H26 A multicenter controlled study of the efficacy safety and dose range of perindopril erbumine with hydrochlorothiazide in hypertension stages 1, 2, and 3

Abstract Background Daprodustat is a hypoxia-inducible factor-prolyl hydroxylase inhibitor currently being investigated as a treatment for anemia of chronic kidney disease (CKD) in both dialysis and nondialysis patients. In clinical studies to date, daprodustat has been administered orally as a once-daily regimen. This randomized, double-blind, placebo-controlled study characterized the initial dose-hemoglobin response as well as the efficacy and safety of three times weekly (TIW) daprodustat in hemodialysis patients switched from stable recombinant human erythropoietin (rhEPO), in accordance with a TIW hemodialysis schedule. Methods 103 patients on hemodialysis with baseline hemoglobin of 9.0 to 11.5 g/dL and previously receiving a stable dose of rhEPO or its analogs were randomized 1:1:1:1:1 to receive daprodustat 10, 15, 25, or 30 mg or placebo TIW over 29 days. Results Mean baseline hemoglobin was 10.6 g/dL for the placebo group and each daprodustat cohort. Daprodustat produced dose-dependent changes in mean hemoglobin from baseline to day 29. Using a Bayesian approach, the estimated dose conversion ratio between once-daily and TIW daprodustat was ~ 2.0 across the evaluated dose range using an Emax model. Daprodustat was generally well tolerated, with an adverse event (AE) profile consistent with the hemodialysis population. Conclusions These data help inform the appropriate dose conversion ratio to be applied to daily doses to obtain equivalent daprodustat TIW doses and suggest TIW treatment with daprodustat can treat anemia of CKD safely, supporting future long-term studies for this indication using a TIW dosing regimen. Trial registration ClinicalTrials.gov Identifier: NCT02689206; date registered: 02/11/2016.

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A Placebo-Controlled Study Evaluating the Efficacy and Safety of Flexible-Dose Desvenlafaxine Treatment in Outpatients with Major Depressive Disorder

CNS Spectrums ◽

10.1017/s1092852900020046 ◽

2009 ◽

Vol 14 (1) ◽

pp. 41-50 ◽

Cited By ~ 28

Author(s):

Alan D. Feiger ◽

Karen A. Tourian ◽

Gregory R. Rosas ◽

S. Krishna Padmanabhan

Keyword(s):

Major Depressive Disorder ◽

Depressive Disorder ◽

Dose Range ◽

Severity Of Illness ◽

Final Evaluation ◽

Analysis Of Covariance ◽

Controlled Study ◽

Double Blind Study ◽

Efficacy And Safety ◽

Major Depressive

ABSTRACTIntroduction: This research compares the efficacy and safety of desvenlafaxine (administered as desvenlafaxine succinate) versus placebo in treating major depressive disorder.Methods: In this randomized, double-blind study, outpatients with major depressive disorder ≥18 years of age received desvenlafaxine 200–400 mg/day or placebo for 8 weeks. Efficacy endpoints included (primary) change in 17-item Hamilton Rating Scale for Depression score at the final evaluation (last observation carried forward, analysis of covariance) and (secondary) Clinical Global Impressions—Improvement and—Severity of Illness scales.Results: The difference between desvenlafaxine (n=117) and placebo (n=118) on the primary endpoint was not significant (−9.1 vs −7.5, P=.078). Week 8 observed cases (desvenlafaxine, n=80; placebo, n=94) results were significant (−10.7 vs −7.9, P=.008). Differences at the final evaluation (last observation carried forward) were significant for Clinical Global Impressions—Improvement (2.9 vs 2.5, P=.037) and Clinical Global Impressions—Severity of Illness (−1.9 vs −1.2, P=.041). Discontinuation rates due to adverse events (AEs) were 12% and 3% for desvenlafaxine and placebo, respectively (P=.008). The most frequently reported AE associated with desvenlafaxine was nausea (36% vs 9% [placebo]).Conclusion: In this study, the primary analysis did not show significant differences between desvenlafaxine and placebo; discontinuations due to AEs associated with the desvenlafaxine dose range may have contributed to the lack of statistical separation.

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Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Oral Doses of Bi 187004, an Inhibitor of 11beta-hydroxysteroid Dehydrogenase-1, in Healthy Male Volunteers With Overweight or Obesity

10.21203/rs.3.rs-102560/v1 ◽

2020 ◽

Author(s):

Susanna Bianzano ◽

Tim Heise ◽

Arvid Jungnik ◽

Cornelia Schepers ◽

Corinna Schoelch ◽

...

Keyword(s):

Adipose Tissue ◽

Single Dose ◽

Adverse Events ◽

Subcutaneous Adipose Tissue ◽

Dose Range ◽

Hydroxysteroid Dehydrogenase ◽

Controlled Study ◽

Once Daily ◽

Subcutaneous Adipose ◽

Overweight Or Obesity

Abstract BackgroundThe study characterizes safety, tolerability, pharmacokinetic and pharmacodynamic profiles of single rising doses of the 11beta-hydroxysteroid dehydrogenase-1 (11beta-HSD1) inhibitor BI 187004 in healthy men with overweight or obesity.MethodsThis was a randomized, double-blind, parallel group, placebo-controlled study with administration of 2.5-360 mg BI 187004 or placebo once daily as single dose in 72 healthy volunteers with overweight or obesity.Assessments included 11beta-HSD1 inhibition in the liver (assessed indirectly by urinary tetrahydrocortisol/tetrahydrocotisone ratio) and in subcutaneous adipose tissue ex vivo and determination of hypothalamus-pituitary-adrenal axis hormones.ResultsBI 187004 was well tolerated and safe in all tested dose groups. The incidence of drug-related adverse events was 16.7% (n=9) for all 9 BI 187004 dose groups and 5.9% (n=1) for placebo. All treatment groups were similar concerning kind and intensity of adverse events. No clinically relevant deviations in clinical laboratory or ECG parameters were reported. Exposure of BI 187004 increased non‑proportionally over the entire dose range tested. The geometric mean apparent terminal half-life decreased from 33.5h (5 mg) to 14.5h (160 mg) remaining stable up to 360 mg. Renal excretion of BI 187004 was low (3-5%). Urinary tetrahydrocortisol/tetrahydrocotisone ratio decreased, indicating liver 11beta-HSD1 inhibition. Median inhibition of 11beta-HSD1 in subcutaneous adipose tissue biopsies following single dosing ranged from 86.8% (10 mg) to 99.5% (360 mg) after 10h and from 59.4% (10 mg) to 98.6% (360 mg) after 24h. ConclusionsBI 187004 as single dose was safe and well tolerated and is suitable for once daily dosing. There was significant, sustained 11beta-HSD1 inhibition in liver and adipose tissue. Trial registry number: ClinicalTrials.gov, NCT01587417, registered on 26-Apr-2012, https://clinicaltrials.gov/ct2/show/study/NCT01587417

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Efficacy and safety of Dexmedetomidine for prevention of withdrawal syndrome in Pediatric Intensive Care Unit Protocol for a prospective, multicenter, randomized, double blind, placebo-controlled, non-profit clinical trial (TIP-15-01)

10.21203/rs.2.491/v1 ◽

2019 ◽

Author(s):

Maria Cristina Mondardini ◽

Giorgio Conti ◽

Fabio Caramelli ◽

Francesca Sperotto ◽

Marco Daverio ◽

...

Keyword(s):

Intensive Care Unit ◽

Intensive Care ◽

Pediatric Intensive Care Unit ◽

Withdrawal Syndrome ◽

Dose Range ◽

Pediatric Intensive Care ◽

Prolonged Treatment ◽

Controlled Study ◽

Double Blind ◽

Double Blind Placebo

Abstract Background: Prolonged treatment with analgesic and sedative drugs in Pediatric Intensive Care Unit (PICU) may lead to undesirable effects as dependence and tolerance. Moreover, during the analgosedation weaning patients may develop clinical signs of withdrawal, known as withdrawal syndrome (WS). Some studies indicated that dexmedetomidine, a selective α2-adrenoceptors agonist, may be useful to prevent WS, but no clear evidences still support this data. Aims of the present study are to evaluate the efficacy of dexmedetomidine in reducing the occurrence of WS during the analgosedation weaning, to evaluate its safety, to identify its optimal dose-range and to quantify its ability in reducing time of weaning, time of mechanical ventilation and PICU-stay. Methods: We will perform a prospective, multicenter, randomized, double-blind, placebo-controlled study. Patients meeting the inclusion criteria will be randomly assigned to treatment A (dexmedetomidine) or treatment B (placebo). Treatments will be started 24 hours before the analgosedation-weaning and will be continued throughout the whole weaning time. Efficacy of treatments will be evaluated by monitoring the signs of WS using the withdrawal assessment tool version 1 score (WAT-1). If WAT-1 score is ≥3, dexmedetomidine/placebo-dose will be increased following a defined protocol. Thus, efficacy will be compared between treatment groups. Safety will be assessed collecting any potentially-related adverse event. Clinical or sedation characteristics will be analyzed to assess any significant association with outcome measures. The sample size assuring a power of 95% is 80 patients for each group (N total=160 patients). The study was approved by the Ethics Committee of the University-Hospital S.Orsola-Malpighi of Bologna on 22 March 2017. Discussion: The present trial will allow to clearly assess the efficacy of dexmedetomidine in reducing the occurrence of WS during the weaning of analgosedation drugs. In addition, the study will provide a unique insight into the safety profile of dexmedetomidine. Trial registration: ClinicalTrials.gov ID NCT03645603, registered on 24 August 2018, https://clinicaltrials.gov/ct2/show/NCT03645603. Retrospectively registered on EudraCT with ID 2015-002114-80, registered on 2 Jan 2019.

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A Controlled Trial with Diclofensine, a New Psychoactive Drug, in the Treatment of Depression

Journal of International Medical Research ◽

10.1177/030006058100900505 ◽

1981 ◽

Vol 9 (5) ◽

pp. 324-329 ◽

Cited By ~ 14

Author(s):

C Cherpillod ◽

L M O Omer

Keyword(s):

Controlled Trial ◽

Dose Range ◽

Severe Depression ◽

Controlled Study ◽

Clinical Effects ◽

Double Blind ◽

Reference Drug ◽

Efficacy Index ◽

Double Blind Design ◽

To Receive

Diclofensine inhibits the uptake of serotonin, noradrenaline and dopamine. In a controlled study, out-patients suffering from moderate to severe depression were treated with the objective of assessing the new drug's therapeutically effective dose range. Maprotiline was used as a reference drug: fourteen patients were assigned to receive diclofensine and thirteen to receive maprotiline in a double-blind design. Depending on tolerance and efficacy, they were treated for periods ranging from 5 to 150 days. Doses were titrated to the optimum. Findings suggest that a 50 mg daily dose of diclofensine would be sufficient for the majority of the patients. The dosage can be safely increased up to 150 mg daily but this offers few therapeutic advantages. While the efficacy index of the two drugs was similar (approximately 60%), they differed greatly in their profile of side-effects. No signs of abrupt dissipation of the achieved clinical effects were observed during continued treatment, and no withdrawal reactions were observed when the treatment was stopped. The new drug may be more effective in treating patients in whom a psycho-energizing and mood alleviating effect is desired.

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Safety, pharmacokinetics and exploratory pro-cognitive effects of HTL0018318, a selective M1 receptor agonist, in healthy younger adult and elderly subjects: a multiple ascending dose study

Alzheimer s Research & Therapy ◽

10.1186/s13195-021-00816-5 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Charlotte Bakker ◽

Tim Tasker ◽

Jan Liptrot ◽

Ellen P. Hart ◽

Erica S. Klaassen ◽

...

Keyword(s):

Blood Pressure ◽

Cognitive Dysfunction ◽

Dose Range ◽

Symptomatic Treatment ◽

Controlled Study ◽

Elderly Subjects ◽

Maximum Plasma ◽

Cognitive Effects ◽

Short Term ◽

Multiple Doses

Abstract Background The cholinergic system and M1 receptor remain an important target for symptomatic treatment of cognitive dysfunction. The selective M1 receptor partial agonist HTL0018318 is under development for the symptomatic treatment of Dementia’s including Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). We investigated the safety, tolerability, pharmacokinetics and exploratory pharmacodynamics of multiple doses of HTL0018318 in healthy younger adults and elderly subjects. Methods This randomised, double blind, placebo-controlled study was performed, investigating oral doses of 15–35 mg/day HTL0018318 or placebo in 7 cohorts of healthy younger adult (n = 36; 3 cohorts) and elderly (n = 50; 4 cohorts) subjects. Safety, tolerability and pharmacokinetic measurements were performed. Pharmacodynamics were assessed using a battery of neurocognitive tasks and electrophysiological biomarkers of synaptic and cognitive functions. Results HTL0018318 was generally well-tolerated in multiple doses up to 35 mg/day and were associated with mild or moderate cholinergic adverse events. There were modest increases in blood pressure and pulse rate when compared to placebo-treated subjects, with tendency for the blood pressure increase to attenuate with repeated dosing. There were no clinically significant observations or changes in blood and urine laboratory measures of safety or abnormalities in the ECGs and 24-h Holter assessments. HTL0018318 plasma exposure was dose-proportional over the range 15–35 mg. Maximum plasma concentrations were achieved after 1–2 h. The apparent terminal half-life of HTL0018318 was 16.1 h (± 4.61) in younger adult subjects and 14.3 h (± 2.78) in elderly subjects at steady state. HTL0018318 over the 10 days of treatment had significant effects on tests of short-term (working) memory (n-back) and learning (Milner maze) with moderate to large effect sizes. Conclusion Multiple doses of HTL0018138 showed well-characterised pharmacokinetics and were safe and generally well-tolerated in the dose range studied. Pro-cognitive effects on short-term memory and learning were demonstrated across the dose range. These data provide encouraging data in support of the development of HTL0018138 for cognitive dysfunction in AD and DLB. Trial registration Netherlands Trial Register identifier NTR5781. Registered on 22 March 2016.

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Application of a Simple Cold Stub to the Direct Observation of Frozen Hydrated Sand

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100071508 ◽

1973 ◽

Vol 31 ◽

pp. 212-213

Author(s):

John M. Wehrung ◽

Richard J. Harniman

Keyword(s):

United States ◽

Surface Water ◽

Direct Observation ◽

Controlled Study ◽

Clay Particles ◽

Organic Debris ◽

Rock Formations ◽

Water Tables ◽

Permeable Rock ◽

Natural Means

Water tables in aquifer regions of the southwest United States are dropping off at a rate which is greater than can be replaced by natural means. It is estimated that by 1985 wells will run dry in this region unless adequate artificial recharging can be accomplished. Recharging with surface water is limited by the plugging of permeable rock formations underground by clay particles and organic debris.A controlled study was initiated in which sand grains were used as the rock formation and water with known clay concentrations as the recharge media. The plugging mechanism was investigated by direct observation in the SEM of frozen hydrated sand samples from selected depths.

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Studies of metaphase chromosomes in the scanning transmission x-ray microscope: Image fidelity, radiation damage and specimen preparation

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100129826 ◽

1992 ◽

Vol 50 (2) ◽

pp. 1038-1039

Author(s):

Shawn Williams ◽

Xiaodong Zhang ◽

Susan Lamm ◽

Jack Van’t Hof

Keyword(s):

Visible Light ◽

Radiation Damage ◽

Cross Section ◽

Imaging Techniques ◽

Dose Range ◽

Specimen Preparation ◽

X Rays ◽

Metaphase Chromosomes ◽

X Ray ◽

Scanning Transmission

The Scanning Transmission X-ray Microscope (STXM) is well suited for investigating metaphase chromosome structure. The absorption cross-section of soft x-rays having energies between the carbon and oxygen K edges (284 - 531 eV) is 6 - 9.5 times greater for organic specimens than for water, which permits one to examine unstained, wet biological specimens with resolution superior to that attainable using visible light. The attenuation length of the x-rays is suitable for imaging micron thick specimens without sectioning. This large difference in cross-section yields good specimen contrast, so that fewer soft x-rays than electrons are required to image wet biological specimens at a given resolution. But most imaging techniques delivering better resolution than visible light produce radiation damage. Soft x-rays are known to be very effective in damaging biological specimens. The STXM is constructed to minimize specimen dose, but it is important to measure the actual damage induced as a function of dose in order to determine the dose range within which radiation damage does not compromise image quality.

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Studies on Ultrastructure and Cytochemistry of Right Ventricular Endomyocardial Biopsy

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100158820 ◽

1990 ◽

Vol 48 (3) ◽

pp. 256-257

Author(s):

Xia Mingyu ◽

Ma Wengshu ◽

Wu Xiangh ◽

Chen Dong

Keyword(s):

Light Microscopy ◽

Right Ventricular ◽

Dilated Cardiomyopathy ◽

Endomyocardial Biopsy ◽

Heart Diseases ◽

Ultrastructural Localization ◽

Controlled Study ◽

Myocardial Biopsy ◽

Morphological Assessment ◽

Rheumatic Heart

This paper describes morphological and cytochemistry changes of endomyocardial biopsy in 94 patients. The samples of myoicardium were taken from 32 patients with dilated cardiomyopathy, and sdudied with light and electron microscop. The cytochemical studies in some of these patients were performed at histological and ultrastructure level. This paper also reported the result of myocardial biopsy in 33 patients with serious dysrythmia.The result of this controlled study indicates that morphological assessment in both cardiomyopathy and congenital or rheumatic heart diseases showed no special changes. In patients of dilated cardiomyopathy, the decreased activity of myosin ATPase was secondary to cardial failure. The change of succinate dehydrogenase (SDHase) was not significant with light microscopy. But ultrastructural localization of SDHase activity is valuable. Its activity was found to be localized in endomembrane and ridge of the mitochondria, the activity of this enzyme was decrease, normal, or increase. SDHase activity was more intense in cardial myocytes well-functioning, or ultrastructurally well preserved hearts.

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Morphometric analysis of peroxisomes in hepatocytes of alcohol-fed rats

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100157486 ◽

1989 ◽

Vol 47 ◽

pp. 1100-1101

Author(s):

D.C. Dominguez ◽

J.T. Ellzey

Keyword(s):

Caloric Intake ◽

Volume Density ◽

Controlled Study ◽

Control Group ◽

Numerical Density ◽

Cacodylate Buffer ◽

Paired Control ◽

Experimental Group ◽

Liver Peroxisomes ◽

Single Lesion

Peroxisomes which participate in 1ipid metabolism have been shown to be altered in several metabolic disorders and toxic conditions. In alcoholic liver disease, the single lesion most frequently found is lipid accumu1ation in hepatocytes. However, the mechanisms for this 1ipid accumu1ation are not clear. The occurrence of modifications of liver peroxisomes due to excess alcohol consumption has not been subjected to a controlled study. We utilized a combination of cytochemica1 and morphometrictechniques to study the size and number of liver peroxisomes in rats fed an alcohol-supplemented diet compared to those of matched-paired control animals.Male Sprague-Daw1ey rats (400-500 g) received a liquid diet. The experimental group (N = 5/group) was fed a diet containing 30% ethanol-derived calories (EDC) and the control group was fed an isocaloric diet to 30% EDC. A pair feeding procedure was employed to control for caloric intake. Small pieces of liver randomly selected, were fixed in 2.3% -glutaraldehyde in 0.1 M sodium cacodylate buffer, pH 7.2, incubated in a DAB medium and postfixed with. 2% aqueous osmium tetroxide. EM photographs were taken from sections of 3 tissue blocks from each sample (7,200X) with a Zeiss EM10-A (60 kV). With the use of a point counting method and a digital planimeter the volume density (Vv) and numerical density (Nv) were determined.

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