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Clujul Medical (1957) 2016Beta-adrenergic antagonists have been established as first line treatment in the medical management of hypertension, acute coronary syndrome and other cardiovascular...
BACKGROUND AND AIM
Beta-adrenergic antagonists have been established as first line treatment in the medical management of hypertension, acute coronary syndrome and other cardiovascular diseases, as well as for the prevention of initial episodes of gastrointestinal bleeding in patients with cirrhosis and esophageal varices, glaucoma, and have recently become the main form of treatment of infantile hemangiomas. The aim of the present study is to calculate for 14 beta-blockers several quantum chemical descriptors in order to interpret various molecular properties such as electronic structure, conformation, reactivity, in the interest of determining how such descriptors could have an impact on our understanding of the experimental observations and describing various aspects of chemical binding of beta-blockers in terms of these descriptors.
METHODS
The 2D chemical structures of the beta-blockers (14 molecules with one stereogenic center) were cleaned in 3D, their geometry was preoptimized using the software MOPAC2012, by PM6 method, and then further refined using standard settings in MOE; HOMO and LUMO descriptors were calculated using semi-empirical molecular orbital methods AM1, MNDO and PM3, for the lowest energy conformers and the quantum chemical descriptors (HLG, electronegativity, chemical potential, hardness and softness, electrophilicity) were then calculated.
RESULTS
According to HOMO-LUMO gap and the chemical hardness the most stable compounds are alprenolol, bisoprolol and esmolol. The softness values calculated for the study molecules revolve around 0.100. Propranolol, sotalol and timolol have among the highest electrophilicity index of the studied beta-blocker molecules. Results obtained from calculations showed that acebutolol, atenolol, timolol and sotalol have the highest values for the electronegativity index.
CONCLUSIONS
The future aim is to determine whether it is possible to find a valid correlation between these descriptors and the physicochemical behavior of the molecules from this class. The HLG could be correlated to the experimentally recorded electrochemical properties of the molecules. HOMO could be correlated to the observed oxidation potential, since the required voltage is related to the energy of the HOMO, because only the electron from this orbital is involved in the oxidation process.
PubMed: 27857521
DOI: 10.15386/cjmed-610 -
British Journal of Clinical Pharmacology Aug 2016Peripheral vasoconstriction has long been described as a vascular adverse effect of β-adrenoceptor blockers. Whether β-adrenoceptor blockers should be avoided in... (Comparative Study)
Comparative Study Meta-Analysis Review
AIM
Peripheral vasoconstriction has long been described as a vascular adverse effect of β-adrenoceptor blockers. Whether β-adrenoceptor blockers should be avoided in patients with peripheral vascular disease depends on pharmacological properties (e.g. preferential binding to β1 -adrenoreceptors or intrinsic sympathomimetic activity). However, this has not been confirmed in experimental studies. We performed a network meta-analysis in order to assess the comparative risk of peripheral vasoconstriction of different β-adrenoceptor blockers.
METHOD
We searched for randomized controlled trials (RCTs) including β-adrenoceptor blockers that were published in core clinical journals in the Pubmed database. All RCTs reporting peripheral vasoconstriction as an adverse effect of β-adrenoceptor blockers and controls were included. Sensitivity analyses were conducted including possibly confounding covariates (latitude, properties of the β-adrenoceptor blockers, e.g. intrinsic sympathomimetic activity, vasodilation, drug indication, drug doses). The protocol and the detailed search strategy are available online (PROSPERO registry CRD42014014374).
RESULTS
Among 2238 records screened, 38 studies including 57 026 patients were selected. Overall, peripheral vasoconstriction was reported in 7% of patients with β-adrenoceptor blockers and 4.6% in the control groups (P < 0.001), with heterogeneity among drugs. Atenolol and propranolol had a significantly higher risk than placebo, whereas pindolol, acebutolol and oxprenolol had not.
CONCLUSION
Our results suggest that β-adrenoceptor blockers have variable propensity to enhance peripheral vasoconstriction and that it is not related to preferential binding to β1 -adrenoceptors. These findings challenge FDA and European recommendations regarding precautions and contra-indications of use of β-adrenoceptor blockers and suggest that β-adrenoceptor blockers with intrinsic sympathomimetic activity could be safely used in patients with peripheral vascular disease.
Topics: Adrenergic beta-Antagonists; Dose-Response Relationship, Drug; Humans; Randomized Controlled Trials as Topic; Sympathomimetics; Vasoconstriction; Vasodilation
PubMed: 27085011
DOI: 10.1111/bcp.12980 -
Medicine Jan 2016Smith-Magenis syndrome (SMS0) is a complex and rare genetic multisystem disorder characterized by a variable pattern of cognitive deficits accompanied by a1 distinctive...
Smith-Magenis syndrome (SMS0) is a complex and rare genetic multisystem disorder characterized by a variable pattern of cognitive deficits accompanied by a1 distinctive behavioral phenotype. SMS is characterized by subtle facial dysmorphology, short stature, sleep disturbances, and neurobehavioral abnormalities. Little is known about the manifestation of his unique case among Arab population and its strategic treatment.This study comes to present a case of SMS in an Arab newborn male who was born in spontaneous delivery on June 29, 2015, with tachypnea, tracheomalacia, and mild hypotonia. The newborn was admitted on the Neonatal Intensive Care Unit (NICU), and various laboratory examinations and clinical examinations were performed.Throughout his hospitalization, feeding difficulties appeared and thus a peripheral venous catheter was inserted in the left leg.After 22 days of follow-up and hospitalizations, the patient status improved and he was discharged with recommendations to be in follow up in pediatric outpatient clinic.However, notwithstanding the different investigations, intermittent tachypnea continued at a rate of 72 to 77 breaths/min. Search for diagnosis begin intensively owing to persistence of tachypnia, mild hypotonia, feeding difficulties, sleep disturbances, and mild dysmorphic facial features. Suspicions of genetic abnormalities were considered and blood samples were sent for chromosome analysis and for fluorescent in situ hybridization (FISH) testing.The genetic results revealed the following: cytogenetic findings: 46, XY, del(17)(p11.2) and the FISH results: del(17)(p11.2p11.2) (D17S29). The chromosome diagnosis revealed an interstitial deletion of 17p11.2 and the diagnosis of the SMS was confirmed.Accurate clinical diagnosis, therapeutic assessments and a holistic management plans, including multidiscipline therapeutic strategies, periodic neuro-developmental assessments, and an early intervention programs, are recommended.However, cytogenetic analysis or FISH using an RAI1-specific probe is the most frequently used technique for DS. Sleep and behavioral disturbances treatment include a combination of the daytime dose of acebutolol with an evening oral dose of melatonin. Melatonin as chronobiotic, antioxidant, and analgesic agent showed to be effective in different primary sleep disorders and in those associated with neurobehavioral disorders. Based on the beneficial effect of melatonin, it will be useful to use serum levels of melatonin as a follow-up test.
Topics: Acebutolol; Adrenergic beta-1 Receptor Antagonists; Antioxidants; Arabs; Chromosome Deletion; Drug Combinations; Humans; In Situ Hybridization, Fluorescence; Infant, Newborn; Israel; Male; Melatonin; Phenotype; Residence Characteristics; Smith-Magenis Syndrome
PubMed: 26817868
DOI: 10.1097/MD.0000000000002362 -
The Cochrane Database of Systematic... Nov 2014Partial agonists are a subclass of beta blockers used to treat hypertension in many countries. Partial agonist act by stimulating beta receptors when they are quiescent... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Partial agonists are a subclass of beta blockers used to treat hypertension in many countries. Partial agonist act by stimulating beta receptors when they are quiescent and blocking beta receptors when they are active. The blood pressure (BP) lowering effect of partial agonist beta blockers has not been quantified.
OBJECTIVES
To quantify the dose-related effects of various partial agonists beta blockers on systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate versus placebo in patients with primary hypertension.
SEARCH METHODS
We searched the Hypertension Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE In-Process, EMBASE and ClinicalTrials.gov for randomized controlled trials up to October 2014. The WHO International Clinical Trials Registry Platform (ICTRP) is searched for inclusion in the Group's Specialised Register.
SELECTION CRITERIA
Randomized double-blinded placebo-controlled parallel or cross-over trials. Studies must contain a partial agonist monotherapy arm with fixed dose. Patients enrolled into the studies must have primary hypertension at baseline (defined as SBP/DBP > 140/90 mmHg). Duration of studies must be between three to 12 weeks.
DATA COLLECTION AND ANALYSIS
Two authors (GW and HB) confirmed the inclusion of studies and extracted the data independently.
MAIN RESULTS
Thirteen randomized double-blinded placebo-controlled trials that examined the blood pressure lowering efficacy of six partial agonists in 605 hypertensive patients were included in this review. Five of the included studies were parallel studies and the other eight were cross-over studies. The overall risk of bias is high in this review due to the small sample size and high risk of detection bias. Pindolol, celiprolol and alprenolol lowered SBP and DBP compared to placebo. Acebutolol lowered SBP but there was no clear evidence that it lowered DBP. There was no clear evidence that pindolol and oxprenolol lowered SBP or DBP. Other than for celiprolol, sample sizes were generally small increasing the uncertainty in findings for individual agents versus placebo. In patients with moderate to severe hypertension, partial agonists (considered as a subclass) lowered peak BP by an average of 8 mmHg systolic (95% CI, -10 to -6, very low quality evidence), 4 mmHg diastolic (95%CI, -5 to -3, very low quality evidence) and reduced heart rate by five beats per minute (95%CI, -6 to -4, very low quality evidence). Higher dose partial agonists did not appear to provide additional BP lowering effects compared to lower dose. The maximum BP lowering effect of the overall subclass occurred at the starting dose. Partial agonists reduced pulse pressure by 4 mmHg (95% CI, -5 to -2, very low evidence). Only one study reported withdrawal due to adverse effects, the risk ratio (95% confidence interval) was 0.72 (0.07, 7.67).
AUTHORS' CONCLUSIONS
There was very low quality evidence that in patients with moderate to severe hypertension, partial agonists lowered peak BP by an average of 8/4 mmHg and reduced heart rate by five beats per minute. There was no evidence of a greater effect at doses higher than the initial doses. This estimate was probably exaggerated as it was subject to a high risk of bias. Based on the indirect comparison of the results in this review and two Cochrane reviews on angiotensin-converting-enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), which also used similar inclusion criteria as this review, the BP lowering effect appeared to be less than the effect in patients with mild to moderate elevated BP who were taking ACE inhibitors and ARBs based on an indirect comparison. Withdrawals due to adverse effects were only reported in one trial so it is impossible to assess the harm of these drugs.
Topics: Adrenergic beta-1 Receptor Antagonists; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Essential Hypertension; Heart Rate; Humans; Hypertension; Randomized Controlled Trials as Topic
PubMed: 25427719
DOI: 10.1002/14651858.CD007450.pub2 -
Journal of the American Society of... Apr 2015Some β-blockers are efficiently removed from the circulation by hemodialysis ("high dialyzability") whereas others are not ("low dialyzability"). This characteristic... (Comparative Study)
Comparative Study
Some β-blockers are efficiently removed from the circulation by hemodialysis ("high dialyzability") whereas others are not ("low dialyzability"). This characteristic may influence the effectiveness of the β-blockers among patients receiving long-term hemodialysis. To determine whether new use of a high-dialyzability β-blocker compared with a low-dialyzability β-blocker associates with a higher rate of mortality in patients older than age 66 years receiving long-term hemodialysis, we conducted a propensity-matched population-based retrospective cohort study using the linked healthcare databases of Ontario, Canada. The high-dialyzability group (n=3294) included patients initiating atenolol, acebutolol, or metoprolol. The low-dialyzability group (n=3294) included patients initiating bisoprolol or propranolol. Initiation of a high- versus low-dialyzability β-blocker was associated with a higher risk of death in the following 180 days (relative risk, 1.4; 95% confidence interval, 1.1 to 1.8; P<0.01). Supporting this finding, we repeated the primary analysis in a cohort of patients not receiving hemodialysis and found no significant association between dialyzability and the risk of death (relative risk, 1.0; 95% confidence interval, 0.9 to 1.3; P=0.71). β-Blocker exposure was not randomly allocated in this study, so a causal relationship between dialyzability and mortality cannot be determined. However, our findings should raise awareness of this potentially important drug characteristic and prompt further study.
Topics: Adrenergic beta-Antagonists; Aged; Aged, 80 and over; Cardiovascular Diseases; Female; Humans; Kidney Failure, Chronic; Male; Ontario; Renal Dialysis; Retrospective Studies
PubMed: 25359874
DOI: 10.1681/ASN.2014040324 -
Acta Poloniae Pharmaceutica 2013The suitability and effectiveness of a few spectrophotometric and chromatographic methods (UV, FT-IR, MS, TLC) for differentiating analysis of 6 beta-blockers:... (Comparative Study)
Comparative Study
The suitability and effectiveness of a few spectrophotometric and chromatographic methods (UV, FT-IR, MS, TLC) for differentiating analysis of 6 beta-blockers: acebutolol, alprenolol, atenolol, metoprolol, pindolol and propranolol have been tested.
Topics: Adrenergic beta-Antagonists; Chromatography, Thin Layer; Mass Spectrometry; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared; Water
PubMed: 24147355
DOI: No ID Found -
American Journal of Botany Jul 2013Global change requires plant ecologists to predict future states of biological diversity to aid the management of natural communities, thus introducing a number of...
Global change requires plant ecologists to predict future states of biological diversity to aid the management of natural communities, thus introducing a number of significant challenges. One major challenge is considering how the many interacting features of biological systems, including ecophysiological processes, plant life histories, and species interactions, relate to performance in the face of a changing environment. We have employed a functional trait approach to understand the individual, population, and community dynamics of a model system of Sonoran Desert winter annual plants. We have used a comprehensive approach that connects physiological ecology and comparative biology to population and community dynamics, while emphasizing both ecological and evolutionary processes. This approach has led to a fairly robust understanding of past and contemporary dynamics in response to changes in climate. In this community, there is striking variation in physiological and demographic responses to both precipitation and temperature that is described by a trade-off between water-use efficiency (WUE) and relative growth rate (RGR). This community-wide trade-off predicts both the demographic and life history variation that contribute to species coexistence. Our framework has provided a mechanistic explanation to the recent warming, drying, and climate variability that has driven a surprising shift in these communities: cold-adapted species with more buffered population dynamics have increased in relative abundance. These types of comprehensive approaches that acknowledge the hierarchical nature of biology may be especially useful in aiding prediction. The emerging, novel and nonstationary climate constrains our use of simplistic statistical representations of past plant behavior in predicting the future, without understanding the mechanistic basis of change.
Topics: Acebutolol; Climate Change; Desert Climate; Ecosystem; Environmental Monitoring; Photosynthesis; Plant Physiological Phenomena; Plants; Population Dynamics; Seasons
PubMed: 23838034
DOI: 10.3732/ajb.1200463 -
Journal of General Internal Medicine Sep 2013Systematic review of preventive pharmacologic treatments for community-dwelling adults with episodic migraine. (Meta-Analysis)
Meta-Analysis
OBJECTIVES
Systematic review of preventive pharmacologic treatments for community-dwelling adults with episodic migraine.
DATA SOURCES
Electronic databases through May 20, 2012.
ELIGIBILITY CRITERIA
English-language randomized controlled trials (RCTs) of preventive drugs compared to placebo or active treatments examining rates of ≥50 % reduction in monthly migraine frequency or improvement in quality of life.
STUDY APPRAISAL AND SYNTHESIS METHODS
We assessed risk of bias and strength of evidence and conducted random effects meta-analyses of absolute risk differences and Bayesian network meta-analysis.
RESULTS
Of 5,244 retrieved references, 215 publications of RCTs provided mostly low-strength evidence because of the risk of bias and imprecision. RCTs examined 59 drugs from 14 drug classes. All approved drugs, including topiramate (9 RCTs), divalproex (3 RCTs), timolol (3 RCTs), and propranolol (4 RCTs); off-label beta blockers metoprolol (4 RCTs), atenolol (1 RCT), nadolol (1 RCT), and acebutolol (1 RCT); angiotensin-converting enzyme inhibitors captopril (1 RCT) and lisinopril (1 RCT); and angiotensin II receptor blocker candesartan (1 RCT), outperformed placebo in reducing monthly migraine frequency by ≥50 % in 200-400 patients per 1,000 treated. Adverse effects leading to treatment discontinuation (68 RCTs) were greater with topiramate, off-label antiepileptics, and antidepressants than with placebo. Limited direct evidence as well as frequentist and exploratory network Bayesian meta-analysis showed no statistically significant differences in benefits between approved drugs. Off-label angiotensin-inhibiting drugs and beta-blockers were most effective and tolerable for episodic migraine prevention.
LIMITATIONS
We did not quantify reporting bias or contact principal investigators regarding unpublished trials.
CONCLUSIONS
Approved drugs prevented episodic migraine frequency by ≥50 % with no statistically significant difference between them. Exploratory network meta-analysis suggested that off-label angiotensin-inhibiting drugs and beta-blockers had favorable benefit-to-harm ratios. Evidence is lacking for long-term effects of drug treatments (i.e., trials of more than 3 months duration), especially for quality of life.
Topics: Adult; Anticonvulsants; Evidence-Based Medicine; Humans; Migraine Disorders; Quality of Life; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 23592242
DOI: 10.1007/s11606-013-2433-1 -
Blood Apr 2013Several groups have shown that that the BCR-ABL1 transcript level measured at 3 or 6 months after starting treatment with tyrosine kinase inhibitors strongly predicts... (Comparative Study)
Comparative Study Randomized Controlled Trial
Several groups have shown that that the BCR-ABL1 transcript level measured at 3 or 6 months after starting treatment with tyrosine kinase inhibitors strongly predicts clinical outcomes for patients with chronic myeloid leukemia. In this work, we asked whether the prognostic value of the 3-month transcript level could be improved by combining the 3- and 6-month results. We classified patients treated with imatinib and patients treated with dasatinib according to their transcript levels at 3 months and 6 months. The patients who met the 3-month landmark but failed the 6-month one had outcomes identical to those of patients who met both landmarks, whereas the patients who failed the first landmark but met the second one had prognoses similar to those who failed both landmarks. In summary, early intervention strategies can be based robustly just on the transcript level at 3 months. This trial was registered at www.clinicaltrials.gov as # NCT01460693.
Topics: Acebutolol; Antineoplastic Agents; Benzamides; Dasatinib; Fusion Proteins, bcr-abl; Genetic Testing; Humans; Imatinib Mesylate; Leukemia, Myeloid, Chronic-Phase; Piperazines; Predictive Value of Tests; Prognosis; Prospective Studies; Protein Kinase Inhibitors; Pyrimidines; Risk Factors; Thiazoles; Time Factors; Treatment Outcome
PubMed: 23380743
DOI: 10.1182/blood-2012-11-466037