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Eye drops containing hydrophilic drugs are commonly used to reduce intraocular pressure (IOP) in glaucoma patients, but compliance to the treatement is commonly reduced by frequent ...dosing and eventual systemic side effects. Sustained-release drug delivery systems, such as ocular inserts, can reduce dosing, limit systemic exposure, reduce side effects, and, then, improve patient adherence to therapy. Here, we developed and evaluated chitosan/hydroxyethyl cellulose-based ocular inserts for sustained release of dorzolamide, a hydrophilic drug. Dorzolamide inserts (DI) were produced by solvent/casting method and characterized by various physicochemical techniques. Pharmacokinetics studies were performed using scintigraphic images and ex vivo biodistribution. The effectiveness of inserts was tested in glaucomatous rats. Characterization studies showed that the drug strongly interacted with the polymeric matrix, but in vitro results showed that DI took only 3 h to release 75% of dorzolamide entraped. However, scintigraphic images and ex vivo biodistribution studies revealed that more than 50% of 99mTc-dorzolamide remained in the eye after 18 h of DI administration, while only about 30% of the drug remained in the eye after drops instilation. DI exerted significant hypotensive effect for two weeks, after single administration, while IOP values remained high in placebo and untreated groups. Eye drops were effective only during the treatment period. Only DI treatment prevented retinal ganglion cells death. Altogether, these findings evidenced the potential application of polymeric-based inserts for sustained release of dorzolamide in glaucoma management.
Lippia alba (Mill.) N.E.Br. ex Britton & P. Wilson is traditionally used in Brazil as an adjunct in the relief of mild anxiety, as an antispasmodic, and as an antidyspeptic. This medicinal species ...was included in the Phytotherapeutic Form of the Brazilian Pharmacopeia 2nd edition (2021) and has already been described as the most used medicinal plant in a study with patients from an Anticoagulation Clinic in Brazil. Meanwhile, no studies were found that support the safety of the use of L. alba in patients using anticoagulants, a drug with several safety limitations.
Provide scientific evidence to ensure the safety of the concomitant use of L. alba and warfarin and support the management of these patients by evaluating its in vitro anticoagulant effect and chemical composition. And, as a timely complementation, evaluate the potential of this medicinal species in the development of new antithrombotics.
The chemical profile of L. alba derivatives was analyzed by chromatographic methods such as Ultra-Performance Liquid Chromatography (UPLC) coupled with electrospray ionization mass spectrometry (ESI-MS), qualitative UPLC using Diode-Array Detection, and Thin Layer Chromatography. The anticoagulant activity was evaluated by the innovative Thrombin Generation Assay by Calibrated Automated Thrombogram method and using traditional coagulometric tests: prothrombin time, activated partial thromboplastin time, and plasma fibrinogen measurement.
Extracts and fractions prolonged the coagulation time in all the tests and reduced thrombin formation in thrombin generation assay. Coagulation times with the addition of ethanloic extract (2.26 mg/mL) was 17.78s, 46.43s and 14.25s respectively in prothrombin time, activated partial thromboplastin time and fibrinogren plasma measurement. In thrombin generation test, this same extract showed ETP as 323 nM/min compared to control (815 nM/min) with high tissue factor and 582 nM/min compared to control (1147 nM/min) using low tissue factor. Presence of flavonoids, phenylpropanoids, and triterpenes were confirmed by chromatographic methods and 13 compounds were identified by UPLC-ESI-MS. Based on these results and on the scientific literature, it is possible to propose that phenylpropanoids and flavonoids are related to the anticoagulant activity observed.
The results demonstrate the in vitro anticoagulant activity of L. alba, probably due to the activation of intrinsic and extrinsic pathways. It is concluded, then, that there is a potential for interaction, which needs to be further studied, between L. alba and warfarin. Also, this medicinal species shows a great potential for use in the development of new antithrombotics.
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•Lippia alba is a medicinal plant widely used by patients on anticoagulation.•L. alba demonstrated anticoagulant activity in vitro in all performed tests.•This activity may indicate potential interaction with drugs that act on hemostasis.•This plant can also be used for the development of new anticoagulants.•Seasonality demonstrated a great impact on the chemical composition and activity.
•The treatments available for vitiligo have many adverse effects and/or contraindications;•Natural alternatives such as mamacadela (Brosimum gaudichaudii) are already a therapeutic option;•There are ...reports of the popular use of a preparation containing coffee (Coffea sp) and sunflower seed (Helianthus annuus) to treat vitiligo;•The chemical composition of these plants supports the rationality of this use;•Further studies are needed in order to optimize the use of these species in the treatment of vitiligo.
Introduction: Vitiligo is a dermatological disease that affects about 0.38% to 2.9% of the world population. Currently, the main treatments used for vitiligo involve the use of topical drugs such as corticosteroids and calcineurin inhibitors, phototherapy, systemic treatment with steroids and even surgical grafts and, in acute cases, depigmenting treatments. Natural products are an alternative for the treatment of vitiligo: mamacadela (Brosimum gaudichaudii), a plant rich in furanocoumarins, and sowthistle (Sonchus oleraceus), rich in phenolic substances, are already used to treat vitiligo. There are also popular reports of the use of a preparation containing coffee (Coffea sp) and sunflower seed (Helianthus annuus) to treat vitiligo. Case report: A female patient, 28 years old, diagnosed with vitiligo, reported having obtained a positive result in the repigmentation of the pale white patches after the daily use of a preparation containing coffee and sunflower seed for about one year. Discussion: Data from the scientific literature demonstrated that chemical constituents of these plants, such as chlorogenic acid and its isomers, which have antioxidant and anti-inflammatory action, and substances such as linoleic acid and vitamins E and B, which help in the process of melanin formation on the skin, may be responsible for the observed repigmentation of the patches. Further research on this case report is important for scientific validation and the development of new therapeutic options, especially with less adverse effects, in the treatment of vitiligo.
Mesalamine (5-ASA) consists of the first-line therapy for the treatment of ulcerative colitis; however, it has low bioavailability, can cause several systemic adverse events, and has low treatment ...adherence due to the inconvenient dosing scheme. In this work, a new drug delivery system consisting of chondroitin sulfate linked to 5-ASA was synthesized using a carbodiimide as conjugating agent. The system was characterized by spectroscopic techniques (UV, ATR-FTIR, XRD, and NMR 1H) and thermal analysis (TG/DTG and DSC), suggesting the conjugation between the drug and the polymer. The in vitro release and the corresponding kinetics were also evaluated, revealing that approximately 40% of the drug linked was released at pH9 for up to 50h, following Higuchi's model. The conjugate did not show cytotoxicity for the human monocytic cell line at the doses tested, and an in vivo biodistribution study showed that the conjugate remained in the lower GIT for up to 8h with no uptake in the upper GIT. These data corroborate with the radiation found per segment of GIT and in blood. For this last test the conjugate was radiolabeled with Technetium-99m to allow the scintigraphy evaluation and radiation quantification. In conclusion, the polymeric conjugate was successfully synthesized and demonstrated a mucoadhesiveness on the colon as desired, thus supporting its potential use in the treatment of ulcerative colitis.
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Stryphnodendron obovatum Benth. is a Brazilian tree used to treat skin ulceration, promote wound healing, and inhibit the growth of protozoa, including Trypanosoma and Leishmania species. Bioguided ...fractionation of the ethanol extract of S. obovatum stem bark was performed, and antileishmanial and antioxidant activities of the standardized fractions were analyzed.
Stationary-phase Leishmania amazonensis promastigotes, murine macrophages, and human red blood cells (RBCs) were exposed to plant extract, standardized fractions or isolated compounds for 48h at 37°C to evaluate their antiparasitic activity and cytotoxicity. The 2,2-diphenyl-1-picryl-hidrazyl assay was used to evaluate antioxidant activity.
The S. obovatum extract and fractions showed antileishmanial and antioxidant activity; however, the organic fraction (OF) showed the best efficacy. We identified gallic acid, gallocatechin, epigallocatechin, catechin, and epigallocatechin gallate in the OF fraction. These compounds effectively inhibited L. amazonensis activity, with gallic acid, gallocatechin, and epigallocatechin gallate showing the highest selectivity. Furthermore, the evaluated compounds had no significant effect on murine macrophages and human RBCs.
The compounds present in the S. obovatum plant bark ethanol extract may provide an alternative therapeutic approach for L. amazonensis treatment.
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In the present study, a Poloxamer 407-based amphotericin B (AmpB)-containing polymeric micelles system (AmpB/M) was employed in the treatment of Leishmania amazonensis-infected BALB/c mice. ...Initially, the in vitro antileishmanial activity (IC50 value) of AmpB/M and B-AmpB/M (empty micelles) against stationary promastigotes and amastigotes-like forms of the parasites was determined, and results were of 1.83 ± 0.4 and 22.1 ± 0.7 μM, respectively, for the promastigotes, and of 2.27 ± 0.5 and 33.98 ± 2.6 μM, respectively, for the amastigotes-like. The cytotoxic concentration (CC50) values of these products were also evaluated, and we found the results of 119.5 ± 9.6 and 134.7 ± 10.3 μM, respectively. With these values, the selectivity index (SI) was calculated and results were of 65.3 and 5.4, respectively, for the promastigotes, and of 59.3 and 3.96, respectively, for the amastigotes-like of the parasites. Free AmpB showed IC50 values of 1.2 ± 0.3 and 2.5 ± 0.5 μM for the promastigotes and amastigotes-like, respectively, whereas the CC50 value was of 9.5 ± 0.4 μM. The SI values of this drug were of 7.9 and 3.8, respectively, for the promastigote and amastigote-like stages of the parasites. After, animals were infected and received saline or were treated subcutaneously with free AmpB, AmpB/M or B-AmpB/M. In the results, free AmpB-treated and infected mice showed reductions in their body weight, which were associated with hepatic and renal damage; however, no organic alteration was observed in the AmpB/M-treated animals. In addition, these animals showed significant reductions in their lesion average size and in the parasite burden in all evaluated infected tissue and organs, when compared to the other groups; as well as significantly higher levels of antileishmanial IFN-γ, IL-12, GM-CSF and nitrite, which were associated with low production of IL-4, IL-10 and IgG1 isotype antibodies. In conclusion, this AmpB/M system could be considered as an alternative for future studies in the treatment of tegumentary leishmaniasis.
Stryphnodendron species, popularly named “barbatimão,” are traditionally used in Brazil as anti-inflammatory agents. This study aimed to investigate the effect of barbatimão and 11 other species on ...the production of tumor necrosis factor-alpha (TNF-α) in lipopolysaccharide- (LPS-) stimulated THP-1 cells, as well as their anti-arthritis activity. The extracts of Stryphnodendron adstringens, Stryphnodendron obovatum, Campomanesia lineatifolia, and Terminalia glabrescens promoted a concentration-dependent inhibition of TNF-α. Mice injected with LPS in the knee joint were treated per os with fractions from the selected extracts. Both the organic (SAO) and the aqueous (SAA) fractions of S. adstringens promoted a dose-dependent reduction of leukocyte migration and neutrophil accumulation into the joint, but none of them reduced CXCL1 concentration in the periarticular tissue. In contrast, treatment with C. lineatifolia and T. glabrescens fractions did not ameliorate the inflammatory parameters. Analyses of SAO by Ultra Performance Liquid Chromatography (UPLC) coupled to electrospray ionization mass spectrometry (ESI-MS) led to the identification of gallic acid along with 11 prodelphinidins, characterized as monomers and dimers of the B-type. Our findings contribute to some extent to corroborating the traditional use of S. adstringens as an anti-inflammatory agent. This activity is probably related to a decrease of leukocyte migration into the inflammatory site. Polyphenols like gallic acid and prodelphinidins, identified in the active fraction, may contribute to the observed activity.
: Evaluate the in-vitro effect of Mentha crispa extract on blood coagulation, compare the conventional coagulometric tests with thrombin generation test (TGT), and study the qualitative ...micromolecular composition of M. crispa. Extract of M. crispa was incubated with plasma and used in the coagulometric tests: prothrombin and activated partial thromboplastin times, fibrinogen, and TGT. A phytochemical prospection was performed to evaluate the chemical composition of this extract. The extract was efficient in prolonging prothrombin time and activated partial thromboplastin time, and reducing fibrinogen levels and TGT parameters, indicating that the extract of M. crispa inhibited the intrinsic and extrinsic pathways of blood coagulation. The results obtained in TGT are in agreement with the results of conventional coagulometric tests and the in-vitro anticoagulant activity of M. crispa suggests that its use by patients using oral anticoagulants deserves caution.
In the present study, a Poloxamer 407-based amphotericin B (AmpB)-containing polymeric micelles system (AmpB/M) was employed in the treatment of Leishmania amazonensis-infected BALB/c mice. ...Initially, the in vitro antileishmanial activity (IC50 value) of AmpB/M and B-AmpB/M (empty micelles) against stationary promastigotes and amastigotes-like forms of the parasites was determined, and results were of 1.83 ± 0.4 and 22.1 ± 0.7 μM, respectively, for the promastigotes, and of 2.27 ± 0.5 and 33.98 ± 2.6 μM, respectively, for the amastigotes-like. The cytotoxic concentration (CC50) values of these products were also evaluated, and we found the results of 119.5 ± 9.6 and 134.7 ± 10.3 μM, respectively. With these values, the selectivity index (SI) was calculated and results were of 65.3 and 5.4, respectively, for the promastigotes, and of 59.3 and 3.96, respectively, for the amastigotes-like of the parasites. Free AmpB showed IC50 values of 1.2 ± 0.3 and 2.5 ± 0.5 μM for the promastigotes and amastigotes-like, respectively, whereas the CC50 value was of 9.5 ± 0.4 μM. The SI values of this drug were of 7.9 and 3.8, respectively, for the promastigote and amastigote-like stages of the parasites. After, animals were infected and received saline or were treated subcutaneously with free AmpB, AmpB/M or B-AmpB/M. In the results, free AmpB-treated and infected mice showed reductions in their body weight, which were associated with hepatic and renal damage; however, no organic alteration was observed in the AmpB/M-treated animals. In addition, these animals showed significant reductions in their lesion average size and in the parasite burden in all evaluated infected tissue and organs, when compared to the other groups; as well as significantly higher levels of antileishmanial IFN-γ, IL-12, GM-CSF and nitrite, which were associated with low production of IL-4, IL-10 and IgG1 isotype antibodies. In conclusion, this AmpB/M system could be considered as an alternative for future studies in the treatment of tegumentary leishmaniasis.
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•Poloxamer 407-based amphotericin B-containing micelles (AmpB/M) were developed.•AmpB/M showed satisfactory antileishmanial activity and selectivity index.•AmpB/M was also shown to be effective in treating Leishmania amazonensis-infected BALB/c mice.
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•Brazilian medicinal plants were evaluated against L. amazonensis.•D. alata and J. cuspidifolia leaves had high selectivity index.•These extracts or fractions had high leishmanicidal ...activity and low cytotoxicity.•The activity of D. alata and J. cuspidifolia could be due to a direct mechanism.•The compounds that could contribute to the observed activity are discussed.
Leishmaniasis is a major public health problem, and the alarming spread of parasite resistance has increased the importance of discovering new therapeutic products. The present study aimed to investigate the in vitro leishmanicidal activity from 16 different Brazilian medicinal plants. Stationary-phase promastigotes of Leishmania amazonensis and murine macrophages were exposed to 44 plant extracts or fractions for 48h at 37°C, in order to evaluate their antileishmanial activity and cytotoxicity, respectively. The most potent extracts against L. amazonensis were the hexanic extract of Dipteryx alata (IC50 of 0.08μg/mL), the hexanic extract of Syzygium cumini (IC50 of 31.64μg/mL), the ethanolic and hexanic extracts of leaves of Hymenaea courbaril (IC50 of 44.10μg/mL and 35.84μg/mL, respectively), the ethanolic extract of H. stignocarpa (IC50 of 4.69μg/mL), the ethanolic extract of Jacaranda caroba (IC50 of 13.22μg/mL), and the ethanolic extract of J. cuspidifolia leaves (IC50 of 10.96μg/mL). Extracts of D. alata and J. cuspidifolia presented higher selectivity index, with high leishmanicidal activity and low cytotoxicity in the mammalian cells. The capacity in treated infected macrophages using the extracts and/or fractions of D. alata and J. cuspidifolia was also analyzed, and reductions of 95.80%, 98.31%, and 97.16%, respectively, in the parasite burden, were observed. No nitric oxide (NO) production could be observed in the treated macrophages, after stimulation with the extracts and/or fractions of D. alata and J. cuspidifolia, suggesting that the biological activity could be due to mechanisms other than macrophage activation mediated by NO production. Based on phytochemistry studies, the classes of compounds that could contribute to the observed activities are also discussed. In conclusion, the data presented in this study indicated that traditional medicinal plant extracts present effective antileishmanial activity. Future studies could focus on the identification and purification of the antileishmanial compounds within these plants for analysis of their in vivo antileishmanial activity.
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