Validation of the International Classification of Diseases, Tenth Revision-Clinical Modification Diagnostic Code for Essential Tremor.

Background: The positive predictive value (PPV) of the International Classification of Diseases, Ninth Revision-Clinical Modification (ICD-9-CM) code for "essential and other specified forms of tremor" in identifying essential tremor (ET) cases was found to be less than 50%. The ability of the ICD-10-CM G25.0 code for "essential tremor" to identify ET has not been determined. The study objective was to determine the PPV of the G25.0 code. Methods: Patients in a tertiary health system with a primary care encounter associated with ICD-10-CM code G25.0 in 2022 underwent medical record review to determine if the consensus criteria from the International Parkinson and Movement Disorder Society for an ET diagnosis were met. Results: 442 patients were included. The PPV of G25.0 in identifying probable ET cases was 74.7% (95% confidence interval (CI) 70.4-78.5%). Among patients prescribed propranolol, the PPV improved to 87.8% (95% CI 78.0-93.6%). Discussion: Compared to the ICD-9-CM code 333.1, G25.0 is superior for identifying ET cases. A potential limitation of this study is that the consensus criteria applied relies on nonspecific physical exam findings which may lead to an overestimation of the PPV of G25.0. Highlights: The ICD-10-CM diagnosis code for essential tremor has not been previously validated. The objective of this study was to determine the PPV of the G25.0 code. The PPV in identifying essential tremor cases was 74.7%. The PPV improved among patients prescribed propranolol.

Greater inhibition of female rat binge alcohol intake by adrenergic receptor blockers using a novel Two-Shot rat binge drinking model.

Binge drinking (BD) contributes strongly to the harms of alcohol use disorder. Most rodent models do not result in binge-level blood alcohol concentrations (BACs), and to better understand individual and sex differences in neurobiological mechanisms related to BD, the use of outbred rat strains would be valuable. Here, we developed a novel BD model where after 3+ months of intermittent access to 20% alcohol Wistar rats drank, twice a week, with two 5-min intake (what we called Two-shot) separated by a 10-min break. Our findings showed during Two-Shot that most animals reached ≥ 80 mg% BAC levels (when briefly food-restricted). However, when increasing alcohol concentrations from 20 to 30%, 40%, or 50%, rats titrated to similar intake levels, suggesting rapid sensing of alcohol effects even when front-loading. Two-Shot drinking was reduced in both sexes by naltrexone (1 mg/kg), validating intake suppression by a clinical therapeutic agent for human problem drinking. Further, both propranolol (ß-adrenergic receptor antagonist) and prazosin (α1-adrenergic receptor antagonist) reduced female but not male BD at the lower dose. Thus, our results provide a novel model for BD in outbred rats and suggest that female binging is more sensitive to adrenergic modulation than males, perhaps providing a novel sex-related therapy.

Preclinical Studies on Mechanisms Underlying the Protective Effects of Propranolol in Traumatic Brain Injury: A Systematic Review.

Traumatic brain injury (TBI) is a leading cause of mortality and morbidity amongst trauma patients. Its treatment is focused on minimizing progression to secondary injury. Administration of propranolol for TBI maydecrease mortality and improve functional outcomes. However, it is our sense that its use has not been universally adopted due to low certainty evidence. The literature was reviewed to explore the mechanism of propranolol as a therapeutic intervention in TBI to guide future clinical investigations. Medline, Embase, and Scopus were searched for studies that investigated the effect of propranolol on TBI in animal models from inception until June 6, 2023. All routes of administration for propranolol were included and the following outcomes were evaluated: cognitive functions, physiological and immunological responses. Screening and data extraction were done independently and in duplicate. The risk of bias for each individual study was assessed using the SYCLE's risk of bias tool for animal studies. Three hundred twenty-three citations were identified and 14 studies met our eligibility criteria. The data suggests that propranolol may improve post-TBI cognitive and motor function by increasing cerebral perfusion, reducing neural injury, cell death, leukocyte mobilization and p-tau accumulation in animal models. Propranolol may also attenuate TBI-induced immunodeficiency and provide cardioprotective effects by mitigating damage to the myocardium caused by oxidative stress. This systematic review demonstrates that propranolol may be therapeutic in TBI by improving cognitive and motor function while regulating T lymphocyte response and levels of myocardial reactive oxygen species. Oral or intravenous injection of propranolol following TBI is associated with improved cerebral perfusion, reduced neuroinflammation, reduced immunodeficiency, and cardio-neuroprotection in preclinical studies.

Label-Free Screening of Drug-Induced Liver Injury Using Stimulated Raman Scattering Microscopy and Spectral Phasor Analysis.

Hepatic toxicity is a leading cause of the termination of clinical trials and the withdrawal of therapeutics following regulatory approval. The detection of drug-induced liver injury (DILI) is therefore of importance to ensure patient safety and the effectiveness of novel small molecules and drugs. DILI encompasses drug-induced steatosis (DIS) and drug-induced phospholipidosis (DIPL) which involve the accumulation of excess intracellular lipids. Here, we develop hyperspectral stimulated Raman scattering (SRS) microscopy as a label-free methodology for discriminating DIS and DIPL in mammalian cell culture. We demonstrate that hyperspectral SRS imaging in tandem with spectral phasor analysis is capable of discriminating DIS and DIPL based on the nature and distribution of intracellular lipids resulting from each process. To demonstrate the practical application of this methodology, we develop a panel of alkyne-tagged propranolol analogues that display varying DILI effects. Using hyperspectral SRS imaging together with spectral phasor analysis, our label-free methodology corroborated the standard fluorescence-based assay for DILI. As a label-free screening method, it offers a convenient and expedient methodology for visualizing hepatotoxicity in cell cultures which could be integrated into the early stages of the drug development process for screening new chemical entities for DILI.

Propranolol Alleviates Cardiac Injury After Acute Catecholamine Infusion Through p38-MAPK Pathways.

ABSTRACT: Hypercatecholaminergic conditions are known to cause heart failure and cardiac fibrosis when severe. Although previous investigations have studied the effects of beta-blockade in experimental models of catecholaminergic states, the detailed benefits of beta-blockade in more realistic models of hyper-adrenergic states were less clear. In this study, we examined acute cardiac changes in rats with hyperacute catecholamine-induced heart failure with and without propranolol treatment. Male Sprague-Dawley rats (n = 12) underwent a 6-hour infusion of epinephrine and norepinephrine alone, with an additional propranolol bolus (1 mg/kg) at hour 1 (n = 6). Cardiac tissues were examined after 6 hours. Cardiac immunohistochemistry revealed significantly decreased expression of phosphorylated p-38 (left ventricle, P = 0.021; right ventricle, P = 0.021), with upregulation of reactive oxidative species and other profibrosis proteins, after catecholamine infusion alone. After 1 propranolol 1 mg/kg bolus, the levels of phosphorylated-p38 returned to levels comparable with sham (left ventricle, P = 0.021; right ventricle, P = 0.043), with additional findings including downregulation of the apoptotic pathway and profibrotic proteins. We conclude that catecholamine-induced heart failure exerts damage through the p-38 mitogen-activated protein kinase pathway and demonstrates profibrotic changes mediated by matrix metalloproteinase 9, alpha-smooth muscle actin, and fibroblast growth factor 23. Changes in these pathways attenuated acute catecholamine-induced heart failure after propranolol bolus 1 mg/kg. We conclude that propranolol bolus at 1 mg/kg is able to mediate the effects of catecholamine excess through the p-38 mitogen-activated protein kinase pathway, profibrosis, and extrinsic apoptosis pathway.

Propranolol attenuates the establishment of conditioned context aversions: differential effects compared to MK-801 in an animal model of anticipatory nausea and vomiting.

Cancer patients often experience anticipatory nausea and vomiting (ANV) due to Pavlovian conditioning. Both N-methyl-D-aspartate and beta-adrenergic receptors are known to mediate memory formation, but their role in the development of ANV remains unclear. This study used a conditioned context aversion (CCA) paradigm, an animal model for ANV, to assess whether administration of the beta-adrenergic receptor antagonist propranolol or the N-methyl-D-aspartate receptor antagonist MK-801 immediately after CCA training has an effect on the later expression of CCA in CD1 male mice. In experiment 1, three groups were injected with lithium chloride (LiCl) to induce aversion in a novel context, resulting in CCA. A control group was injected with sodium chloride (NaCl). Following conditioning, two of the LiCl-treated groups received different doses of MK-801 (0.05 or 0.2 mg/kg), while the remaining LiCl-treated and NaCl-treated groups received a second NaCl injection. In experiment 2, two groups were injected with LiCl, and one group was injected with NaCl. After conditioning, one of the LiCl-treated groups received a propranolol injection (10 mg/kg). The remaining LiCl-treated and NaCl-treated groups received NaCl injections. Water consumption was measured in all groups 72 h later within the conditioning context. Postconditioning administration of propranolol, but not MK-801, attenuated CCA, as revealed by similar levels of water consumption in animals that received LiCl and propranolol relative to NaCl-treated animals. These findings suggest that beta-adrenergic receptor activation is crucial for the development of CCA. Therefore, propranolol may represent a novel therapeutic approach for cancer patients at high risk of ANV.

Nineteen-Year-Old Woman with Symptomatic Intramuscular Thigh Hemangioma-Radiographic Changes and Management: A Case Report.

CASE: We report a case of an intramuscular thigh hemangioma in a 19-year-old woman with a several year history of atraumatic thigh pain. Radiographs obtained by her primary care physician demonstrated periosteal bone reaction, prompting referral to Orthopaedic Oncology department. The patient had successful symptomatic management with propranolol. CONCLUSION: The case highlights the diagnosis and potential treatments. In a stepwise approach to care for symptomatic benign vascular lesions, propranolol has been a proven therapeutic option and may be a useful first-line therapy for symptomatic hemangiomas.

Qualification of In Vitro Dissolution Absorption System 2 (IDAS2) with Caco-2 and MDCK Cell Monolayers: Dose Sensitivity Study Using BCS Class I and III Drugs.

This study aimed to validate the In vitro Dissolution Absorption System 2 (IDAS2) containing a biological barrier of Caco-2 or Madin-Darby canine kidney (MDCK) cell monolayer through dose sensitivity studies. Metoprolol and propranolol were selected as Biopharmaceutics Classification System (BCS) Class I model drugs, and atenolol as a Class III model drug. The IDAS2 is comprised of a dissolution vessel (500 mL) and two permeation chambers (2 × 8.0 mL) mounted with Caco-2 or MDCK cell monolayer. One or two immediate-release tablet(s) of the model drug were added to the dissolution vessel, and the time profiles of dissolution and permeation were observed. Greater than 85% of metoprolol and propranolol (tested at two dosing concentrations) were dissolved by 15 min, and all drugs were fully dissolved by 30 min. All three drugs were more permeable across Caco-2 cells than MDCK cells with a linear increase in permeation across both cells at both dose concentrations. Thus, the dose sensitivity of the IDAS2 was demonstrated using both cell barriers. These results indicate a successful qualification of IDAS2 for the development/optimization of oral formulations and that MDCK cells can be utilized as a surrogate for Caco-2 cells.

A Case of Superficial Kaposiform Hemangioendothelioma Treated with Oral Propranolol Combined with Topical Sirolimus.

Kaposiform hemangioendothelioma(KHE) without Kasabach-Merritt phenomenon is a rare tumor primarily observed in pediatric patients; however, its documentation in the literature remains limited. We reported about a 1-year-old boy diagnosed with superficial KHE who received oral propranolol in combination with topical sirolimus and reviewed relevant reports and treatment of superficial KHE.

Role of transforming growth factor-ß1 pathway in angiogenesis induced by chronic stress in colorectal cancer.

BACKGROUND: Chronic stress can induce stress-related hormones; norepinephrine (NE) is considered to have the highest potential in cancer. NE can stimulate the expression of hypoxia-inducible factor-1α (HIF-1α), which is associated with vascular endothelial growth factor (VEGF) secretion and tumor angiogenesis. However, the underlying mechanisms are poorly understood. METHODS: Tumor-bearing mice were subjected to chronic restraint stress and treated with normal saline, human monoclonal VEGF-A neutralizing antibody bevacizumab, or ß-adrenergic receptor (ß-AR) antagonist (propranolol). Tumor growth and vessel density were also evaluated. Human colorectal adenocarcinoma cells were treated with NE, propranolol, or the inhibitor of transforming growth factor-ß (TGF-ß) receptor Type I kinase (Ly2157299) in vitro. TGF-ß1 in mouse serum and cell culture supernatants was quantified using ELISA. The expression of HIF-1α was measured using Real time-PCR and western blotting. Cell migration and invasion were tested. RESULTS: Chronic restraint stress attenuated the efficacy of bevacizumab and promoted tumor growth and angiogenesis in a colorectal tumor model. Propranolol blocked this effect and inhibited TGF-ß1 elevation caused by chronic restraint stress or NE. NE upregulated HIF-1α expression, which was reversed by propranolol or Ly2157299. Propranolol and Ly2157199 blocked NE-stimulated cancer cell migration and invasion. CONCLUSIONS: Our results demonstrate the effect of NE on tumor angiogenesis and the critical role of TGF-ß1 signaling during this process. In addition, ß-AR/TGF-ß1 signaling/HIF-1α/VEGF is a potential signaling pathway. This study also indicates that psychosocial stress might be a risk factor which weakens the efficacy of anti-angiogenic therapy.

Predatory Odor Exposure as a Potential Paradigm for Studying Emotional Modulation of Memory Consolidation-The Role of the Noradrenergic Transmission in the Basolateral Amygdala.

The pivotal role of the basolateral amygdala (BLA) in the emotional modulation of hippocampal plasticity and memory consolidation is well-established. Specifically, multiple studies have demonstrated that the activation of the noradrenergic (NA) system within the BLA governs these modulatory effects. However, most current evidence has been obtained by direct infusion of synthetic NA or beta-adrenergic agonists. In the present study, we aimed to investigate the effect of endogenous NA release in the BLA, induced by a natural aversive stimulus (coyote urine), on memory consolidation for a low-arousing, hippocampal-dependent task. Our experiments combined a weak object location task (OLT) version with subsequent mild predator odor exposure (POE). To investigate the role of endogenous NA in the BLA in memory modulation, a subset of the animals (Wistar rats) was treated with the non-selective beta-blocker propranolol at the end of the behavioral procedures. Hippocampal tissue was collected 90 min after drug infusion or after the OLT test, which was performed 24 h later. We used the obtained samples to estimate the levels of phosphorylated CREB (pCREB) and activity-regulated cytoskeleton-associated protein (Arc)-two molecular markers of experience-dependent changes in neuronal activity. The result suggests that POE has the potential to become a valuable behavioral paradigm for studying the interaction between BLA and the hippocampus in memory prioritization and selectivity.

Supramolecular Interaction of Atenolol and Propranolol with ß-Cyclodextrin Spectroscopic Characterization and Analytical Application.

Atenolol (ATE) and propranolol (PRO) inclusion complexes with ß-cyclodextrin have been investigated in aqueous solution. The aqueous solution was examined and characterized using UV-vis, fluorescence spectroscopy, and 1H NMR. The physical mixture was characterized using FTIR. The existence of inclusion complexes is confirmed by observing changes in spectroscopic properties. The ATE complex with ß-CD exhibited an interaction as host and (ß-CD) as a guest in a 1:1 ratio, with an inclusion constant K of 2.09 × 10-3 µM-1, as determined by the typical double-reciprocal graphs. Similarly, the PRO complex with ß-CD exhibited an interaction as host and (ß-CD) guest in 1:1 and 1:2 stoichiometry at the same time; the inclusion constants were K1 = 5.80 × 10-5 µM-1 and K2 = 4.67 × 10-8 µM-1, as determined by typical double-reciprocal graphs. The variables influencing the formation of the inclusion complexes were investigated and optimized. Based on the enhancement in fluorescence intensity due to the formation of inclusion complexes, spectrofluorometric methods were developed and validated for determination of each drug's pharmaceutical formulation. The quantification of the fluorescence intensity for ATE and PRO was conducted at λex/λem 226/302 nm and λex/λem 231/338 nm, respectively. Under the optimal reaction circumstances, linear relationships with good correlation coefficients of 0.9918 and 0.99 were found in the concentration ranges of 0.3-1.7 µM, and 0.1-1.1 µM for ATE and PRO, respectively. The limits of detection (LODs) were found to be 0.13 and 0.01 µM for ATE and PRO, respectively. The suggested approach was effectively applied to the analysis of both drugs' pharmaceutical formulations.

No harmful effect of propranolol administered prior to fear memory extinction in rats and humans.

Exposure therapy is an evidence-based treatment option for anxiety-related disorders. Many patients also take medication that could, in principle, affect exposure therapy efficacy. Clinical and laboratory evidence indeed suggests that benzodiazepines may have detrimental effects. Large clinical trials with propranolol, a common beta-blocker, are currently lacking, but several preclinical studies do indicate impaired establishment of safety memories. Here, we investigated the effects of propranolol given prior to extinction training in 9 rat studies (N = 215) and one human study (N = 72). A Bayesian meta-analysis of our rat studies provided strong evidence against propranolol-induced extinction memory impairment during a drug-free test, and the human study found no significant difference with placebo. Two of the rat studies actually suggested a small beneficial effect of propranolol. Lastly, two rat studies with a benzodiazepine (midazolam) group provided some evidence for a harmful effect on extinction memory, i.e., impaired extinction retention. In conclusion, our midazolam findings are in line with prior literature (i.e., an extinction retention impairment), but this is not the case for the 10 studies with propranolol. Our data thus support caution regarding the use of benzodiazepines during exposure therapy, but argue against a harmful effect of propranolol on extinction learning.

Effect of ultra-high-density polyethylene microplastic on the sorption and biodegradation of organic micropollutants.

Microplastics and organic micropollutants are two emerging contaminants that interact with each other in environmental and engineered systems. Sorption of organic micropollutants, such as pharmaceuticals, pesticides and industrial compounds, to microplastics can modify their bioavailability and biodegradation. The present study investigated the capacity of ultra-high density polyethylene particles (125 µm in diameter), before and after aging, to sorb 21 organic micropollutants at different environmentally relevant concentration. Furthermore, the biodegradation of these organic micropollutants by a biofilm microbial community growing on the microplastic surface was compared with the biodegradation by a microbial community originating from activated sludge. Among all tested organic micropollutants, propranolol (70%), trimethoprim (25%) and sotalol (15%) were sorbed in the presence of polyethylene particles. Growth of a biofilm on the polyethylene particles had a beneficial effect on the sorption of bromoxynil, caffeine and chloridazon and on the biodegradation of irbesartan, atenolol and benzotriazole. On the other hand, the biofilm limited the sorption of trimethoprim, propranolol, sotalol and benzotriazole and the biodegradation of 2,4-D. These results showed that ultra-high density polyethylene particles can affect both in a positive and negative way for the abiotic and biotic removal of organic micropollutants in wastewater. This project highlights the need for further investigation regarding the interaction between microplastics and organic micropollutants in the aquatic environment.

Neutrophil extracellular traps formation may be involved in the association of propranolol with the development of portal vein thrombosis.

BACKGROUND & AIMS: Nonselective ß blockers (NSBBs) facilitate the development of portal vein thrombosis (PVT) in liver cirrhosis. Considering the potential effect of NSBBs on neutrophils and neutrophil extracellular traps (NETs), we speculated that NSBBs might promote the development of PVT by stimulating neutrophils to release NETs. MATERIALS AND METHODS: Serum NETs biomarkers were measured, use of NSBBs was recorded, and PVT was evaluated in cirrhotic patients. Carbon tetrachloride and ferric chloride (FeCl3) were used to induce liver fibrosis and PVT in mice, respectively. After treatment with propranolol and DNase I, neutrophils in peripheral blood, colocalization and expression of NETs in PVT specimens, and NETs biomarkers in serum were measured. Ex vivo clots lysis analysis was performed and portal vein velocity and coagulation parameters were tested. RESULTS: Serum MPO-DNA level was significantly higher in cirrhotic patients treated with NSBBs, and serum H3Cit and MPO-DNA levels were significantly higher in those with PVT. In fibrotic mice, following treatment with propranolol, DNase I significantly shortened the time of FeCl3-induced PVT formation, lowered the peripheral blood neutrophils labelled by CD11b/Ly6G, inhibited the positive staining of H3Cit and the expression of H3Cit and MPO proteins in PVT tissues, and reduced serum nucleosome level. Furthermore, the addition of DNase I to tissue plasminogen activator (tPA) significantly accelerated clots lysis as compared with tPA alone. Propranolol reduced portal vein velocity in fibrotic mice, but did not influence coagulation parameters. CONCLUSION: Our study provides a clue to the potential impact of NETs formation on the association of NSBBs with the development of PVT.

Practical surgical technique using the SMISS approach for lip reduction in involuted lip infantile hemangiomas.

BACKGROUND: Lip infantile hemangiomas tend to show less volumetric regression and are more susceptible to visible sequelae in the involuted stage. Some of them still require surgical management after propranolol therapy. This study aimed to evaluate the efficacy and safety of the Stepwise, Multi-Incisional, and Single-Stage (SMISS) approach applied to lip reduction for those with involuted lip hemangiomas. METHODS: A retrospective review was performed to evaluate patients with lip hemangioma who received previous propranolol treatment and underwent the aforementioned procedure. Demographic characteristics, lesion morphology, and medical history were reviewed. The Visual Analog Scale was applied to assess the postoperative appearance. Complications within 12 months postoperatively were recorded. RESULTS: A total of 18 patients with lip hemangioma were eligible. All patients received oral propranolol therapy before surgery, with treatment duration ranging from 6.0 to 23.0 months. Their age at surgery ranged from 2.5 to 9.0 years. The median Visual Analog Scale scores were 8.0, ranging from 4.0 to 10.0. No severe complications were reported. CONCLUSIONS: This modified technique based on the SMISS approach has proven reliable and effective in improving the aesthetic outcome for involuted lip infantile hemangiomas. Practical surgical techniques still play an important part in the propranolol era.

Effect of propranolol on pharmacokinetics of clozapine in schizophrenic patients: a meta-analysis.

PURPOSE: Clozapine is the effective therapy for treatment-refractory schizophrenia. However, the use of clozapine is limited by its adverse effects. As propranolol is frequently used for the prevention and treatment of clozapine-induced tachycardia, we performed a meta-analysis to evaluate the effects of propranolol on steady state pharmacokinetics of clozapine in schizophrenic patients. METHODS: We included 16 retrospective studies on the effects of propranolol on steady state pharmacokinetics of clozapine in schizophrenic patients, with data from both generic and brand name treatment phases in eight clozapine bioequivalence studies conducted in a single center in China from 2018 to 2022. Review Manager 5.4 was used for meta-analysis of the included studies. RESULTS: The SMDs with 95% CIs of AUC0-12, Cmax,ss, C, and C were calculated to be 0.44 (0.23, 0.64), 0.40 (0.20, 0.61), 0.43 (0.22, 0.63), and 0.44 (0.23, 0.64), respectively. These findings proved that combination with propranolol would increase the systemic exposure of clozapine. T1/2 of clozapine was significantly longer in the presence of propranolol than in the absence of propranolol (SMD = 0.32, 95% CI [0.12, 0.52], p = 0.002). There was no statistically significant difference for T of clozapine in the presence or absence of propranolol (SMD = - 0.05, 95% CI [- 0.25, 0.15], p = 0.63). CONCLUSION: The combination with propranolol could significantly increase systemic exposure and extended T1/2 of clozapine, and thus need to be considered in prescribing decisions.

Elucidating the enhanced role of carbonate radical in propranolol degradation by UV/peroxymonosulfate system.

Carbonate radical (CO3•-) has been proved to be an important secondary radical in advanced oxidation processes due to various radical reactions involved HCO3-/CO32-. However, the roles and contributions of CO3•- in organic micropollutant degradation have not been explored systematically. Here, we quantified the impact of CO3•- on the degradation kinetics of propranolol, a representative pollutant in the UV/peroxymonosulfate (PMS) system, by constructing a steady-state radical model. Substantially, the measured values were coincident with the predictive values, and the contributions of CO3•- on propranolol degradation were the water matrix-dependent. Propranolol degradation increased by 130% in UV/PMS system containing 10 mM HCO3-, and the contribution of CO3•- was as high as 58%. Relatively high pH values are beneficial for propranolol degradation in pure water containing HCO3-, and the contributions of CO3•- also enhanced, while an inverse phenomenon was shown for the effects of propranolol concentrations. Dissolved organic matter exhibited significant scavenging effects on HO•, SO4•-, and CO3•-, substantially retarding the elimination process. The developed model successfully predicted oxidation degradation kinetics of propranolol in actual sewage, and CO3•- contribution was up to 93%, which in indicative of the important role of CO3•- in organic micropollutant removal via AOPs treatment.