bluuebunny/crossref_metadata_2025 huggingface dataset:
Ethanol extract of Crocus sativus L. Antagonizes the inhibitory action of ethanol on hippocampal long‐term potentiation in vivo
Authors: Sugiura Minoru , Saito Hiroshi , Abe Kazuho , Shoyama Yukihiro
Published: October 2006

The effect of an ethanol extract of Crocus sativus L. (CSE) on the long‐term potentiation (LTP) of the evoked potential in the dentate gyrus of the hippocampus was investigated using anaesthetized rats. CSE (250 mg/kg, p.o.) alone did not affect the generation of LTP by application of subthreshold or suprathreshold tetanic stimulation (20 or 30 pulses at 60 Hz). Oral administration of ethanol (10–30%, 10 mL/kg) blocked the LTP induced by tetanic stimulation of 30 pulses at 60 Hz, but the LTP‐blocking effect of ethanol was significantly attenuated by pre‐administration of CSE (125 and 250 mg/kg, p.o.). The blockade of LTP induction by intravenously injected ethanol (30%, 2 mL/kg) was also antagonized by administration of CSE at doses of 125 and 250 mg/kg (p.o.). Oral administration of CSE antagonized also the LTP‐blocking effect of ethanol directly injected into the brain, although it required a higher dose (500 mg/kg, p.o.). These results suggest that oral administration of CSE exerts an antagonistic effect on ethanol‐induced impairment of hippocampal synaptic plasticity, which is possibly mediated by both direct action on the central nervous system and peripheral action.
Effects of glycowithanolides from Withania somnifera on an animal model of Alzheimer's disease and perturbed central cholinergic markers of cognition in rats
Authors: Bhattacharya Salil K. , Kumar Ashok , Ghosal Shibnath
Published: October 2006

The active principles of Withania somnifera (WS, 20–50 mg/kg, p.o.), consisting of equimolar amounts of sitoindosides. VII–X and withaferin A, were investigated for putative nootropic activity in an experimentally validated Alzheimer's disease (AD) model. The syndrome was induced by ibotenic acid (IA) lesioning of the nucleus basalis magnocellularis (NBM) in rats. Cognitive deficits induced in NMB‐lesioned rats were assessed by attenuation of a learned active avoidance task and a decrease in frontal cortical and hippocampal acetylcholine (ACh) concentrations, choline acetyltransferase (ChAT) activity and muscarinic cholinergic receptor (MCR) binding. IA‐induced NBM lesioning in rats caused a marked cognitive deficit, as evidenced by severe reduction of the learned task, and was accompanied by a significant decrease in frontal cortex and hippocampal ACh levels, ChAT activity and MCR binding. WS (50 mg/kg) significantly reversed both IA‐induced cognitive deficit and the reduction in cholinergic markers after 2 weeks of treatment. The findings validate the medharasayan (promoter of learning and memory) effect of W. somnifera, as has been reported in Ayurveda.
Preliminary studies of the effects of a herbal prescription, Hokoei‐to, on the endocrine system in parous rats
Authors: Yokozawa Takako , Ogama Takako , Tsuji Atsutoshi , Hattori Masao , Kuginuki Fuji
Published: October 2006

Hokoei‐to extract was administered orally to parous rats for 25 days to examine its effects on sex hormones. Hokoei‐to, containing Taraxaci Radix collected in autumn, induced a significant increase of progesterone and oestradiol and a significant decrease of luteinizing hormone (LH) and follicle‐stimulating hormone (FSH). With Hokoei‐to extract containing Taraxaci Radix collected in spring, progesterone was also increased significantly, but oestradiol increased only slightly, and LH and FSH showed a tendency to decrease, without any statistically significant changes. The effects of this type of Hokoei‐to were thus weaker than those of Hokoei‐to containing Taraxaci Radix collected in autumn. Our findings suggest that the latter also has some effect on serum chemical constituents, such as triglyceride, albumin, glutamic oxaloacetic transaminase and glutamic pyruvic transaminase.
The antiinflammatory effect of several composite from South America. Extracts in rats
Authors: Pérez F. , Marín E. , Adzet T.
Published: October 2006

Extracts of different polarity from Artemisia copa, Baccharis incarum, Mutisia kurtzii and Pluchea sagittalis were screened for antiinflammatory activity. Aqueous extracts from Mutisia kurtzii and Pluchea sagittalis, and dichloromethane extracts from Baccharis incarum and Pluchea sagittalis evoked a marked antioedema action in the carrageenan‐foot oedema test.
Effect of Carica papaya seed extract on female rat ovaries and uteri
Authors: Chinoy N. J. , Dilip Trivedi , Harsha Joshi
Published: October 2006

The effect of an aqueous extract of Carica papaya seed for 7 and 15 days on the physiology of rat ovaries and uterus was studied. The possible reversibility of the induced effects was also investigated. The results revealed that the effects were more pronounced in the ovary than in the uterus. The changes in biochemical profile of the ovary and uterus involved alterations in the levels of ascorbic acid, ascorbigen (ASG), ascorbic acid utilization (AUU), ascorbic acid macromolecular (AA‐MM) complexing, ascorbic acid free radical (AA‐FR) formation, total ascorbic acid and glutathione (GSH), cholesterol, protein and glycogen. The increase in ascorbate turnover is an adaptation to overcome the harmful effect of the extract. The fertility test was 100% negative and the oestrus cycle was irregular with a predominance of dioestrus. The uterine contractility was increased. The above mentioned changes indicate that the extract manifested antifertility, antiimplantation and abortifacient effects in the treated animals. The withdrawal of treatment overcame the adverse effects of the treatment in ovary and the uterus and restored fertility.
Antiherpetic in vitro activity of Gamochaeta simplicicaulis extract
Authors: Cavallaro L. , Garcia G. , Broussalis A. , Ferraro X. , Martino V. , Coussio J. , de Torres R. , Campos R.
Published: October 2006

Aqueous extracts of Gamochaeta simplicicaulis present true antiviral activity in vitro against different members of the herpesvirus family (herpes simplex virus types 1 and 2, human cytomegalovirus, bovine herpes virus and lower activity with pseudorabies virus). The extract had no activity against some RNA (naked and enveloped) viruses and adenoviruses. The extract was not virucidal but its antiviral index (AI) was high enough to justify further analysis. Different experimental approaches indicate that an early step of viral replication, at least the adsorption period, was involved in the antiviral activity.
Schisandra Chinensis‐derived antioxidant activities in ‘Sheng Mai San’ a compound formulation, in vivo and in vitro
Authors: Ko K. M. , Yick P. K. , Poon M. K. T. , Chet C. T. , Ng K. H. , Kong Y. C.
Published: October 2006

Sheng Mai San (SMS), a compound formulation in traditional Chinese medicine comprising Panax ginseng, Schisandra chinensis and Ophiopogon japonicus, is used for the treatment of ischaemic heart disease. In the present study, we have demonstrated the presence of both in vivo and in vitro antioxidant activities in SMS, as indicated by its ability to protect against CCl4 induced hepatotoxicity in rats and to scavenge superoxide radicals generated in an in vitro system. Our results indicate that the antioxidant activity of SMS is derived mainly from Schisandra chinensis.
Neuropharmacologial effects of Cystoseira usneoides extract
Authors: Vázquez‐Freire M. J. , Castro E. , Lamela M. , Calleja J. M.
Published: October 2006

The effects were studied of an extract of the brown algae Cystoseira usneoides on the central nervous system (CNS) of mice. At doses between 6.25 and 25 mg/kg the extract had significant effects on spontaneous locomotor activity, exploratory behaviour, D‐amphetamine‐induced hypermotility, body temperature, pentobarbitalinduced hypnosis, motor coordination and pentylenetetrazole‐induced convulsions. Dopamine, 3,4‐dihydroxy‐phenylacetic acid, 3‐methoxytyramine and homovanilic acid levels were determined in rat striatum and they were slightly modified. The extract also displayed analgesic activity. We conclude that the extract of Cystoseira usneoides is a CNS depressant with slight analgesic effects.
Inhibitory effects of various ayurvedic and Panamanian medicinal plants on the infection of herpes simplex virus‐1 in vitro and in vivo
Authors: Hattori Masao , Nakabayashi Takeshi , Lim Yasmina Aura , Miyashiro Hirotsugu , Kurokawa Masahiko , Shiraki Kimiyasu , Gupta Mahabir P. , Correa Mireya , Pilapitiya Upali
Published: October 2006

Extracts of 40 Ayurvedic medicines and 39 Panamanian medicinal plants were screened for their inhibitory activity on the plaque formation of herpes simplex virus type 1 (HSV‐1) in cultured cells. The extracts of 11 plant species showed potent inhibitory activity at a concentration of 100 μg/mL, while those of ten species showed moderate activities. Repeated oral administration of each extract of Rhus acuminata (galls), Saraca indica (bark), Strychnos potatrum (seeds) appreciably suppressed the development of typical skin lesions induced by infection of HSV‐1 in BALB/c mice. The extract of S. potatrum prolonged both development of skin lesion and mean survival time. This indicates that S. potatrum is a possible candidate for therapeutic application for HSV‐1 infection.
Pharmacological activities of extracts of Daniellia oliveri (Rolfe) Hutch. and Dalz. (Leguminosae)
Authors: Onwukaeme N. D.
Published: October 2006

Extracts of the stem bark of Daniellia oliveri using hexane, ethyl acetate and methanol were tested for analgesic, antipyretic and antiinflammatory activities. The hexane extract exhibited a dose related analgesic activity whilst the methanolic extract was active in the induced inflammatory condition. The ethyl acetate extract was relatively inactive and none of the extracts showed any antipyretic activity. Metabolic cage studies showed that a 70% ethanolic extract of the bark caused significant decreases in body weight, food intake, urine and stool output of rats. This extract also exhibited a competitive antagonism on histamine‐induced contractions of the guinea‐pig ileum and a non‐competitive inhibition of acetyl choline‐induced contraction of the frog rectus abdominis muscle.
Several compounds from Chinese traditional and herbal medicine as immunomodulators
Authors: Zhang Ling‐Hua , Huang Yi , Wang Li‐Wei , Xiao Pei‐Gen
Published: October 2006

In the past 20 years, hundreds of Chinese traditional and herbal medicines with immunomodulating functions have been screened. In this paper, the immunopharmacological studies of several potent compounds isolated from them are reviewed; their medicinal plant sources and chemical structures are also presented.
Uraemic toxin reduction: A newly found effect of hydrolysable‐type tannin‐containing crude drug and gallotannin
Authors: Yokozawa Takako , Fujioka Koji , Oura Hikokichi , Tanaka Takashi , Nonaka Gen‐Ichiro , Nishioka Itsuo
Published: October 2006

The levels of urea nitrogen, creatinine, methylguanidine and guanidinosuccinic acid, which accumulate in blood in parallel with the progress of renal failure after adenine administration, were decreased significantly in rats given Galla Rhois, Moutan Cortex or Paeoniae Radix extract. Administration of Galla Rhois extract was found to be more effective than the other two crude drugs in decreasing the uraemic toxin parameters. A uraemic toxin‐decreasing effect similar to that of crude drug was also obtained using 1,3,6‐tri‐O‐galloyl‐β‐D‐glucopyranose and 1,2,3,4,6‐penta‐O‐galloyl‐β‐D‐glucopyranose.
Effect of fetal calf serum on the cytotoxic activity of mistletoe (Viscum albumL.) lectins in cell culture
Authors: Ribéreau‐Gayon Gilles , Jung Marie‐Louise , Beck Jean‐Paul , Anton R.
Published: October 2006

Mistletoe (Viscum album L.) contains three cytotoxic lectins, ML I, ML II and ML III. The interaction between these lectins and the fetal calf serum (FCS) commonly added to cell culture media was studied on human leukaemia Molt 4 cells. When these cells were grown in RPMI 1640 medium supplemented with 10% FCS, the lectins were about 40 times less toxic than when the former were grown in serum‐free Ultraculture medium. An addition of FCS to the serum‐free Ultraculture medium produced a dose‐dependent inhibition of the cytotoxic activities of the lectins, by up to 50 fold. Moreover, FCS increased by 2 to 3 fold the protective action of anti‐ML I antibodies against the toxicity of the lectins. The data suggest that FCS contains glycoproteins or glycolipids which interact with the lectins.
Effect of Rubia cordifolia extract on acetaminophen and CCl4‐induced hepatotoxicity
Authors: Gilani Anwar‐Ul Hassan , Janbaz Khalid Hussain
Published: October 2006

The hepatoprotective activity of an aqueous‐methanol extract of Rubia cordifolia (Rubiaceae) was investigated against acetaminophen and CCl4‐induced hepatic damage. Acetaminophen produced 100% mortality at a dose of 1 g/kg in mice while pretreatment of animals with plant extract (500 mg/kg) reduced the death rate to 30%. Acetaminophen at a dose of 640 mg/kg produced liver damage in rats as manifested by the rise in serum levels of GOT and GPT to 1447±182 and 899±201 IU/L (n = 10) respectively, compared with respective control values of 97±10 and 36±11. Pretreatment of rats with plant extract (500 mg/kg) lowered significantly (p <0.005) the respective serum GOT and GPT levels to 161±48 and 73±29. Similarly, hepatotoxic dose of CCl4 (1.5 mL/kg; orally) raised the serum transaminases (GOT and GPT) levels to 422±102 and 354±74 IU/L (n = 10) respectively compared with respective control values of 99±15 and 29±08 IU/L. The same dose of plant extract (500 mg/kg) was able to prevent significantly (p <0.01) the CCl4‐induced rise in serum enzymes and the estimated values of GOT and GPT were 95±09 and 33±07 IU/L, respectively. Moreover, it prevented CCl4‐induced prolongation in pentobarbital sleeping time confirming the hepatoprotective effects of the extract.
Decrease in uraemic toxins, a newly found beneficial effect of Ephedrae Herba
Authors: Yokozawa Takako , Fujioka Koji , Oura Hikokichi , Tanaka Takashi , Nonaka Gen‐Ichiro , Nishioka Itsuo
Published: October 2006

The levels of urea nitrogen, creatinine, methylguanidine and guanidinosuccinic acid, which accumulate in the blood in parallel with the progress of renal failure after adenine administration, were decreased markedly and significantly in rats given Ephedrae Herba extract. Administration of the fraction III of Ephedrae Herba extract was found to be more effective than any of the other fractions in decreasing uraemic toxin parameters. Analysis of the fractions by means of thin layer chromatography revealed that the fraction III contains condensed tannin.
Anthelmintic and pesticidal activity of Acorus gramineus (Araceae) is associated with phenylpropanoid asarones
Authors: Perrett Sheena , Whitfield Philip J.
Published: October 2006

The hexane extract of the Chinese medicinal plant Acorus gramineus (Araceae) has previously been shown to possess significant bioactivity towards a range of organisms in in vitro bioassays including digenean, nematode and arthropod targets. In the present study the principal active components in A. gramineus were identified as the phenylpropanoids α‐ and β‐asarone by comparing TLC, HPLC, UV and bioassay data obtained using the hexane extract with those derived with commercially available pure compounds. The known mammalian toxicity and carcinogenicity of asarones means that they are unlikely to have any utility as lead compounds for the development of practical anthelmintics and insecticides.
Antioxidant property of Rubia cordifolia extract and its comparison with vitamin E and parabenzoquinone
Authors: Tripathi Y. B. , Shukla Savita , Sharma Mukta , Shukla V. K.
Published: October 2006

This report investigates the antioxidant properties of R. cordifolia extract for protection against lipid peroxidation and reduced glutathione (GSH) content in rat liver homogenate compared with vitamin E and parabenzoquinone (PBQ). R. cordifolia protects against depletion of glutathione in a dose and time dependent manner, an inverse correlation was observed between reduced glutathione depletion and malondialdehyde (MDA) formation. Interestingly, parabenzoquinone showed a better response than R. cordifolia on cumene hydroperoxide (CHP) induced malon‐dialdehyde (MDA) release but there was no response in the rate of reduced glutathione (GHS) depletion. Thus it appears that R. cordifolia is a potent antiperoxidative and antioxidant. The mechanism of action is different to that of vitamin E and parabenzoquinone (PBQ).
Immunoactivities of the polysaccharides from Morus alba, Chlamydomonas mexicana and Poria cocos
Authors: Shuxiu Wang , Yuanying Wen , Changxu Hu
Published: October 2006

Polysaccharides were extracted from young branches of Morus alba L. (M); a green alga, Chlamydomonas mexicana Lewin, (C1 and C2) and a fungus, Poria cocos (Fr.) Wolf, (P1 and P2). M consisted of rhamnose, arabinose, xylose, mannose, galactose and glucose, C1 of fucose, 2‐MeO‐arabinose, ribose, arabinose, 6‐MeO‐mannose, xylose, 2‐deoxy‐galactose, mannose, galactose and glucose, C2 of 3‐MeO‐arabinose, arabinose, xylose, 2‐MeO‐galactose, galactose and glucose, P1 was mannose, galactose, glucose and a small amount of ribose and P2 consisted of erythritol, arabinose, glucose and muramic acid with the ratio of 1:1:4:1. Pharmacological tests for all of these polysaccharides were performed. Based on the results, M was less effective, but C1 and C2 were immunostimulant either in humoral immunity or in cellular immunity. C2 was effective in nonspecific immunity only, and P1 was as effective in humoral or in nonspecific immunities. P2 expressed enhancement in humoral, cellular or nonspecific immunities, but its activities were less than P1.
Shilajit‐induced potentiation of the hypoglycaemic action of insulin and inhibition of streptozotocin induced diabetes in rat
Authors: Kanikkannan N. , Ramarao P. , Ghosal S.
Published: October 2006

The effects of subcutaneous (s.c.) administration of processed shilajit (PS) alone and in combination with insulin (s.c.) on plasma glucose levels (PGL) were determined in either sex of streptozotocin‐induced diabetic (SID) rats. PS (50 μ/kg; s.c.) did not alter plasma glucose levels in SID rats. Insulin (0.25‐1.0 U/kg; s.c.), dose‐dependently produced hypoglycaemia in SID rats. PS (50 μg/kg; s.c.) potentiated and prolonged the hypoglycaemic action of insulin when administered concurrently. Chronic administration of PS (0.1–10 mg/kg; b.i.d. for 10 days; i.p.) had no influence per se on plasma glucose levels. Chronic administration of PS (1.0 mg/kg; b.i.d. for 10 days; i.p.) prevented the streptozotocin (STZ)‐induced diabetes in rats, whereas a relatively lower (0.1 mg/kg; b.i.d. for 10 days; i.p.) and significantly higher dose (10 mg/kg; b.i.d. for 10 days; i.p.) of PS had no influence on the STZ‐induced diabetes. The results suggest that administration of PS along with insulin would potentiate the insulin‐induced hypoglycaemia, and chronic administration of a carefully determined dose of PS would inhibit the development of STZ‐induced diabetes.
Experimental study of the therapeutic effect of You‐Gui‐Wan on hypogonadism in rats
Authors: Zheng Ping Dong , Mao Zheng Li , Gong Bin , Yokozawa Takako , Oura Hikokichi
Published: October 2006

Rats raised on a diet containing 0.5% adenine showed atrophy of the testes and retrogressive degeneration of the convoluted seminiferous tubules. The development of spermatids was suppressed, and the cell count decreased. In these rats, the activity of 3β‐hydroxysteroid dehydrogenase was markedly decreased, and the blood levels of testosterone and oestradiol were also very low. However, in rats that were also given You‐Gui‐Wan, retrogressive degeneration of the testes was milder, and the blood levels of testosterone and oestradiol were higher, indicating the beneficial effects of You‐Gui‐Wan on the histomorphology of the testes.
Antibacterial activity of flavanone isolated from Sophora exigua against methicillin‐resistant Staphylococcus aureus and its combination with antibiotics
Authors: Sato M. , Tsuchiya H. , Takase I. , Kureshiro H. , Tanigaki S. , Iinuma M.
Published: October 2006

5,7,2′,4′‐Tetrahydroxy‐8‐lavandulyl‐flavanone, isolated from Sophora exigua, completely inhibited the growth of 21 strains of methicillin‐resistant Staphylococcus aureus (MRSA) at concentrations of 3.13–6.25 μg/mL. The anti‐MRSA effect was based on bactericidal action. In combinations of the flavanone with vancomycin, minocycline and rifampicin, the fractional inhibitory concentration indices were 0.90, 0.88 and 0.85, respectively, indicating partial synergistic effects with anti‐MRSA antibiotics. The proposed flavanone would be a potent phytotherapeutic agent against MRSA infections.
Protection against galactosamine and tert‐butyl hydroperoxide induced hepatocyte damage by Melothria maderaspatana extract
Authors: Thabrew M. Ira , Gove Christopher D. , Hughes Robin D. , McFarlane Ian G. , Williams Roger
Published: October 2006

The aqueous extract of Melothria maderaspatana is used by traditional medical practitioners to treat jaundice in man. The effect of Melothria maderaspatana extract on damage induced in freshly isolated rat hepatocytes by D‐galactosamine and tert‐butyl hydroperoxide (TBH) has been investigated. On incubation of hepatocytes with galactosamine or TBH in the presence of the plant extract, a significant dose‐dependent protection against hepatocyte damage was observed, with maximum protection at a concentration of 500 μg/mL. At this concentration the galactosamine‐induced release of lactate dehydrogenase (LDH) and aspartate amino‐transferase (AST) were reduced by 40.7% ± 4.2% and 37.7% ± 6.1% respectively, compared with control incubations. The TBH‐induced lipid peroxidation (estimated from malondialdehyde production) was decreased by 26.0 ± 3.7% together with a 38.4% ± 4.4% and 40.8 ± 7.6% reduction in the release of cellular LDH and AST respectively into the incubation medium. On post‐treatment with the plant extract the protective activity was found to decrease with increase in time of exposure of the cells to either of the toxins. The direct protective effects of Melothria extract on hepatocytes support the use of this plant as a herbal remedy.
Effects of Ganoderma lucidum on cellular immunocompetence in γ‐irradiated mice
Authors: Chen Wang‐Chi , Hau Dou‐Mong
Published: October 2006

We have investigated the effects on mice treated with Ganoderma lucidum (GI) when the whole body was exposed to 400 rad γ‐irradiation. The mice were divided into five groups. Group A was the normal control; group B, the experimental control, was treated with GI; group C was the radiation control (RT); group D was treated with RT and GI; group E was treated with GI, RT and GI. The results revealed that the relative spleen weight had increased significantly in groups B and E on day 7 and increased in all experimental groups on day 28 after irradiation. The leukocyte counts decreased obviously in groups C, D and E on day 7, and recovered in groups D and E was faster than that in group C on day 28. The blastogenic response of splenocytes to LPS, Con A and PHA in groups administered GI were higher than that in group C on days 7 and 28. Therefore, GI seemed to assist the recovery of cellular immunocompetence in γ‐irradiated mice.
Effects of Salvia lavandulifolia Vahl. ssp. Oxyodon extract on pancreatic endocrine tissue in streptozotocin‐diabetic rats
Authors: Jiménez I. , Jiménez J. , Gámez M. J. , González M. , De Medina F. Sánchez , Zarzuelo A. , Osuna I.
Published: October 2006

We have investigated the antidiabetic activity of Salvia lavandulifolia ssp. oxyodon extract on rats pancreotomized by streptozotocin (STZ). At a dose of 10 mg dry residue/kg the extract produced: an increase in Langerhans islet number and size; an increase in pancreatic insulin content. When both Salvia extract (10 mg/kg) and glibenclamide (1 mg/kg) were administered concurrently to STZ‐diabetic rats, a significant decrease in glycaemic level (>40%) and mortality index was achieved.
The analgesic‐antiinflammatory extract from Araujia sericifera lacks ulcerogenic activity on stress‐gastric damage model
Authors: Bello R. , Martínez‐Cuesta M. A. , Moreno L. , Esplugues J. , Primo‐Yúfera E.
Published: October 2006

The present study evaluates the ulcerogenic activity of the hexane extract from dry fruits of Araujia sericifera in an experimental model of cold‐restraint stress. Treatment of rats with 200 mg/kg (i.p.) of hexane extract did not affect the gastric lesions induced by cold‐restraint stress. However, it was confirmed that a dose of 300 mg/kg (i.p.) of acetylsalicylic acid (ASA) which induced a similar analgesic‐antiinflammatory effect, increased significantly the level of gastric damage. Thus, the hexane extract from the fruits of A. sericifera seems to possess analgesic‐antiinflammatory properties which are not linked to gastrolesive effects.
Synergistic effects of inchin‐ko‐to (Yin‐Chen‐Hao‐Tang) and ursodeoxycholic acid on cholestasis caused by α‐naphthyl isothiocyanate
Authors: Nomura Masaaki , Hida Tatsuhito , Miyamoto Ken‐Ichi , Ohshima Taeyuki , Hayashi Hisao , Sawanishi Hiroyuki
Published: October 2006

The effects of the combination of Inchin‐ko‐to, a kampo formulation, and ursodeoxycholic acid on experimental cholestasis were investigated. When administered intraduodenally at noneffective doses of these drugs to rats with intrahepatic cholestasis caused by α‐naphthyl isothiocyanate, the bile flow returned to a near‐normal level and the serum bile acid profile was improved. Among the major components of the kampo formula, Artemisiae capillaris Flos contributed to the change in the bile flow, and Gardeniae Fructus contributed to the improved serum bile acid profile, because ursodeoxycholic acid increased and cholic acid decreased. The results show that urosdeoxycholic acid and Inchin‐ko‐to synergistically improved experimental cholestasis and that this effect occurred because of different functions of the components of Inchin‐ko‐to.
Antiulcer activity of Tinospora cordifolia Miers and Centella asiatica linn extracts
Authors: Sarma D. N. K. , Khosa R. L. , Chansauria J. P. N. , Sahai M.
Published: October 2006

The ethanol extracts of the roots of T. cordifolia Miers and C. asiatica Linn were observed to induce a marked protective action against an 8 h restraint stress induced ulcerization, the activity being comparable to that of diazepam.
Comparative hepatoprotective activity of three Phyllanthus species, P. urinaria, P. niruri and P. simplex, on carbon tetrachloride induced liver injury in the rat
Authors: Prakash A. , Satyan K. S. , Wahi S. P. , Singh R. P.
Published: October 2006

The effect of alcohol extracts of three Phyllanthus species was compared on carbon tetrachloride‐induced (chronic) hepatic damage in rats. Alcohol extracts of P. niruri, P. urinaria and P. simplex were administered orally at three different doses. Statistically significant reversal of the elevated serum levels of transaminases (GOT and GPT) were used as the biochemical indices for hepatoprotection. The results of the study indicated that only the extracts of P. niruri and P. urinaria afforded protection of liver in the chronic model. The hepatoprotective activity of P. urinaria is about 60% in comparison with P. niruri. Therefore, P. urinaria may be considered as a good substitute for P. niruri in cases of liver disorders in actual practice.
On a Fragment Approach to Structure‐activity Correlations
Authors: Randić Milan , Jurs Peter C.
Published: October 2006

In searching for better structure‐activity correlations frequently one considers various fragments as the underlying key elements for improving the correlation. We address here the search for useful fragments and discuss some criteria for their selection. The approach, which is essentially a graph theoretical one, is based on characterization of fragments by suitably weighted paths. As an illustration we re‐examined the correlation between the antiviral activity of a series of alkyl substituted benzimidazoles and their structures represented by connectivity indices. Fragment path numbers provide an alternative representation which allows additional discussion and additional conclusions concerning QSAR applications.
Hydrogen Bonding 12. A New QSAR for Upper Respiratory Tract Irritation by Airborne Chemicals in Mice
Authors: Abraham Michael H. , Whiting Gary S. , Alarie Yves , Morris Jeffrey J. , Taylor Peter J. , Doherty Ruth M. , Taft Robert W. , Nielsen Gunnar D.
Published: October 2006

Upper respiratory tract irritation of male Swiss OF1 mice by airborne chemicals is well correlated by the following equations for the toxicity of nonreactive compounds, magnified image FRD′50 is the concentration in mol 1−1 of the airborne chemical required to elicit a 50% decrease in respiratory rate, and the explanatory variables are δ2 a polarisability correction term, π the solute dipolarity, α the solute hydrogen‐bond acidity, Vx the characteristic volume, and L16 the gas/hexadecane partition coefficient. These equations considerably resemble corresponding equations for gas/liquid partition coefficients into organic bases such as tricresylphosphate, but do not resemble an equation for gas/water partition coefficients.
The QSAR Application of a New Steric Parameter Set for Aromatic Substituents Defined by the Acidic Hydrolysis Rate of Ortho‐substituted Benzamides
Authors: Sotomatsu Tomoko , Fujita Toshio
Published: October 2006

We examined applications of a new steric parameter set for aromatic substituents, Es(AMD), recently defined by the rate constants for acidic hydrolysis of ortho‐substituted benzamides, to the QSAR study of biologically active compounds. The scale of the Es(AMD) constant was put as close as possible to that of the Taft‐Kutter‐Hansch (TKH) Es parameter. For alkyl and halogen substituents, the Es(AMD) value was very close to the TKH Es value, but not for methoxy, isopropoxy, and such planar π‐bonded substituents as NO2 and Ph. Agrochemical and medicinal activities of various series of aromatic compounds taken from our earlier studies and the literature were analyzed quantitatively in terms of steric, electronic, and hydrophobic parameters, and the correlation equations formulated with Es(AMD) and Es for the steric effect of substituents, mostly those at ortho positions to the functional group, were compared. For several series of compounds, the Es(AMD) value gave better results than the TKH Es.
Quantitative Structure‐Property Relationships for the Polarizability, Solvatochromic Parameters and Lipophilicity
Authors: Schüürmann Gerrit
Published: October 2006

The polarizability αvol, the solvatochromic parameters π* and β and the lipophilicity as expressed by log Kow are subjected to regression analyses using calculated molecular parameters within the MNDO scheme. The resulting linear one‐ and more‐variable regression equations enable rapid approximate calculations for αvol, π* and β and log Kow of untested compounds; in particular, αvol is split into a molecular size and an electronic part which offers new possibilities for applications in quantitative structure‐activity relationships.
An Application of Unsupervised Neural Network Methodology Kohonen Topology‐Preserving Mapping to QSAR Analysis
Authors: Rose Valerie S. , Croall Ian F. , Macfie Halliday J. H.
Published: October 2006

The concept and methodology of artificial neural networks is introduced. Like pattern recognition, the techniques can be classified as supervised (requiring a priori knowledge of class membership) and unsupervised (making no assumptions about class membership). An unsupervised neural network method, Kohonen Topology‐Preserving Mapping, is applied to a wide matrix of physicochemical property data for a set of antifilarial antimycin analogues containing structural outliers. Principal component analysis failed to give a good 2D representation of the data set as a whole due to linear constraints in the model which gave undue influence to the outliers. Kohonen mapping compared favourably with non‐linear unsupervised statistical pattern recognition methods for 2D representation of compound similarity and for classification based on antifilarial activity. It may prove a valuable technique for QSAR in situations where a linear method does not model the data well and a high throughput of test compounds is indicated.
MULTICASE 1. A Hierarchical Computer Automated Structure Evaluation Program
Authors: Klopman Gilles
Published: October 2006

A new algorithm is presented to analyze the structural features relevant to the biological activity of a set of molecules. The program called MULTICASE can, as its predecessor CASE (Computed Automated Structure Evaluator), automatically identify molecular sub‐structures that have a high probability of being relevant or responsible for the observed biological activity of a learning set comprised of a mix of active and inactive molecules of diverse composition. New, untested molecules can then be submitted to the program, and an expert prediction of the potential activity of the new molecule is obtained. MULTICASE differs from CASE in a great many ways, but the major algorithmic difference is the use of Hierarchy in the selection of descriptors, leading to the concept of Biophores and Modulators.
β‐Adrenoceptor Ligands: Characterization and Quantification of Drug Effects
Authors: Lemoine Horst
Published: October 2006

Several methods based on receptor theory are introduced which are useful to characterize βAR in functional and biochemical experiments. βAR subtypes, β1AR and β2AR, which coexist in most organs of mammals including man, can be characterized in intact tissues analyzing the concentration‐dependent blockade of agonist‐induced effects by subtype‐selective antagonists. Non‐linear regression analyses allow the estimation of dissociation constants for antagonists and of fractional stimuli of agonists from which functional subtype‐selectivities can be deduced. A comparison of dissociation constants assessed by functional methods and by radioligand binding revealed an affinity loss of β1AR‐selective antagonists in plasmalemmal membranes. The analysis of binding of β2AR‐selective agonists, which are used for pharmacotherapy of bronchial asthma, in the absence and presence of GTP revealed characteristic differences in affinity for high and low affinity states of β2AR which correlate to different IA of agonists in stimulation of adenylate cyclase and of smooth muscle relaxation. A new agonist‐radioligand, 3H‐formoterol, is introduced which allows the measurement of binding kinetics. The slow dissociation of 3H‐formoterol may underlie the long‐lasting action of formoterol as assessed in its therapeutical use.
Comparison of Electrotopological State Indexes with Molecular Orbital Parameters: Inhibition of MAO by Hydrazides
Authors: Hall Lowell H. , Mohney Brian K. , Kier Lemont B.
Published: October 2006

QSAR models for inhibition of monoamine oxidase (MAO) by aryloxyacetohydrazide derivatives were developed for a series of MO parameters computed with the AM1 Hamiltonian. These models were compared to those based on the recently developed electrotopological state index for. skeletal atoms. The structure interpretation is the same for both types of models: the NH group adjacent to the carbonyl group together with the carbon atom, gamma to the NH group, in the hydrocarbon substituent, account for more than 90% of the computed activity. However, the model based on E‐state indexes (r2 = 0.9012) is significantly superior to the one based on MO parameters (r2 = 0.7985); the standard deviation for the MO based model (s = 0.27) is 50% larger than that from the E‐state based model (r = 0.19). Several points of comparison between the models are presented. This study supports the idea that the electrotopological state is a useful representation of molecular structure information.
On Identifying Likely Determinants of Biological Activity in High Dimensional QSAR Problems
Authors: McFarland James W. , Gans Daniel J.
Published: October 2006

A new approach to identifying descriptors associated with biological activity in ‘asymmetric’ data sets has been developed for high dimensional QSAR problems. As an example we have applied this approach to a problem first described by Selwood et al. [3]. Using Cluster Significance Analysis (CSA) in an explicit predetermined sequence of steps, we identified six likely determinants of antifilarial activity among antimycin analogs characterized by 53 descriptors. These determinants were ATCH5, ATCH2, VDWVOL, S8_1DX, ATCH4 and DIPV_X. Of them, only ATCH5, ATCH4 and DIPV_X were significant (R = 0.83) in a stepwise multiple regression analysis (MRA). These results are compared with those of the original workers and others who analyzed the data by different methods. By combining these descriptors with those identified by the other groups, we discovered a still better correlation. Jointly, ATCH5, ATCH4, DIPV_X, LOGP and MOFI_Y correlate highly with antifilarial potency (R = 0.91). The problem of discovering the ‘true’ determinants of biological activity in high dimensional asymmetric data sets is discussed.
Modelling the Toxicity of Organophosphates: a Comparison of the Multiple Linear Regression and PLS Regression Methods
Authors: Verhaar Henk J. M. , Eriksson Lennart , Sjöström Michael , Schüürmann Gerrit , Seinen Willem , Hermens Joop L. M.
Published: October 2006

A set of nine biological endpoints, comprising data for bioconcentration, biotransformation, AChE inhibition and acute aquatic toxicity, for a set of twelve organophosphorothionates was modelled using a set of ten non‐empirical, mainly quantum‐chemical, descriptors, employing two different techniques, viz. Multiple Linear Regression and Partial Least Squares projection to latent variables regression.

For these compounds and biological endpoints, PLS models are not only quantitatively better than MLR models, as judged by model fit (r2) and ‘predictivity’ (PRESS/SSY), but it is also shown that there exist ways of mechanistically interpreting the results of the PLS models. These interpretations can be used to come to a better understanding of the processes involved in organophosphorothionate toxicity and to generate even better, more mechanistically based models. This finding clearly refutes the commonly held belief that PLS models are inherently more difficult to interpret than comparable MLR models.
Theoretical Study on the Metabolism of Caffeine by Cytochrome P‐450 1A2 and its Inhibition
Authors: Sanz Ferran , López‐de‐Briñas Elena , Rodríguez Jesüs , Manaut Francesc
Published: October 2006

The primary metabolism of caffeine (1,3,7‐trimethylxanthine) is catalyzed by the isozyme P‐450 1A2 which has toxicological relevance because it is involved in the activation of some chemicals to carcinogenic compounds. A theoretical model for the demethylation of caffeine is proposed by means of the study of the molecular electrostatic potential (MEP) distributions of caffeine and other xanthine derivatives that are inhibitors of this metabolic process. Negative zones of these distributions show a common triangular pattern in the xanthine plane. The model proposes that the alignment of the caffeine molecule in the active site is determined by these negative MEP zones. An interesting finding was that all the methyl groups to be removed have at least a MEP minimum at a distance of approximately 3 Å. This feature would explain the preference for the N3 demethylation leading to paraxanthine (1,7‐dimethylxanthine) because only this methyl group is placed at a distance of 3 Å from the deepest MEP minimum. Another experimental observation consistent with the proposed model is the inhibition of caffeine demethylation by several 8‐methylxanthines. Among them, 1,3,8‐trimethylxanthine, furafylline (1,8‐dimethyl‐3‐(2‐furfuryl)xanthine) and 1,8‐dimethyl‐3‐phenylxanthine were considered in the present study. The inhibition is explained by the fact that all these compounds have a methyl on C8 placed at a distance of 3 Å from the deepest MEP minimum.
Variable Selection in QSAR Studies. I. An Evolutionary Algorithm
Authors: Kubiny Hxugo
Published: October 2006

In QSAR studies of large data sets, variable selection and model building is a difficult, time‐consuming and ambiguous procedure. While most often stepwise regression procedures are applied for this purpose, other strategies, like neural networks, cluster significance analysis or genetic algorithms have been used. A simple and efficient evolutionary strategy, including iterative mutation and selection, but avoiding crossover of regression models, is described in this work. The MUSEUM (Mutation and Selection Uncover Models) algorithm starts from a model containing any number of randomly chosen variables. Random mutation, first by addition or elimination of only one or very few variables, afterwards by simultaneous random additions, eliminations and/or exchanges of several variables at a time, leads to new models which are evaluated by an appropriate fitness function. In contrast to common genetic algorithm procedures, only the “fittest” model is stored and used for further mutation and selection, leading to better and better models. In the last steps of mutation, all variables inside the model are eliminated and all variables outside the model are added, one by one, to control whether this systematic strategy detects any mutation which still improves the model. After every generation of a better model, a new random mutation procedure starts from this model. In the very last step, variables not significant at the 95% level are eliminated, starting with the least significant variable. In this manner, “stable” models are produced, containing only significant variables. A comparison of the results for the Selwood data set (n = 31 compounds, k = 53 variables) with those obtained by other groups shows that more relevant models are derived by the evolutionary approach than by other methods.
Molecular Similarity Determination of Heteroaromatics Using CoMFA and Multivariate Data Analysis
Authors: Langer Thierry
Published: October 2006

The molecular similarity concept serves as a tool for rationalizing the design of potential bioactive molecules. This report examines a way to determine molecular similarity among heteroaromatic moieties by calculating new QSAR descriptors using the CoMFA approach. The descriptors for heteroaromatic substituents in organic molecules derived in this study permit to take into account differences in anchoring positions of such substructures in a given molecule. The aromatic moieties 1‐37 have been characterized by their interaction energies calculated using the CoMFA method. Principal component analysis of the interaction energy matrices was performed in order to derive new ‘principal properties’ of the heteroaromatics. A partitioning of the heteroaromatic substituents into families has been done both by hierarchical clustering of the obtained principal components and by applying a factorial design method. These procedures allow a classification of structures according to their molecular similarity.
Description of the Reversed‐Phase High‐Performance Liquid Chromatography (RP‐HPLC) Capacity Factors and Octanol‐Water Partition Coefficients of 2‐Pyrazine and 2‐Pyridine Analogues Directly from the Three‐Dimensional Structures Using Comparative Molecular Field Analysis (CoMFA) Approach
Authors: Kim Ki Hwan
Published: October 2006

Excellent correlations were obtained between the logarithm of capacity factors (log k′) previously measured from the reverse‐phase high‐performance liquid chromatography (RP‐HPLC) and the octanol‐water partition coefficients (log P) of 2‐substituted pyrazine and 2‐substituted pyridine derivatives and the descriptors obtained directly from the three‐dimensional structures using comparative molecular field analysis (CoMFA) approach. The results presented in this study illustrate the applicability of CoMFA in calculating log k′ and log P values directly from the three‐dimensional structures of the molecules.
Quantitative Structure‐Activity Relationships for Antimicrobial Nitroheterocyclic Drugs
Authors: Rozenski Jef , De Ranter Camiel J. , Verplanken Hilda
Published: October 2006

The antimicrobial activity of a series of nitro‐heterocyclic drugs was determined and correlated with a number of physicochemical properties. The best correlation is found with the polarographic half‐wave potential, while the partition coefficient and LUMO‐values contribute poorly to the relationship. The value of the dipole moments can be used to discriminate between active 2‐nitro and 5‐nitroimidazoles and inactive 4‐nitroimidazoles. Free‐Wilson analysis emphasizes the need of structural parameters like the presence of the nitro group in position 2 or 5 or a methyl substituent on the imidazole ring. The activity is enhanced by a vinyl group in position 2 and is decreased by the presence of a phenyl substituent.
Physicochemical Significance of Topological Parameters: Molecular Connectivity Index and Information Content: Part 2. Correlation Studies With Molar Refractivity and Lipophylicity
Authors: Saxena Anil K.
Published: October 2006

The studies on physicochemical significance of molecular connectivity index (1χ, 2χv) have shown that connectivity indices correlate to a greater extent with MR than with hydrophobicity (π). In order to verify these results, a set of 183 compounds of different chemical classes viz. alcohols, amines, esters, hydrocarbons, ethers, carboxylic acids etc. was chosen. In the earlier studies on this set of compounds, molecular connectivity (1χ) had been found to correlate with Log P. The correlation of valence molecular connectivity (1χ) with MR and Log P has been studied where MR showed better correlation with 2χv than Log P. The comparative correlation studies of 1χ with Log P and MR has also been carried out where 1χ shows better correlation with MR than with Log P for the total set of 183 compounds.
QSAR in Toxicology. 3. Prediction of Chronic Toxicities
Authors: Cronin Mark T. D. , Dearden John C.
Published: October 2006

A critical review is given of quantitative and qualitative structure‐activity relationships (QSAR) for the prediction of some chronic toxicological endpoints required for regulatory purposes. Many methodological approaches have been applied to the prediction of carcinogenicity and mutagenicity based on either identification of the molecular substructures that account for electrophilic reactivity or quantitative description of the hydrophobicity and reactivity of the molecule. A recent blind trial, however, found the opinion of human experts still to be most successful. Analyses of the interrelationship between carcinogenicity and mutagenicity data are also discussed.

Relatively little work has been performed in the QSAR analysis of developmental toxicity. This whole area is hindered by a lack of quality in vivo toxicity data to model, and by the mechanisms of action not being fully understood.
A Fast Algorithm For Selecting Sets Of Dissimilar Molecules From Large Chemical Databases
Authors: Holliday John D. , Ranade Sonia S. , Willett Peter
Published: October 2006

Current algorithms for the selection of a set of n dissimilar molecules from a dataset of N molecules have an expected time complexity of O(n2N). This paper describes an improved algorithm that has an expected time complexity of O(nN) and that will identify exactly the same set of molecules as the normal algorithm if the cosine coefficient is used for the calculation of the inter‐molecular (dis)similarities. The algorithm is applicable to any type of representation that characterises a molecule by a set of attribute values and to any procedure that involves calculating a sum of inter‐molecular similarities. It is also both more effective and more efficient than our implementation of a genetic algorithm for the selection of maximally‐dissimilar sets of molecules.