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Diabetes & Metabolism Journal Dec 2020Obesity is among the leading causes of morbidity and mortality worldwide and its prevalence continues to increase globally. Because obesity is a chronic, complex, and... (Review)
Review
Obesity is among the leading causes of morbidity and mortality worldwide and its prevalence continues to increase globally. Because obesity is a chronic, complex, and heterogeneous disease influenced by genetic, developmental, biological, and environmental factors, it is necessary to approach obesity with an integrated and comprehensive treatment strategy. As it is difficult to achieve and sustain successful long-term weight loss in most patients with obesity through lifestyle modifications (e.g., diet, exercise, and behavioral therapy), pharmacological approaches to the treatment of obesity should be considered as an adjunct therapy. Currently, four drugs (orlistat, naltrexone extended-release [ER]/bupropion ER, phentermine/topiramate controlled-release, and liraglutide) can be used long-term (>12 weeks) to promote weight loss by suppressing appetite or decreasing fat absorption. Pharmacotherapy for obesity should be conducted according to a proper assessment of the clinical evidence and customized to individual patients considering the characteristics of each drug and comorbidities associated with obesity. In this review, we discuss the mechanisms of action, efficacy, and safety of these available long-term anti-obesity drugs and introduce other potential agents under investigation. Furthermore, we discuss the need for research on personalized obesity medicine.
Topics: Anti-Obesity Agents; Benzazepines; Humans; Orlistat; Phentermine; Weight Loss
PubMed: 33389955
DOI: 10.4093/dmj.2020.0258 -
European Journal of Clinical... Aug 2015Hyponatraemia is a very common medical condition that is associated with multiple poor clinical outcomes and is often managed suboptimally because of inadequate...
BACKGROUND
Hyponatraemia is a very common medical condition that is associated with multiple poor clinical outcomes and is often managed suboptimally because of inadequate assessment and investigation. Previously published guidelines for its management are often complex and impractical to follow in a hospital environment, where patients may present to divergent specialists, as well as to generalists.
DESIGN
A group of senior, experienced UK clinicians, met to develop a practical algorithm for the assessment and management of hyponatraemia in a hospital setting. The latest evidence was discussed and reviewed in the light of current clinical practicalities to ensure an up-to-date perspective. An algorithm was largely developed following consensus opinion, followed up with subsequent additions and amendments that were agreed by all authors during several rounds of review.
RESULTS
We present a practical algorithm which includes a breakdown of the best methods to evaluate volume status, simple assessments for the diagnosis of the various causes and a straightforward approach to treatment to minimise complexity and maximise patient safety.
CONCLUSION
The algorithm we have developed reflects the best available evidence and extensive clinical experience and provides practical, useable guidance to improve patient care.
Topics: Algorithms; Anti-Bacterial Agents; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Demeclocycline; Fluid Therapy; Hospitalization; Humans; Hyponatremia; Inappropriate ADH Syndrome; Practice Guidelines as Topic; Tolvaptan; Water-Electrolyte Imbalance
PubMed: 25995119
DOI: 10.1111/eci.12465 -
Clinical Journal of the American... Jan 2023Tolvaptan slows expansion of kidney volume and kidney function decline in adults with autosomal dominant polycystic kidney disease (ADPKD). Progression during childhood... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Tolvaptan slows expansion of kidney volume and kidney function decline in adults with autosomal dominant polycystic kidney disease (ADPKD). Progression during childhood could be treated before irreversible kidney damage occurs, but trial data are lacking. We evaluated the safety and efficacy of tolvaptan in children/adolescents with ADPKD.
METHODS
This was the 1-year, randomized, double-blind, portion of a phase 3b, two-part trial being conducted at 20 academic pediatric nephrology centers. Key eligibility criteria were ADPKD and eGFR ≥60 ml/min per 1.73 m2. Participants aged 12-17 years were the target group (group 1, enrollment goal n≥60); participants aged 4-11 years could additionally enroll (group 2, anticipated enrollment approximately 40). Treatments were tolvaptan or placebo titrated by body weight and tolerability. Coprimary end points, change from baseline in spot urine osmolality and specific gravity at week 1, assessed inhibition of antidiuretic hormone activity. The key secondary end point was change in height-adjusted total kidney volume (htTKV) to month 12 in group 1. Additional end points were safety/tolerability and quality of life. Statistical comparisons were exploratory and post hoc.
RESULTS
Among the 91 randomized (group 1, n=66; group 2, n=25), least squares (LS) mean reduction (±SEM) in spot urine osmolality at week 1 was greater with tolvaptan (-390 [28] mOsm/kg) than placebo (-90 [29] mOsm/kg; P<0.001), as was LS mean reduction in specific gravity (-0.009 [0.001] versus -0.002 [0.001]; P<0.001). In group 1, the 12-month htTKV increase was 2.6% with tolvaptan and 5.8% with placebo (P>0.05). For tolvaptan and placebo, respectively, 65% and 16% of subjects experienced aquaretic adverse events, and 2% and 0% experienced hypernatremia. There were no elevated transaminases or drug-induced liver injuries. Four participants discontinued tolvaptan, and three discontinued placebo. Quality-of-life assessments remained stable.
CONCLUSIONS
Tolvaptan exhibited pharmacodynamic activity in pediatric ADPKD. Aquaretic effects were manageable, with few discontinuations.
CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER
Safety, Pharmacokinetics, Tolerability and Efficacy of Tolvaptan in Children and Adolescents With ADPKD (Autosomal Dominant Polycystic Kidney Disease) NCT02964273.
Topics: Adult; Humans; Adolescent; Child; Tolvaptan; Polycystic Kidney, Autosomal Dominant; Antidiuretic Hormone Receptor Antagonists; Quality of Life; Benzazepines; Kidney
PubMed: 36719158
DOI: 10.2215/CJN.0000000000000022 -
The New England Journal of Medicine Nov 2017In a previous trial involving patients with early autosomal dominant polycystic kidney disease (ADPKD; estimated creatinine clearance, ≥60 ml per minute), the... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In a previous trial involving patients with early autosomal dominant polycystic kidney disease (ADPKD; estimated creatinine clearance, ≥60 ml per minute), the vasopressin V-receptor antagonist tolvaptan slowed the growth in total kidney volume and the decline in the estimated glomerular filtration rate (GFR) but also caused more elevations in aminotransferase and bilirubin levels. The efficacy and safety of tolvaptan in patients with later-stage ADPKD are unknown.
METHODS
We conducted a phase 3, randomized withdrawal, multicenter, placebo-controlled, double-blind trial. After an 8-week prerandomization period that included sequential placebo and tolvaptan run-in phases, during which each patient's ability to take tolvaptan without dose-limiting side effects was assessed, 1370 patients with ADPKD who were either 18 to 55 years of age with an estimated GFR of 25 to 65 ml per minute per 1.73 m of body-surface area or 56 to 65 years of age with an estimated GFR of 25 to 44 ml per minute per 1.73 m were randomly assigned in a 1:1 ratio to receive tolvaptan or placebo for 12 months. The primary end point was the change in the estimated GFR from baseline to follow-up, with adjustment for the exact duration that each patient participated (interpolated to 1 year). Safety assessments were conducted monthly.
RESULTS
The change from baseline in the estimated GFR was -2.34 ml per minute per 1.73 m (95% confidence interval [CI], -2.81 to -1.87) in the tolvaptan group, as compared with -3.61 ml per minute per 1.73 m (95% CI, -4.08 to -3.14) in the placebo group (difference, 1.27 ml per minute per 1.73 m; 95% CI, 0.86 to 1.68; P<0.001). Elevations in the alanine aminotransferase level (to >3 times the upper limit of the normal range) occurred in 38 of 681 patients (5.6%) in the tolvaptan group and in 8 of 685 (1.2%) in the placebo group. Elevations in the aminotransferase level were reversible after stopping tolvaptan. No elevations in the bilirubin level of more than twice the upper limit of the normal range were detected.
CONCLUSIONS
Tolvaptan resulted in a slower decline than placebo in the estimated GFR over a 1-year period in patients with later-stage ADPKD. (Funded by Otsuka Pharmaceuticals and Otsuka Pharmaceutical Development and Commercialization; REPRISE ClinicalTrials.gov number, NCT02160145 .).
Topics: Adolescent; Adult; Aged; Alanine Transaminase; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Bilirubin; Double-Blind Method; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Middle Aged; Polycystic Kidney, Autosomal Dominant; Tolvaptan; Young Adult
PubMed: 29105594
DOI: 10.1056/NEJMoa1710030 -
The Alkaloids. Chemistry and Biology 2017Cephalotaxus alkaloids represent a family of plant secondary metabolites known for 60 years. Significant activity against leukemia in mice was demonstrated for extracts... (Review)
Review
Cephalotaxus alkaloids represent a family of plant secondary metabolites known for 60 years. Significant activity against leukemia in mice was demonstrated for extracts of Cephalotaxus. Cephalotaxine (CET) (1), the major alkaloid of this series was isolated from Cephalotaxus drupacea species by Paudler in 1963. The subsequent discovery of promising antitumor activity among new Cephalotaxus derivatives reported by Chinese, Japanese, and American teams triggered extensive structure elucidation and biological studies in this family. The structural feature of this cephalotaxane family relies mainly on its tetracyclic alkaloid backbone, which comprises an azaspiranic 1-azaspiro[4.4]nonane unit (rings C and D) and a benzazepine ring system (rings A and B), which is linked by its C3 alcohol function to a chiral oxygenated side chain by a carboxylic function alpha to a tetrasubstituted carbon center. The botanical distribution of these alkaloids is limited to the Cephalotaxus genus (Cephalotaxaceae). The scope of biological activities of the Cephalotaxus alkaloids is mainly centered on the antileukemic activity of homoharringtonine (HHT) (2), which in particular demonstrated marked benefits in the treatment of orphan myeloid leukemia and was approved as soon as 2009 by European Medicine Agency and by US Food and Drug Administration in 2012. Its exact mechanism of action was partly elucidated and it was early recognized that HHT (2) inhibited protein synthesis at the level of the ribosome machinery. Interestingly, after a latency period of two decades, the topic of Cephalotaxus alkaloids reemerged as a prolific source of new natural structures. To date, more than 70 compounds have been identified and characterized. Synthetic studies also regained attention during the past two decades, and numerous methodologies were developed to access the first semisynthetic HHT (2) of high purity suitable for clinical studies, and then high grade enantiomerically pure CET (1), HHT (2), and analogs.
Topics: Animals; Antineoplastic Agents, Phytogenic; Harringtonines; Humans
PubMed: 28838429
DOI: 10.1016/bs.alkal.2017.07.001 -
Nephrology, Dialysis, Transplantation :... Mar 2018In TEMPO 3:4, the vasopressin V2 receptor antagonist tolvaptan slowed total kidney volume (TKV) growth and estimated glomerular filtration rate (eGFR) decline relative... (Comparative Study)
Comparative Study Randomized Controlled Trial
Multicenter, open-label, extension trial to evaluate the long-term efficacy and safety of early versus delayed treatment with tolvaptan in autosomal dominant polycystic kidney disease: the TEMPO 4:4 Trial.
BACKGROUND
In TEMPO 3:4, the vasopressin V2 receptor antagonist tolvaptan slowed total kidney volume (TKV) growth and estimated glomerular filtration rate (eGFR) decline relative to placebo.
METHODS
TEMPO 4:4 was designed to provide an additional 2 years of data on the long-term safety and efficacy of tolvaptan in subjects completing TEMPO 3:4. The objective was to assess the disease-modifying effects of tolvaptan on TKV and eGFR end-points including change from baseline over the combined duration of TEMPO 3:4 and TEMPO 4:4, and non-inferiority of slopes during TEMPO 4:4.
RESULTS
Of the 1445 subjects randomized to TEMPO 3:4, 871 (60.3%) enrolled in TEMPO 4:4. Percent changes in TKV from TEMPO 3:4 baseline to TEMPO 4:4 Month 24 were 29.9% and 31.6% (prior tolvaptan versus prior placebo, P = 0.38). Adjusting for baseline covariates improved the TKV treatment difference at Month 24 in TEMPO 4:4 from -1.70% to - 4.15% between the groups (P = 0.04). Slopes of TKV growth during TEMPO 4:4 were higher in early- versus delayed-treatment groups (6.16% versus 4.96% per year, P = 0.05). Analysis of secondary eGFR endpoints demonstrated a persistent effect on eGFR (3.15 mL/min/1.73 m2, P < 0.001), and non-inferiority in eGFR slopes. The safety profile on exposure to tolvaptan in TEMPO 4:4 was similar to that in TEMPO 3:4.
CONCLUSIONS
The results of TEMPO 4:4 support a sustained disease-modifying effect of tolvaptan on eGFR. The lack of a sustained treatment difference on TKV may be accounted for by limitations of the trial design, including loss of randomization and baseline imbalances ensuing TEMPO 3:4. The safety profile was similar to that observed in TEMPO 3:4.
Topics: Adult; Antidiuretic Hormone Receptor Antagonists; Benzazepines; Female; Glomerular Filtration Rate; Humans; Male; Polycystic Kidney, Autosomal Dominant; Prognosis; Time-to-Treatment; Tolvaptan
PubMed: 28379536
DOI: 10.1093/ndt/gfx043 -
Journal of the American College of... Oct 2017The clinical use of ivabradine has and continues to evolve along channels that are predicated on its mechanism of action. It selectively inhibits the funny current (I)... (Review)
Review
The clinical use of ivabradine has and continues to evolve along channels that are predicated on its mechanism of action. It selectively inhibits the funny current (I) in sinoatrial nodal tissue, resulting in a decrease in the rate of diastolic depolarization and, consequently, the heart rate, a mechanism that is distinct from those of other negative chronotropic agents. Thus, it has been evaluated and is used in select patients with systolic heart failure and chronic stable angina without clinically significant adverse effects. Although not approved for other indications, ivabradine has also shown promise in the management of inappropriate sinus tachycardia. Here, the authors review the mechanism of action of ivabradine and salient studies that have led to its current clinical indications and use.
Topics: Benzazepines; Cardiovascular Agents; Cardiovascular Diseases; Cyclic Nucleotide-Gated Cation Channels; Heart Rate; Humans; Ivabradine
PubMed: 28958335
DOI: 10.1016/j.jacc.2017.08.038 -
Trends in Cardiovascular Medicine Aug 2016Heart failure is common and results in substantial morbidity and mortality. Current guideline-based therapies for heart failure with reduced ejection fraction, including... (Review)
Review
Heart failure is common and results in substantial morbidity and mortality. Current guideline-based therapies for heart failure with reduced ejection fraction, including beta blockers, angiotensin converting enzyme (ACE) inhibitors, and aldosterone antagonists aim to interrupt deleterious neurohormonal pathways and have shown significant success in reducing morbidity and mortality associated with heart failure. Continued efforts to further improve outcomes in patients with heart failure with reduced ejection fraction have led to the first new-in-class medications approved for heart failure since 2005, ivabradine and sacubitril/valsartan. Ivabradine targets the If channels in the sinoatrial node of the heart, decreasing heart rate. Sacubitril/valsartan combines a neprilysin inhibitor that increases levels of beneficial vasodilatory peptides with an angiotensin receptor antagonist. On a background of previously approved, guideline-directed medical therapies for heart failure, these medications have shown improved clinical outcomes ranging from decreased hospitalizations in a select group of patients to a reduction in all-cause mortality across all pre-specified subgroups. In this review, we will discuss the previously established guideline-directed medical therapies for heart failure with reduced ejection fraction, the translational research that led to the development of these new therapies, and the results from the major clinical trials of ivabradine and sacubitril/valsartan.
Topics: Aminobutyrates; Angiotensin II Type 1 Receptor Blockers; Anti-Arrhythmia Agents; Benzazepines; Biphenyl Compounds; Cyclic Nucleotide-Gated Cation Channels; Drug Combinations; Heart Failure; Heart Rate; Humans; Ivabradine; Neprilysin; Practice Guidelines as Topic; Protease Inhibitors; Recovery of Function; Signal Transduction; Stroke Volume; Tetrazoles; Treatment Outcome; Valsartan
PubMed: 27038558
DOI: 10.1016/j.tcm.2016.02.008 -
Nature Communications Jul 2022The dearomative functionalization of aromatic compounds represents a fascinating but challenging transformation, as it typically needs to overcome a great kinetic...
The dearomative functionalization of aromatic compounds represents a fascinating but challenging transformation, as it typically needs to overcome a great kinetic barrier. Here, a catalyst-free dearomative rearrangement of o-nitrophenyl alkyne is successfully established by leveraging the remote oxygen transposition and a weak N-O bond acceleration. This reaction features high atom-, step- and redox-economy, which provides a divergent entry to a series of biologically important benzazepines and bridged polycycloalkanones. The reaction is proposed to proceed through a tandem oxygen transfer cyclization/(3 + 2) cycloaddition/(homo-)hetero-Claisen rearrangement reaction. The resulting polycyclic system is richly decorated with transformable functionalities, such as carbonyl, imine and diene, which enables diversity-oriented synthesis of alkaloid-like polycyclic framework.
Topics: Alkaloids; Benzazepines; Cyclization; Cycloaddition Reaction; Oxygen
PubMed: 35906217
DOI: 10.1038/s41467-022-31920-1 -
Circulation Journal : Official Journal... Jun 2022
Topics: Antidiuretic Hormone Receptor Antagonists; Benzazepines; Humans; Tolvaptan
PubMed: 35545552
DOI: 10.1253/circj.CJ-22-0194