Blending Ethnomedicine with Modern Technology-From Conventional to Tailored Products: Modulating Biopharmaceutical Properties of Berberis Extract by Solid Lipid Nanoparticles for Wound Healing.

Drug-delivery systems employing phytopharmaceuticals based on the leads in traditional knowledge offers not only an alternative but quicker and more economic strategy for drug development. Nanophytopharmaceuticals promise remarkable opportunities with the ability to overcome challenges associated with herbal medicines, such as low solubility and bioavailability, poor target specificity, and shelf life. Berberis extracts documented as Ropana (wound healer) in Sushruta Samhita are a popular traditional remedy that is amiss in the modern system of medicine as it exhibits very poor biopharmaceutical properties. Poor solubility and bioavailability necessitate the administration of high doses to achieve the desired therapeutic effects. Exploiting the diversified type of compounds with pleiotropic properties present in Berberis, the biopharmaceutical properties were engineered using an optimized freeze-dried extract and developed solid lipid nanoparticles (SLNs) as an effective drug-delivery system. An industrially viable and environment-friendly hot high-pressure homogenization technique led to a stable formulation with an average particle size of 178.4 nm, as well as a 7-fold increase in loading and a significant entrapment of 91 ± 1.25%. The pharmacodynamic studies of developed nanosystems in excision-wound models showed faster and complete healing of wounds with no scars.

Pharmaceutical Cocrystals of Famotidine: Structural and Biopharmaceutical Evaluation.

Famotidine (FMT) an anti-ulcer drug, recently being repurposed in COVID-19 treatment, suffers from poor aqueous solubility and restricted bioavailability (<40%). To conquer the limitations endured by this potent anti-ulcer agent, two novel 1:1 cocrystals of FMT, namely Famotidine-Sorbic Acid (FSOR) and Famotidine-Syringic Acid (FSY), were synthesized using the liquid-assisted grinding method and evaluated. Distinct DSC thermograms and PXRD patterns advocate the existence of a new crystalline form. The unique organization of the hydrogen-bonded network, in the prepared cocrystals, is inferred by variation in characteristic vibrational frequencies in FT-IR spectroscopic analysis and supported by crystal structure determination. FSOR cocrystallize in orthorhombic PNCB and FSY in triclinic P 1 crystal system. Further, a significant amplification in the solubility (9 to 5-fold) and dissolution (8 to 5-fold) of FMT in cocrystalline form, with simultaneous augmentation in peak plasma concentration (2 to 1.5-fold higher) and relative bioavailability (approx. 200% to 135%). This is associated with the remarkable increment in their anti-ulcer and anti-oxidant potential. Thus, the study illustrates that cocrystallization as a worthy approach in the efficient delivery of neutral compounds suffering from inadequate solubility crisis.

Neuroprotective effect of standardized extracts of three Lactuca sativa Linn. varieties against 3-NP induced Huntington's disease like symptoms in rats.

OBJECTIVES: The study was aimed to evaluate the efficacy of three commonly consumed Lactuca sativa (LS) Linn. varieties viz., Grand rapid, Lollo rosso and Iceberg (Asteraceae) against 3-NP induced HD like symptoms in rats. METHODS: Ethanol extracts of leaves of three LS varieties were prepared, and standardized on the basis of quercetin content using HPLC. These extracts (100 and 200 mg kg, p.o. for 20 days) were evaluated for their neuroprotective effect against 3-NP (10 mg/kg, i.p. for 14 days) induced neurotoxicity in male Wistar rats. The extract that exhibited maximum activity was successively fractionated using hexane, ethyl acetate, n-butanol and aqueous in increasing order of polarity. These fractions were also evaluated (dose equivalent to the dose of the extract of LS variety exhibiting maximum activity) for their neuroprotective effect. The protective effect of extracts and fractions was evaluated using different behavioral (rota rod, actophotometer, beam walk and Morris water maze) and biochemical (malondialdehyde, nitrite, superoxide dismutase, catalase and reduced glutathione) parameters. RESULTS: 3-NP elicit marked deterioration in motor coordination, locomotor activity and memory in comparison to control group. Standardized ethanol extract of grand rapid (200 mg/kg) exhibited maximum activity amongst the three tested varieties. Therefore, its fractions were also evaluated, and n-butanol fraction (40 mg/kg) exhibited maximum attenuation of 3-NP induced HD like symptoms which was evident from improved behavioral and biochemical parameters. DISCUSSION: The results exhibit that LS (Grand rapid variety) prophylaxis mitigated 3-NP induced neurotoxicity and HD like symptoms in rats due to its potent antioxidant potential.

Engineering a Remedy to Modulate and Optimize Biopharmaceutical Properties of Rebamipide by Synthesizing New Cocrystal: In Silico and Experimental Studies.

PURPOSE: Rebamipide (REB) a potent anti-ulcer agent, has not been exploited to its full potential, owing to it extremely poor solubility, leading to highly diminutive bioavailability (<10%). The purpose is to carry out its solid-state modification. METHOD: Cocrystallisation was done with three GRAS coformers namely citric acid (CA), 3,4-dihydroxybenzoic acid (DHBA) and oxalic acid (OXA) employing the liquid-assisted grinding method. Cocrystal formation was based upon amide-carboxyl and amide-hydroxyl supramolecular synthons. Characterization of novel cocrystals i.e. RCA, RDHBA and ROXA was carried out by DSC, PXRD and additionally by FT-IR spectroscopy. Chemical structures have been determined utilizing the PXRD pattern by Material Studio®. Furthermore, cocrystals were subjected to solubility and intrinsic dissolution rate (IDR) evaluation. Also, pharmacodynamic and pharmacokinetic studies were performed and compared with pure rebamipide. RESULT: The appearances of a single sharp melting endotherm in DSC, along with novel characteristic peaks in PXRD infer the existence of a new crystalline form. Shifting in characteristic vibrations in FT-IR spectroscopy supports the establishment of distinct hydrogen-bonded networks. Structural determination revealed that RCA crystallizes in 'Bb2b' space groups whereas RDHBA in 'P1' and ROXA crystallize out in the 'P-1' space group. All the cocrystals exhibited superior apparent solubility and almost 7-13 folds increase in IDR. Furthermore, 1.6-2.5 folds enhancement in relative bioavailability and remarkable amplification in anti-ulcer, anti-inflammatory and the antioxidant potential of these cocrystals were observed. CONCLUSION: The study ascertains the advantages of cocrystallization, with RCA showing greatest potential and suggests a viable alternative approach for improved formulation of rebamipide.

Daidzein cocrystals: An opportunity to improve its biopharmaceutical parameters.

The present study involves the contribution of cocrystallization towards the modification of the biopharmaceutical parameters of poorly watersoluble plant-originated isoflavone, daidzein (DAID). The cocrystals were prepared with GRAS status coformers i.e., isonicotinamide, theobromine and cytosine using mechanochemical grinding and characterized by various analytical techniques (DSC, FT-IR, PXRD and solid-state NMR). Crystal structures were obtained from PXRD data using BIOVIA Materials Studio software and compared in terms of supramolecular motifs. An additional qualitative and quantitative insight into interactions between both components of the cocrystal illustrated the presence of OH⋯N and OH⋯O=C heterosynthons and revealed a stabilizing role of hydrogen bonding. The cocrystals were further evaluated for their solubility, intrinsic dissolution and in vivo profile. Solubility and dissolution studies of pure daidzein and its cocrystals, namely daidzein-isonicotinamide (DIS), daidzein-cytosine (DCYT) and daidzein-theobromine (DTB) exhibited an almost 2-fold improvement. Evaluation of maximum concentration (Cmax) of cocrystals reveals that the DIS cocrystal shows the highest Cmax of 1848.7 ng/ml followed by DCYT cocrystal (1614.9 ng/ml) and DTB cocrystal (1326.0 ng/ml) in comparison to DAID which has a Cmax 870.5 ng/ml. Each of these cocrystals showed significant enhancement in in vivo and in vitro activities in comparison to daidzein. Thus, this report suggests cocrystallization as a viable approach to resolve the solubility and bioavailability issues that circumvent the use of a therapeutically potential isoflavone, daidzein.

Is Failure of Cocrystallization Actually a Failure? Eutectic Formation in Cocrystal Screening of Hesperetin.

Cocrystal screening of hesperetin with certain countermolecules generated highly soluble noncovalent derivatives in the form of eutectics, instead of expected cocrystals. As adhesive forces established by complimentary functional groups on hesperetin and coformers were unable to overcome the stress due to size shape mismatch of component molecules, thus, eutectics were formed. Hesperetin, a polyphenolic antioxidant with potent anticancer and cardioprotective effects, has an underdeveloped role in modern therapeutics on account of its critically low aqueous solubility resulting in stunted bioavailability. The liquid-assisted cogrinding of hesperetin and coformers generated binary-phase eutectics in fixed stoichiometry with theophylline (1:1.5), adenine (2:1), gallic acid (1.5:1), and theobromine (2:1). Primarily characterized by lower melting endotherm in differential scanning calorimetry, the eutectics showed complete melting in hot-stage microscopy. Apart from characteristic V-shaped binary-phase diagram, no discernible changes in the FTIR and powder X-ray diffraction spectra further confirm eutectic formation. The morphological differences were analyzed by SEM measurements. A 2 to 4 times enhanced dissolution profile of the eutectics measured in pH 7.4 aqueous buffer was coupled with the in vitro (1,1-diphenyl-2-picryl hydroxyl free radical antioxidant assay and RBC antihemolytic assay) studies to present a complete preliminary data on the improved bioavailability of hesperetin eutectics.

Plant parts substitution based approach as a viable conservation strategy for medicinal plants: A case study of Premna latifolia Roxb.

BACKGROUND: Rapid population growth and catastrophic harvesting methods of wild medicinal plants especially trees, result in the exploitation of natural sources and its management is the need of the hour. Dashamoolarishta is an amalgam of roots of ten plants of a popular Ayurvedic FDC formulation consisting of the root of Premna latifolia Roxb. as one of its ingredients. Presently, their populations like many other trees are under threat due to extensive use of the roots by the herbal drug industry. OBJECTIVE: With an aim to conserve the biodiversity, a systematic study based on a rational approach by substituting root/root bark with alternative and renewable parts was conducted. MATERIALS AND METHODS: The fingerprint profile together with anti-inflammatory and analgesic effect of different parts of the plant was established for comparison. RESULTS: The results based on chemical and biological study indicated close similarity between the roots and the leaves and suggest the possible use of latter over root/root bark. CONCLUSION: The study proposes that the substitution of the root with alternate renewable parts of the same plant shall form the best strategy towards conservation of the trees like P. latifolia.

Ameliorating effect of Celastrus paniculatus standardized extract and its fractions on 3-nitropropionic acid induced neuronal damage in rats: possible antioxidant mechanism.

CONTEXT: Celastrus paniculatus Wild. (Celasteraceae) (CP) is a well-known Ayurvedic 'Medhya Rasayana' (nervine tonic), used extensively as a neuro-protective and memory enhancer, and in different central nervous system disorders. OBJECTIVE: To evaluate the effect of CP against 3-nitropropionic acid (3-NP) induced Huntington's disease (HD) like symptoms in Wistar male rats. MATERIALS AND METHODS: The ethanol extract of CP seeds (CPEE), prepared by maceration, was standardized on the basis of linoleic acid content (6.42%) using thin layer chromatography densitometric analysis. Protective effect of CPEE (100 and 200 mg/kg) and its various fractions, viz., petroleum ether (40 mg/kg), ethyl acetate (2.5 mg/kg), n-butanol (7 mg/kg) and aqueous (18 mg/kg), administered orally for 20 days, against 3-NP (10 mg/kg, i.p. for 14 days) was assessed by their effect on body weight, locomotor activity, grip strength, gait pattern and cognitive dysfunction and biochemical parameters for oxidative damage in the striatum and cortex regions of the brain. RESULTS: CPEE (100 and 200 mg/kg) treated animals exhibited a significant (p < 0.05) improvement in behavioural and oxidative stress parameters in comparison to only 3-NP treated animals. Amongst various tested fractions of CPEE, aqueous fraction (AF) at 18 mg/kg exhibited maximum reversal of 3-NP induced behavioural and biochemical alterations, and was therefore also tested at 9 and 36 mg/kg. CPEE (100 mg/kg) and AF (36 mg/kg) exhibited maximum and significant (p < 0.05) attenuation of 3-NP induced alterations in comparison to 3-NP treated rats. CONCLUSIONS: CPEE has a protective action against 3-NP induced HD like symptoms due to its strong antioxidant effect.

Dietary Soy Isoflavone: A Mechanistic Insight.

Soy, a major component of the diet for centuries contains the largest concentration of isoflavones, a class of phytoestrogens. A variety of health benefits are associated with the consumption of soy primarily because of the isoflavones genistein, daidzein, and glycitein with a potential protective effect against a number of chronic diseases. Owing to the pharmaceutical and nutraceutical properties allied with isoflavonoids and their use in functional foods, there is a growing interest in these compounds. This review throws light on the chemistry, and significant pharmacological and biopharmaceutical aspects of soy isoflavones. This article critically describes the mechanisms of action, infers conclusions and shows opportunity for future research.

Chrysin cocrystals: Characterization and evaluation.

Solvent free mechanochemical approach is utilized to synthesise new cocrystals of chrysin using supramolecular chemistry based upon reliable synthons. Chrysin, a flavone nutraceutical with wide range of beneficial effects has critically low bioavailability on account of its poor aqueous solubility and consequently poor absorption from the gastrointestinal tract. The present study focuses on this critical aspect and has exploited non covalent interactions to prepare its cocrystals with cytosine and thiamine hydrochloride. Various techniques were used for characterization including Differential Scanning Calorimetry (DSC), Fourier Transform Infrared Spectroscopy (FT-IR), Solid State NMR Spectroscopy (SSNMR) and Powder X-Ray Diffraction (PXRD). The molecules in the cocrystals crystallized in neutral forms and assembled in a molecular layer by means of hydrogen bonding which was confirmed by structural characterization. The cocrystals share a common supramolecular motif being the OH⋯Narom interaction, involving phenolic moiety of C7 functionality of the parent molecule. Approximately 3-4 fold increase in solubility and dissolution profile of cocrystals was observed which was further corroborated by improved in vitro and in vivo activities including antioxidant, antihaemolytic and anti-inflammatory thus, opening a new viable technique for the exploitation of useful phytonutrients.

Current Perspective in the International Trade of Medicinal Plants Material: An Update.

BACKGROUND: The recent years have seen an increased interest in medicinal plants together with the therapeutic use of phytochemicals. Medicinal plants are utilized by the industry for the production of extracts, phytopharmaceuticals, nutraceuticals and cosmeceuticals and their use is expected to grow faster than the conventional drugs. The enormous demand of medicinal plant material has resulted in huge trade both at domestic and international levels. METHODS: The trade data of medicinal plant material with commodity code HS 1211 (SITC.4, code 292.4) and their derived/related products which are traded under different commodity codes has been acquired from COMTRADE, Trade Map, country reports, technical documents etc for the period 2001 to 2014. The data was analyzed using statistical tools to draw conclusions. RESULTS: The significant features of the global trade; the leading source, consumer, import and export countries; and the striking trends are presented. The trade of the ten key countries and the selected important items is also discussed in detail. The conservative figure of trade of medicinal plants materials and their derived/related products including extracts, essential oils, phytopharmaceuticals, gums, spices used in medicine, tannins for pharmaceutical use, ingredients for cosmetics etc. as calculated from the global export data for the year 2014 is estimated at USD 33 billion. The average global export in medicinal plants under HS 1211 for the fourteen year period was USD 1.92 billion for 601,357 tons per annum and for the year 2014 it stood at 702,813 tons valued at USD 3.60 billion. CONCLUSION: For the studied period, an annual average growth rate (AAGR) of 2.4% in volumes and 9.2% in values of export was observed. Nearly 30% of the global trade is made up by top two countries of the import and export. China and India from Asia; Egypt and Morocco from Africa; Poland, Bulgaria and Albania from Europe; Chile and Peru from South America are important supply sources. The USA, Japan and Europe are the major consumers of the world.

Amelioration of testosterone induced benign prostatic hyperplasia by Prunus species.

ETHNOPHARMACOLOGICAL RELEVANCE: Benign prostatic hyperplasia (BPH) is a common urological disorder of men. The ethnomedicinal use of an African plant Prunus africana (Hook.f.) Kalkman (Pygeum) in treating men's problems made it a popular remedy all over the globe for the treatment of BPH and related disorders. However, rampant collections made from the wild in Africa have pushed the plant to Appendix II of CITES demanding conservation of the species. AIM OF THE STUDY: In the present study, the aim was to unearth the protective effect of bark of different species of Prunus against BPH. The five selected Indian plants of family Rosaceae viz. Prunus amygdalus Stokes, Prunus armeniaca L., Prunus cerasoides Buch.-Ham. ex D. Don, Prunus domestica L. and Prunus persica (L.) Batsch were evaluated against P. africana (Hook.f.) Kalkman for a suitable comparison of efficacy as antiBPH agents. MATERIALS AND METHODS: The antiBPH activity was evaluated in testosterone (2mg/kg/day, s.c, 21 days) induced BPH in Wistar rats. The parameters studied were body weights; histopathological examination, immunohistochemistry (PCNA) and biochemical estimations of the prostate; supported by prostatic index, testicular index, creatinine, testosterone levels; antioxidant and anti-inflammatory evaluation. The study also included chemical profiling using three markers (ß-sitosterol, docosyl ferulate and ursolic acid) and estimation of ß-sitosterol content through GC. RESULTS: The Prunus species showed the presence of all the three markers in their TLC fingerprint profile and maximum amount of ß-sitosterol by GC was observed in P. domestica. Interestingly, all the species exhibited significant amelioration in testosterone induced parameters with P. domestica showing the most encouraging effect as indicated from histopathological examination, immunohistochemistry and biochemical studies. The Prunus species further showed remarkable anti-inflammatory and antioxidant activity signifying their role in interfering with various possible factors involved in BPH. CONCLUSIONS: These findings are suggestive of a meaningful inhibitory effect of testosterone induced BPH by the bark of different species of Prunus in the order of P. domestica, P. persica, P. amygdalus, P. cerasoides and P. armeniaca with an efficacy of P. domestica comparable to P. africana and can be used as the potential backup of Pygeum for the management of BPH.

Attenuating effect of bioactive coumarins from Convolvulus pluricaulis on scopolamine-induced amnesia in mice.

Convolvulus pluricaulis Chois. (Convolvulaceae) has been used in Ayurveda as Medhya Rasyana (nervine tonic) to treat various mental disorders. This study was designed to isolate the bioactive compound(s) of this plant and to evaluate their effect against scopolamine-induced amnesia. Column chromatography of the chloroform and ethyl-acetate fractions led to the isolation of three coumarins identified as scopoletin, ayapanin and scopolin. All the three compounds at 2.5, 5, 10 and 15 mg/kg, p.o. were evaluated for memory-enhancing activity against scopolamine-induced amnesia using elevated plus maze and step down paradigms. Effect on acetylcholinesterase activity in mice brain was also evaluated. Scopoletin and scopolin, in both the paradigms, significantly and dose dependently attenuated the scopolamine-induced amnesic effect. Furthermore, these compounds at 10 and 15 mg/kg exhibited activity comparable to that of standard drug, donepezil. The compounds also exhibited significant acetylcholinesterase inhibitory activity.

Hepatoprotective effect of trimethylgallic acid esters against carbon tetrachloride-induced liver injury in rats.

Gallic acid and its derivatives are potential therapeutic agents for treating various oxidative stress mediated disorders. In the present study, we investigated the hepatoprotective effects of newly synthesized conjugated trimethylgallic acid (TMGA) esters against carbon tetrachloride (CCl4)-induced hepatotoxicity in rats. Animals were pre-treated with TMGA esters at their respective doses for 7 days against CCl4-induced hepatotoxicity. The histopathological changes were evaluated to find out degenerative fatty changes including vacuole formation, inflammation and tissue necrosis. Various biomarkers of oxidative stress (lipid peroxidation, glutathione levels, and endogenous antioxidant enzyme activities), liver enzymes (AST and ALT), triacylglycerol and cholesterol were evaluated. Pre-treatment with TMGA esters (MRG, MGG, MSG, and MUG at the dose of 28.71, 30.03, 31.35, 33.62 mg/kg/day), respectively reversed the CCl4-induced liver injury scores (reduced vacuole formation, inflammation and necrosis), biochemical parameters of plasma (increased AST, ALT, TG, and cholesterol), antioxidant enzymes (increased lipid peroxidation and nitrite levels; decreased glutathione levels, superoxide dismutase and catalase activities) in liver tissues and inflammatory surge (serum TNF-α) significantly. The study revealed that TMGA esters exerted hepatoprotective effects in CCl4-induced rats, specifically by modulating oxidative-nitrosative stress and inflammation.

Effect of trimethylgallic acid esters against chronic stress-induced anxiety-like behavior and oxidative stress in mice.

BACKGROUND: Many studies have shown that the levels of oxidative stress (increased lipid peroxidation, decreased glutathione levels and endogenous antioxidant enzyme activities) and proinflammatory cytokines (e.g., TNF-α) are increased in patients with chronic fatigue syndrome. Gallic acid and other phenolic compounds are potent antioxidants and inhibitor of cytokine production. The present study was designed to investigate the effect of newly synthesized conjugated esters of trimethylgallic acid in an experimental model of chronic stress. METHODS: The animals were forced to swim individually for a period of 6min every day for 15 days to induce chronic stress. The locomotor activity, anxiety-like behavior, and memory retention were evaluated in chronically stressed animals, followed by biochemical estimations and neuroinflammatory surge in the brain. RESULTS: Chronic treatment with trimethylgallic acid esters for 15 days significantly reversed the chronic stress-induced behavioral (impaired locomotor activity, anxiety-like behavior, and decreased percentage of memory retention), biochemical (increased lipid peroxidation and nitrite levels; decreased glutathione levels, superoxide dismutase and catalase activities), and inflammation surge (serum TNF-α) in stressed mice. CONCLUSIONS: The study revealed that trimethylgallic acid esters could ameliorate chronic stress-induced various behavioral and biochemical alterations in mice, showing protective effects against chronic stress.

Nootropic, anxiolytic and CNS-depressant studies on different plant sources of shankhpushpi.

CONTEXT: Shankhpushpi, a well-known drug in Ayurveda, is extensively used for different central nervous system (CNS) effects especially memory enhancement. Different plants are used under the name shankhpushpi in different regions of India, leading to an uncertainty regarding its true source. Plants commonly used under the name shankhpushpi are: Convolvulus pluricaulis Chois., Evolvulus alsinoides Linn., both from Convolvulaceae, and Clitoria ternatea Linn. (Leguminosae). OBJECTIVE: To find out the true source of shankhpushpi by evaluating and comparing memory-enhancing activity of the three above mentioned plants. Anxiolytic, antidepressant and CNS-depressant activities of these three plants were also compared and evaluated. MATERIALS AND METHODS: The nootropic activity of the aqueous methanol extract of each plant was tested using elevated plus-maze (EPM) and step-down models. Anxiolytic, antidepressant and CNS-depressant studies were evaluated using EPM, Porsolt?s swim despair and actophotometer models, respectively. RESULTS: C. pluricaulis extract (CPE) at a dose of 100 mg/kg, p.o. showed maximum nootropic and anxiolytic activity (p < 0.001). E. alsinoides extract (EAE) and C. ternatea extract (CTE) showed maximum memory-enhancing and anxiolytic activity (p < 0.001) at 200 and 100?mg/kg, respectively. Amongst the three plants, EAE and CTE showed significant (p < 0.05), while CPE did not exhibit any antidepressant activity. All the three plants showed CNS-depressant action at higher dose levels. DISCUSSION AND CONCLUSIONS: The above results showed all the three plants possess nootropic, anxiolytic and CNS-depressant activity. The results of memory-enhancing activity suggest C. pluricaulis to be used as true source of shankhpushpi.