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Scientific Reports Sep 2022Adenosine occasionally results in overestimation of fractional flow reserve (FFR) values, compared with other hyperemic stimuli. We aimed to elucidate the association of...
Adenosine occasionally results in overestimation of fractional flow reserve (FFR) values, compared with other hyperemic stimuli. We aimed to elucidate the association of overestimation of FFR by adenosine with anatomically significant but functionally non-significant lesions (anatomical-functional mismatch) and its influence on reclassification of functional significance. Distal-to-aortic pressure ratio (Pd/Pa) was measured using adenosine (Pd/Pa) and papaverine (Pd/Pa) in 326 patients (326 vessels). The overestimation of FFR was calculated as Pd/Pa-Pd/Pa. The anatomical-functional mismatch was defined as diameter stenosis > 50% and Pd/Pa > 0.80. Reclassification was indicated by Pd/Pa > 0.80 and Pd/Pa ≤ 0.80. The mismatch (n = 72) had a greater overestimation of FFR than the non-mismatch (n = 99): median 0.02 (interquartile range 0.01-0.05) versus 0.01 (0.00-0.04), p = 0.014. Multivariable analysis identified the overestimation of FFR (p = 0.003), minimal luminal diameter (p = 0.001), and non-left anterior descending artery (LAD) location (p < 0.001) as determinants of the mismatch. Reclassification was indicated in 29% of the mismatch and was more frequent in the LAD than in the non-LAD (52% vs. 20%, p = 0.005). The overestimation of FFR is an independent determinant of anatomical-functional mismatch. Anatomical-functional mismatch, specifically in the LAD, may suggest a false-negative result.
Topics: Adenosine; Cardiac Catheterization; Coronary Angiography; Coronary Stenosis; Coronary Vessels; Fractional Flow Reserve, Myocardial; Humans; Predictive Value of Tests; Severity of Illness Index
PubMed: 36056128
DOI: 10.1038/s41598-022-19330-1 -
Frontiers in Pharmacology 2022This present study aims to delineate crude extract (Rd.Cr), n-Hexane, ethyl acetate, aqueous fractions (Rd.n-Hex, Rd.ETAC, and Rd.Aq), and emodin for antidiarrheal,...
This present study aims to delineate crude extract (Rd.Cr), n-Hexane, ethyl acetate, aqueous fractions (Rd.n-Hex, Rd.ETAC, and Rd.Aq), and emodin for antidiarrheal, antisecretory effects, anti-spasmodic, gastrointestinal transient time, anti-, antiulcer effects, and toxicology. Plant extracts attributed dose-dependent protection against castor oil-induced diarrhea and dose-dependently inhibited intestinal fluid secretions in mice. They decreased the distance transverse by charcoal in the gastrointestinal transit model in rats. In rabbit jejunum preparations, it causes a concentration-dependent relaxation of both spontaneous and K (80 mM)-induced contraction, Rd.n-Hex and verapamil were relatively potent against K-induced contractions and shifted the Ca concentration-response curves (CRCs) to the right, Rd.Cr and Rd.ETAC shifted the isoprenaline-induced inhibitory CRCs to the left, showing potentiating effect similar to papaverine. Rd.n-Hex showed anti- effect. Extracts and emodin also show an inhibitory effect against H/K-ATPase. showed a gastroprotective and antioxidant effect. Histopathological evaluation showed improvement in cellular architecture and decrease in the expression of inflammatory markers such as cyclooxygenase (COX2), tumor necrosis factor (TNF-α), and phosphorylated nuclear factor kappa B (p-NFƙB), validated through immunohistochemistry, ELISA, and western blot techniques. In RT-PCR, it decreases H/K-ATPase mRNA levels. was analyzed for certain safety aspects and exhibited a relative safety profile as no impairment was observed in kidneys, heart, liver, and brain further assisted by biochemical and hematological analysis. Docking studies revealed that emodin against H/K-ATPase pump and voltage gated L-type calcium channel showed E-value of -7.9 and -7.4 kcal/mol, respectively. MD simulations and molecular mechanics Poisson Boltzmann surface area and molecular mechanics Generalized Born surface area MMPBSA/GBSA findings are consistent with the and docking results. In conclusion, extracts and its phytoconstituent could be considered a potent antioxidant and anti-inflammatory drug candidates that possess anti-diarrheal, anti-secretary, antispasmodic, anti- and anti-ulcer potential. Toxicity studies were done according to OECD standards 425. It belongs to group 5 (LD50 > 2000 mg/kg), which suggests that it is in the lower toxicity class.
PubMed: 36052146
DOI: 10.3389/fphar.2022.936161 -
Proceedings of the National Academy of... Aug 2022Tetrahydropapaverine (THP) and papaverine are plant natural products with clinically significant roles. THP is a precursor in the production of the drugs atracurium and...
Tetrahydropapaverine (THP) and papaverine are plant natural products with clinically significant roles. THP is a precursor in the production of the drugs atracurium and cisatracurium, and papaverine is used as an antispasmodic during vascular surgery. In recent years, metabolic engineering advances have enabled the production of natural products through heterologous expression of pathway enzymes in yeast. Heterologous biosynthesis of THP and papaverine could play a role in ensuring a stable supply of these clinically significant products. Biosynthesis of THP and papaverine has not been achieved to date, in part because multiple pathway enzymes have not been elucidated. Here, we describe the development of an engineered yeast strain for de novo biosynthesis of THP. The production of THP is achieved through heterologous expression of two enzyme variants with activity on nonnative substrates. Through protein engineering, we developed a variant of -methylcoclaurine hydroxylase with activity on coclaurine, enabling de novo norreticuline biosynthesis. Similarly, we developed a variant of scoulerine 9--methyltransferase capable of -methylating 1-benzylisoquinoline alkaloids at the 3' position, enabling de novo THP biosynthesis. Flux through the heterologous pathway was improved by knocking out yeast multidrug resistance transporters and optimization of media conditions. Overall, strain engineering increased the concentration of biosynthesized THP 600-fold to 121 µg/L. Finally, we demonstrate a strategy for papaverine semisynthesis using hydrogen peroxide as an oxidizing agent. Through optimizing pH, temperature, reaction time, and oxidizing agent concentration, we demonstrated the ability to produce semisynthesized papaverine through oxidation of biosynthesized THP.
Topics: Biological Products; Cytochrome P-450 Enzyme System; Hydrogen Peroxide; Oxidants; Papaverine; Plant Proteins; Protein Engineering; Saccharomyces cerevisiae
PubMed: 35939674
DOI: 10.1073/pnas.2205848119 -
Clinical, Cosmetic and Investigational... 2022Blindness caused by embolization of fillers is a rare but catastrophic complication after cosmetic injection. Vision improvement is rarely reported among the various...
Blindness caused by embolization of fillers is a rare but catastrophic complication after cosmetic injection. Vision improvement is rarely reported among the various studies on potential clinical treatments. In this case, the patient suffered from ophthalmic artery occlusion with no light perception 48 h after hyaluronic acid injection. After two intra-arterial thrombolytic therapy sessions and traditional sequential therapy, ocular appearance was restored to normal, blood supply to the retina and visual function were improved, and visual acuity was restored to hand motion levels. Our results suggest that intra-arterial thrombolytic therapy with hyaluronidase and papaverine has a positive effect on hyaluronic acid-induced visual loss and is worthy of clinical promotion.
PubMed: 35935598
DOI: 10.2147/CCID.S367481 -
Foods (Basel, Switzerland) Jul 2022In this work, the thermal degradation of tropane and opium alkaloids was studied in samples of breadsticks prepared with corn flour, contaminated with seeds of , and...
Evaluation of Thermal Degradation of Tropane and Opium Alkaloids in Gluten-Free Corn Breadsticks Samples Contaminated with Stramonium Seeds and Baked with Poppy Seeds under Different Conditions.
In this work, the thermal degradation of tropane and opium alkaloids was studied in samples of breadsticks prepared with corn flour, contaminated with seeds of , and containing seeds of L. A total of seven different samples were prepared and eight alkaloids were studied, three tropane (atropine, scopolamine, and anisodamine) and five opium (morphine, codeine, thebaine, papaverine, and noscapine) alkaloids. For this purpose, a fast, easy and efficient method based on solid-liquid extraction (SLE) prior to the analysis by high-performance liquid chromatography with a diode array detector (HPLC-DAD) was developed and validated. Thermal degradation studies showed a decrease in the TAs and OAs content under baking (180 °C for 20 min) that was between 7-65% for atropine, depending on the preparation conditions used, between 35-49% for scopolamine and anisodamine, up to 100% for morphine and codeine and between 14-58% for thebaine, papaverine, and noscapine. Results also evidenced that degradation of morphine and codeine was higher when the seeds were added as topping to the breadsticks.
PubMed: 35892780
DOI: 10.3390/foods11152196 -
Toxins Jul 2022Isoquinoline alkaloids have multiple biological activities, which might be associated with positive pharmacological effects as well as negative adverse reactions. As...
Isoquinoline alkaloids have multiple biological activities, which might be associated with positive pharmacological effects as well as negative adverse reactions. As bleeding was suggested to be a side effect of the isoquinoline alkaloid berberine, we decided to ascertain if different isoquinoline alkaloids could influence hemocoagulation through the inhibition of either platelet aggregation or blood coagulation. Initially, a total of 14 compounds were screened for antiplatelet activity in whole human blood by impedance aggregometry. Eight of them demonstrated an antiplatelet effect against arachidonic acid-induced aggregation. Papaverine and bulbocapnine were the most potent compounds with biologically relevant IC values of 26.9 ± 12.2 μM and 30.7 ± 5.4 μM, respectively. Further testing with the same approach confirmed their antiplatelet effects by employing the most physiologically relevant inducer of platelet aggregation, collagen, and demonstrated that bulbocapnine acted at the level of thromboxane receptors. None of the alkaloids tested had an effect on blood coagulation measured by a mechanical coagulometer. In conclusion, the observed antiplatelet effects of isoquinoline alkaloids were found mostly at quite high concentrations, which means that their clinical impact is most likely low. Bulbocapnine was an exception. It proved to be a promising antiplatelet molecule, which may have biologically relevant effects.
Topics: Alkaloids; Blood Platelets; Humans; Isoquinolines; Platelet Aggregation; Platelet Aggregation Inhibitors
PubMed: 35878229
DOI: 10.3390/toxins14070491 -
Frontiers in Pharmacology 2022Erectile dysfunction is increasingly affecting men, from the elderly to young adults, being a sexual disorder related to the inability to generate or maintain a penile... (Review)
Review
Erectile dysfunction is increasingly affecting men, from the elderly to young adults, being a sexual disorder related to the inability to generate or maintain a penile erection. This disorder is related to psychosocial factors such as anxiety, depression, and low self-esteem, to organic factors such as the presence of preexisting conditions like hypertension, diabetes and dyslipidemia. The pathophysiology of the disease is related to changes in the neurotransmission of the autonomic or the non-cholinergic non-adrenergic nervous system, as well as the release of local mediators, such as thromboxane A and endothelin, and hormonal action. These changes lead to impaired relaxation of cavernous smooth muscle, which reduces local blood flow and impairs penile erection. Currently, therapy is based on oral vasodilation, such as sildenafil, tadalafil, vardenafil and iodenafil, or by direct administration of these agents into the corpus cavernosum or by intraurethral route, such as alprostadil and papaverine. Despite this, studies that consolidate the understanding of its pathophysiological process contribute to the discovery of new more efficient drugs for the treatment of erectile dysfunction. In this sense, in the present work an extensive survey was carried out of the mechanisms already consolidated and the most recent ones related to the development of erectile dysfunction.
PubMed: 35865945
DOI: 10.3389/fphar.2022.895044 -
Journal of Controlled Release :... Aug 2022Melanin binding of drugs is known to increase drug concentrations and retention in pigmented eye tissues. Even though the correlation between melanin binding in vitro...
Melanin binding of drugs is known to increase drug concentrations and retention in pigmented eye tissues. Even though the correlation between melanin binding in vitro and exposure to pigmented eye in vivo has been shown, there is a discrepancy between rapid drug release from melanin particles in vitro and the long in vivo retention in the pigmented tissues. We investigated mechanisms and kinetics of pigment-related drug retention experimentally using isolated melanin particles from porcine retinal pigment epithelium and choroid, isolated porcine eye melanosomes, and re-pigmented ARPE-19 cells in a dynamic flow system. The experimental studies were supplemented with kinetic simulations. Affinity and capacity of levofloxacin, terazosin, papaverine, and timolol binding to melanin revealed K values of ≈ 50-150 μM and B ≈ 40-112 nmol.mg. The drugs were released from melanin in <1 h (timolol) or in 6-12 h (other drugs). The drugs were released slower from the melanosomes than from melanin; the experimental differences ranged from 1.2-fold (papaverine) to 7.4-fold (timolol). Kinetic simulations supported the role of the melanosomal membrane in slowing down the release of melanin binders. In release studies from the pigmented ARPE-19 cells, drugs were released from the cellular melanin to the extracellular space in ≈ 1 day (timolol) and ≈ 11 days (levofloxacin), i.e., much slower than the release from melanin or melanosomes. Simulations of drug release from pigmented cells in the flow system matched the experimental data and enabled further sensitivity analyses. The simulations demonstrated a significant prolongation of drug retention in the cells as a function of decreasing drug permeability in the melanosomal membranes and increasing melanin content in the cells. Overall, we report the impact of cellular factors in prolonging drug retention and release from melanin-containing cells. These data and simulations will facilitate the design of melanin binding drugs with prolonged ocular actions.
Topics: Animals; Computer Simulation; Levofloxacin; Melanins; Papaverine; Retinal Pigment Epithelium; Swine; Timolol
PubMed: 35738465
DOI: 10.1016/j.jconrel.2022.05.059 -
Drug Development Research Sep 2022The causative agent of coronavirus disease-2019 (COVID-19), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), enters the host cells via an...
The causative agent of coronavirus disease-2019 (COVID-19), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), enters the host cells via an angiotensin-converting enzyme 2 (ACE2)-mediated endocytosis-dependent manner. Because ACE2 is highly expressed in the heart, SARS-CoV-2 can severely infect heart tissue and arteries, causing acute and chronic damage to the cardiovascular system. Therefore, special attention should be paid to finding appropriate agents to protect this vital system during COVID-19 treatment. Papaverine is a unique vasodilator alkaloid that is clinically used in the treatment of vasospasm. Interestingly, this compound has potent and direct effects on a wide range of viruses, and could also prevent viral exploitation mechanisms of the host cell facilities by inhibiting some cellular signaling pathways such as p38 MAPK. This pathway was recently introduced as a promising target for the treatment of COVID-19. Papaverine also has anti-inflammatory effects which is useful in combating the hyper-inflammatory phase of the COVID-19. Unlike some medications that have severe dosage-restrictions in the treatment of COVID-19 due to cardiac side effects, papaverine is recommended for use in many heart disorders. The ability of papaverine to treat COVID-19 has become more promising when the results of some extensive screenings showed the strong ability of this compound to inhibit the cytopathic effects of SARS-CoV-2 with EC of 1.1 μM. Having several therapeutic effects along with desired safety profile raises this hypothesis that papaverine could be a promising compound for the suppression of SARS-CoV-2 and prevention of ischemia/vasoconstriction-related complications in COVID-19 disease, especially in patients with underlying cardiovascular diseases (CVDs).
Topics: Angiotensin-Converting Enzyme 2; COVID-19; Cardiovascular Diseases; Humans; Papaverine; Peptidyl-Dipeptidase A; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35706384
DOI: 10.1002/ddr.21961 -
Neuropsychopharmacology Reports Sep 2022Oxycodone (OXY) is classified as a "strong opioid" in the World Health Organization system of cancer pain treatment. However, OXY also causes severe adverse reactions,...
Oxycodone (OXY) is classified as a "strong opioid" in the World Health Organization system of cancer pain treatment. However, OXY also causes severe adverse reactions, such as respiratory depression. Thus, in order to adjust the dosage of OXY for well-managed pain relief with less toxicity, we tried establishing and validating a system for measuring plasma concentrations of OXY using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Human pooled plasma samples containing OXY diluted with 0.1% formic acid solution and internal standard (papaverine) were used for solid-phase extraction. The eluents were injected into LC-MS/MS with Unison UK-Silica column (100 × 2 mm, 3 μm, Imtakt). Mobile phase was a mixture of 1 mM ammonium formate solution and acetonitrile containing 0.1% formic acid (50:50). OXY in plasma could be measurable with good linearity in a concentration range of 2-100 ng/ml by using 100 μl of plasma within 4 min. Relative standard deviations of all validation results were within ±15%. These results suggest that our established method using LC-MS/MS to measure OXY in plasma would be useful to adjust the dosage of OXY in order to obtain its efficacy and to avoid its adverse reactions.
Topics: Acetonitriles; Analgesics, Opioid; Chromatography, Liquid; Formates; Humans; Oxycodone; Papaverine; Silicon Dioxide; Tandem Mass Spectrometry
PubMed: 35689429
DOI: 10.1002/npr2.12268