Pharmacogenetics of Anticancer Drugs: Clinical Response and Toxicity.

Cancer is the most challenging disease for medical professionals to treat. The factors underlying the complicated situation include anticancer drug-associated toxicity, non-specific response, low therapeutic window, variable treatment outcomes, development of drug resistance, treatment complications, and cancer recurrence. The remarkable advancement in biomedical sciences and genetics, over the past few decades, however, is changing the dire situation. The discovery of gene polymorphism, gene expression, biomarkers, particular molecular targets and pathways, and drug-metabolizing enzymes have paved the way for the development and provision of targeted and individualized anticancer treatment. Pharmacogenetics is the study of genetic factors having the potential to affect clinical responses and pharmacokinetic and pharmacodynamic behaviors of drugs. This chapter emphasizes pharmacogenetics of anticancer drugs and its applications in improving treatment outcomes, selectivity, toxicity of the drugs, and discovering and developing personalized anticancer drugs and genetic methods for prediction of drug response and toxicity.

Antiurolithic effects of medicinal plants: results of in vivo studies in rat models of calcium oxalate nephrolithiasis-a systematic review.

Urolithiasis is one of the oldest diseases affecting humans, while plants are one of our oldest companions providing food, shelter, and medicine. In spite of substantial progress in understanding the pathophysiological mechanisms, treatment options are still limited, often expensive for common people in most parts of the world. As a result, there is a great interest in herbal remedies for the treatment of urinary stone disease as an alternative or adjunct therapy. Numerous in vivo and in vitro studies have been carried out to understand the efficacy of herbs in reducing stone formation. We adopted PRISMA guidelines and systematically reviewed PubMed/Medline for the literature, reporting results of various herbal products on in vivo models of nephrolithiasis/urolithiasis. The Medical Subject Heading Terms (Mesh term) "Urolithiasis" was used with Boolean operator "AND" and other related Mesh Unique terms to search all the available records (July 2019). A total of 163 original articles on in vivo experiments were retrieved from PubMed indexed with the (MeshTerm) "Urolithiasis" AND "Complementary Therapies/Alternative Medicine, "Urolithiasis" AND "Plant Extracts" and "Urolithiasis" AND "Traditional Medicine". Most of the studies used ethylene glycol (EG) to induce hyperoxaluria and nephrolithiasis in rats. A variety of extraction methods including aqueous, alcoholic, hydro-alcoholic of various plant parts ranging from root bark to fruits and seeds, or a combination thereof, were utilized. All the investigations did not study all aspects of nephrolithiasis making it difficult to compare the efficacy of various treatments. Changes in the lithogenic factors and a reduction in calcium oxalate (CaOx) crystal deposition in the kidneys were, however, considered favorable outcomes of the various treatments. Less than 10% of the studies examined antioxidant and diuretic activities of the herbal treatments and concluded that their antiurolithic activities were a result of antioxidant, anti-inflammatory, and/or diuretic effects of the treatments.

Multiple Mechanisms of Flaxseed: Effectiveness in Inflammatory Bowel Disease.

MATERIALS AND METHODS: Aqueous-methanolic crude extracts of Flaxseed (Fs.Cr) and Flaxseed oil were tested against 6% acetic acid- (AA-) induced colitis in BALB/c mice. Microscopic damage parameters of the hematoxylin and eosin-stained and periodic acid-Schiff-alcian blue-stained sections of the colon were scored to be assessed. Possible antispasmodic mechanism was studied on isolated rabbit jejunum, while antibacterial activity was assessed in vitro for microbes implicated in IBD. RESULTS: In AA-induced colitis, Flaxseed oil was found to be more effective in reducing mortality and colonic ulcers than Fs.Cr at 500 mg/kg dose. Fs.Cr was more efficacious in increasing mucin content as compared to oil, exhibiting slightly greater anti-inflammatory effect (50% vs 35%) and reducing depth of lesion (55% vs 42.31%, respectively). Antispasmodic activity of Fs.Cr (0.03 and 0.1 mg/ml) was mediated by phosphodiesterase inhibitors (PDEI, possibly PDE-4 subtype) with a resultant increase in cAMP levels. Flaxseed oil PDEI activity was mild (1 and 3 mg/ml). Fs.Cr (0.1 and 0.3 mg/ml) was potent in exhibiting anticholinergic activity, similar to dicyclomine, whereas Flaxseed oil showed anticholinergic effect at 1 and 3 mg/ml. Flaxseed oil (9 and 14 µg/ml) was bactericidal against enteropathogenic E.coli (EPEC), enterotoxigenic E.coli (ETEC), and enteroaggregative E.coli (EAEC), whereas Fs.Cr exhibited bactericidal effect against EPEC at 100 µg/ml. CONCLUSIONS: Results of this study, taken together with previous studies, suggest that Flaxseed possesses anti-inflammatory, antibacterial, and antispasmodic action through multiple pathways and thus offers promising potential to be developed for IBD.

Pharmacological importance of Manilkara zapota and its bioactive constituents / Importancia farmacologica de Manilkara zapota y sus constituyentes bioactivos

Manilkara zapota (Sapotaceae), commonly known as Sapodilla, is widely known for its delicious fruit. Various parts of this plant are also used in folk medicine to treat a number of conditions including fever, pain, diarrhoea, dysentery, haemorrhage and ulcers. Scientific studies have demonstrated analgesic, anti-inflammatory, antioxidant, cytotoxic, antimicrobial, antidiarrheal, anti-hypercholesteremic, antihyperglycemic and hepatoprotective activities in several parts of the plant. Phytochemical studies have revealed the presence of phenolic compounds including protocatechuic acid quercitrin, myricitrin, catechin, gallic acid, vanillic acid, caffeic acid, syringic acid, coumaric acid, ferulic acid, etc. as main constituents of the plant. Several fatty acids, carotenoids, triterpenes, sterols, hydrocarbons and phenylethanoid compounds have also been isolated from M. zapota. The present review is a comprehensive description focused on pharmacological activities and phytochemical constituents of M. zapota.

Manilkara zapota (Sapotaceae), comúnmente conocida como Sapodilla, es ampliamente conocida por su delicioso fruto. Variadas partes de esta planta se usan en medicina popular para tratar una serie de afecciones, como fiebre, dolor, diarrea, disentería, hemorragia y úlceras. Estudios científicos han demostrado actividad analgésica, antiinflamatoria, antioxidante, citotóxica, antimicrobiana, antidiarreica, antihipercolesterolémica, antihiperglucémica y hepatoprotectora en diferentes partes de la planta. Los estudios fitoquímicos han revelado la presencia de compuestos fenólicos que incluyen ácido protocatechúico, quercitrina, miricitrina, catequina, ácido galico, ácido vanílico, ácido cafeico, ácido sirínico, ácido cumárico, ácido fúnico y ácido ferúlico como componentes principales de la planta. Varios ácidos grasos, carotenoides, triterpenos, esteroles, hidrocarburos y compuestos feniletanoides también han sido aislados de M. zapota. La presente revisión es una descripción exhaustiva centrada en las actividades farmacológicas y los constituyentes fitoquímicos de M. zapota.

Pharmacological Evaluation of Gut Modulatory and Bronchodilator Activities of Achyranthes aspera Linn.

Achyranthes aspera L. is traditionally used to relieve constipation, diarrhea, and asthma. Its crude extract (Aa.Cr) was evaluated through in vivo and ex vivo experiments to rationalize these medicinal uses of A. aspera and to provide their scientific basis. Aa.Cr, at 3 and 10 mg/kg, increased fecal output, similar to castor oil, whereas at 30, 100, 300, and 700 mg/kg, it protected against castor oil-induced diarrhea in mice when administered orally. Aa.Cr caused spasmogenic effect on rabbit jejunum and guinea pig ileum preparations, which was partially inhibited by atropine while completely blocked by cyproheptadine preincubation. Aa.Cr also relaxed high K+ (80 mM)-induced contraction in rabbit jejunum. Aa.Cr inhibited CCh (100 µg/kg)-induced bronchospasm in rats, similar to aminophylline. Like dicyclomine, Aa.Cr relaxed high K+ and CCh (1 µM)-induced contractions in guinea pig trachea and caused rightwards parallel shift of CCh concentration-response curves at the lower concentrations followed by non-parallel shift at the higher concentrations. On activity-directed fractionation, spasmogenic and spasmolytic activities of Aa.Cr were concentrated in aqueous and organic fraction, respectively. This study suggests the presence of dose-specific laxative and antidiarrheal effects in A. aspera, possibly mediated through cyproheptadine-sensitive receptors and dual cholinergic and calcium channel blockade, respectively. The latter combination is also a suggested mechanism underlying its bronchodilator effect. Copyright © 2017 John Wiley & Sons, Ltd.

Dual Inhibition of Ca(+2) Influx and Phosphodiesterase Enzyme Provides Scientific Base for the Medicinal Use of Chrozophora prostrata Dalz. in Respiratory Disorders.

The crude ethanolic extract of Chrozophora prostrata (Cp.Cr) was tested using in vivo and ex vivo assays for its possible bronchodilatory effects in order to validate its medicinal use in respiratory disorders, like asthma and cough. Cp.Cr exhibited dose-dependent inhibition of carbachol (CCh)-induced bronchospasm in anesthetized rats, similar to aminophylline. When tested on guinea-pig tracheal preparations, Cp.Cr caused relaxation of both CCh (1 µM) and high K(+) (80 mM)-induced contractions with comparable potencies, similar to papaverine, a dual inhibitor of phosphodiesterse (PDE) and Ca(+2) influx. Pre-treatment of the tracheal tissues with Cp.Cr resulted in potentiation of the inhibitory effect of isoprenaline on CCh-induced contractions, like that caused by papaverine indicative of PDE inhibitory activity, which was confirmed when Cp.Cr concentration dependently (1 and 3 mg/mL) increased intracellular cAMP levels of the tracheal preparations, like papaverine. Cp.Cr shifted concentrationresponse curves of Ca(+2) constructed in guinea-pig tracheal preparation towards right with suppression of the maximum response, similar to both verapamil and papaverine. These data indicate bronchodilator activity of Chrozophora prostrata mediated possibly through dual inhibition of PDE and Ca(+2) influx, thus, showing therapeutic potential in asthma with effect enhancing and side-effect neutralizing potential Copyright © 2016 John Wiley & Sons, Ltd.

Pharmacological basis for the medicinal use of Linum usitatissimum (Flaxseed) in infectious and non-infectious diarrhea.

ETHNOPHARMACOLOGICAL RELEVANCE: Linum usitatissimum, commonly known as Flaxseed has traditionally been used for the management of diarrhea and gastrointestinal infections. This study was planned to assess pharmacological basis for the medicinal use of Flaxseed in infectious and non-infectious diarrhea. MATERIALS AND METHODS: The crude aqueous-methanolic extract of Flaxseed was studied using the in vivo castor oil-induced diarrhea, gut motility and enteropooling assays. Mechanistic basis was further elucidated by testing the inhibitory effect on spontaneously contracting isolated rabbit jejunum preparations, suspended in a 10ml tissue bath containing Tyrode׳ solution, maintained at 37°C and aerated with carbogen. Antibacterial efficacy of the Flaxseed extract was tested against different enteric and non-enteric pathogenic bacteria using in vitro antibacterial assays. RESULTS: Flaxseed extract reduced the diarrheal score in mice, by 39%, 63.90% and 68.34% at the respective doses of 100, 300 and 500mg/kg. Intestinal secretions were reduced by 24.12%, 28.09% and 38.80%, whereas the intestinal motility was reduced by 31.66%, 46.98% and 56.20% at respective doses of 100, 300 and 500mg/kg. When tested on isolated rabbit jejunum preparations, Flaxseed extract produced a dose-dependent inhibition of both spontaneous and high K(+) (80mM)-induced contractions, and shifted the concentration-response curves of Ca(++) to the right with suppression of the maximum response, similar to that caused by verapamil. Flaxseed extract was found to possess bactericidal activity at the tested concentrations of 12.5mg/ml, against vancomycin-resistant Enterococcus faecalis (100%), Escherichia coli K1 (88.88%), methicillin-resistant Staphylococcus aureus (98.76%), Bacillus cereus (92.64%), Pseudomonas aeruginosa (76.83%) and Salmonella typhi (26.91±3.35%). The concentration of 10mg/ml showed bactericidal effects against all the aforementioned pathogens except Escherichia coli K1, whereas for Pseudomonas aeruginosa and Salmonella typhi, it was bacteriostatic at this concentration. CONCLUSIONS: Our results indicate that Linum usitatissimum (Flaxseed) extract exhibits antidiarrheal and antispasmodic activities by virtue of its antimotility and antisecretory effects which are mediated possibly through inhibition of Ca(++) channels, though additional mechanism(s) cannot be ruled out. Flaxseed extract proved effective against both enteric and non-enteric pathogens causing diarrhea, thus ensuring wide coverage and rationalizing its medicinal use in both the infectious and non-infectious diarrhea.

Pharmacological studies on the antispasmodic, bronchodilator and anti-platelet activities of Abies webbiana.

This study evaluated the antispasmodic, bronchodilator and anti-platelet activities of Abies webbiana to rationalize some of its folk uses in gut and airways disorders and inflammation. The crude extract of A. webbiana (Aw.Cr) caused a complete relaxation of both spontaneous and K(+) (80 mM)-induced contractions in isolated rabbit jejunum in a concentration-dependent manner. Aw.Cr shifted the Ca(++) concentration-response curves (CRCs) to the right, in a fashion similar to verapamil, confirming its Ca(++) channel blocking (CCB) effect. In isolated rabbit tracheal preparations, it caused relaxation of carbachol (1 µM) and K(+) (80 mM)-induced contractions comparable to verapamil suggesting that the bronchodilatory effect may possibly be mediated through CCB activity. Aw.Cr was found to be the inhibitor of both ADP- and epinephrine-induced aggregation of human platelets thereby suggesting therapeutic potential in this plant against thrombo-embolic conditions. The exhibited anti-platelet effect was observed at low doses against epinephrine as compared to ADP. This study confirmed the presence of spasmolytic activity in Abies webbiana through possible blockade of Ca(++) channels providing evidence for its folkloric use in gut and respiratory disorders in addition to anti-platelet activity.

Calcium channel blocking activity in Desmostachya bipinnata (L.) explains its use in gut and airways disorders.

Desmostachya bipinnata, despite of its popular medicinal uses, has not been widely studied for its effect in diarrhea, indigestion, and asthma. The aim of the present investigation was to provide scientific rationale for these applications. The crude aqueous-methanolic extract of D. bipinnata (Db.Cr) was evaluated through in vivo and in vitro experiments. Db.Cr (100-500 mg/kg) protected mice against castor oil-induced diarrhea, similar to loperamide. When tested on gut preparations, Db.Cr produced an atropine-sensitive spasmogenic effect in rabbit jejunum up to 5 mg/mL, followed by a partial relaxation at 10 mg/mL. With atropine preincubation, a verapamil-like inhibitory effect was evident against spontaneous and high K(+) (80 mM)-induced contractions. The maximum stimulant effect was comparable with the acetylcholine-induced maximum contraction and was similarly reproducible in guinea pig ileum. Db.Cr inhibited carbachol (1 µM)-induced contraction in rabbit trachea but caused an atropine-sensitive accentuation of high K(+) -induced contraction at 0.003-0.3 mg/mL followed by inhibition at 1-5 mg/mL. On activity-directed fractionation, inhibitory effect was concentrated on organic and stimulant effect in aqueous fraction. This study, suggesting the presence of calcium antagonist activity, possibly underlying its medicinal effect in hyperactive gut and respiratory disorders, and cholinergic activity, possibly underlying its digestive effect, provides rationale for these therapeutic uses of D. bipinnata.

Evaluation of gut modulatory and bronchodilator activities of Amaranthus spinosus Linn.

BACKGROUND: The aqueous-methanolic extract of Amaranthus spinosus (A. spinosus Linn.,) whole plant, was studied for its laxative, spasmolytic and bronchodilator activities to validate some of its medicinal uses. METHODS: The crude extract of A. spinosus was studied in-vivo for bronchodilator and laxative activities and in-vitro using isolated tissue preparations which were mounted in tissue baths assembly containing physiological salt solutions, maintained at 37°C and aerated with carbogen, to assess the spasmolytic effect and to find out the possible underlying mechanisms. RESULTS: In the in-vivo experiments in mice, the administration of A. spinosus increased fecal output at doses of 100 and 300 mg/kg showing laxative activity. It also inhibited carbachol-induced bronchospasm in anesthetized rats at 1, 3, 10 and 30 mg/kg indicative of bronchodilator activity. When tested on isolated gut preparations, the plant extract showed a concentration-dependent (0.01-10.0 mg/ml) spasmogenic effect in spontaneously contracting rabbit jejunum and guinea-pig ileum. The spasmogenic effect was partially blocked in tissues pretreated with atropine (0.1 µM). When tested on K+ (80 mM)-induced sustained contractions in isolated rabbit jejunum, the plant extract caused complete relaxation and also produced a shift in the Ca++ concentration-response curves (CRCs) towards right, similar to diltiazem. In rabbit trachea, the plant extract completely inhibited K+ (80 mM) and carbachol (CCh, 1 µM)-induced contractions at 1 mg/ml but pretreatment of tissue with propranolol (1 µM), caused around 10 fold shift in the inhibitory CRCs of the plant extract constructed against CCh-induced contraction. The plant extract (up to 0.3 mg/ml) also increased both force and rate of spontaneous contractions of isolated guinea-pig atria, followed by relaxation at higher concentration (1.0-5.0 mg/ml). The cardio-stimulant effect was abolished in the presence of propranolol, similar to that of isoprenaline. Activity-directed fractionation revealed that the spasmolytic component(s) was separated in the organic fraction, whereas the spasmogenic component was concentrated in the aqueous fraction. CONCLUSION: These results indicate that A. spinosus possesses laxative activity partially mediated through cholinergic action. The spasmolytic effect was mediated through calcium channel blocking (CCB), while bronchodilator activity through a combination of ß-adrenergic and CCB pathways, which may explain the traditional uses of A. spinosus in gut and airways disorders.

Mechanisms underlying the antidiarrheal, antispasmodic and bronchodilator activities of Fumaria parviflora and involvement of tissue and species specificity.

ETHNOPHARMACOLOGICAL RELEVANCE: In the Greco-Arab (Unani) traditional medicine, Fumaria parviflora Linn. is widely used in hypreractive gut and respiratory disorders including diarrhea, abdominal cramps, indigestion and asthma but scientific studies to provide rational for these medicinal uses are sparse. This study was therefore undertaken to provide ethnopharmacological basis for its medicinal use in diarrhea, abdominal cramps and asthma. MATERIALS AND METHODS: The in vivo studies were conducted in mice and rats while isolated gut and tracheal preparations of rat, guinea-pig and rabbit were suspended in respective tissue baths to measure the isotonic and isometric responses, using Power Lab electronic recorder. RESULTS: The aqueous-methanol extract of Fumaria parviflora (Fp.Cr) protected against diarrhea caused by castor oil in rats and mice, similar to loperamide and dicyclomine, and bronchospasm caused by carbachol (CCh) in rats, similar to aminophylline. In the in vitro studies, Fp.Cr relaxed CCh and isotonic high K(+) physiological salts solutions-induced contractions in jejunum, ileum and tracheal preparations of rat, guinea-pig and rabbit. Fp.Cr was predominately more potent against CCh than isotonic high K(+) solutions-induced contractions, similar to dicyclomine, suggesting the presence of anticholinergic and calcium channel blocking (CCB) activities, which were confirmed when Fp.Cr shifted the CCh and Ca(2+) concentration-response curves, constructed in rat ileum and trachea, towards right. Among intestinal preparations from various species, both anticholinergic and CCB effects of Fp.Cr were exhibited at lower concentrations in rat than the other species. In tracheal preparations, Fp.Cr was the most potent in its CCB effect in rabbit. Within species, CCB effect of Fp.Cr was produced at lower concentrations in rat jejunum than ileum and trachea, whereas, anticholinergic effect was produced at higher concentration in rat trachea than intestine. CONCLUSION: This study, showing the presence of antidiarrheal, antispasmodic and bronchodilator activities in Fumaria parviflora possibly mediated through dual blockade of muscarinic receptors and Ca(2+) channels, provides sound basis for its medicinal uses in diarrhea, abdominal cramps and may be used as bronchodilator in asthma. Species and tissue-dependency of these effects underscores the importance of utilizing multiple tissues and species to get more meaningful results.

Gastrointestinal stimulant effect of Urginea indica Kunth. and involvement of muscarinic receptors.

Urginea indica Kunth. (Family; Liliaceae) was studied for its gastrointestinal stimulant effect to rationalize the traditional medicinal uses as a digestive aid, stomachic and laxative. The crude aqueous-methanol extract of Urginea indica bulb (Ui.Cr) was tested on mice and isolated gut preparations. Ui.Cr, which was tested positive for alkaloids, tannins and coumarins, increased faecal output and accelerated charcoal meal transit in mice (6-12 mg/kg, p.o.), similar to that caused by carbachol (10 mg/kg). Ui.Cr (0.01-1 mg/mL) caused a spasmogenic effect in guinea-pig ileum that was reproduced in rabbit jejunum (0.01-0.3 mg/mL) followed by relaxation at a higher concentration. Like carbachol, the stimulant effect of Ui.Cr was blocked by atropine, suggesting the activation of muscarinic receptors mediating the prokinetic effect. Ui.Cr (0.01-5.0 mg/mL) also inhibited K(+) (80 mm)-induced contraction in rabbit jejunum and shifted the Ca(2+) concentration-response curves to the right, similar to verapamil, a standard calcium channel blocker. These data, indicating the presence of a gastrointestinal stimulant effect in Urginea indica possibly mediated through a cholinergic mechanism, provide a rationale for the use of Urginea indica in indigestion and constipation. The presence of a calcium antagonist effect in the plant may help to alleviate untoward effects of the plant that may result from an excessive increase in gut motility.

Antiurolithic activity of Origanum vulgare is mediated through multiple pathways.

BACKGROUND: Origanum vulgare Linn has traditionally been used in the treatment of urolithiasis. Therefore, we investigated the crude extract of Origanum vulgare for possible antiurolithic effect, to rationalize its medicinal use. METHODS: The crude aqueous-methanolic extract of Origanum vulgare (Ov.Cr) was studied using the in vitro and in vivo methods. In the in vitro experiments, supersaturated solution of calcium and oxalate, kidney epithelial cell lines (MDCK) and urinary bladder of rabbits were used, whereas, in the in vivo studies, rat model of urolithiasis was used for the study of preventive and curative effect. RESULTS: In the in vitro experiments, Ov.Cr exhibited a concentration-dependent (0.25-4 mg/ml) inhibitory effect on the slope of nucleation and aggregation and also decreased the number of calcium oxalate monohydrate crystals (COM) produced in calcium oxalate metastable solutions. It also showed concentration-dependent antioxidant effect against DPPH free radical and lipid peroxidation induced in rat kidney tissue homogenate. Ov.Cr reduced the cell toxicity using MTT assay and LDH release in renal epithelial cells (MDCK) exposed to oxalate (0.5 mM) and COM (66 µg/cm(2)) crystals. Ov.Cr relaxed high K(+) (80 mM) induced contraction in rabbit urinary bladder strips, and shifted the calcium concentration-response curves (CRCs) towards right with suppression of the maximum response similar to that of verapamil, a standard calcium channel blocker. In male Wistar rats receiving lithogenic treatment comprising of 0.75% ethylene glycol in drinking water given for 3 weeks along with ammonium chloride (NH(4)Cl) for the first 5 days, Ov.Cr treatment (10-30 mg/kg) prevented as well as reversed toxic changes including loss of body weight, polyurea, crystalluria, oxaluria, raised serum urea and creatinine levels and crystal deposition in kidneys compared to their respective controls. CONCLUSION: These data indicating the antiurolithic activity in Ov.Cr, possibly mediated through inhibition of CaOx crystallization, antioxidant, renal epithelial cell protective and antispasmodic activities, rationalizes its medicinal use in urolithiasis.

Antispasmodic and Antidiarrheal Activities of Valeriana hardwickii Wall. Rhizome Are Putatively Mediated through Calcium Channel Blockade.

Valeriana hardwickii is indigenous to Pakistan, Burma and Ceylon, where it is traditionally being used as an antispasmodic and antidiarrheal, besides its culinary use as spice. The aim of this paper was to provide pharmacological validation to these medicinal uses. The crude aqueous-methanolic extract of Valeriana hardwickii rhizome (Vh.Cr) was studied on isolated rabbit jejunum and castor oil-induced diarrhea in mice for spasmolytic and antidiarrheal properties, respectively. Vh.Cr caused concentration-dependent (0.01-1 mg/mL) relaxation of spontaneous contractions in isolated rabbit jejunum and inhibited K(+)-induced contractions (0.01-0.3 mg/mL), similar to verapamil, suggestive of calcium channel blockade (CCB). The CCB effect was confirmed when pretreatment of the jejunum preparations with Vh.Cr produced a concentration-dependent (0.03-0.1 mg/mL) rightward shift in the Ca(++) concentration-response curves, as caused by verapamil. Vh.Cr exhibited dose-dependent (100-300 mg/kg) protection against castor oil-induced diarrhea in mice. Loperamide, a standard antidiarrheal drug, similarly prevented the diarrhea. These data indicate the presence of CCB effect in the extract of Valeriana hardwickii rhizome, possibly mediating its antispasmodic and antidiarrheal activities and provide a scientific base for its traditional use in hyperactive gut disorders.

Antiurolithic effect of berberine is mediated through multiple pathways.

Berberine is an isoquinoline alkaloid, occurring in nature as the main constituent of several plants with medicinal use in kidney stone disease. This work was undertaken to evaluate its antiurolithic potential and explore the possible underlying mechanism(s). Berberine was tested in vitro for the antioxidant effect and in vivo for diuretic and antiurolithic effects on an animal model of calcium oxalate urolithiasis. Berberine exhibited concentration-dependent (50-150µg/ml) antioxidant effect against ferrous-ascorbate induced lipid peroxidation in rat kidney homogenate with potency slightly higher than the reference antioxidant, butylated hydroxytoluene. In Wistar rats, berberine (5-20mg/kg) increased urine output accompanied by increased pH and Na(+) and K(+) excretion and decreased Ca(2+) excretion, similar to hydrochlorothiazide. In an animal model of calcium oxalate urolithiasis developed in male Wistar rats by adding 0.75% ethylene glycol in drinking water, berberine (10mg/kg) prevented as well as eliminated calcium oxalate crystal deposition in renal tubules and protected against deleterious effects of lithogenic treatment including weight loss, impaired renal function and oxidative stress, manifested as increased malondialdehyde and protein carbonyl contents, depleted GSH and decreased antioxidant enzyme activities of the kidneys. In naïve rats, berberine (10mg/kg) increased urine volume and pH and decreased Ca(2+) excretion. Results of this study suggest the presence of antiurolithic effects in berberine against calcium oxalate stones mediated through a combination of antioxidant, diuretic, urinary alkalinizing and hypocalciuric effects. These data invite future studies on berberine to establish its efficacy for clinical use.

Pharmacological basis for the medicinal use of Holarrhena antidysenterica in gut motility disorders.

CONTEXT: Holarrhena antidysenterica Wall. (Apocynaceae) is widely used in traditional medical system for treatment of constipation, colic, and diarrhea. AIM: This study was carried out to provide pharmacological basis for medicinal use of Holarrhena antidysenterica in gastrointestinal disorders. MATERIALS AND METHODS: Hydro-ethanolic crude extract of Holarrhena antidysenterica (HaCE) and its fractions were studied in various gastrointestinal isolated tissue preparations. RESULTS: In guinea pig ileum tissues, HaCE at 0.3-10 mg/mL caused pyrilamine-sensitive spasmogenic effect. When tested in spontaneously contracting rabbit jejunum preparations, HaCE (0.01-3.0 mg/mL) caused moderate stimulation, followed by a relaxant effect at next higher concentrations. In presence of pyrilamine, the contractile effect was blocked and the relaxation was observed at lower concentrations (0.01-0.3 mg/mL). HaCE inhibited the high K(+) (80 mM)-induced contractions at concentration range of 0.01-1.0 mg/mL and shifted Ca(++) concentration response curves to the right, like that caused by verapamil. Activity-directed fractionation revealed that the spasmogenic component was concentrated in the aqueous fraction, while the spasmolytic component was concentrated in the organic fraction. DISCUSSION AND CONCLUSION: These results indicate that the gut stimulant and relaxant activities of Holarrhena antidysenterica are mediated possibly through activation of histamine receptors and Ca(++) channel blockade, respectively and this study provides sound mechanistic background for its usefulness in gut motility disorders such as constipation, colic, and possibly diarrhea.

Berberis vulgaris root bark extract prevents hyperoxaluria induced urolithiasis in rats.

Berberis vulgaris is a widely used plant for the treatment of urolithiasis. To evaluate its antiurolithic potential, the crude aqueous-methanol extract of Berberis vulgaris root bark (Bv.Cr) was tested in an animal model of urolithiasis, developed in male Wistar rats by adding 0.75% ethylene glycol in drinking water. Bv.Cr (50 mg/kg) inhibited CaOx crystal deposition in renal tubules and protected against associated changes including polyuria, weight loss, impaired renal function and the development of oxidative stress in kidneys. Activity-guided fractionation revealed the concentration of antiurolithic constituent(s) mainly in the aqueous fraction. These data, indicating the presence of antiurolithic activity in Berberis vulgaris root bark, rationalize its medicinal use for the treatment of urolithiasis.

Antiurolithic effect of Bergenia ligulata rhizome: an explanation of the underlying mechanisms.

ETHNOPHARMACOLOGICAL RELEVANCE: Bergenia ligulata is widely used plant in South Asia, mainly India and Pakistan, as a traditional medicine for treatment of urolithiasis. AIM OF THE STUDY: To rationalize the Bergenia ligulata use in kidney stones and to explain the underlying mechanisms. MATERIALS AND METHODS: The crude aqueous-methanolic extract of Bergenia ligulata rhizome (BLR) was studied using in vitro and in vivo methods. RESULTS: BLR inhibited calcium oxalate (CaC(2)O(4)) crystal aggregation as well as crystal formation in the metastable solutions and exhibited antioxidant effect against 1,1-diphenyl-2-picrylhydrazyl free radical and lipid peroxidation in the in vitro. BLR caused diuresis in rats accompanied by a saluretic effect. In an animal model of urolithiasis, developed in male Wistar rats by adding 0.75% ethylene glycol (EG) in drinking water, BLR (5-10 mg/kg) prevented CaC(2)O(4) crystal deposition in the renal tubules. The lithogenic treatment caused polyuria, weight loss, impairment of renal function and oxidative stress, manifested as increased malondialdehyde and protein carbonyl contents, depleted reduced glutathione and decreased antioxidant enzyme activities of the kidneys, which were prevented by BLR. Unlike the untreated animals, EG intake did not cause excessive hyperoxaluria and hypocalciuria in BLR treated groups and there was a significant increase in the urinary Mg(2+), instead of a slight decrease. CONCLUSIONS: These data indicate the antiurolithic activity in Bergenia ligulata mediated possibly through CaC(2)O(4) crystal inhibition, diuretic, hypermagneseuric and antioxidant effects and this study rationalizes its medicinal use in urolithiasis.

Coriander fruit exhibits gut modulatory, blood pressure lowering and diuretic activities.

AIM OF THE STUDY: Coriander (Coriandrum sativum) is traditionally used for various gastrointestinal and cardiovascular disorders and this study was designed to rationalize its use in dyspepsia, abdominal colic, diarrhea, hypertension and as diuretic. MATERIALS AND METHODS: Coriander crude extract (Cs.Cr) was evaluated through in vitro and in vivo techniques. RESULTS: Cs.Cr caused atropine sensitive stimulatory effect in isolated guinea-pig ileum (0.1-10 mg/ml). In rabbit jejunum preparations, Cs.Cr evoked a similar contractile response but in the presence of atropine, it exhibited relaxation against both spontaneous and high K(+) (80 mM)-induced contractions as well as shifted the Ca(2+) concentration-response curves to right, similar to that caused by verapamil. Cs.Cr (1-30 mg/ml) caused fall in arterial blood pressure of anesthetized animals, partially blocked by atropine. Cs.Cr produced vasodilatation against phenylephrine and K(+) (80 mM)-induced contractions in rabbit aorta and cardio-depressant effect in guinea-pig atria. Cs.Cr produced diuresis in rats at 1-10mg/kg. Bio-assay-directed fractionation revealed the separation of spasmogenic and spasmolytic components in the aqueous and organic fractions respectively. CONCLUSIONS: These results indicate that coriander fruit exhibits gut stimulatory, inhibitory and hypotensive effects mediating possibly through cholinergic, Ca(2+) antagonist and the combination of these mechanisms respectively. Diuretic activity adds value to its use in hypertension.

Antihypertensive, antioxidant, antidyslipidemic and endothelial modulating activities of a polyherbal formulation (POL-10).

The present investigation was aimed at providing the pharmacological basis for the medicinal use of a polyherbal formulation (POL-10) in hypertension and dyslipidemia. In spontaneously hypertensive rats, POL-10 significantly (p<0.05) reduced blood pressure to 183.2+/-2.97 vs 198.1+/-5.2 mmHg (Mean+/-S.E.M; n=7-10), improved endothelial dysfunction (p<0.01) by increasing acetylcholine-induced relaxation up to 46.0+/-6.7% vs 24.6+/-3.8% (n=5-10) and decreased serum triglycerides (TG) to 54.5+/-3.3 vs. 93.84+/-5.7 mg/dl (p<0.001). In high fat diet-induced hypercholesterolemia, POL-10 caused reduction in total cholesterol (TC), low density lipoproteins (LDL) levels and the atherogic index (TC-HDL/HDL). It decreased TG levels in tyloxapol-induced hyperlipidemia and increased high-density lipoprotein cholesterol (HDL-C) and reduced atherogenic index in normotensive rats. It exhibited strong antioxidant activity in different in vitro assays. In isolated smooth muscle preparation, POL-10 exhibited calcium channel blocking (CCB) activity by inhibition of high K(+)- induced contractions and rightward shift of Ca(++) concentration-response curves similar to that of verapamil. In conclusion, these findings rationalize the medicinal use of POL-10 in cardiovascular disorders which are mediated through multiple pathways such as, antioxidant, CCB, inhibition of lipid biosynthesis and absorption.