-
Pharmaceutics Jan 2023Particle size reduction is a commonly used process to improve the solubility and the dissolution of drug formulations. The solubility of a drug in the gastrointestinal...
Particle size reduction is a commonly used process to improve the solubility and the dissolution of drug formulations. The solubility of a drug in the gastrointestinal tract is a crucial parameter, because it can greatly influence the bioavailability. This work provides a comprehensive investigation of the effect of the particle size, pH, biorelevant media and polymers (PVA and PVPK-25) on the solubility and dissolution of drug formulations using three model compounds with different acid-base characteristics (papaverine hydrochloride, furosemide and niflumic acid). It was demonstrated that micronization does not change the equilibrium solubility of a drug, but it results in a faster dissolution. In contrast, nanonization can improve the equilibrium solubility of a drug, but the selection of the appropriate excipient used for nanonization is essential, because out of the two used polymers, only the PVPK-25 had an increasing effect on the solubility. This phenomenon can be explained by the molecular structure of the excipients. Based on laser diffraction measurements, PVPK-25 could also inhibit the aggregation of the particles more effectively than PVA, but none of the polymers could hold the nanonized samples in the submicron range until the end of the measurements.
PubMed: 36678907
DOI: 10.3390/pharmaceutics15010278 -
Scientific Reports Jan 2023Adenosine occasionally overestimates fractional flow reserve (FFR) values (i.e., insufficient adenosine-induced hyperemia), leading to low non-hyperemic pressure ratios...
Adenosine occasionally overestimates fractional flow reserve (FFR) values (i.e., insufficient adenosine-induced hyperemia), leading to low non-hyperemic pressure ratios (NHPR)-high FFR discordance. We investigated the impact of insufficient adenosine-induced hyperemia on NHPR-FFR discordance and the reclassification of functional significance. We measured resting distal-to-aortic pressure ratio (Pd/Pa) and FFR by using adenosine (FFR) and papaverine (FFR) in 326 patients (326 vessels). FFR overestimation was calculated as FFR - FFR. We explored determinants of low Pd/Pa - high FFR discordance (Pd/Pa ≤ 0.92 and FFR > 0.80) versus high Pd/Pa - low FFR discordance (Pd/Pa > 0.92 and FFR ≤ 0.80). Reclassification of functional significance was defined as FFR > 0.80 and FFR ≤ 0.80. Multivariable analysis identified FFR overestimation (p = 0.002) and heart rate at baseline (p = 0.048) as independent determinants of the low Pd/Pa-high FFR discordance. In the low Pd/Pa-high FFR group (n = 26), papaverine produced a further decline in the FFR value in 21 vessels (81%) compared with FFR, and the reclassification was observed in 17 vessels (65%). Insufficient adenosine-induced hyperemia is a major determinant of the low resting Pd/Pa-high FFR discordance. Physicians should bear in mind that the presence of low NHPR-high FFR discordance may indicate a false-negative FFR result.
Topics: Humans; Adenosine; Vasodilator Agents; Fractional Flow Reserve, Myocardial; Papaverine; Coronary Stenosis; Hyperemia; Coronary Angiography; Cardiac Catheterization; Coronary Vessels; Predictive Value of Tests; Severity of Illness Index
PubMed: 36639567
DOI: 10.1038/s41598-023-27929-1 -
Pharmaceuticals (Basel, Switzerland) Dec 2022The advancement of high-throughput sequencing and genomic analysis revealed that acute lymphoblastic leukemia (ALL) is a genetically heterogeneous disease. The abundance...
The advancement of high-throughput sequencing and genomic analysis revealed that acute lymphoblastic leukemia (ALL) is a genetically heterogeneous disease. The abundance of such genetic data in ALL can also be utilized to identify potential targets for drug discovery and even drug repurposing. We aimed to determine potential genes for drug development and further guide the identification of candidate drugs repurposed for treating ALL through integrated genomic network analysis. Genetic variants associated with ALL were retrieved from the GWAS Catalog. We further applied a genomic-driven drug repurposing approach based on the six functional annotations to prioritize crucial biological ALL-related genes based on the scoring system. Lastly, we identified the potential drugs in which the mechanisms overlapped with the therapeutic targets and prioritized the candidate drugs using Connectivity Map (CMap) analysis. Forty-two genes were considered biological ALL-risk genes with topping the list. Based on potentially druggable genes that we identified, palbociclib, sirolimus, and tacrolimus were under clinical trial for ALL. Additionally, chlorprothixene, sirolimus, dihydroergocristine, papaverine, and tamoxifen are the top five drug repositioning candidates for ALL according to the CMap score with dasatinib as a comparator. In conclusion, this study determines the practicability and the potential of integrated genomic network analysis in driving drug discovery in ALL.
PubMed: 36559013
DOI: 10.3390/ph15121562 -
Molecules (Basel, Switzerland) Dec 2022The study was performed to assess and rationalize the traditional utilization of the fruit part of Grewia tenax (G. tenax). The phytoconstituents present in the...
The study was performed to assess and rationalize the traditional utilization of the fruit part of Grewia tenax (G. tenax). The phytoconstituents present in the methanolic extract were analyzed using Gas-Chromatography-Mass Spectroscopy (GC-MS), while the anti-diarrheal activity was investigated in the Swiss albino mice against castor oil-provoked diarrhea in vivo. The antispasmodic effect and the possible pharmacodynamics of the observed antispasmodic effect were determined in an isolated rat ileum using the organ bath setup as an ex vivo model. GC-MS findings indicate that G. tenax is rich in alcohol (6,6-dideutero-nonen-1-ol-3) as the main constituent (20.98%), while 3-Deoxy-d-mannoic lactone (15.36%) was detected as the second major constituents whereas methyl furfural, pyranone, carboxylic acid, vitamin E, fatty acid ester, hydrocarbon, steroids, sesquiterpenes, phytosterols, and ketones were verified as added constituents in the methanolic extract. In mice, the orally administered G. tenax inhibited the diarrheal episodes significantly (p < 0.05) at 200 mg/kg (40% protection), and this protection was escalated to 80% with the next higher dose of 400 mg/kg. Loperamide (10 mg/kg), a positive control drug, imparted 100% protection, whereas no protection was shown by saline. In isolated rat ileum, G. tenax completely inhibited the carbamylcholine (CCh; 1 µM) and KCl (high K+; 80 mM)-evoked spasms in a concentrations-mediated manner (0.03 to 3 mg/mL) by expressing equal potencies (p > 0.05) against both types of evoked spasms, similar to papaverine, having dual inhibitory actions at phosphodiesterase enzyme (PDE) and Ca2+ channels (CCB). Similar to papaverine, the inhibitory effect of G. tenax on PDE was further confirmed indirectly when G. tenax (0.1 and 0.3 mg/mL) preincubated ileal tissues shifted the isoprenaline-relaxation curve towards the left. Whereas, pre-incubating the tissue with 0.3 and 1 mg/mL of G. tenax established the CCB-like effect by non-specific inhibition of CaCl2−mediated concentration-response curves towards the right with suppression of the maximum peaks, similar to verapamil, a standard CCB. Thus, the present investigation revealed the phytochemical constituents and explored the detailed pharmacodynamic basis for the curative use of G. tenax in diarrhea and hyperactive gut motility disorders.
Topics: Rats; Mice; Animals; Parasympatholytics; Antidiarrheals; Grewia; Papaverine; Jejunum; Fruit; Gas Chromatography-Mass Spectrometry; Plant Extracts; Diarrhea; Phosphoric Diester Hydrolases; Spasm
PubMed: 36558012
DOI: 10.3390/molecules27248880 -
Frontiers in Pharmacology 2022This study aimed to establish a pharmacological basis for evaluating the effects of bergapten (5-methoxypsoralen) in gastrointestinal diseases and assessment of its...
Pharmacological basis of bergapten in gastrointestinal diseases focusing on H/K ATPase and voltage-gated calcium channel inhibition: A toxicological evaluation on vital organs.
This study aimed to establish a pharmacological basis for evaluating the effects of bergapten (5-methoxypsoralen) in gastrointestinal diseases and assessment of its toxicological profile. The pharmacokinetic profile was evaluated using the SwissADME tool. AUTODOCK and PyRx were used for evaluating the binding affinities. The obtained results were further investigated for a post-dock analysis using Discovery Studio Visualizer 2016. The Desmond software package was used to conduct molecular dynamic simulations of best bound poses. Bergapten was further investigated for antidiarrheal, anti-secretory, charcoal meal transit time, anti-ulcer, anti- activity. Bergapten at a dose of 50, 100, and 200 mg/kg was proved effective in reducing diarrheal secretions, intestinal secretions, and distance moved by charcoal meal. Bergapten at the aforementioned doses acts as a gastroprotective agent in the ethanol-induced ulcer model that can be attributed to its effectiveness against Bergapten shows concentration-dependent relaxation of both spontaneous and K (80 mM)-induced contractions in the isolated rabbit jejunum model; the Ca concentration-response curves (CRCs) were shifted to the right showing potentiating effect similar to papaverine. For molecular investigation, the H/K ATPase inhibitory assay indicated inhibition of the pump comparable to omeprazole. Oxidative stress markers GST, GSH, and catalase showed increased expression, whereas the expression of LPO (lipid peroxidation) was reduced. Histopathological examination indicated marked improvement in cellular morphology. ELISA and western blot confirmed the reduction in inflammatory mediator expression. RT-PCR reduced the mRNA expression level of H/K ATPase, confirming inhibition of the pump. The toxicological profile of bergapten was evaluated by an acute toxicity assay and evaluated for behavioral analysis, and the vital organs were used to analyze biochemical, hematological, and histopathological examination. Bergapten at the tested doses proved to be an antioxidant, anti-inflammatory, anti-ulcer, and antidiarrheal agent and relatively safe in acute toxicity assay.
PubMed: 36467058
DOI: 10.3389/fphar.2022.1005154 -
European Heart Journal. Case Reports Nov 2022The severity of peripheral artery disease (PAD) is usually diagnosed by physiological assessments, such as the ankle brachial index (ABI) or peak systolic velocity (PSV)...
BACKGROUND
The severity of peripheral artery disease (PAD) is usually diagnosed by physiological assessments, such as the ankle brachial index (ABI) or peak systolic velocity (PSV) on ultrasonography. We examined peripheral fractional flow reserve (pFFR: distal mean pressure divided by proximal mean pressure) measured by a pressure wire and pressure gradient to diagnose PAD patients who do not have lowered ABI or high PSV on ultrasonography.
CASE SUMMARY
An 84-year-old woman with intermittent claudication in her left leg had severe calcification in the left common femoral artery (CFA) on angiography. The exercise-stress ABI of pre-endovascular therapy (EVT) was 1.05/0.98. In addition, the PSV of the left CFA on ultrasonography was 230 cm/s. However, the pFFR using papaverine and alprostadil in the left CFA was 0.86, which was a significant score. In addition, the systolic pressure gradient between the distal and proximal regions was >20 mmHg. We performed EVT for the lesion, and the pFFR improved to 0.96. The systolic pressure gradient was only 1 mmHg at the lesion.
DISCUSSION
Symptomatic PAD patients whose ABI or PSV on ultrasonography is insufficient for EVT could be diagnosed with ischaemia using a pressure gradient and pFFR.
PubMed: 36405536
DOI: 10.1093/ehjcr/ytac426 -
Cells Oct 2022Papaverine (PPV), a benzylisoquinoline alkaloid, extracted from the plant, is currently in clinical use as a vasodilator. Research has shown that PPV inhibits... (Review)
Review
Papaverine (PPV), a benzylisoquinoline alkaloid, extracted from the plant, is currently in clinical use as a vasodilator. Research has shown that PPV inhibits phosphodiesterase 10A (PDE10A,) resulting in the accumulation of cyclic adenosine 3', 5'-monophosphate (cAMP) that affects multiple downstream pathways, including phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), a mammalian target of rapamycin (mTOR) and vascular endothelial growth factor (VEGF). The accumulation of cAMP can further affect mitochondrial metabolism through the activation of protein kinase A (PKA), which activates the mitochondrial complex I. Literature has shown that PPV exerts anti-proliferative affects in several tumorigenic cell lines including adenocarcinoma alveolar cancer (A549) and human hepatoma (HepG-2) cell lines. Cell cycle investigations have shown varying results with the effects dependent on concentration and cell type with data suggesting an increase in cells occupying the sub-G phase, which is indicative of cell death. These results suggest that PPV may be a beneficial compound to explore for the use in anticancer studies. More insight into the effects of the compound on cellular and molecular mechanisms is needed. Understanding the effects PPV may exert on tumorigenic cells may better researchers' understanding of phytomedicines and the effects of PPV and PPV-derived compounds in cancer.
Topics: Humans; Papaverine; Phosphatidylinositol 3-Kinases; Vascular Endothelial Growth Factor A; Cyclic AMP-Dependent Protein Kinases; Cell Cycle; Neoplasms; Phosphoric Diester Hydrolases
PubMed: 36359780
DOI: 10.3390/cells11213385 -
Nature Communications Nov 2022Opium poppy accumulates copious amounts of several benzylisoquinoline alkaloids including morphine, noscapine, and papaverine, in the specialized cytoplasm of...
Opium poppy accumulates copious amounts of several benzylisoquinoline alkaloids including morphine, noscapine, and papaverine, in the specialized cytoplasm of laticifers, which compose an internal secretory system associated with phloem throughout the plant. The contiguous latex includes an abundance of related proteins belonging to the pathogenesis-related (PR)10 family known collectively as major latex proteins (MLPs) and representing at least 35% of the total cellular protein content. Two latex MLP/PR10 proteins, thebaine synthase and neopione isomerase, have recently been shown to catalyze late steps in morphine biosynthesis previously assigned as spontaneous reactions. Using a combination of sucrose density-gradient fractionation-coupled proteomics, differential scanning fluorimetry, isothermal titration calorimetry, and X-ray crystallography, we show that the major latex proteins are a family of alkaloid-binding proteins that display altered conformation in the presence of certain ligands. Addition of MLP/PR10 proteins to yeast strains engineered with morphine biosynthetic genes from the plant significantly enhanced the conversion of salutaridine to morphinan alkaloids.
Topics: Papaver; Latex; Alkaloids; Benzylisoquinolines; Morphine; Saccharomyces cerevisiae
PubMed: 36351903
DOI: 10.1038/s41467-022-34313-6 -
Plastic and Reconstructive Surgery.... Nov 2022Temporary or prolonged vascular spasm can be appreciated when perivascular dissection is performed for microvascular reconstruction. Due to a lack of reliable assessment...
Temporary or prolonged vascular spasm can be appreciated when perivascular dissection is performed for microvascular reconstruction. Due to a lack of reliable assessment modalities, the resolution of spasm at the periphery of perforators cannot be determined by naked eyes or surgical loupes. To address this conundrum, we aimed to observe the state of perforator vessel spasm after flap elevation using video-capillaroscopy. Between November 2021 and February 2022, seven free flaps were evaluated with video-capillaroscopy to determine the incidence of vasospasm in less than 1 mm-diameter perforators. The type of perforator spasm after flap elevation was divided into six types according to the video-capillaroscopy findings: type A, no spasm/decreased pulsation (S/DP); type B, S/DP with recovery within 5 minutes; type C, S/DP requiring papaverine hydrochloride spraying and hot water treatment (PHS+HWT) resulting in recovery within 5 minutes; type D, S/DP requiring PHS+HWT resulting in recovery within 10 minutes; type E, S/DP requiring PHS+HWT resulting in recovery within 15 minutes; and type F, S/DP with no recovery of pulsation even after PHS+HWT. Twenty-five perforators were evaluated, 3.57 perforators (range, 3-4) per flap. Using our classification for perforator vessel spasms on video-capillaroscopy, observations of five perforating branches were classified as type A, seven as type B, six as type C, five as type D, and two as type E. No type F spasm was observed. With video-capillaroscopy it is possible to confirm if blood flow deterioration occurs even in areas that are difficult to determine macroscopically. Video-capillaroscopy, a noninvasive imaging modality, is a useful alternative for the intraoperative evaluation of perforator flow and spasm.
PubMed: 36348753
DOI: 10.1097/GOX.0000000000004613 -
International Journal of Molecular... Sep 2022Conventional cancer treatment is mainly based on the surgical removal of the tumor followed by radiotherapy and/or chemotherapy. When surgical removal is not possible,... (Review)
Review
Conventional cancer treatment is mainly based on the surgical removal of the tumor followed by radiotherapy and/or chemotherapy. When surgical removal is not possible, radiotherapy and, less often, chemotherapy is the only way to treat patients. However, despite significant progress in understanding the molecular mechanisms of carcinogenesis and developments in modern radiotherapy techniques, radiotherapy (alone or in combination) does not always guarantee treatment success. One of the main causes is the radioresistance of cancer cells. Increasing the radiosensitivity of cancer cells improves the processes leading to their elimination during radiotherapy and prolonging the survival of cancer patients. In order to enhance the effect of radiotherapy in the treatment of radioresistant neoplasms, radiosensitizers are used. In clinical practice, synthetic radiosensitizers are commonly applied, but scientists have recently focused on using natural products (phytocompounds) as adjuvants in radiotherapy. In this review article, we only discuss naturally occurring radiosensitizers currently in clinical trials (paclitaxel, curcumin, genistein, and papaverine) and those whose radiation sensitizing effects, such as resveratrol, have been repeatedly confirmed by many independent studies.
Topics: Biological Products; Curcumin; Genistein; Humans; Neoplasms; Paclitaxel; Papaverine; Radiation Tolerance; Radiation, Ionizing; Radiation-Sensitizing Agents; Resveratrol
PubMed: 36142554
DOI: 10.3390/ijms231810627