Population Pharmacokinetic of the Diterpenes ent-Polyalthic Acid and Dihydro-ent-Agathic Acid from Copaifera Duckei Oil Resin in Rats.

Copaifera duckei oleoresin is a plant product extensively used by the Brazilian population for multiple purposes, such as medicinal and cosmetic. Despite its ethnopharmacological relevance, there is no pharmacokinetic data on this important medicinal plant. Due to this, we determined the pharmacokinetic profile of the major nonvolatile compounds of C. duckei oleoresin. The diterpenes ent-polyalthic acid and dihydro-ent-agathic acid correspond to approximately 40% of the total oleoresin. Quantification was performed using LC-MS/MS, and the validated analytical method showed to be precise, accurate, robust, reliable, and linear between 0.57 and 114.74 µg/mL plasma and 0.09 to 18.85 µg/mL plasma, respectively, for ent-polyalthic acid and dihydro-ent-agathic acid, making it suitable for application in preclinical pharmacokinetic studies. Wistar rats received a single 200 mg/kg oral dose (gavage) of C. duckei oleoresin, and blood was collected from their caudal vein through 48 h. Population pharmacokinetics analysis of ent-polyalthic and dihydro-ent-agathic acids in rats was evaluated using nonlinear mixed-effects modeling conducted in NONMEN software. The pharmacokinetic parameters of ent-polyalthic acid were absorption constant rate = 0.47 h-1, central and peripheral apparent volume of distribution = 0.04 L and 2.48 L, respectively, apparent clearance = 0.15 L/h, and elimination half-life = 11.60 h. For dihydro-ent-agathic acid, absorption constant rate = 0.28 h-1, central and peripheral apparent volume of distribution = 0.01 L and 0.18 L, respectively, apparent clearance = 0.04 L/h, and elimination half-life = 3.49 h. The apparent clearance, central apparent volume of distribution, and peripheral apparent volume of distribution of ent-polyalthic acid were approximately 3.75, 4.00-, and 13.78-folds higher than those of dihydro-ent-agathic.

Andrographis paniculata Formulations: Impact on Diterpene Lactone Oral Bioavailability.

Diterpene lactones have been identified as active compounds in several medicinal plants, including Andrographis paniculata (Burm. f.) Nees, which is a medicinal plant that has been used for centuries across the world. Andrographolide is the major diterpene from A. paniculata and the main bioactive constituent of this species. The effectiveness of diterpenes can be affected by factors that limit their oral bioavailability, such as their poor water solubility, slow dissolution rates, low gastrointestinal absorption, high chemical and metabolic instability, and rapid excretion. In this context, the purpose of the present review is to compile and compare literature data on the bioavailability of diterpene lactones from A. paniculata after oral administration in medicinal plant extracts or in their free forms and to highlight strategies that have been used to improve their oral bioavailability. Considering that medicinal plant extracts are commonly used as dried powder that is reconstituted in water before oral administration, novel pharmaceutical formulation strategies that are used to overcome difficulties with diterpene solubility are also compiled in this review. The use of self-microemulsifying drug delivery systems is a good strategy to enhance the dissolution and consequently the bioavailability of andrographolide after oral administration of A. paniculata extract formulations. On the other hand, herbosome technology, pH-sensitive nanoparticles, nanosuspensions, nanoemulsions, nanocrystal suspensions, nanocrystal-based solid dispersions, and solid dispersion systems are useful to formulate andrographolide in its free form and increase its oral bioavailability. The use of a suitable andrographolide delivery system is essential to achieve its therapeutic potential.

Andrographolide, an Anti-Inflammatory Multitarget Drug: All Roads Lead to Cellular Metabolism.

Andrographolide is a labdane diterpene and the main active ingredient isolated from the herb Andrographis paniculata. Andrographolide possesses diverse biological effects including anti-inflammatory, antioxidant, and antineoplastic properties. Clinical studies have demonstrated that andrographolide could be useful in therapy for a wide range of diseases such as osteoarthritis, upper respiratory diseases, and multiple sclerosis. Several targets are described for andrographolide, including the interference of transcription factors NF-κB, AP-1, and HIF-1 and signaling pathways such as PI3K/Akt, MAPK, and JAK/STAT. In addition, an increase in the Nrf2 (nuclear factor erythroid 2-related factor 2) signaling pathway also supports its antioxidant and anti-inflammatory properties. However, this scenario could be more complex since recent evidence suggests that andrographolide targets can modulate glucose metabolism. The metabolic effect of andrographolide might be the key to explaining the diverse therapeutic effects described in preclinical and clinical studies. This review discusses some of the most recent evidence about the anti-inflammatory and metabolic effects of andrographolide.

Ligand and Structure-based Virtual Screening of Lamiaceae Diterpenes with Potential Activity against a Novel Coronavirus (2019-nCoV).

BACKGROUND: The emergence of a new coronavirus (CoV), named 2019-nCoV, as an outbreak originated in the city of Wuhan, China, has resulted in the death of more than 3,400 people this year alone and has caused worldwide an alarming situation, particularly following previous CoV epidemics, including the Severe Acute Respiratory Syndrome (SARS) in 2003 and the Middle East Respiratory Syndrome (MERS) in 2012. Currently, no exists for infections caused by CoVs; however, some natural products may represent potential treatment resources, such as those that contain diterpenes. OBJECTIVE: This study aimed to use computational methods to perform a virtual screening (VS) of candidate diterpenes with the potential to act as CoV inhibitors. METHODS: 1,955 diterpenes, derived from the Nepetoideae subfamily (Lamiaceae), were selected using the SistematX tool (https://sistematx.ufpb.br), which were used to make predictions. From the ChEMBL database, 3 sets of chemical structures were selected for the construction of predictive models. RESULTS: The chemical structures of molecules with known activity against SARS CoV, two of which were tested for activity against specific viral proteins and one of which was tested for activity against the virus itself, were classified according to their pIC50 values [-log IC50 (mol/l)]. CONCLUSION: In the consensus analysis approach, combining both ligand- and structure-based VSs, 19 compounds were selected as potential CoV inhibitors, including isotanshinone IIA (01), tanshinlactone (02), isocryptotanshinone (03), and tanshinketolactone (04), which did not present toxicity within the evaluated parameters.

Ingenol mebutate in the treatment of actinic keratoses: clearance rate and adverse effects.

BACKGROUND: Actinic keratoses are benign intraepithelial skin neoplasms that develop in photoexposed areas and can progress to invasive carcinoma. They are seen frequently in dermatological practice, occurring in 5.1% of consultations. Ingenol mebutate (IM) was recently approved in Brazil as a topical therapy for field cancerization in actinic keratosis. OBJECTIVE: To evaluate the clearance rate and adverse events in the treatment of actinic keratoses with ingenol mebutate. METHODS: A longitudinal, prospective, non-randomized, interventional, open, single-center study was conducted. Patients with actinic keratoses applied ingenol mebutate on a 25cm2 area of the face and/or scalp for three consecutive days (0.015%) or on the forearm for two days (0.05%). RESULTS: 27 patients completed the protocol, of whom 13 on the face and/or scalp and 14 on the forearm. Complete clearance occurred in 53.8% in the first group and 42.8% in the second. Partial response was observed in 15.4% and 35.7%, respectively. The most common side effects were erythema, edema, desquamation, pruritus, and local erosion. STUDY LIMITATIONS: The study had a small sample and was not randomized, double-blind, placebo-controlled, or vehicle-controlled. CONCLUSION: Ingenol mebutate is well-tolerated for the treatment of actinic keratosis, with good patient adherence thanks to the short treatment period.

Ingenol mebutate in the treatment of actinic keratoses: clearance rate and adverse effects

Abstract: Background: Actinic keratoses are benign intraepithelial skin neoplasms that develop in photoexposed areas and can progress to invasive carcinoma. They are seen frequently in dermatological practice, occurring in 5.1% of consultations. Ingenol mebutate (IM) was recently approved in Brazil as a topical therapy for field cancerization in actinic keratosis. Objective: To evaluate the clearance rate and adverse events in the treatment of actinic keratoses with ingenol mebutate. Methods: A longitudinal, prospective, non-randomized, interventional, open, single-center study was conducted. Patients with actinic keratoses applied ingenol mebutate on a 25cm2 area of the face and/or scalp for three consecutive days (0.015%) or on the forearm for two days (0.05%). Results: 27 patients completed the protocol, of whom 13 on the face and/or scalp and 14 on the forearm. Complete clearance occurred in 53.8% in the first group and 42.8% in the second. Partial response was observed in 15.4% and 35.7%, respectively. The most common side effects were erythema, edema, desquamation, pruritus, and local erosion. Study limitations: The study had a small sample and was not randomized, double-blind, placebo-controlled, or vehicle-controlled. Conclusion: Ingenol mebutate is well-tolerated for the treatment of actinic keratosis, with good patient adherence thanks to the short treatment period.

An Overview of Biotransformation and Toxicity of Diterpenes.

Diterpenes have been identified as active compounds in several medicinal plants showing remarkable biological activities, and some isolated diterpenes are produced at commercial scale to be used as medicines, food additives, in the synthesis of fragrances, or in agriculture. There is great interest in developing methods to obtain derivatives of these compounds, and biotransformation processes are interesting tools for the structural modification of natural products with complex chemical structures. Biotransformation processes also have a crucial role in drug development and/or optimization. The understanding of the metabolic pathways for both phase I and II biotransformation of new drug candidates is mandatory for toxicity and efficacy evaluation and part of preclinical studies. This review presents an overview of biotransformation processes of diterpenes carried out by microorganisms, plant cell cultures, animal and human liver microsomes, and rats, chickens, and swine in vivo and highlights the main enzymatic reactions involved in these processes and the role of diterpenes that may be effectively exploited by other fields.

Pharmacokinetic profile and oral bioavailability of Kaurenoic acid from Copaifera spp. in rats.

Kaurenoic acid (KA) is a kaurane diterpene found in several medicinal plants that displays biological activities, such as anti-inflammatory, smooth muscle relaxant and hypotensive response. However, there are no pharmacokinetic data available about this molecule. The purpose of the study was to determine the pharmacokinetic profile and the oral bioavailability of KA in rats. Wistar rats submitted to jugular vein cannulation received 50 mg/kg of KA by intravenous or oral route. The implanted cannula allowed intravenous administration and serial blood collection along 10 h. Analytical quantification was performed by reversed phase HPLC-UV and mobile phase composed by acetonitrile:acidified water (70:30 v/v). The validated analytical method showed precision, accuracy, robustness, reliability and linearity between 0.75 and 100 µg/mL. KA administered intravenously showed a linear and two-compartment kinetic behavior at the tested dose. The following pharmacokinetic parameters were determined: Cmax = 22.17 ±â€¯1.65 mg/L; V = 14.53 ±â€¯1.47 L/kg; CL = 17.67 ±â€¯1.50 mL/min/kg; AUC0-∞ = 2859.65 ±â€¯278.42 mg·min/L, K = 0.073 ±â€¯0.005 h-1 and t1/2ß = 9.52 ±â€¯0.61 h. Oral treatment did not provide detectable plasma levels of KA, avoiding the determination of its bioavailability.

Use of nonprohibited hallucinogenic plants: increasing relevance for public health? A case report and literature review on the consumption of Salvia divinorum (Diviner's Sage).

INTRODUCTION: : We want to call attention to a mint plant, called diviner's sage ( Salvia divinorum), originally used in shamanic ceremonies of the Mazatec Indians of Mexico. On numerous websites of the internet, this ancient herbal drug and its extracts are offered as a legal means of widening individual awareness. Regarding its dose-response relationship, the active ingredient, salvinorin A, is one of the most potent naturally occurring hallucinogens. Laws on controlled substances, except for Finland, Denmark and Australia, do not prohibit cultivating, consuming or dealing with Salvia divinorum. Ingestion by smoking, vaporising or chewing, induces a short-lived inebriant state with intense, bizarre feelings of depersonalization. This article wants to be a signal for physicians or psychotherapists to take Salvia into consideration, when exploring young people for drug use. METHODS: We report the individual perceptions of a young man consuming Salvia divinorum. We review the scarce scientific literature and consider relevant internet websites. DISCUSSION: We define open issues for further investigations and try to discuss why Salvia divinorum may be of interest for teenagers and young adults in Europe.

Evidence for the mechanisms underlying the effects of pimaradienoic acid isolated from the roots of Viguiera arenaria on rat aorta.

The present study examines the effects of the diterpene ENT-pimara-8(14),15-dien-19-oic acid (PA) on rat thoracic aorta. PA (10(-5), 3 x 10(-5) and 10(-4) mol/l) caused concentration-dependent inhibition of phenylephrine (Phe)-induced contraction in either endothelium-intact or endothelium-denuded aortic rings. PA attenuated the contraction induced by CaCl(2) in Ca(2+)-free solution containing Phe (10(-7) mol/l) or KCl (30 mmol/l). This diterpene did not interfere with Ca(2+) release from intracellular stores mediated by either Phe (10(-6) mol/l) or caffeine (30 mmol/l). PA (10(-6) to 3 x 10(-4) mol/l) concentration dependently relaxed Phe-pre-contracted rings with intact (92.64 +/- 7.60%) or denuded endothelium (98.82 +/- 1.56%). Pre-incubation of denuded aortic rings with N(G)-nitro-L-arginine methyl ester (10(-4) mol/l), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (10(-6) mol/l) or indomethacin (10(-5) mol/l) reduced PA-induced relaxation (percentage of relaxation: 77.50 +/- 3.95, 78.56 +/- 2.81, 77.11 +/- 6.22, respectively). However, the relaxant responses induced by PA on Phe-pre-contracted rings were unaffected by tetraethylammonium (1 and 5 mmol/l). PA also relaxed KCl-pre-contracted rings with intact (97.44 +/- 3.66%) or denuded endothelium (95.95 +/- 3.72%). Collectively, these results support the notion that the effects elicited by PA on vascular smooth muscle are endothelium-independent and involve extracellular Ca(2+) influx blocked. In addition, PA effects are partly dependent on the release of nitric oxide from the vascular smooth muscle through an activation of guanylyl cyclase-dependent mechanism and are related to the release of metabolites derived from the arachidonic acid pathway. Finally, our results demonstrated that the PA relaxant action is not related with the opening of potassium (K(+)) channels.

Biotransformation of diterpenes and diterpene derivatives by Beauveria bassiana ATCC 7159.

The biohydroxylation of stemodin and stemodinone by Beauveria bassiana ATCC 7159 gave exclusively 2alpha,13,18-trihydroxystemodane and 13,18-dihydroxystemodan-2-one respectively. Stemarin was converted to the novel 1beta,13,19-trihydroxystemarane and 13-hydroxystemarane-19-carboxylic acid. The synthesis and biotransformation of various derivatives of stemodin have also been studied.

The biotransformation of ent-kaur-16-en-19-oic acid by Rhizopus stolonifer.

Microbial transformation of ent-kaur-16-en-19-oic acid was carried out with R. stolonifer. After seven days of incubation, two metabolites, ent-7 alpha-hydroxy-kaur-16-en-19-oic acid and ent-12 beta-hydroxy-kaur-9(11),16-dien-19-oic acid, were isolated as a result of hydroxylation and hydroxylation/dehydrogenation, respectively. Incubation for 15 days also afforded ent-16 beta,17-dihydroxy-kauran-19-oic acid. The metabolites were identified by spectroscopic methods.

Biotransformation of the diperpenoid, isosteviol, by Aspergillus niger, Penicillium chrysogenum and Rhizopus arrhizus.

The biotransformation of isosteviol (ent-16-ketobeyeran-19-oic acid) by three fungi is described. Aspergillus niger produced the 7 beta-OH derivative, ent-7 alpha-hydroxy-16-ketobeyeran-19-oic, and the 1 alpha, 7 beta-diOH derivative, ent-1 beta, 7 alpha-dihydroxy-16-ketobeyeran-19-oic acid. The 17-OH compound, ent-17-hydroxy-16-ketobeyeran-19-oic acid, was obtained with Penicillium chrysogenum. Rhizopus arrhizus produced the 7 beta-OH derivative, ent-7 alpha-hydroxy-16-ketobeyeran-19-oic acid. The isolated metabolites were characterised by IR, NMR and MS.

Scopadulcic acid B, a new tetracyclic diterpenoid from Scoparia dulcis L. Its structure, H+, K(+)-adenosine triphosphatase inhibitory activity and pharmacokinetic behaviour in rats.

The structure of scopadulcic acid B (2, SDB), a major ingredient of the Paraguayan herb "Typychá kuratu" (Scoparia dulcis L.), was elucidated mainly by comparison of its spectral data with that of scopadulcic acid A (1). SDB inhibited both the K(+)-dependent adenosine triphosphatase (ATPase) activity of a hog gastric proton pump (H+, K(+)-ATPase) with a value of 20-30 microM for IC50 and proton transport into gastric vesicles. Pharmacokinetic studies of SDB in rats indicated that plasma SDB concentrations after i.v. injection of the sodium salt of SDB (SDB-Na) were described reasonably well by a two-compartment open model with Michaelis-Menten elimination kinetics. Plasma concentrations after oral administration of SDB-Na or SDB showed a much slower decline than what was expected following the i. v. study. It was suggested that the sustained plasma level of SDB after oral administration of SDB-Na or SDB was accounted for by relatively slow but efficient gastro-intestinal absorption in rats.