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Determination of a novel growth hormone secretagogue (MK-677) in human plasma at picogram levels by liquid chromatography with atmospheric pressure chemical ionization tandem mass spectrometry.

A sensitive and specific method for the determination of N-[1(R)¿[1,2-dihydro-1-methylsulfonylspiro(3H-indole-3,4'-piper idin)-1'-yl]carbonyl¿-2-(phenylmethoxy)ethyl]-2-amino-2-meth ylpropanamide (MK-677, I), a growth hormone secretagogue, has been developed. The method is based on high-performance liquid chromatography (HPLC) with tandem mass spectrometric (MS-MS) detection. The analyte and internal standard (II) were isolated from the basified plasma using a liquid-liquid extraction with methyl-tert.-butyl ether (MTBE). The organic extract was evaporated to dryness, the residue was reconstituted in mobile phase and injected into the HPLC system. The MS-MS detection was performed on a PE Sciex API III Plus tandem mass spectrometer using a heated nebulizer interface. Multiple reaction monitoring of parent-->product ion combinations at m/z 529-->267 and 527-->267 was used to quantify I and II, respectively. The assay was validated in human plasma in the concentration range of 0.1 to 100 ng/ml, and the limit of quantification (LOQ) was 0.1 ng/ml. The precision of the assay, as expressed as coefficients of variation (C.V.,%) was less than 7% at all concentrations within the standard curve range, with adequate assay specificity and accuracy. The HPLC-MS-MS method provided sufficient sensitivity to completely map the pharmacokinetic time-course following a single 5-mg oral dose of I.

Chromatography, Liquid↗

Kava-Kava administration reduces anxiety in perimenopausal women.

OBJECTIVE: Disturbances of mood, such as anxiety and depression, increase in the perimenopausal period. Hormone replacement therapy or neuroactive drugs represent useful treatments for these disturbances but may be contraindicated or not accepted. Herein it was investigated the efficacy of Kava-Kava, an extract of Piper Methysticum, on mood of perimenopausal women. DESIGN: A 3-months randomized prospective open study investigating in perimenopausal women modifications induced by calcium supplementation (control; n=34), calcium plus Kava-Kava at the dose of 100 mg/day (n=15) or calcium plus Kava-Kava at the dose 200 mg/day (n=19). Anxiety was evaluated by the State Trait Anxiety Inventory (STAI); depression by the Zung's scale (SDS), and climacteric symptoms by the Greene's scale. Evaluations were performed at baseline and after 1 and 3 months. RESULTS: In the control group during the 3 months, anxiety, depression and climacteric symptoms tended to decline, but not significantly. During Kava-Kava anxiety declined (P<0.001) at 1 (-3.8+/-1.03) and 3 (-5.03+/-1.2) months, depression declined at 3 months (-5.03+/-1.4; P<0.002) and climacteric score declined (P<0.0006) at 1 (-2.87+/-1.5) and 3 (-5.38+/-1.3) months. Only the decline of anxiety induced by Kava-Kava was significantly greater than that spontaneously occurring in controls (P<0.009). CONCLUSIONS: The present data indicate that, in perimenopausal women, administration of Kava-Kava induces an improvement of mood, particularly of anxiety.

Anxiety↗

Embryotoxicity and teratogenicity studies of an ayurvedic contraceptive--pippaliyadi vati.

An ayurvedic contraceptive--pippaliyadi vati, containing equal parts of powdered seeds or fruit berries of Embelia ribes, fruit of Piper longum and borax powder was fed orally to two groups of pregnant rats: 2.5 times to one and five times to the other; the recommended dose for humans. The foetuses of mothers fed with pippaliyadi had low birth weights and were smaller in length. The mothers gained less weight during gestation. Developmental defects of soft tissues and skeletons were analyzed. There were instances of herniation of the intestines into the umbilical cord in foetuses of mothers who were administered pippaliyadi. The control and the gum acacia groups did not show such herniation.

Abnormalities, Drug-Induced↗

Antiviral and antimicrobial activities of Colombian medicinal plants.

Strong antiviral and antimicrobial activities were detected in methanolic extracts of 24 plants used medicinally in the treatment of skin infections in four different regions of Colombia. Thirteen extracts displayed activity against herpes simplex virus (HSV) whereas none was active against poliovirus. The antiviral activity was indicated by a total inhibition of viral cytopathic effects (CPE) at a non-cytotoxic concentration of the extract. The most potent extract was obtained from Byrsonima verbascifolia (L.) HBK. which showed anti-HSV activity at a concentration as low as 2.5 microg/ml. Antimicrobial screening was conducted using the disc diffusion assay against Klebsiella pneumoniae, Escherichia coli, Streptococcus faecalis, Mycobacterium phlei, Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeruginosa, Salmonella typhimurium and the human pathogenic yeast, Candida albicans. Anti-Candida activity was observed for Piper lanceaefolium HBK. and Juglans neotropica Diels. Twenty-two extracts displayed activity against Gram-positive bacteria whereas none was active against the Gram-negative species. We concluded that these Colombian medicinal plants represent an untapped source of potentially useful antivirals and are worthy of further study.

Animals↗

Screening of the topical anti-inflammatory activity of some Central American plants.

Hexane, chloroform and methanol extracts of seven herbal drugs used in the folk medicine of Central America against skin disorders (Aristolochia trilobata leaves and bark, Bursera simaruba bark, Hamelia patens leaves, Piper amalago leaves, and Syngonium podophyllum leaves and bark) were evaluated for their topical anti-inflammatory activity against the Croton oil-induced ear oedema in mice. Most of the extracts induced a dose-dependent oedema reduction. The chloroform extract of almost all the drugs exhibited interesting activities with ID(50) values ranging between 108 and 498 micro g/cm(2), comparable to that of indomethacin (93 micro g/cm(2)). Therefore, the tested plants are promising sources of principles with high anti-inflammatory activity.

Administration, Topical↗

Hypoglycemic effects of Potentilla fulgens L in normal and alloxan-induced diabetic mice.

Tap roots of Potentilla fulgens L. traditionally chewed along with betel nut (Areca catechu) and betel leaves (Piper betel), are commonly used by local practitioners for various types of ailments. The crude methanolic extract of the roots was tested for its effects in normoglycemic and alloxan-induced diabetic mice. Hypoglycemic activity was observed to be dose- and time- dependent. The extracts reduced blood glucose level 2 h following administration in both normal and alloxan-induced diabetic mice. In alloxan-induced diabetic mice blood glucose was markedly reduced by 63%, while in normal mice a 31% reduction was observed 24 h after the effective dose of extract was administered. Further, in the diabetic mice a prolonged anti-hyperglycemic action was observed where glucose levels was, found to be significantly low (79%) when compared with control even on the third day. Glucose tolerance was also improved in both normal and diabetic mice. The results were compared against those of insulin, glibenclamide, metformin, and the probable mechanism of action is discussed.

Alloxan↗

Anti-inflammatory activity of Chinese medicinal vine plants.

Anti-inflammatory activities of ethanol extracts from nine vine plants used in traditional Chinese medicine to treat inflammatory conditions were evaluated against a panel of key enzymes relating to inflammation. The enzymes included cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), phospholipase A(2) (PLA(2)), 5-lipoxygenase (5-LO) and 12-lipoxygenase (12-LO). The vine plants studied were: the stem of Spatholobus suberectus Dunn, the stem of Trachelospermum jasminoides Lem., the root from Tripterygium wilfordii Hook. f., the stem of Sinomenium acutum Rehder and Wilson, the stem of Piper kadsura (Choisy) Ohwi, the stem of Polygonum multiflorum Thunb., the root and stem from Tinospora sagittata Gagnep., the root of Tinospora sinensis (Lour.) Merrill, and the stem of Clematis chinensis Osbeck. All of the plant extracts showed inhibitory activities against at least one of the enzymes in various percentages depending upon the concentrations. The extract from S. suberectus was found to be active against all enzymes except COX-2. Its IC(50) values were 158, 54, 31 and 35 microg/ml in COX-1, PLA(2), 5-LO and 12-LO assays, respectively. T. jasminoides showed potent inhibitory activities against both COX-1 (IC(50) 35 microg/ml) and PLA(2) (IC(50) 33 microg/ml). The most potent COX-1, COX-2 and 5-LO inhibition was observed in the extract of T. wilfordii with the IC(50) values of 27, 125 and 22 microg/ml, respectively. The findings of this study may partly explain the use of these vine plants in traditional Chinese medicine for the treatment of inflammatory conditions.

Anti-Inflammatory Agents↗

Management of giardiasis by a herbal drug 'Pippali Rasayana': a clinical study.

Pippali Rasayana (PR), an Indian ayurvedic drug prepared from Palash (Butea monosperma (Lamk) Kuntze; Leguminaceae) and Pippali (Piper longum L.; Piperaceae), was administered at a dose of 1 g p.o. three times daily for a period of 15 days to patients (25 treated, 25 placebo controls) suffering from giardiasis with clinical signs and symptoms, and stools positive for trophozoites/cysts of Giardia lamblia. After 15 days of drug treatment there was a complete disappearance of G. lamblia (trophozoites/cysts) from the stools of 23 out of 25 patients. General signs and symptoms of ill health and abdominal discomfort, presence of mucus, pus cells and RBCs were significantly reduced. There was a marked improvement in the clinical and haematological profile of the patients. Spontaneous recovery in 20% cases was recorded in placebo controls.

Adjuvants, Immunologic↗

Influence of spices on the bacterial (enzyme) activity in experimental colon cancer.

In the presence of a known colon carcinogen, 1,2-dimethyl hydrazine (DMH), the activity of beta-glucuronidase was found to be significantly increased in the distal colon, distal intestine, liver and colon contents and the activity of mucinase was increased in both the colon and fecal contents when compared to control rats. Chilli (Capsicum annum L., Solanaceae) administration also showed an increase when compared to control rats, whereas supplementation with cumin (Cuminum cyminum L., Apiaceae) and black pepper (Piper nigrum L., Piperaceae) in the presence of DMH, showed more or less similar values as that of the control rats. The increase in beta-glucuronidase activity may increase the hydrolysis of glucuronide conjugates, liberating the toxins, while the increase in mucinase activity may enhance the hydrolysis of the protective mucins in the colon. Thus cumin and black pepper may protect the colon by decreasing the activity of beta-glucuronidase and mucinase. Histopathological studies also showed lesser infiltration into the submucosa, fewer papillae and lesser changes in the cytoplasm of the cells in the colon in cumin and black pepper groups when compared to the DMH and chilli treated animals.

1,2-Dimethylhydrazine↗

Antiinflammatory and antioxidant activity of plants used in traditional medicine in Ecuador.

Ethanolic extracts from 15 plant species, representing eight different families, used in traditional medicine in Ecuador were evaluated for antiinflammatory and antioxidant activities. Conyza floribunda, Eupatorium articulatum, Bonafousia longituba, Bonafousia sananho, Tagetes pusilla and Piper lenticellosum extracts showed a significant antiinflammatory activity in vivo in the carrageenan-induced paw oedema model in mice. The extracts were also tested in vitro for their ability to inhibit lipid peroxidation and to scavenge superoxide and hydroxyl radicals. E. articulatum extract possesses both activities. Baccharis trinervis, E. articulatum and Phytolacca rivinoides extracts were active as antioxidants.

Animals↗

Antimicrobial properties of Honduran medicinal plants.

Ninety-two plants used in the traditional pharmacopoeia of the Pech and neighboring Mestizo peoples of central Honduras are reported. The results of in vitro antimicrobial screens showed that 19 of the extracts from medicinal plants revealed signs of antifungal activity while 22 demonstrated a measurable inhibitory effect on one or more bacterial cultures. Bioassay-guided fractionation of extracts from Mikania micrantha, Neurolaena lobata and Piper aduncum produced weak to moderately active isolates. The broad spectrum of activity of the extracts helps to explain the widespread use of these plants for wound healing and other applications.

Anti-Bacterial Agents↗

Antimalarial activity of extracts of Malaysian medicinal plants.

In vitro and in vivo studies revealed that Malaysian medicinal plants, Piper sarmentosum, Andrographis paniculata and Tinospora crispa produced considerable antimalarial effects. Chloroform extract in vitro did show better effect than the methanol extract. The chloroform extract showed complete parasite growth inhibition as low as 0.05 mg/ml drug dose within 24 h incubation period (Andrographis paniculata) as compared to methanol extract of drug dose of 2.5 mg/ml but under incubation time of 48 h of the same plant spesies. In vivo activity of Andrographis paniculata also demonstrated higher antimalarial effect than other two plant species.

Animals↗

Measuring the symptom experience of seriously ill cancer and noncancer hospitalized patients near the end of life with the memorial symptom assessment scale.

The objectives of this study were twofold: (1) to explore and compare the symptom experience of seriously ill hospitalized cancer and noncancer patients near the end of life using the Memorial Symptom Assessment Scale (MSAS) and (2) to determine if the MSAS is a valid and useful measure of symptom distress for patients with noncancer conditions. This was a prospective cohort study of hospitalized patients with end-stage congestive heart disease, chronic pulmonary disease, cirrhosis, or metastatic cancer. Eligible patients were interviewed to ascertain symptom prevalence, severity and distress using the MSAS and levels of fatigue using the Piper Fatigue Scale (PFS). Sixty-six patients with metastatic cancer and 69 patients with end-stage disease were enrolled in the study. There was a significant difference in the prevalence of selected physical symptoms, but not psychological symptoms, between cancer and noncancer patients. There were no significant differences in symptom distress scores, a computed score of frequency, severity and distress, if the symptom was present. In both groups the principal components factor analysis with varimax rotation yielded one factor comprising psychological symptoms and a second factor comprising three subgroups of physical symptoms. Internal consistency was high for the psychological subscale (Cronbach alpha coefficients of 0.85 for the cancer group and 0.77 for the noncancer group) and for the physical subscale groupings, with coefficients ranging between 0.78 to 0.87. The symptom scores were significantly correlated with perceptions of fatigue. These findings show that both seriously ill cancer and noncancer patients experience symptom distress, and that the MSAS seems to be a reliable measure of symptom distress in noncancer patients, as well as with cancer patients.

Aged↗

Modulation of platelet aggregation by areca nut and betel leaf ingredients: roles of reactive oxygen species and cyclooxygenase.

There are 2 to 6 billion betel quid (BQ) chewers in the world. Areca nut (AN), a BQ component, modulates arachidonic acid (AA) metabolism, which is crucial for platelet function. AN extract (1 and 2 mg/ml) stimulated rabbit platelet aggregation, with induction of thromboxane B2 (TXB2) production. Contrastingly, Piper betle leaf (PBL) extract inhibited AA-, collagen-, and U46619-induced platelet aggregation, and TXB2 and prostaglandin-D2 (PGD2) production. PBL extract also inhibited platelet TXB2 and PGD2 production triggered by thrombin, platelet activating factor (PAF), and adenosine diphosphate (ADP), whereas little effect on platelet aggregation was noted. Moreover, PBL is a scavenger of O2(*-) and *OH, and inhibits xanthine oxidase activity and the (*)OH-induced PUC18 DNA breaks. Deferoxamine, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) and neomycin prevented AN-induced platelet aggregation and TXB2 production. Indomethacin, genistein, and PBL extract inhibited only TXB2 production, but not platelet aggregation. Catalase, superoxide dismutase, and dimethylthiourea (DMT) showed little effect on AN-induced platelet aggregation, whereas catalase and DMT inhibited the AN-induced TXB2 production. These results suggest that AN-induced platelet aggregation is associated with iron-mediated reactive oxygen species production, calcium mobilization, phospholipase C activation, and TXB2 production. PBL inhibited platelet aggregation via both its antioxidative effects and effects on TXB2 and PGD2 production. Effects of AN and PBL on platelet aggregation and AA metabolism is crucial for platelet activation in the oral mucosa and cardiovascular system in BQ chewers.

Animals↗

Effects of (+/-)-kavain on voltage-activated inward currents of dorsal root ganglion cells from neonatal rats.

Kava pyrones extracted from pepper Piper methysticum are pharmacologically active compounds. Since kava pyrones exhibit anticonvulsive, analgesic and centrally muscle relaxing properties, the influence of a synthetic kava pyrone, (+/-)-kavain, on voltage-dependent ion channel currents was studied. Effects of (+/-)-kavain on voltage-activated inward currents were analysed in cultured dorsal root ganglion cells derived from neonatal rats. Voltage-activated Ca2+ and Na+ currents were elicited in the whole-cell configuration of the patch clamp technique. Extracellularly applied (+/-)-kavain dissolved in hydrous salt solutions reduced voltage-activated Ca2+ and Na+ channel currents within 3-5 min. As the solubility of (+/-)-kavain in hydrous solutions is low, dimethyl sulfoxide (DMSO) was added to the saline as a solvent for the drug in most experiments. When (+/-)-kavain was dissolved in DMSO, the drug induced a fast and pronounced reduction of both Ca2+ and Na+ currents, which partly recovered within 2-5 min even in the presence of the drug. The present study indicates that (+/-)-kavain reduces currents through voltage-activated Na+ and Ca2+ channels.

Animals↗

Element analysis and biological studies on ten oriental spices using XRF and Ames test.

Ten oriental spices were analyzed for their element composition using X-ray fluorescence (XRF): nutmeg (Myristica fragrans), coriander (Coriandrum sativum), safflower (Carthamus tinctorius), caraway (Carum carvi), Sicilian sumac (Rhus coriaria), aniseed (Anisum vulgare), black pepper (Piper nigrum), cardamom (Elettaria cardamomum), cumin (Cuminum cyminum) and nigella (Nigella sativum). The spices were found to contain the following elements: Mg, Al, Si, P, S, Cl, K, Ca, Ti, Mn, Fe, Cu and Zn, with varying concentrations. Mutagenic studies using Salmonella typhimurium strains TA97a, TA98, TA100, and TA102 showed that the above spices have no base pair substitution mutagenic activity. However, a weak frameshift mutagenicity has been shown by nutmeg and a very weak oxidative mutagenic action has been revealed by cumin.

Asia↗

Perylene diimide G-quadruplex DNA binding selectivity is mediated by ligand aggregation.

Two N,N'-disubstituted perylene diimide G-quadruplex DNA ligands, PIPER [N,N'-bis-(2-(1-piperidino)ethyl)-3,4,9,10-perylene tetracarboxylic acid diimide] and Tel01 [N,N'-bis-(3-(4-morpholino)-propyl)-3,4,9,10-perylene tetracarboxylic acid diimide] were studied. Visible absorbance, resonance light scattering, and fluorescence spectroscopy were used to characterize the pH-dependent aggregation of these ligands. The G-quadruplex DNA binding selectivity of these ligands as monitored by absorption spectroscopy is also pH-dependent. The ligands bind to both duplex and G-quadruplex DNA under low pH conditions, where the ligands are not aggregated. At higher pH, where the ligands are extensively aggregated, the apparent G-quadruplex DNA binding selectivity is high.

Anthracenes↗

Complementary and alternative interventions in asthma, allergy, and immunology.

OBJECTIVE: To review which herbs are most commonly used as complementary and alternative medicine (CAM) for treatment of asthma, allergy, and immunologic conditions. DATA SOURCES: A review of the literature was performed using the PubMed and OVID databases searching the keywords asthma, allergy, and CAM to identify studies published between 1980 and 2003 that focused on Echinacea (Echinacea augustifolia, Echinacea pallida, and Echinacea purpurea); garlic (Allium); angelica; chamomile; ephedra; gingko; grape seed extract; licorice root (Glycyrrhiza); St. John's wort (Hypericum); kava kava (Piper); peppermint oil and leaf (Mentha); stinging nettle (Urtica); and ginseng (Panax) published in the English and German literature. STUDY SELECTION: Studies included in vitro and in vivo clinical trials and case reports selected according to the expert opinion of the author. RESULTS: Echinacea is one of the most common herbs used to treat symptoms of the "common cold" or upper respiratory tract allergies. Although no common drug interactions have been reported, there is a risk of hepatotoxicity, exacerbation of allergies and asthma, and anaphylactic reactions. Garlic is primarily used for cardiovascular health and relief of cough, colds, and rhinitis. Adverse effects commonly include gastrointestinal disturbances, change in body odor through the sweat and breath, and rarely allergic reactions or hypoglycemia. Other CAM agents, including angelica, German chamomile flower, ephedra, gingko, grape seed extract, licorice root, St. John's wort, kava kava rhizome, peppermint, stinging nettle, and ginseng, are also associated with significant adverse effects. CONCLUSION: The specialty of allergy and immunology has seen the second largest increase in the popularity of CAM (second only to practitioners who treat lower back pain). Almost all of the CAM interventions have displayed adverse effects, usually in the form of a hypersensitivity reaction. Allergists and clinical immunologists need to become more knowledgeable about CAM so that they can inform patients about the use and possible abuse of these modalities.

Asthma↗