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Pharmaceuticals (Basel, Switzerland) Oct 2023We report a 4-year-old with Gorham-Stout disease (GSD) who was treated with a combination of bisphosphonate, sirolimus, and atenolol. A previously healthy 4-year-old...
We report a 4-year-old with Gorham-Stout disease (GSD) who was treated with a combination of bisphosphonate, sirolimus, and atenolol. A previously healthy 4-year-old girl presented with back pain after falling on her back 2 months prior. Thoracolumbar spine X-ray revealed diffuse compression spinal fractures in T9-L2. Magnetic resonance imaging (MRI) confirmed multiple compression fractures at T9-L5 and revealed a paraspinal mass along the T1-L1 level. Based on clinical, radiological, and histopathological findings, Gorham-Stout disease was diagnosed. Treatment with sirolimus (0.5 mg twice daily, 1.6 mg/m) was initiated and intravenous bisphosphonate (pamidronate, 1 mg/kg for 3 days, total 3 mg/kg every 4 months) was added for back pain; she had immediate improvement in back pain. After 9 months with this treatment, she had a mild increase in paraspinal lymphangiomatosis and aggravation in T9-L5 compression fractures; atenolol was administered. The patient underwent 11 months of combination treatment with bisphosphonate, sirolimus, and atenolol, and MRI showed mild degree of reduction in the paraspinal lesions at L1-L5. The patient is currently in stable condition with no back pain or side effects. The triple combination treatment with bisphosphonate, sirolimus, and atenolol may be helpful in stabilizing the disease course of GSD.
PubMed: 37895975
DOI: 10.3390/ph16101504 -
Nicotine & Tobacco Research : Official... Apr 2024Evidence is mounting that electronic cigarette (e-cig) use induces cardiac sympathetic dominance and electrical dysfunction conducive to arrhythmias and dependent upon...
INTRODUCTION
Evidence is mounting that electronic cigarette (e-cig) use induces cardiac sympathetic dominance and electrical dysfunction conducive to arrhythmias and dependent upon nicotine. A variety of nicotine types and concentrations are available in e-cigs, but their relative cardiovascular effects remain unclear. Here we examine how different nicotine forms (racemic, free base, and salt) and concentrations influence e-cig-evoked cardiac dysfunction and arrhythmogenesis and provide a mechanism for nicotine-salt-induced autonomic imbalance.
METHODS
ECG-telemetered C57BL/6J mice were exposed to filtered air (FA) or e-cig aerosols from propylene glycol and vegetable glycerin solvents either without nicotine (vehicle) or with increasing nicotine concentrations (1%, 2.5%, and 5%) for three 9-minute puff sessions per concentration. Spontaneous ventricular premature beat (VPB) incidence rates, heart rate, and heart rate variability (HRV) were compared between treatments. Subsequently, to test the role of β1-adrenergic activation in e-cig-induced cardiac effects, mice were pretreated with atenolol and exposed to either FA or 2.5% nicotine salt.
RESULTS
During puffing and washout phases, ≥2.5% racemic nicotine reduced heart rate and increased HRV relative to FA and vehicle controls, indicating parasympathetic dominance. Relative to both controls, 5% nicotine salt elevated heart rate and decreased HRV during washout, suggesting sympathetic dominance, and also increased VPB frequency. Atenolol abolished e-cig-induced elevations in heart rate and declines in HRV during washout, indicating e-cig-evoked sympathetic dominance is mediated by β1-adrenergic stimulation.
CONCLUSIONS
Our findings suggest that inhalation of e-cig aerosols from nicotine-salt-containing e-liquids could increase the cardiovascular risks of vaping by inducing sympathetic dominance and cardiac arrhythmias.
IMPLICATIONS
Exposure to e-cig aerosols containing commercially relevant concentrations of nicotine salts may increase nicotine delivery and impair cardiac function by eliciting β1-adrenoceptor-mediated sympathoexcitation and provoking ventricular arrhythmias. If confirmed in humans, our work suggests that regulatory targeting of nicotine salts through minimum pH standards or limits on acid additives in e-liquids may mitigate the public health risks of vaping.
Topics: Animals; Nicotine; Electronic Nicotine Delivery Systems; Mice; Mice, Inbred C57BL; Heart Rate; Male; Arrhythmias, Cardiac; Autonomic Nervous System; Aerosols
PubMed: 38011908
DOI: 10.1093/ntr/ntad237 -
The Lancet. Global Health Oct 2023A cardiovascular polypill containing generic drugs might facilitate sustained implementation of and adherence to evidence-based treatments, especially in... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
A cardiovascular polypill containing generic drugs might facilitate sustained implementation of and adherence to evidence-based treatments, especially in resource-limited settings. However, the impact of a cardiovascular polypill in mitigating atherosclerotic risk among stroke survivors has not been assessed. We aimed to compare a polypill regimen with usual care on carotid intima-media thickness (CIMT) regression after ischaemic stroke.
METHODS
In SMAART, a phase 2 parallel, open-label, assessor-masked, randomised clinical trial, we randomly allocated individuals (aged ≥18 years) who had an ischaemic stroke within the previous 2 months, using a computer-generated randomisation sequence (1:1), to either a polypill or usual care group at a tertiary centre in Ghana. The polypill regimen was a fixed-dose pill containing 5 mg ramipril, 50 mg atenolol, 12·5 mg hydrochlorothiazide, 20 mg simvastatin, and 100 mg aspirin administered as two capsules once per day for 12 months. Usual care was tailored guideline-recommended secondary prevention medications. The primary outcome was the change in CIMT over 12 months with adjustment for baseline values, compared using ANCOVA in all participants with complete data at month 12. Safety was analysed in all randomly assigned participants. This trial is registered at ClinicalTrials.gov, NCT03329599, and is completed.
FINDINGS
Between Feb 12, 2019, and Dec 4, 2020, we randomly assigned 148 participants (74 to the usual care group and 74 to the polypill group), 74 (50%) of whom were male and 74 (50%) female. CIMT was assessed in 62 (84%) of 74 participants in the usual care group and 59 (80%) of 74 participants in the polypill group; the main reason for loss to follow-up was participants not completing the study. The mean CIMT change at month 12 was -0·092 mm (95% CI -0·130 to -0·051) in the usual care group versus -0·017 mm (-0·067 to 0·034) in the polypill group, with an adjusted mean difference of 0·049 (-0·008 to 0·109; p=0·11). Serious adverse events occurred among two (3%) participants in the usual care group, and eight (11%) participants in the polypill group (p=0·049).
INTERPRETATION
The polypill regimen resulted in similar regression in subclinical atherosclerosis and many secondary and tertiary outcome measures as the tailored drug regimen, but with more serious adverse events. Larger, longer-term, event-based studies, including patients with stroke in primary care settings, are warranted.
FUNDING
US National Institutes of Health.
TRANSLATION
For the Akan (Twi) translation of the abstract see Supplementary Materials section.
Topics: United States; Humans; Female; Male; Adolescent; Adult; Stroke; Secondary Prevention; Ghana; Brain Ischemia; Carotid Intima-Media Thickness; Ischemic Stroke
PubMed: 37734804
DOI: 10.1016/S2214-109X(23)00347-9 -
Archiv Der Pharmazie Aug 2023Greenness-by-design (GbD) is an approach that integrates green chemistry principles into the method development stage of analytical processes, aiming to reduce their...
Greenness-by-design (GbD) is an approach that integrates green chemistry principles into the method development stage of analytical processes, aiming to reduce their environmental impact. In this work, we applied GbD to a novel univariate double divisor corrected amplitude (DDCA) method that can resolve a quaternary pharmaceutical mixture in a fixed-dose polypill product. We also used a genetic algorithm as a chemometric modeling technique to select the informative variables for the analysis of the overlapping mixture. This resulted in more accurate and efficient predictive models. We used a computational approach to study the effect of solvents on the spectral resolution of the mixture and to minimize the spectral interferences caused by the solvent, thus achieving spectral resolution with minimal analytical effort and ecological footprint. The validated methods showed wide linear concentration ranges for the four components (1-30 µg/mL for losartan, 2.5-30 µg/mL for atorvastatin and aspirin, and 2.5-35 µg/mL for atenolol) and achieved high scores on the hexagon and spider charts, demonstrating their eco-friendliness.
Topics: Structure-Activity Relationship; Spectrophotometry; Chemistry, Pharmaceutical; Chemometrics; Algorithms
PubMed: 37276368
DOI: 10.1002/ardp.202300216 -
Journal of Pharmaceutical Sciences May 2024This study aims to explore the impact of ADME on the Oral Bioavailability (OB) of drugs and to construct a machine learning model for OB prediction. The model is then...
OBJECTIVE
This study aims to explore the impact of ADME on the Oral Bioavailability (OB) of drugs and to construct a machine learning model for OB prediction. The model is then applied to predict the OB of modified berberine and atenolol molecules to obtain structures with higher OB.
METHODS
Initially, a drug OB database was established, and corresponding ADME characteristics were obtained. The relationship between ADME and OB was analyzed using machine learning, with Morgan fingerprints serving as molecular descriptors. Compounds from the database were input into Random Forest, XGBoost, CatBoost, and LightGBM machine learning models to train the OB 7prediction model and evaluate its performance. Subsequently, berberine and atenolol were modified using Chemdraw software with ten different substituents for mono-substitution, and chlorine atoms for a full range of double substitutions. The modified molecular structures were converted into the same format as the training set for OB prediction. The predicted OB values of the modified structures of berberine and atenolol were compared.
RESULTS
An OB database of 386 drugs was obtained. It was found that smaller molecular weight and a higher number of rotatable bonds (ten or less) could potentially lead to higher OB. The four machine learning models were evaluated using MSE, R2 score, MAE, and MFE as metrics, with Random Forest performing the best. The models' predictions for the test set were particularly accurate when OB ranged from 30% to 90%. After mono-substitution and double substitution of berberine and atenolol, the OB of both drugs was significantly improved.
CONCLUSIONS
This study found that some ADME properties of molecules do not have an absolute impact on OB. The database played a decisive role in the process of the machine learning OB prediction model, and the performance of the model was evaluated based on predictions within a range of strong generalization ability. In most cases, mono-substitution and double substitution were beneficial for enhancing the OB of berberine and atenolol. In summary, this study successfully constructed a machine learning regression prediction model that can accurately predict drug OB, which can guide drug design to achieve higher OB to some extent.
Topics: Biological Availability; Atenolol; Berberine; Machine Learning; Software
PubMed: 38430955
DOI: 10.1016/j.xphs.2024.02.026 -
Toxics May 2024In small populations and scattered communities, wastewater treatment through vegetation filters (VFs), a nature-based solution, has proved to be feasible, especially for...
In small populations and scattered communities, wastewater treatment through vegetation filters (VFs), a nature-based solution, has proved to be feasible, especially for nutrient and organic matter removal. However, the presence of pharmaceuticals in wastewater and their potential to infiltrate through the vadose zone and reach groundwater is a drawback in the evaluation of VF performances. Soil amended with readily labile carbon sources, such as woodchips, enhances microbial activity and sorption processes, which could improve pharmaceutical attenuation in VFs. The present study aims to assess if woodchip amendments to a VF's soil are able to abate concentrations of selected pharmaceuticals in the infiltrating water by quantitatively describing the occurring processes through reactive transport modelling. Thus, a column experiment using soil collected from an operating VF and poplar woodchips was conducted, alongside a column containing only soil used as reference. The pharmaceuticals acetaminophen, naproxen, atenolol, caffeine, carbamazepine, ketoprofen and sulfamethoxazole were applied daily to the column inlet, mimicking a real irrigation pattern and periodically measured in the effluent. Ketoprofen was the only injected pharmaceutical that reached the column outlet of both systems within the experimental timeframe. The absence of acetaminophen, atenolol, caffeine, carbamazepine, naproxen and sulfamethoxazole in both column outlets indicates that they were attenuated even without woodchips. However, the presence of 10,11-epoxy carbamazepine and atenolol acid as transformation products (TPs) suggests that incomplete degradation also occurs and that the effect of the amendment on the infiltration of TPs is compound-specific. Modelling allowed us to generate breakthrough curves of ketoprofen in both columns and to obtain transport parameters during infiltration. Woodchip-amended columns exhibited K and μ values from one to two orders of magnitude higher compared to soil column. This augmentation of sorption and biodegradation processes significantly enhanced the removal of ketoprofen to over 96%.
PubMed: 38787113
DOI: 10.3390/toxics12050334 -
The Journal of the Association of... Sep 2023β-adrenergic blocker group of medicines has been traditionally used to control high blood pressure since propranolol was discovered by Sir James Black almost 50 years...
β-adrenergic blocker group of medicines has been traditionally used to control high blood pressure since propranolol was discovered by Sir James Black almost 50 years ago. They were the drug of choice in hypertension (HTN) associated with ischemic heart disease, tachyarrhythmias including atrial fibrillation (AF), and anxiety. Congestive cardiac failure was a relative contraindication, but with major advances in science, it became an absolute indication. However, with the advent of newer antihypertensives, especially calcium channel blocker (CCBs) and renin-angiotensin-aldosterone inhibitors, comparative studies were done, and depending on the outcomes of these trials, β-blockers (BBs) were downgraded to fourth or fifth-line therapy, except in the conditions mentioned above, along with HTN in pregnancy. But clinicians never rejected BBs as important antihypertensives, as evidenced by various real-world data. Also, many investigators found the unfairness of the trial designs where BBs were poor performers. The fact that all BBs are not similar, and differ widely in various properties, added to the question of downgrading all BBs on the basis of trials mostly with atenolol, which is also used once daily. Moreover, trials like ASCOT could not show the reduction of most of the events after long-term follow-up with the use of newer antihypertensives. Added to the issue is the fact that the majority of the trials used BBs with diuretics, and selecting BBs as the sole nonperformer appears to be unjustified and illogical. The recent European Society of HTN (ESH) guideline reemphasized the fact that all the five major classes of antihypertensives, including BBs, can be used as first-line medicine and also can be used interchangeably. Moreover, apart from the traditional indications of BBs, this guideline listed nineteen other conditions, including high heart rate (HR), chronic obstructive pulmonary disease (COPD), and obstructive sleep apnoea, as the conditions where BBs are preferred agents as antihypertensive. So, the life history of BBs in HTN has completed a full cycle, and they are ready now for prime time again. How to cite this article: Ray S, Saboo B, Joshi S, β-blockers as the First Line of Treatment for Hypertension Management. J Assoc Physicians India 2023;71(9):95-100.
Topics: Humans; Adrenergic beta-Antagonists; Antihypertensive Agents; Hypertension; Evidence-Based Medicine; Practice Guidelines as Topic
PubMed: 38700308
DOI: 10.59556/japi.71.0341 -
Peptides Aug 2023Excessive activation of the sympathetic nervous system is involved in cardiovascular damage including cardiac hypertrophy. Natriuretic peptides are assumed to exert...
Excessive activation of the sympathetic nervous system is involved in cardiovascular damage including cardiac hypertrophy. Natriuretic peptides are assumed to exert protective actions for the heart, alleviating hypertrophy and/or fibrosis of the myocardium. In contrast to this assumption, we show in the present study that both atrial and C-type natriuretic peptides (ANP and CNP) potentiate cardiac hypertrophic response to noradrenaline (NA) in rats. Nine-week-old male Wistar rats were continuously infused with subcutaneous 30 micro-g/h NA without or with persistent intravenous administration of either 1.0 micro-g/h ANP or CNP for 14 days. Blood pressure (BP) was recorded under an unrestrained condition by a radiotelemetry system. Cardiac hypertrophic response to NA was evaluated by heart weight/body weight (HW/BW) ratio and microscopic measurement of myocyte size of the left ventricle. Mean BP levels at the light and dark cycles rose by about 20 mmHg following NA infusion for 14 days, with slight increases in HW/BW ratio and ventricular myocyte size. Infusions of ANP and CNP had no significant effects on mean BP in NA-infused rats, while two natriuretic peptides potentiated cardiac hypertrophic response to NA. Cardiac hypertrophy induced by co-administration of NA and ANP was attenuated by treatment with prazosin or atenolol. In summary, both ANP and CNP potentiated cardiac hypertrophic effect of continuously infused NA in rats, suggesting a possible pro-hypertrophic action of natriuretic peptides on the heart.
Topics: Rats; Animals; Male; Rats, Wistar; Norepinephrine; Atrial Natriuretic Factor; Cardiomegaly; Blood Pressure; Natriuretic Peptide, C-Type; Natriuretic Peptide, Brain
PubMed: 37263541
DOI: 10.1016/j.peptides.2023.171035 -
Georgian Medical News Sep 2023The data on the polycontamination of multimedication in polymorbid patients with a heterogeneous class of carcinogens/nitrosamines, NDSRIs (classified according to the...
NITROSAMINE CONTAMINATION WITHIN CARDIAC MULTIMEDICATION - SARTANS (VALSARTAN), CALCIUM CHANNEL BLOCKERS (AMLODIPINE AND NIFEDIPINE), AND ANTIARRHYTHMICS (PROPAFENONE) AS A SIGNIFICANT FACTOR IN THE DEVELOPMENT AND PROGRESSION OF MULTIPLE KERATINOCYTIC CANCERS: ADVANCEMENT ROTATION FLAP FOR...
The data on the polycontamination of multimedication in polymorbid patients with a heterogeneous class of carcinogens/nitrosamines, NDSRIs (classified according to the FDA regulation to the companies of 2023 to those with a carcinogenic potency between 1 and 5), are one of the most important steps to clarify the concept of skin cancer nitrosogenesis/ pathogenesis. The FDA is the first regulatory institution in the world to courageously declare that a problem exists and should be addressed. The main and currently unexplained and somewhat controversial issue lies in 1) the sporadic nature of polycontamination in different geographical regions, and 2) the lack of official data from the established international, but also regional pharmaceutical market regulators on the results of the checks conducted for nitrosamine contamination of the respective batches. It is this that leads scientists to the idea of (albeit seemingly) speculative but entirely possible controlled contamination of the production in certain geographical regions. This (hypo)thesis is supported, albeit indirectly, by the fact that: a recent regional check for possible contamination of sartans in a particular geographical region was not indicative of the presence of any nitrosamines/NDSRIs. But this fact is indicative of several extremely important things: 1) contamination is not ubiquitous, its genesis is heterogeneous; 2) contamination could be completely avoided at production level in certain geographical regions; 3) ˝controlled contamination˝ or carelessness of a heterogeneous nature should be excluded by the relevant regulators. Regular inspection and certification of medicinal products in relevant geographical regions to exclude contamination with nitrosamines/NDSRIs would be the surest method to protect public health globally. The initial parameters of the restrictive processes for the availability of nitrosamines in medicines have been established by the most powerful regulator globally in the face of the FDA, with the hope being that manufacturers will find a short-term solution to the problem. We report another patient who simultaneously developed 2 cutaneous tumors under potentially/actually nitrosamine contaminated drugs such as: beta blockers- atenolol, calcium antagonists- nifedipine/amlodipine, sartans- valsartan and antiarrhythmics- propafenone. One of the tumors was localized in the upper lip area (keratoacanthoma) and the other in the right shoulder area (basal cell carcinoma). Successful surgical treatment of the tumors was performed in the form of upper lip advancement rotation flap and elliptical excision of the second lesion. The evolution/growth rate of the tumors in relation to the potential mutagens/carcinogens heterogeneous in their potency contained in the drugs is commented.
Topics: Humans; Nitrosamines; Valsartan; Angiotensin II Type 1 Receptor Blockers; Propafenone; Calcium Channel Blockers; Nifedipine; Amlodipine; Keratoacanthoma; Shoulder; Carcinogens; Anti-Arrhythmia Agents; Neoplasms; Surgical Flaps
PubMed: 37991972
DOI: No ID Found -
Journal of Chromatography. B,... Jul 2024Single-pass intestinal perfusion (SPIP) method is a widely used experimental model to determine the intestinal permeability of drugs. These studies are performed in the...
Single-pass intestinal perfusion (SPIP) method is a widely used experimental model to determine the intestinal permeability of drugs. These studies are performed in the presence of a reference standard (metoprolol, MT) and a zero permeability marker (phenol red, PR). Therefore, it is important to develop a validated method for simultaneous determination of the investigated compound along with MT and PR. The aim of this study was to develop a reversed phase high-performance liquid chromatography (RP-HPLC) method with UV-detection for the simultaneous determination of atenolol (ATN), MT, and PR in the perfusion medium used in SPIP experiments. Separation of compounds were performed using an InertSustain C18 (250 × 4.6 mm, 5 µm) HPLC column at 35 °C. The mobile phase was a mixture of acetonitrile and phosphate buffer (pH 7.0, 12.5 mM) in gradient elution, and was delivered at a flow rate of 1 mL/min. The acetonitrile ratio of the mobile phase increased linearly from 10 to 35 % over 15 min. The injection volume was 20 µL, and ATN, MT and PR were detected at 224 nm. The retention times under optimum HPLC conditions were 5.028 min, 12.401 min, and 13.507 min for ATN, MT and PR, respectively. The developed RP-HPLC method was validated for selectivity, specificity, calibration curve and range, accuracy and precision, carry-over effect, stability, reinjection reproducibility, recovery and robustness. The method was linear for ATN (0.76-50 μg/mL), MT (1.14-50 μg/mL), and PR (0.47-20 μg/mL) with determination coefficients of 0.9999, 0.9994 and 0.9998, respectively. The results obtained for all validation parameters of the developed RP-HPLC method met the required limits of the ICH M10 Guideline.
Topics: Chromatography, High Pressure Liquid; Animals; Atenolol; Metoprolol; Rats; Chromatography, Reverse-Phase; Reproducibility of Results; Linear Models; Phenolsulfonphthalein; Male; Limit of Detection; Rats, Wistar; Perfusion
PubMed: 38781808
DOI: 10.1016/j.jchromb.2024.124160