scholarly journals Identification of mundulone and mundulone acetate as natural products with tocolytic efficacy in mono- and combination-therapy with current tocolytics

2021 ◽  
Author(s):  
Shajila Siricilla ◽  
Christopher J. Hansen ◽  
Jackson H. Rogers ◽  
Carolyn L. Simpson ◽  
Stacey L. Crockett ◽  
...  
Keyword(s):  
Natural Products ◽  
Preterm Labor ◽  
Ex Vivo ◽  
Ductus Arteriosus ◽  
Therapeutic Index ◽  
Pregnant Mouse ◽  
Myometrial Cells ◽  
Myometrial Contractility ◽  
Synergistic Combinations

Currently, there are a lack of FDA-approved tocolytics for the management of preterm labor. We previously observed that the isoflavones mundulone and mundulone acetate (MA) inhibit intracellular Ca2+-regulated myometrial contractility. Here, we further probed the potential of these natural products to be small molecule leads for discovery of novel tocolytics by: (1) examining uterine-selectivity by comparing concentration-response between human primary myometrial cells and a major off-target site, aortic vascular smooth muscle cells (VSMCs), (2) identifying synergistic combinations with current clinical tocolytics to increase efficacy or and reduce off-target side effects, (3) determining cytotoxic effects and (4) investigating the efficacy, potency and tissue-selectivity between myometrial contractility and constriction of fetal ductus arteriosus (DA), a major off-target of current tocolytics. Mundulone displayed significantly greater efficacy (Emax = 80.5% vs. 44.5%, p=0.0005) and potency (IC50 = 27 μM and 14 μM, p=0.007) compared to MA in the inhibition of intracellular-Ca2+ from myometrial cells. MA showed greater uterine-selectivity, compared to mundulone, based on greater differences in the IC50 (4.3 vs. 2.3 fold) and Emax (70% vs. 0%) between myometrial cells compared to aorta VSMCs. Moreover, MA demonstrated a favorable in vitro therapeutic index of 8.8, compared to TI = 0.8 of mundulone, due to its significantly (p<0.0005) smaller effect on the viability of myometrial (hTERT-HM), liver (HepG2) and kidney (RPTEC) cells. However, mundulone exhibited synergism with two current tocolytics (atosiban and nifedipine), while MA only displayed synergistic efficacy with only nifedipine. Of these synergistic combinations, only mundulone + atosiban demonstrated a favorable TI = 10 compared to TI=0.8 for mundulone alone. While only mundulone showed concentration-dependent inhibition of ex vivo mouse myometrial contractions, neither mundulone or MA affected mouse fetal DA vasoreactivity. The combination of mundulone and atosiban yielded greater tocolytic efficacy and potency on term pregnant mouse and human myometrial tissue compared to single-drugs. Collectively, these data highlight the difference in uterine‐selectivity of Ca2+‐mobilization, effects on cell viability and tocolytic efficacy between mundulone and MA. These natural products could benefit from medicinal chemistry efforts to study the structural activity relationship for further development into a promising single- and/or combination-tocolytic therapy for management of preterm labor.

Biochemical and Pharmacological Properties of SANORG 34006, a Potent and Long-Acting Synthetic Pentasaccharide

Blood ◽  
1998 ◽  
Vol 91 (11) ◽  
pp. 4197-4205 ◽  
Author(s):  
J.M. Herbert ◽  
J.P. Hérault ◽  
A. Bernat ◽  
R.G.M. van Amsterdam ◽  
J.C. Lormeau ◽  
...  
Keyword(s):  
Thrombin Generation ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Factor Xa ◽  
Therapeutic Index ◽  
Inhibitory Effect ◽  
Experimental Models ◽  
Treatment And Prevention ◽  
Long Acting

Abstract SANORG 34006 is a new sulfated pentasaccharide obtained by chemical synthesis. It is an analog of the “synthetic pentasaccharide” (SR 90107/ ORG 31540) which represents the antithrombin (AT) binding site of heparin. SANORG 34006 showed a higher affinity to human AT than SR 90107/ORG 31540 (kd = 1.4 ± 0.3 v 48 ± 11 nmol/L), and it is a potent and selective catalyst of the inhibitory effect of AT on factor Xa (1,240 ± 15 anti–factor Xa U/mg v850 ± 27 anti-factor Xa U/mg for SR 90107/ORG 31540). In vitro, SANORG 34006 inhibited thrombin generation occurring via both the extrinsic and intrinsic pathway. After intravenous (IV) or subcutaneous (SC) administration to rabbits, SANORG 34006 displayed a long-lasting anti–factor Xa activity and inhibition of thrombin generation (TG) ex vivo. SANORG 34006 was slowly eliminated after IV or SC administration to rats, rabbits, and baboons, showed exceptionally long half-lives (between 9.2 hours in rats and 61.9 hours in baboons), and revealed an SC bioavailability near 100%. SANORG 34006 displayed antithrombotic activity by virtue of its potentiation of the anti–factor Xa activity of AT. It strongly inhibited thrombus formation in experimental models of thromboplastin/stasis-induced venous thrombosis in rats (IV) and rabbits (SC) (ED50values = 40.0 ± 3.4 and 105.0 ± 9.4 nmol/kg, respectively). The duration of its antithrombotic effects closely paralleled the ex vivo anti–factor Xa activity. SANORG 34006 enhanced rt-PA–induced thrombolysis and inhibited accretion of125I-fibrinogen onto a preformed thrombus in the rabbit jugular vein suggesting that concomitant use of SANORG 34006 during rt-PA therapy might be helpful in facilitating thrombolysis and preventing fibrin accretion onto the thrombus under lysis. Contrary to standard heparin, SANORG 34006 did not enhance bleeding in a rabbit ear incision model at a dose that equals 10 times the antithrombotic ED50 in this species and, therefore, exhibited a favorable therapeutic index. We suggest that SANORG 34006 is a promising compound in the treatment and prevention of various thrombotic diseases.

scholarly journals Unraveling Natural Products’ Role in Osteoarthritis Management—An Overview

Antioxidants ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 348 ◽  
Author(s):  
Georgia-Eirini Deligiannidou ◽  
Rafail-Efraim Papadopoulos ◽  
Christos Kontogiorgis ◽  
Anastasia Detsi ◽  
Eugenia Bezirtzoglou ◽  
...  
Keyword(s):  
Natural Products ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Meta Analysis ◽  
Term Treatment ◽  
Naturally Occurring ◽  
Long Term Treatment ◽  
Living Organisms

The natural process of aging gradually causes changes in living organisms, leading to the deterioration of organs, tissues, and cells. In the case of osteoarthritis (OA), the degradation of cartilage is a result of both mechanical stress and biochemical factors. Natural products have already been evaluated for their potential role in the prevention and treatment of OA, providing a safe and effective adjunctive therapeutic approach. This review aimed to assess the therapeutic potential of natural products and their derivatives in osteoarthritis via a systematic search of literature after 2008, including in vitro, in vivo, ex vivo, and animal models, along with clinical trials and meta-analysis. Overall, 170 papers were obtained and screened. Here, we presented findings referring to the preventative and therapeutic potential of 17 natural products and 14 naturally occurring compounds, underlining, when available, the mechanisms implicated. The nature of OA calls to initially focus on the management of symptoms, and, in that context, several naturally occurring compounds have been utilized. Underlying a global need for more sustainable natural sources for treatment, the evidence supporting their chondroprotective potential is still building up. However, arriving at that kind of solution requires more clinical research, targeting the implications of long-term treatment, adverse effects, and epigenetic implications.

Aminophylline and progesterone prevent inflammation-induced preterm parturition in the mouse†

2019 ◽  
Vol 101 (4) ◽  
pp. 813-822 ◽  
Author(s):  
Bronwen R Herbert ◽  
Danijela Markovic ◽  
Ektoras Georgiou ◽  
Pei F Lai ◽  
Natasha Singh ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Phosphodiesterase Inhibitor ◽  
Adenosine Monophosphate ◽  
Cytokine Gene Expression ◽  
Intracellular Camp ◽  
Myometrial Cells ◽  
Anti Inflammatory ◽  
Camp Levels

Abstract Although progesterone (P4) supplementation is the most widely used therapy for the prevention of preterm labor (PTL), reports of its clinical efficacy have been conflicting. We have previously shown that the anti-inflammatory effects of P4 can be enhanced by increasing intracellular cyclic adenosine monophosphate (cAMP) levels in primary human myometrial cells. Here, we have examined whether adding aminophylline (Am), a non-specific phosphodiesterase inhibitor that increases intracellular cAMP levels, to P4 might improve its efficacy using in vivo and in vitro models of PTL. In a mouse model of lipopolysaccharide (LPS)-induced PTL, we found that the combination of P4 and Am delayed the onset of LPS-induced PTL, while the same dose of P4 and Am alone had no effect. Pup survival was not improved by either agent alone or in combination. Myometrial prolabor and inflammatory cytokine gene expression was reduced, but the reduction was similar in P4 and P4/Am treated mice. There was no effect of the combination of P4 and Am on an ex vivo assessment of myometrial contractility. In human myometrial cells and myometrial tissue explants, we found that the combination had marked anti-inflammatory effects, reducing cytokine and COX-2 mRNA and protein levels to a greater extent than either agent alone. These data suggest that the combination of P4 and Am has a more potent anti-inflammatory effect than either agent alone and may be an effective combination in women at high-risk of PTL.

scholarly journals Using Porcine Jejunum Ex Vivo to Study Absorption and Biotransformation of Natural Products in Plant Extracts: Pueraria lobata as a Case Study

Metabolites ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 541
Author(s):  
Joëlle Houriet ◽  
Yvonne E. Arnold ◽  
Léonie Pellissier ◽  
Yogeshvar N. Kalia ◽  
Jean-Luc Wolfender
Keyword(s):  
Natural Products ◽  
Ex Vivo ◽  
Folk Medicine ◽  
In Vivo Studies ◽  
Pueraria Lobata ◽  
Intestinal Membrane ◽  
Untargeted Metabolite Profiling ◽  
The Impact

Herbal preparations (HPs) used in folk medicine are complex mixtures of natural products (NPs). Their efficacy in vivo after ingestion depends on the uptake of the active ingredient, and, in some cases, their metabolites, in the gastrointestinal tract. Thus, correlating bioactivities measured in vitro and efficacy in vivo is a challenge. An extract of Pueraria lobata rich in different types of isoflavones was used to evaluate the capacity of viable porcine small intestine ex vivo to elucidate the absorption of HP constituents, and, in some cases, their metabolites. The identification and transport of permeants across the jejunum was monitored by liquid chromatography-mass spectrometry (LC-MS), combining targeted and untargeted metabolite profiling approaches. It was observed that the C-glycoside isoflavones were stable and crossed the intestinal membrane, while various O-glycoside isoflavones were metabolized into their corresponding aglycones, which were then absorbed. These results are consistent with human data, highlighting the potential of using this approach. A thorough investigation of the impact of absorption and biotransformation was obtained without in vivo studies. The combination of qualitative untargeted and quantitative targeted LC-MS methods effectively monitored a large number of NPs and their metabolites, which is essential for research on HPs.

Design, Synthesis and In Vitro Evaluation of Novel Anti-HIV 3-Pyrazol-3- yl-Pyridin-2-One Analogs

2019 ◽  
Vol 15 (5) ◽  
pp. 561-570 ◽  
Author(s):  
Sanjay Kumar ◽  
Shiv Gupta ◽  
Shraddha Gaikwad ◽  
Leila F. Abadi ◽  
Late K. K. Bhutani ◽  
...  
Keyword(s):  
Natural Products ◽  
In Silico ◽  
Chemical Space ◽  
Therapeutic Index ◽  
In Silico Prediction ◽  
New Class ◽  
Ic50 Values ◽  
Anti Hiv ◽  
Hiv 1

Background: Natural products have shown potent anti-HIV activity, but some of these also possess toxicity. The pharmacophoric fragments of these natural products have scope of combination with other pharmacophoric fragment and derivatization to reduce toxicity and increase the potency. Combination of natural product fragments from different classes of anti–HIV compounds may lead to a new class of potent anti–HIV agents. Objective: Design, in silico prediction of drug-likeness, ADMET properties and synthesis of pyrazol– pyridones. Evaluation of the anti–HIV–1 activity of synthesized pyrazol–pyridones. Methods: Pyrazol–pyridones were designed by combining reported anti–HIV pharmacophoric fragments. Designed molecules were synthesized after in silico prediction of drug-likeness and ADMET properties. Compounds were evaluated for activity against HIV–1VB59 and HIV–1UG070. Results: QED value of designed pyrazol–pyridones was greater than the known drug zidovudine. The designed compounds were predicted to be noncarcinogenic and nonmutagenic in nature. Seventeen novel pyrazol–pyridones were synthesized with good yield. Compound 6q and 6l showed activity with IC50 values 6.14 µM and 15.34 µM against HIV–1VB59 and 16.21 µM and 18.21 µM against HIV–1UG070, respectively. Conclusion: Compound 6q was found to be most potent among the synthesized compounds with a therapeutic index of 54.31against HIV–1VB59. This is the first report of anti–HIV–1 activity of pyrazol–pyridone class of compounds. Although the anti–HIV–1 activity of these compounds is moderate, this study opens up a new class for exploration of chemical space for anti–HIV–1 activity.

scholarly journals Topical Nanoemulgel for the Treatment of Skin Cancer: Proof-of-Technology

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 902
Author(s):  
Sreeharsha Nagaraja ◽  
Girish Meravanige Basavarajappa ◽  
Mahesh Attimarad ◽  
Swati Pund
Keyword(s):  
Skin Cancer ◽  
Ex Vivo ◽  
L929 Cell ◽  
Therapeutic Index ◽  
In Vitro Cytotoxicity ◽  
Apparent Permeability ◽  
Efficient Treatment ◽  
Formidable Challenge ◽  
Novel Approach

The present study is a mechanistic validation of ‘proof-of-technology’ for the effective topical delivery of chrysin nanoemulgel for localized, efficient treatment of melanoma-affected skin. Background: Currently available treatments for skin cancer are inefficient due to systemic side effects and poor transcutaneous permeation, thereby presenting a formidable challenge for the development of novel nanocarriers. Methods: We opted for a novel approach and formulated a nanocomplex system composed of hydrophobic chrysin dissolved in a lipid mix, which was further nanoemulsified in Pluronic® F-127 gel to enhance physicochemical and biopharmaceutic characteristics. Chrysin, a flavone extracted from passion flowers, exhibits potential anti-cancer activities; however, it has limited applicability due to its poor solubility. Pseudo-ternary phase diagrams were constructed to identify the best self-nanoemulsifying region by varying the compositions of oil, Caproyl® 90 surfactant, Tween® 80, and co-solvent Transcutol® HP. Chrysin-loaded nanoemulsifying compositions were characterized for various physicochemical properties. Results: This thermodynamically stable, self-emulsifying drug delivery system showed a mean droplet size of 156.9 nm, polydispersity index of 0.26, and viscosity of 9100 cps after dispersion in gel. Mechanical characterization using Texture Analyzer exhibited that the gel had a hardness of 487 g and adhesiveness of 500 g. Ex vivo permeation through rat abdominal skin revealed significant improvement in percutaneous absorption measured as flux, the apparent permeability coefficient, the steady-state diffusion coefficient, and drug deposition. In vitro cytotoxicity on A375 and SK-MEL-2 cell lines showed a significantly improved therapeutic effect, thus ensuring reduction in dose. The safety of the product was established through biocompatibility testing on the L929 cell line. Conclusion: Aqueous, gel-based, topical, nanoemulsified chrysin is a promising technology approach for effective localized transcutaneous delivery that will help reduce the frequency and overall dose usage and ultimately improve the therapeutic index.

Formulation, development, and in-vitro/ex-vivo evaluation of vaginal bioadhesive salbutamol sulfate tablets for preterm labor

2020 ◽  
Vol 25 (8) ◽  
pp. 989-998
Author(s):  
Amal S. M. Abu El-Enin ◽  
Asmaa M. Elbakry ◽  
Rania El Hosary ◽  
Marwa Ahmed Fouad Lotfy
Keyword(s):  
Preterm Labor ◽  
Ex Vivo ◽  
Formulation Development ◽  
Salbutamol Sulfate

Biochemical and Pharmacological Properties of SANORG 34006, a Potent and Long-Acting Synthetic Pentasaccharide

Blood ◽  
1998 ◽  
Vol 91 (11) ◽  
pp. 4197-4205 ◽  
Author(s):  
J.M. Herbert ◽  
J.P. Hérault ◽  
A. Bernat ◽  
R.G.M. van Amsterdam ◽  
J.C. Lormeau ◽  
...  
Keyword(s):  
Thrombin Generation ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Factor Xa ◽  
Therapeutic Index ◽  
Inhibitory Effect ◽  
Experimental Models ◽  
Treatment And Prevention ◽  
Long Acting

SANORG 34006 is a new sulfated pentasaccharide obtained by chemical synthesis. It is an analog of the “synthetic pentasaccharide” (SR 90107/ ORG 31540) which represents the antithrombin (AT) binding site of heparin. SANORG 34006 showed a higher affinity to human AT than SR 90107/ORG 31540 (kd = 1.4 ± 0.3 v 48 ± 11 nmol/L), and it is a potent and selective catalyst of the inhibitory effect of AT on factor Xa (1,240 ± 15 anti–factor Xa U/mg v850 ± 27 anti-factor Xa U/mg for SR 90107/ORG 31540). In vitro, SANORG 34006 inhibited thrombin generation occurring via both the extrinsic and intrinsic pathway. After intravenous (IV) or subcutaneous (SC) administration to rabbits, SANORG 34006 displayed a long-lasting anti–factor Xa activity and inhibition of thrombin generation (TG) ex vivo. SANORG 34006 was slowly eliminated after IV or SC administration to rats, rabbits, and baboons, showed exceptionally long half-lives (between 9.2 hours in rats and 61.9 hours in baboons), and revealed an SC bioavailability near 100%. SANORG 34006 displayed antithrombotic activity by virtue of its potentiation of the anti–factor Xa activity of AT. It strongly inhibited thrombus formation in experimental models of thromboplastin/stasis-induced venous thrombosis in rats (IV) and rabbits (SC) (ED50values = 40.0 ± 3.4 and 105.0 ± 9.4 nmol/kg, respectively). The duration of its antithrombotic effects closely paralleled the ex vivo anti–factor Xa activity. SANORG 34006 enhanced rt-PA–induced thrombolysis and inhibited accretion of125I-fibrinogen onto a preformed thrombus in the rabbit jugular vein suggesting that concomitant use of SANORG 34006 during rt-PA therapy might be helpful in facilitating thrombolysis and preventing fibrin accretion onto the thrombus under lysis. Contrary to standard heparin, SANORG 34006 did not enhance bleeding in a rabbit ear incision model at a dose that equals 10 times the antithrombotic ED50 in this species and, therefore, exhibited a favorable therapeutic index. We suggest that SANORG 34006 is a promising compound in the treatment and prevention of various thrombotic diseases.

Effects of the Tibetan herbal preparation PADMA 28 on blood lipids and lipid oxidisability in subjects with mild hypercholesterolaemia

VASA ◽  
2005 ◽  
Vol 34 (1) ◽  
pp. 11-17 ◽  
Author(s):  
Brunner-La Rocca ◽  
Schindler ◽  
Schlumpf ◽  
Saller ◽  
Suter
Keyword(s):  
Endothelial Dysfunction ◽  
Blood Lipids ◽  
Ex Vivo ◽  
Hdl Cholesterol ◽  
Blood Lipid ◽  
Tibetan Medicine ◽  
Double Blind ◽  
Intraarterial Infusion ◽  
Padma 28

Background: Previous studies showed an anti-atherosclerotic effect of PADMA 28, an herbal formula based on Tibetan medicine. As the mechanisms of action are not fully understood, we investigated whether PADMA 28 may lower blood lipids and lipid oxidisability, and affect early endothelial dysfunction. Patients and methods: Sixty otherwise healthy subjects with total cholesterol ≥5.2 mmol/l and < 8.0 mmol/l were randomly assigned to placebo or PADMA 28, 3 x 2 capsules daily, for 4 weeks (double-blind). Blood lipids (total, LDL-, and HDL-cholesterol, triglycerides, Apo-lipoprotein A1 and B) and ex vivo lipid oxidisability were measured before and after treatment. In a subset of 24 subjects, endothelial function was assessed using venous occlusion plethysmography with intraarterial infusion of acetylcholine. Isolated LDL and plasma both untreated and pre-treated with PADMA 28 extract were oxidised by the radical generator AAPH. Conjugated diene formation was measured at 245 nm. Results: Blood lipids did not change during the study in both groups. In contrast to previous reports in mild hypercholesterolaemia, no endothelial dysfunction was seen and, consequently, was not influenced by therapy. Ex vivo blood lipid oxidisability was significantly reduced with PADMA 28 (area under curve: 5.29 ± 1.62 to 4.99 ± 1.46, p = 0.01), and remained unchanged in the placebo group (5.33 ± 1.88 to 5.18 ± 1.78, p > 0.1). This effect persisted one week after cessation of medication. In vitro experiments confirmed the prevention of lipid peroxidation in the presence of PADMA 28 extracts. Persistent protection was also seen for LDL isolated from PADMA 28-pretreated blood after being subjected to rigorous purification. Conclusions: This study suggests that the inhibition of blood lipid oxidisability by PADMA 28 may play a role in its anti-atherosclerotic effect.

The Role of Polyphenols in the Modulation of Plasma Non-Enzymatic Antioxidant Capacity (NEAC)

2012 ◽  
Vol 82 (3) ◽  
pp. 228-232 ◽  
Author(s):  
Mauro Serafini ◽  
Giuseppa Morabito
Keyword(s):  
Antioxidant Capacity ◽  
Dietary Intervention ◽  
Ex Vivo ◽  
The Body ◽  
Dietary Polyphenols ◽  
Enzymatic Antioxidant ◽  
Endogenous Antioxidant

Dietary polyphenols have been shown to scavenge free radicals, modulating cellular redox transcription factors in different in vitro and ex vivo models. Dietary intervention studies have shown that consumption of plant foods modulates plasma Non-Enzymatic Antioxidant Capacity (NEAC), a biomarker of the endogenous antioxidant network, in human subjects. However, the identification of the molecules responsible for this effect are yet to be obtained and evidences of an antioxidant in vivo action of polyphenols are conflicting. There is a clear discrepancy between polyphenols (PP) concentration in body fluids and the extent of increase of plasma NEAC. The low degree of absorption and the extensive metabolism of PP within the body have raised questions about their contribution to the endogenous antioxidant network. This work will discuss the role of polyphenols from galenic preparation, food extracts, and selected dietary sources as modulators of plasma NEAC in humans.

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