutes [95% confidence interval 11-45], p < 0.01). Somnolence was reported in 4.2% of suvorexant-treated patients and 1.4% of placebo-treated patients., Discussion: Suvorexant improved TST in patients with probable AD dementia and insomnia., (© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)
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- 2020
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14. Phase II Proof-of-Concept Trial of the Orexin Receptor Antagonist Filorexant (MK-6096) in Patients with Major Depressive Disorder.
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Connor KM, Ceesay P, Hutzelmann J, Snavely D, Krystal AD, Trivedi MH, Thase M, Lines C, Herring WJ, and Michelson D
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- Adult, Antidepressive Agents adverse effects, Double-Blind Method, Female, Humans, Male, Middle Aged, Orexin Receptor Antagonists adverse effects, Piperidines adverse effects, Proof of Concept Study, Pyrimidines adverse effects, Treatment Failure, Young Adult, Antidepressive Agents therapeutic use, Depressive Disorder, Major drug therapy, Orexin Receptor Antagonists therapeutic use, Piperidines therapeutic use, Pyrimidines therapeutic use
- Abstract
Background: We evaluated the orexin receptor antagonist filorexant (MK-6096) for treatment augmentation in patients with major depressive disorder., Methods: We conducted a 6-week, double-blind, placebo-controlled, parallel-group, Phase II, proof-of-concept study. Patients with major depressive disorder (partial responders to ongoing antidepressant therapy) were randomized 1:1 to once-daily oral filorexant 10 mg or matching placebo., Results: Due to enrollment challenges, the study was terminated early, resulting in insufficient statistical power to detect a prespecified treatment difference; of 326 patients planned, 129 (40%) were randomized and 128 took treatment. There was no statistically significant difference in the primary endpoint of change from baseline to week 6 in Montgomery Asberg Depression Rating Scale total score; the estimated treatment difference for filorexant-placebo was -0.7 (with negative values favoring filorexant) (P=.679). The most common adverse events were somnolence and suicidal ideation., Conclusions: The interpretation of the results is limited by the enrollment, which was less than originally planned, but the available data do not suggest efficacy of orexin receptor antagonism with filorexant for the treatment of depression. (Clinical Trial Registry: clinicaltrials.gov: NCT01554176)., (© The Author 2017. Published by Oxford University Press on behalf of CINP.)
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- 2017
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15. Suvorexant in Elderly Patients with Insomnia: Pooled Analyses of Data from Phase III Randomized Controlled Clinical Trials.
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Herring WJ, Connor KM, Snyder E, Snavely DB, Zhang Y, Hutzelmann J, Matzura-Wolfe D, Benca RM, Krystal AD, Walsh JK, Lines C, Roth T, and Michelson D
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- Aged, Azepines adverse effects, Double-Blind Method, Female, Humans, Male, Meta-Analysis as Topic, Polysomnography, Sleep Aids, Pharmaceutical therapeutic use, Triazoles adverse effects, Azepines therapeutic use, Sleep Initiation and Maintenance Disorders drug therapy, Triazoles therapeutic use
- Abstract
Objective: Suvorexant is an orexin receptor antagonist approved for treating insomnia at doses of 10-20 mg. Previously reported phase III results showed that suvorexant was effective and well-tolerated in a combined-age population (elderly and nonelderly adults). The present analysis evaluated the clinical profile of suvorexant specifically in the elderly., Methods: Prespecified subgroup analyses of pooled 3-month data from two (efficacy) and three (safety) randomized, double-blind, placebo-controlled, parallel-group trials. In each trial, elderly (≥65 years) patients with insomnia were randomized to suvorexant 30 mg, suvorexant 15 mg, and placebo. By design, fewer patients were randomized to 15 mg. Patient-reported and polysomnographic (subset of patients) sleep maintenance and onset endpoints were measured., Results: Suvorexant 30 mg (N = 319) was effective compared with placebo (N = 318) on patient-reported and polysomnographic sleep maintenance, and onset endpoints at Night 1 (polysomnographic endpoints)/Week 1 (patient-reported endpoints), Month 1, and Month 3. Suvorexant 15 mg (N = 202 treated) was also effective across these measures, although the onset effect was less evident at later time points. The percentages of patients discontinuing because of adverse events over 3 months were 6.4% for 30 mg (N = 627 treated), 3.5% for 15 mg (N = 202 treated), and 5.5% for placebo (N = 469 treated). Somnolence was the most common adverse event (8.8% for 30 mg, 5.4% for 15 mg, 3.2% for placebo)., Conclusion: Suvorexant generally improved sleep maintenance and onset over 3 months of nightly treatment and was well-tolerated in elderly patients with insomnia (clinicaltrials.gov; NCT01097616, NCT01097629, NCT01021813)., (Copyright © 2017 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
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16. Clinical profile of suvorexant for the treatment of insomnia over 3 months in women and men: subgroup analysis of pooled phase-3 data.
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Herring WJ, Connor KM, Snyder E, Snavely DB, Zhang Y, Hutzelmann J, Matzura-Wolfe D, Benca RM, Krystal AD, Walsh JK, Lines C, Roth T, and Michelson D
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- Adult, Aged, Azepines adverse effects, Disorders of Excessive Somnolence chemically induced, Double-Blind Method, Female, Humans, Male, Middle Aged, Polysomnography trends, Sleep drug effects, Sleep physiology, Sleep Aids, Pharmaceutical adverse effects, Sleep Initiation and Maintenance Disorders diagnosis, Time Factors, Treatment Outcome, Triazoles adverse effects, Azepines therapeutic use, Sleep Aids, Pharmaceutical therapeutic use, Sleep Initiation and Maintenance Disorders drug therapy, Statistics as Topic trends, Triazoles therapeutic use
- Abstract
Rationale: Sex-related differences in the clinical profiles of some insomnia medications have been previously reported., Objective: To evaluate the clinical profile of suvorexant, a novel orexin receptor antagonist approved for treating insomnia at doses up to 20 mg, by sex subgroups., Methods: Efficacy analyses by sex were based on pooled data from two similar phase 3, randomized, double-blind, placebo-controlled, 3-month trials in elderly (≥65 years) and non-elderly (18-64 years) insomnia patients. Two age-adjusted (non-elderly/elderly) dose regimes of 40/30 and 20/15 mg were evaluated, with fewer patients assigned to 20/15 mg. Efficacy was assessed by patient-reported outcomes (N = 1264 women, 707 men) and by polysomnography endpoints in ~75% of patients. Safety analyses by sex (N = 1744 women, 1065 men) included pooled data from the two 3-month trials plus 3-month data from a safety trial of 40/30 mg., Results: The sex subgroup efficacy analyses mirrored the improvements seen for suvorexant 40/30 and 20/15 mg over placebo on patient-reported outcomes and polysomnography sleep maintenance and onset endpoints in the primary analyses; 95% CIs excluded zero in favor of suvorexant for most endpoints in both sexes, and similar efficacy was observed between sexes (95% CIs overlapped). Suvorexant was well-tolerated in women and men, although women in all treatment groups (including placebo) reported more adverse events than men. The most frequent adverse event was somnolence (women: 11.1% for 40/30 mg, 8.5% for 20/15 mg, 2.3% for placebo; men: 10.1% for 40/30 mg, 3.4% for 20/15 mg, 4.2% for placebo)., Conclusion: Suvorexant was generally effective and well-tolerated in both women and men with insomnia. ClinicalTrials.gov trial registration numbers: NCT01097616, NCT01097629, NCT01021813.
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- 2017
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17. Suvorexant in Patients with Insomnia: Pooled Analyses of Three-Month Data from Phase-3 Randomized Controlled Clinical Trials.
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Herring WJ, Connor KM, Snyder E, Snavely DB, Zhang Y, Hutzelmann J, Matzura-Wolfe D, Benca RM, Krystal AD, Walsh JK, Lines C, Roth T, and Michelson D
- Subjects
- Adolescent, Adult, Aged, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Male, Middle Aged, Treatment Outcome, Young Adult, Azepines therapeutic use, Sleep Aids, Pharmaceutical therapeutic use, Sleep Initiation and Maintenance Disorders drug therapy, Triazoles therapeutic use
- Abstract
Study Objectives: Suvorexant is an orexin receptor antagonist approved for treating insomnia at a maximum dose of 20 mg. Phase-3 trials evaluated two age-adjusted (non-elderly/elderly) dose-regimes of 40/30 mg and 20/15 mg with the primary focus on 40/30 mg. We report here results from pooled analyses of the 20/15 mg dose-regime, which was evaluated as a secondary objective in the trials., Methods: Prespecified analysis of pooled data from two identical randomized, double-blind, placebo-controlled, parallel-group, 3-month trials in non-elderly (18-64 years) and elderly (≥ 65 years) patients with insomnia. Patients were randomized to suvorexant 20/15 mg (non-elderly/elderly), suvorexant 40/30 mg (non-elderly/elderly), or placebo; by design, fewer patients were randomized to 20/15 mg. Efficacy was assessed by self-reported and polysomnography (PSG; subset of patients) sleep maintenance and onset endpoints., Results: Suvorexant 20/15 mg (N = 493 treated) was effective compared to placebo (N = 767 treated) on patient-reported and PSG sleep maintenance and onset endpoints at Night-1 (PSG endpoints) / Week-1 (subjective endpoints), Month-1 and Month-3, except for effects on PSG sleep onset at Month-3. Suvorexant 20/15 mg was generally well tolerated, with 3% of patients discontinuing due to adverse events over 3 months vs. 5.2% on placebo. Somnolence was the most common adverse event (6.7% vs. 3.3% for placebo). There was no systematic evidence of rebound or withdrawal signs or symptoms when suvorexant was discontinued after 3 months of nightly use., Conclusions: Suvorexant 20/15 mg improved sleep onset and maintenance over 3 months of nightly treatment and was generally safe and well tolerated., Clinical Trial Registration: ClinicalTrials.gov trial registration numbers: NCT01097616, NCT01097629., (© 2016 American Academy of Sleep Medicine.)
- Published
- 2016
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18. A Phase II Dose-Ranging Study Evaluating the Efficacy and Safety of the Orexin Receptor Antagonist Filorexant (MK-6096) in Patients with Primary Insomnia.
- Author
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Connor KM, Mahoney E, Jackson S, Hutzelmann J, Zhao X, Jia N, Snyder E, Snavely D, Michelson D, Roth T, and Herring WJ
- Subjects
- Adolescent, Adult, Cross-Over Studies, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Male, Middle Aged, Orexin Receptor Antagonists adverse effects, Orexin Receptor Antagonists therapeutic use, Piperidines adverse effects, Polysomnography, Pyrimidines adverse effects, Treatment Outcome, Young Adult, Piperidines therapeutic use, Pyrimidines therapeutic use, Sleep Initiation and Maintenance Disorders drug therapy
- Abstract
Background: Filorexant (MK-6096) is an orexin receptor antagonist; here, we evaluate the efficacy of filorexant in the treatment of insomnia in adults., Methods: A double-blind, placebo-controlled, randomized, two 4-week-period, adaptive crossover polysomnography study was conducted at 51 sites worldwide. Patients (18 to <65 years) with insomnia received 1 of 4 doses of oral filorexant (2.5, 5, 10, 20mg) once daily at bedtime during one period and matching placebo in the other period in 1 of 8 possible treatment sequences. Polysomnography was performed on night 1 and end of week 4 of each period. The primary endpoint was sleep efficiency at night 1 and end of week 4. Secondary endpoints included wakefulness after persistent sleep onset and latency to onset of persistent sleep., Results: A total of 324 patients received study treatment, 315 received ≥1 dose of placebo, and 318 ≥1 dose of filorexant (2.5mg, n=79; 5mg, n=78; 10mg, n=80; 20mg, n=81). All filorexant doses (2.5/5/10/20mg) were significantly superior to placebo in improving sleep among patients with insomnia as measured by sleep efficiency and wakefulness after persistent sleep onset on night 1 and end of week 4. The 2 higher filorexant doses (10/20mg) were also significantly more effective than placebo in improving sleep onset as measured by latency to onset of persistent sleep at night 1 and end of week 4. Filorexant was generally well tolerated., Conclusions: Orexin receptor antagonism by filorexant significantly improved sleep efficiency in nonelderly patients with insomnia. Dose-related improvements in sleep onset and maintenance outcomes were also observed with filorexant., (© The Author 2016. Published by Oxford University Press on behalf of CINP.)
- Published
- 2016
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19. Suvorexant in Patients With Insomnia: Results From Two 3-Month Randomized Controlled Clinical Trials.
- Author
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Herring WJ, Connor KM, Ivgy-May N, Snyder E, Liu K, Snavely DB, Krystal AD, Walsh JK, Benca RM, Rosenberg R, Sangal RB, Budd K, Hutzelmann J, Leibensperger H, Froman S, Lines C, Roth T, and Michelson D
- Subjects
- Aged, Azepines adverse effects, Double-Blind Method, Female, Humans, Male, Middle Aged, Orexin Receptor Antagonists adverse effects, Polysomnography, Treatment Outcome, Triazoles adverse effects, Azepines administration & dosage, Orexin Receptor Antagonists administration & dosage, Sleep drug effects, Sleep Initiation and Maintenance Disorders drug therapy, Triazoles administration & dosage, Wakefulness drug effects
- Abstract
Background: Suvorexant is an orexin receptor antagonist for treatment of insomnia. We report results from two pivotal phase 3 trials., Methods: Two randomized, double-blind, placebo-controlled, parallel-group, 3-month trials in nonelderly (18-64 years) and elderly (≥65 years) patients with insomnia. Suvorexant doses of 40/30 mg (nonelderly/elderly) and 20/15 mg (nonelderly/elderly) were evaluated. The primary focus was 40/30 mg, with fewer patients randomized to 20/15 mg. There was an optional 3-month double-blind extension in trial 1. Each trial included a 1-week, randomized, double-blind run-out after double-blind treatment to assess withdrawal/rebound. Efficacy was assessed at week 1, month 1, and month 3 by patient-reported subjective total sleep time and time to sleep onset and in a subset of patients at night 1, month 1, and month 3 by polysomnography end points of wakefulness after persistent sleep onset and latency to onset of persistent sleep (LPS). One thousand twenty-one patients were randomized in trial 1 and 1019 patients in trial 2., Results: Suvorexant 40/30 mg was superior to placebo on all subjective and polysomnography end points at night 1/week 1, month 1, and month 3 in both trials, except for LPS at month 3 in trial 2. Suvorexant 20/15 mg was superior to placebo on subjective total sleep time and wakefulness after persistent sleep onset at night 1/week 1, month 1, and month 3 in both trials and at most individual time points for subjective time to sleep onset and LPS in each trial. Both doses of suvorexant were generally well tolerated, with <5% of patients discontinuing due to adverse events over 3 months. The results did not suggest the emergence of marked rebound or withdrawal signs or symptoms when suvorexant was discontinued., Conclusions: Suvorexant improved sleep onset and maintenance over 3 months of nightly treatment and was generally safe and well tolerated., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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20. Safety and efficacy of suvorexant during 1-year treatment of insomnia with subsequent abrupt treatment discontinuation: a phase 3 randomised, double-blind, placebo-controlled trial.
- Author
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Michelson D, Snyder E, Paradis E, Chengan-Liu M, Snavely DB, Hutzelmann J, Walsh JK, Krystal AD, Benca RM, Cohn M, Lines C, Roth T, and Herring WJ
- Subjects
- Adult, Age Factors, Aged, Double-Blind Method, Female, Follow-Up Studies, Humans, Hypnotics and Sedatives pharmacology, Male, Middle Aged, Retrospective Studies, Time Factors, Treatment Outcome, Azepines therapeutic use, Hypnotics and Sedatives therapeutic use, Orexin Receptor Antagonists, Sleep Initiation and Maintenance Disorders drug therapy, Triazoles therapeutic use
- Abstract
Background: Suvorexant (MK-4305) is an orexin receptor antagonist shown to be efficacious for insomnia over 3 months. We aimed to assess its clinical profile during and after 1 year of treatment., Methods: We did a randomised, placebo-controlled, parallel-group trial at 106 investigational centres in the Americas, Australia, Europe, and South Africa from December, 2009, to August, 2011. Patients aged 18 years or older with primary insomnia by DSM-IV-TR criteria were assigned using a computer-generated randomised allocation schedule to receive nightly suvorexant (40 mg for patients younger than 65 years, 30 mg for patients aged 65 years or older) or placebo at a 2:1 ratio for 1 year with a subsequent 2-month randomised discontinuation phase in which patients on suvorexant either continued suvorexant or were abruptly switched to placebo while patients on placebo remained on placebo. Treatment assignment was masked from patients and investigators. The primary objective was to assess the safety and tolerability of suvorexant for up to 1 year. Secondary objectives were to assess the efficacy of suvorexant for improving patient-reported subjective total sleep time (sTST) and time to sleep onset (sTSO) over the first month of treatment. Efficacy endpoints over the first month were assessed with a mixed model with terms for baseline value of the response variable, age, sex, region, treatment, time, and treatment by time interaction. This trial is registered with ClinicalTrials.gov, number NCT01021813., Findings: 322 (62%) of 522 patients randomly assigned to receive suvorexant and 162 (63%) of 259 assigned to receive placebo completed the 1-year phase. Over 1 year, 362 (69%) of 521 patients treated with suvorexant experienced any adverse events compared with 164 (64%) of 258 treated with placebo. Serious adverse events were recorded in 27 patients (5%) who received suvorexant and 17 (7%) who received placebo. The most common adverse event, somnolence, was reported for 69 patients (13%) who received suvorexant and seven (3%) who received placebo. At month 1, suvorexant (517 patients in the efficacy population) showed greater efficacy than placebo (254 in the efficacy population) in improving sTST (38·7 min vs 16·0 min; difference 22·7, 95% CI 16·4 to 29·0; p<0·0001) and sTSO (-18·0 min vs -8·4 min, difference -9·5, -14·6 to -4·5; p=0·0002)., Interpretation: Our findings show that suvorexant was generally safe and well tolerated over 1 year of nightly treatment in patients with insomnia, with efficacy noted for subjective measures of sleep onset and maintenance., Funding: Merck & Co Inc., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
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21. Alertness and psychomotor performance effects of the histamine-3 inverse agonist MK-0249 in obstructive sleep apnea patients on continuous positive airway pressure therapy with excessive daytime sleepiness: a randomized adaptive crossover study.
- Author
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Herring WJ, Liu K, Hutzelmann J, Snavely D, Snyder E, Ceesay P, Lines C, Michelson D, and Roth T
- Subjects
- Adolescent, Adult, Benzhydryl Compounds administration & dosage, Combined Modality Therapy, Cross-Over Studies, Disorders of Excessive Somnolence therapy, Double-Blind Method, Female, Humans, Male, Middle Aged, Modafinil, Sleep Apnea, Obstructive therapy, Treatment Outcome, Wakefulness-Promoting Agents administration & dosage, Young Adult, Continuous Positive Airway Pressure, Disorders of Excessive Somnolence drug therapy, Histamine Agonists administration & dosage, Psychomotor Performance drug effects, Quinazolinones administration & dosage, Sleep Apnea, Obstructive drug therapy, Wakefulness drug effects
- Abstract
Objectives: We aimed to evaluate the efficacy of the selective H3 receptor inverse agonist MK-0249 to treat excessive daytime sleepiness (EDS)., Methods: In this three-period, double-blind, crossover study, 125 patients (100 men, 25 women; mean age, 48.6 years) with obstructive sleep apnea receiving nasal continuous positive airway pressure therapy who had refractory EDS were randomized to 2 weeks each of daily MK-0249 (5, 8, 10, or 12 mg, adaptively assigned), modafinil 200 mg, and placebo. At baseline and after each treatment period, six maintenance of wakefulness tests (MWT) and Psychomotor Vigilance Tasks (PVT) were conducted at 2-h intervals, beginning 1h postdose (∼09:00). The Epworth sleepiness scale (ESS), Clinical Global Impression of Severity (CGIS) and Digit Symbol Substitution Test (DSST) also were assessed. The primary end point was MWT sleep latency averaged over the first four time points (MWT-early)., Results: MWT-early mean change from baseline sleep latency at week 2 was 1.2 min for placebo, 2.1 min for MK-0249 (top two doses pooled; P>.05 vs. placebo), and 5.9 min for modafinil (P < or = .001 vs. placebo). MK-0249 showed improvements vs placebo on secondary and exploratory end points of ESS, CGIS, PVT, and DSST. Insomnia adverse events (AEs) were greater for MK-0249 (combined doses, 17.5%) than for placebo (0.9%) or modafinil (1.8%)., Conclusion: MK-0249 did not significantly affect MWT sleep latency. However, the pattern of improvement on subjective ratings and psychomotor performance end points suggested that MK-0249 was associated with changes in aspects of cognition and performance not captured by the MWT., (Copyright © 2013 Elsevier B.V. All rights reserved.)
- Published
- 2013
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22. A comparison of the efficacy and tolerability of dorzolamide and acetazolamide as adjunctive therapy to timolol. Oral to Topical CAI Study Group.
- Author
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Hutzelmann JE, Polis AB, Michael AJ, and Adamsons IA
- Subjects
- Acetazolamide administration & dosage, Acetazolamide adverse effects, Administration, Oral, Administration, Topical, Adrenergic beta-Antagonists administration & dosage, Adrenergic beta-Antagonists adverse effects, Adult, Aged, Aged, 80 and over, Carbonic Anhydrase Inhibitors administration & dosage, Carbonic Anhydrase Inhibitors adverse effects, Chemotherapy, Adjuvant, Double-Blind Method, Female, Humans, Intraocular Pressure drug effects, Male, Middle Aged, Ophthalmic Solutions administration & dosage, Ophthalmic Solutions adverse effects, Ophthalmic Solutions therapeutic use, Safety, Sulfonamides administration & dosage, Sulfonamides adverse effects, Thiophenes administration & dosage, Thiophenes adverse effects, Timolol administration & dosage, Timolol adverse effects, Treatment Outcome, Acetazolamide therapeutic use, Adrenergic beta-Antagonists therapeutic use, Carbonic Anhydrase Inhibitors therapeutic use, Glaucoma, Open-Angle drug therapy, Ocular Hypertension drug therapy, Sulfonamides therapeutic use, Thiophenes therapeutic use, Timolol therapeutic use
- Abstract
Purpose: To compare the efficacy and tolerability of dorzolamide to acetazolamide., Methods: Following a timolol and acetazolamide run-in, 105 patients with elevated intraocular pressure (IOP) were randomized to dorzolamide or acetazolamide, in addition to timolol, for 12 weeks., Results: More patients receiving acetazolamide discontinued due to clinical adverse experiences than patients receiving dorzolamide; 13 (25%) vs. 1 (2%); p<0.001. The prevalence of systemic adverse experiences for the dorzolamide group dropped by 50% by Week 12, but remained unchanged for the acetazolamide group, as compared to baseline; p<0.001. Ocular burning/stinging was more common in the dorzolamide group (21% vs. 0%; p<0.001). The mean trough IOP at Day 1 and Week 12 were 20.5 mmHg and 21.8 mmHg for the dorzolamide group, and 20.4 mmHg and 20.5 mmHg for the acetazolamide group. The mean peak IOP at Dayl and Week 12 were 18.9 mmHg and 20.0 mmHg for the dorzolamide group, and 18.7 mmHg and 18.6 mmHg for the acetazolamide group., Conclusions: Mean IOP was slightly lower (by approximately 1 mmHg) with acetazolamide, while dorzolamide demonstrated much better tolerability.
- Published
- 1998
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23. Plasminogen activator inhibitor-1 binds to fibrin and inhibits tissue-type plasminogen activator-mediated fibrin dissolution.
- Author
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Reilly CF and Hutzelmann JE
- Subjects
- Binding, Competitive, Cell Line, Dexamethasone pharmacology, Electrophoresis, Polyacrylamide Gel, Fibrinogen isolation & purification, Fibrosarcoma, Humans, Kinetics, Light, Molecular Weight, Plasminogen Inactivators isolation & purification, Protein Binding, Scattering, Radiation, Fibrin metabolism, Fibrinogen metabolism, Fibrinolysis drug effects, Plasminogen Inactivators metabolism, Plasminogen Inactivators pharmacology, Tissue Plasminogen Activator antagonists & inhibitors
- Abstract
Plasminogen activator inhibitor-1 (PAI-1) accumulates within thrombi and forming whole blood clots. To explore this phenomenon at the molecular level, PAI-1 binding to fibrin was examined. The experiments were performed by adding 125I-PAI-1, which retains its complete tissue-type plasminogen (t-PA) inhibitory activity, to fibrin matrices formed in 2-cm2 tissue culture wells. Guanidine HCl-activated PAI-1 binding was reversible and was inhibited in the presence of excess, unlabeled PAI-1. Activated 125I-PAI-1 recognized 2 sites on fibrin: a very small number of high affinity sites (Kd less than 1 nM) and principally a large number of low affinity sites with an approximate Kd of 3.8 microM. Latent PAI-1 bound to fibrin at a site indistinguishable from the lower affinity site recognized by activated PAI-1. Fibrin, pretreated with activated PAI-1, was protected from t-PA-mediated plasmin degradation in a PAI-1 dose-responsive manner (IC50 = 12.3 nM). Clot protection correlated with partial occupancy of the low affinity PAI-1 binding site on fibrin and was due to the formation of sodium dodecyl sulfate-stable, PAI-1.t-PA complexes. Latent PAI-1 (27 nM) did not protect the fibrin from dissolution. The localization of PAI-1 to a thrombus by virtue of its fibrin binding potential could result in significant protection of the thrombus from the degradative effects of the fibrinolytic system.
- Published
- 1992
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