bluuebunny/crossref_metadata_2025_split huggingface dataset:
In-vitro activity and tissue distribution of new fluorinated meso-tetrahydroxyphenylporphyrin photosensitizers
Authors: Songca Sandile P 
Published: July 2003

Abstract
Tetra(hydroxyphenyl)porphyrins started to attract interest as potential photosensitizers for photodynamic therapy in the early eighties. Subsequently, a number of derivatives of these compounds have been studied. In 1997 we reported the synthesis of the fluorinated derivatives 5,10,15,20-tetrakis(2-fluoro-3-hydroxyphenyl)porphyrin (8), 5,10,15,20-tetrakis(2,4-difluoro-3-hydroxyphenyl)porphyrin (9), and 5,10,15,20-tetrakis(3,5-difluoro-4-hydroxyphenyl)porphyrin (10). We have measured their biological activity, using the MTT test, against cancer cell cultures in-vitro. The test showed that these compounds were as potent as 5,10,15,20-tetrakis(3-hydroxyphenyl)chlorin (5), one of the leading photosensitizers in photodynamic therapy. The highest photoactivity was shown by the meta-hydroxy compounds 8 and 9. The para-compound showed high toxicity in the dark. Distribution of these compounds between normal and cancer tissue was studied using 19F NMR spectroscopy. The highest cancer tissue localization was also shown by the meta-hydroxy compounds 8 and 9. The para compound showed poor localization in tumour tissue. This study has shown that 19F NMR spectroscopy can be used to estimate the tissue distribution of fluorinated tetrahydroxyphenylporphyrins in-vivo.
Effects of cholesterol and model transmembrane proteins on drug partitioning into lipid bilayers as analysed by immobilized-liposome chromatography
Authors: Lagerquist Caroline , Beigi Farideh , Karlén Anders , Lennernäs Hans , Lundahl Per 
Published: July 2003

Abstract
We have analysed how cholesterol and transmembrane proteins in phospholipid bilayers modulate drug partitioning into the bilayers. For this purpose we determined the chromatographic retention of drugs on liposomes or proteoliposomes entrapped in gel beads. The drug retention per phospholipid amount (the capacity factor Ks) reflects the drug partitioning. Cholesterol in the bilayers decreased the Ks value and hence the partitioning into the membrane in proportion to the cholesterol fraction. On average this cholesterol effect decreased with increasing temperature. Model transmembrane proteins, the glucose transporter GLUT1 and bacteriorhodopsin, interacted electrostatically with charged drugs to increase or decrease the drug partitioning into the bilayers. Bacteriorhodopsin proteoliposomes containing cholesterol combined the effects of the protein and the cholesterol and approached the partitioning properties of red blood cell membranes. For positively charged drugs the correlation between calculated intestinal permeability and log Ks was fair for both liposomes and bacteriorhodopsin-cholesterol proteoliposomes. Detailed modeling of solute partitioning into biological membranes may require an extensive knowledge of their structures.
Synthesis and in-vitro/in-vivo evaluation of orally administered entacapone prodrugs
Authors: Leppänen Jukka , Savolainen Jouko , Nevalainen Tapio , Forsberg Markus , Huuskonen Juhani , Taipale Hannu , Gynther Jukka , Männistö Pekka T , Järvinen Tomi 
Published: July 2003

Abstract
Entacapone is a new inhibitor of catechol-O-methyltransferase (COMT) that is used as an adjunct to l-dopa therapy in the treatment of Parkinson's disease. The bioavailability of orally administered entacapone is, however, relatively low (29–46%). In this study we have prepared more lipophilic acyl and acyloxyacyl esters, an acyloxy alkyl ether and an alkyloxycarbonyl ester of entacapone, and we have evaluated them as potential prodrugs to enhance the oral bioavailability of entacapone. All the derivatives fulfilled prodrug criteria and released entacapone in human serum in-vitro. The oral bioavailability of monopivaloyl (1a) and dipivaloyl (1b) esters of entacapone were investigated further in rats. The lipophilicity of 1b was high (log Papp 4.0 at pH 7.4) but its oral bioavailability was low (F = 0.6%), most probably due to its low aqueous solubility. The monopivaloyl ester of entacapone (1a) had a higher lipophilicity (log Papp 0.80) than entacapone (log Papp 0.18) at pH 7.4 while maintaining an aqueous solubility equal to entacapone. However, oral bioavailability was not increased when compared with the parent drug entacapone (F = 7.0% and 10.4%, respectively).
Comparison of vaginal aminopeptidase enzymatic activities in various animals and in humans
Authors: Acartürk Füsun , Parlatan Zehra I , Saracoĝlu Ömer F 
Published: July 2003

Abstract
The specific enzymatic activity of four different aminopeptidases (aminopeptidase N, leucine aminopeptidase, aminopeptidase A and aminopeptidase B) in vaginal homogenates from rabbit, rat, guinea-pig, sheep and humans was compared. The purpose of the study was to find an appropriate animal model that can be used in degradation studies of protein and peptide drugs. Different substrates were used as the relative specific substrates for the determination of aminopeptidase enzymatic activity: 4-methoxy-2-naphthylamide of l-alanine for amino-peptidase N, 4-methoxy-2-naphthylamide of l-leucine for leucine aminopeptidase, 4-methoxy-2-naphthylamide of l-glutamic acid for aminopeptidase A and 4-methoxy-2-naphthylamide of l-arginine for aminopeptidase B. The vaginal aminopeptidase enzymatic activity of different species was determined spectrofluorometrically. The inhibition of aminopeptidase activity in the presence of bestatin and puromycin inhibitors was also investigated. The results showed the presence of aminopeptidase enzymatic activity in all vaginal homogenates in the order: sheep &gt; guinea-pig &gt; rabbit ≥ human ≥ rat. Based on the results of the hydrolysis and inhibition of the 4-methoxy-2-naphthylamide substrates, it was difficult to have an exact decision on the aminopeptidase type in the vaginal homogenates from the species studied. It was found that the aminopeptidase activity in rat, rabbit and humans was not statistically different. Therefore, we suggest that rats and rabbits could be used as model animals for vaginal enzymatic activity studies and for determination of the degradation of protein and peptide drugs in the vagina.
Design, synthesis and biological testing of a novel series of anti-inflammatory drugs
Authors: Duffy Judith C , Dearden John C , Rostron Chris 
Published: July 2003

AbstractMany of the non-steroidal anti-inflammatory drugs (NSAIDs) currently marketed produce severe gastro-toxic side effects. The benefits of producing NSAIDs without these side effects are obvious, particularly for patients requiring long-term therapy. The aim of this investigation was to produce novel NSAIDs, based on paracetamol, that exhibit little or no gastro-toxicity. The work covers design, synthesis and testing of 13 drug candidates. The analgesic and anti-inflammatory potencies of the drug candidates were measured using the mouse abdominal constriction assay and the carrageenan-induced rat paw oedema assay, respectively. The stomachs of the rats were examined post-mortem, to assess the gastro-toxicity of the drugs. Of the 13 compounds described herein, 11 were shown to possess analgesic activity at 2–10 times the potency of aspirin, while 8 demonstrated anti-inflammatory activity at 3–10 times the potency of aspirin. Significantly, all of the compounds showed very low gastro-toxicity when compared with aspirin. The results of this study indicate that it is possible to develop novel, potent NSAIDs based on the structure of paracetamol. These compounds have the advantage of demonstrating much lower gastro-toxicity than NSAIDs currently available. Drugs of this type may, in future, provide effective treatments for inflammatory disorders.
Ethnopharmacology of the Popoluca, Mexico: an evaluation
Authors: Leonti Marco , Vibrans Heike , Sticher Otto , Heinrich Michael 
Published: July 2003

Abstract
Medicinal plants are an essential part of indigenous pharmaceutical systems. We studied the medicinal plants used by the Popoluca of the Sierra Santa Marta (Eastern Mexico). This study is part of a series on the ethnopharmacology of various Macro-Mayan groups. During 16 months of ethnobotanical fieldwork, 614 taxa used medicinally and 4488 individual use-reports were documented. The data are analysed using the concept of the “healers' consensus” in order to identify culturally important medicinal plants. The medicinal uses of the plants were grouped into 13 illness categories. The responses for each species were summarized for each of the categories and were ordered by frequency of mention. The most frequently recorded medicinal plants of the Popoluca are Hamelia patens, used to stop bleeding from wounds, and Byrsonima crassifolia, used against diarrhoea. The high-ranked medicinal species were assessed pharmacognostically using published phytochemical and pharmacological data. Popoluca medicinal uses were fairly consistent with published data on active ingredients for those plants for which such data exist. However, data is still lacking for many other species. Toxicological studies are particularly scarce. This study will be used as a basis for subsequent studies on the pharmacology and phytochemistry of medicinal plant species.
Effects of the Class III antiarrhythmic agent dofetilide (UK-68,798) on L-type calcium current from rabbit ventricular myocytes
Authors: Paul A A , Leishman D J , Witchel H J , Hancox J C 
Published: July 2003

Abstract
The methanesulphonanilide agent dofetilide (UK-68,798) exerts Class III antiarrhythmic effects by inhibiting the cardiac rapid delayed rectifier potassium current (IKr) encoded by HERG. The aim of the present study was to determine whether dofetilide also exhibits Class IV (L-type calcium-channel blocking) effects. L-type calcium current (ICa,L) was measured from rabbit isolated ventricular myocytes, using the whole-cell patch-clamp technique under selective recording conditions. Positive control experiments demonstrated inhibition of ICa,L elicited by pulses to + 10 mV by both nifedipine and externally applied Ni2+ ions. Three concentrations of dofetilide were tested: 100 nm, 1 μm and 10 μm. ICa,L magnitude was not significantly reduced by any of the concentrations tested (P&gt;0.05; n = minimum of seven cells per drug concentration). The inactivation time-course of ICa,L was also unaffected by 10 μm dofetilide. Heterologously expressed HERG current (IHERG) recorded from Chinese Hamster Ovary cells was extensively inhibited by 100 nm and 1 μm dofetilide, with inhibition at 1 μm not significantly different from 100% (P&gt; 0.1). It is concluded that dofetilide produced no ICa,L blocking effects at concentrations up to and exceeding that required for maximal IHERG inhibition. The findings support the notion that dofetilide is a highly selective Class III antiarrhythmic agent, devoid of Class IV antiarrhythmic activity.
Cyclooxygenase-1 and cyclooxygenase-2 selectivity of non-steroidal anti-inflammatory drugs: investigation using human peripheral monocytes
Authors: Kato Miyako , Nishida Shinichi , Kitasato Hidero , Sakata Natsue , Kawai Shinichi 
Published: July 2003

Abstract
Since the pharmacological profiles of various non-steroidal anti-inflammatory drugs (NSAIDs) might depend on their differing selectivity for cyclooxygenase 1 (COX-1) and 2 (COX-2), we developed a new screening method using human peripheral monocytes. Monocytes from healthy volunteers were separated, and the cells were incubated with or without lipopoly-saccharide (LPS). Monocytes without LPS stimulation exclusively expressed COX-1 on Western blotting analysis, whereas LPS stimulation induced COX-2 expression. Unstimulated monocytes (COX-1) and LPS-stimulated monocytes (COX-2) were then used to determine the COX selectivity of various NSAIDs. The respective mean IC50 values for COX-1 and COX-2 IC50 (μm), and the COX-1/COX-2 ratio of each NSAID were as follows: celecoxib, 82, 6.8, 12; diclofenac, 0.076, 0.026, 2.9; etodolac, &gt; 100, 53, &gt; 1.9; ibuprofen, 12, 80, 0.15; indometacin, 0.0090, 0.31, 0.029; meloxicam, 37, 6.1, 6.1; 6-MNA (the active metabolite of nabumetone), 149, 230, 0.65; NS-398, 125, 5.6, 22; piroxicam, 47,25, 1.9; rofecoxib, &gt; 100,25, &gt; 4.0; S-2474, &gt; 100,8.9, &gt; 11; SC-560, 0.0048, 1.4, 0.0034. The percentage inhibition of COX-1 activity at the IC50 of COX-2 also showed a wide variation among these NSAIDs. The bioassay system using human monocytes to assess the inhibitory effects of various NSAIDs on COX-1 and COX-2 may become a clinically useful screening method.
Relationship between gamma-hydroxybutyrate plasma concentrations and its electroencephalographic effects in the rat
Authors: Van Sassenbroeck Diederik K , De Paepe Peter , Belpaire Frans M , Rosseel Marie-Thérèse , Martens Patrick , Boon Paul A , Buylaert Walter A 
Published: July 2003

Abstract
In view of the potential interest in an objective parameter for the depth of coma in intoxications with the recreational drug gamma-hydroxybutyrate (GHB), we have studied the relationship between the plasma concentrations and the electroencephalographic (EEG) changes induced by GHB in the rat. Fifteen rats randomly received either 150 (n = 3), 200 (n = 6) or 300 mg kg−1 (n = 6) GHB over 5 min, followed by a supramaximal dose of 450 mg kg−1 over 5 min at the end of the experiment. Plasma concentrations were determined with HPLC. The EEG was continuously recorded and the amplitude in the 15.5–30 Hz frequency band was quantified using aperiodic analysis. The plasma concentration-time profiles were fitted to a two-compartment model with Michaelis-Menten elimination. The pharmacokinetic parameters Vmax, Km and the apparent volume of distribution (Vd) proved to be independent of the dose and the mean pooled values were Vmax 2068 ± 140 μg mL−1 kg−1, Km 58 ± 16 μg mL−1 and Vd 476 ± 12 mL kg−1. The EEG amplitude in the 15.5–30 Hz frequency band displayed a monophasic inhibition and the effect-plasma concentration curve showed hysteresis. This hysteresis between EEG effect and plasma concentrations was minimized by simultaneous calculation of hypothetical effect-site concentrations and fitting the effect vs effect-site concentration curve to a sigmoid inhibitory Emax model. The descriptors of this Emax model (Emax, EC50, ke,0, γ and E0) were independent of the dose with an equilibration half-life t½ke,0 of 5.6 ± 0.3 min (mean value of the pooled results of the 5-min treatment groups). To investigate the origin of this hysteresis, a dose of 600 mg kg−1 GHB was infused over either 45 or 60 min each in three animals. The hysteresis was much less pronounced with 45 min than with 5 min and was absent with 60-min infusions. This indicated that the hysteresis was due to a distribution delay between the central compartment and the effect site. This study showed that the concentration-effect relationship of GHB could be characterized in individual rats using aperiodic analysis in the 15.5–30 Hz frequency band.
Enhancement of salivary secretion and neuropeptide (substance P, α-calcitonin gene-related peptide) levels in saliva by chronic anethole trithione treatment
Authors: Nagano Toshiaki , Takeyama Masaharu 
Published: July 2003

Abstract
Anethole trithione, a choleretic, has been reported to be effective in the treatment of dry mouth. We have examined the effects of chronic treatment with anethole trithione on salivary secretion, substance P immunoreactive substance (SP-IS) and α-calcitonin gene-related peptide immunoreactive substance (α-CGRP-IS) concentrations in human saliva. Anethole trithione caused significant increases of saliva SP-IS concentrations from the day 13 (25.3 ± 1.6 pg mL−1) to day 14 (25.8 ± 1.7 pg mL−1) compared with day 1 (19.9 ± 1.9 pg mL−1). Anethole trithione caused significant increase in saliva α-CGRP-IS concentration on day 14 (39.9 ± 4.7 pg mL−1) compared with day 1 (27.7 ± 4.7 pg mL−1). Anethole trithione significantly increased the sialosis volumes from day 11 to day 14 (1.6 ± 0.1–1.7 ± 0.2 mL) compared with the day 1 (1.2 ± 0.2 mL). Simple linear regression of the increase in sialosis volume with saliva SP-IS (r = 0.94) and α-CGRP-IS (r = 0.97) concentrations was found. These results demonstrated that chronic treatment with anethole trithione affected saliva SP-IS and α-CGRP-IS concentration in human saliva and sialosis volume.
Mechanism of AVP release and synthesis in chronic salt-loaded rats
Authors: Morita Masahiko , Kita Yasuhiro , Notsu Yoshitada 
Published: July 2003

Abstract
Arginine vasopressin (AVP) is involved in osmotic regulation in the brain and peripheral tissues. To elucidate the regulatory mechanism that involves AVP release in hyperosmolality, we investigated the regulation of the synthesis and release of AVP in chronic salt-loaded rats. In chronic salt-loaded rats, which were generated by free access to water containing 2% NaCl for 7 days, plasma osmolality was significantly increased compared with control value. When tested, the AVP content was significantly higher in plasma but lower in the pituitary and whole brain (hypothalamus, cortex and striatum) than in control rats. The expression of AVP mRNA in the brain was significantly up-regulated compared with that in control rats. These data lead to the suggestion that hyperosmolality stimulates AVP release from the brain and subsequently induces AVP synthesis in the brain. On the other hand, mRNA levels of vasopressin V1a receptor (V1aR), whose down-regulation is known to be a counteraction to the V1aR activation, was not changed in the brain, suggesting that the AVP seems not to interact with the V1aR in the brain. These results suggest that hyperosmosis promotes the release of AVP into plasma, the subsequent induction of AVP mRNA in the brain and its action on the peripheral tissues.
Anti-inflammatory effects of 5-aminosalicylic acid conjugates with chenodeoxycholic acid and ursodeoxycholic acid on carrageenan-induced colitis in guinea-pigs
Authors: Goto Michitaka , Okamoto Yasuhiro , Yamamoto Magobei , Aki Hatsumi 
Published: July 2003

Abstract
Two epimeric bile acid conjugates, 5-aminosalicylic acid-chenodeoxycholic acid (5-ASA-CDCA) and 5-aminosalicylic acid-ursodeoxycholic acid (5-ASA-UDCA), were synthesized to deliver 5-ASA to the large intestine by oral administration. The movement of the conjugates down the gastrointestinal tract and the anti-inflammatory effects on ulcerative colitis were investigated by administering the conjugates to guinea-pigs with an inflammatory bowel disease induced by 2% degraded carrageenan solution. The conjugates were protected from deconjugation in stomach and small intestine and reached the caecum and the colon, where 5-ASA was more easily liberated from 5-ASA-CDCA than from 5-ASA-UDCA. The conjugates at doses equivalent to 50 or 150 mg kg−1 5-ASA were orally administered once a day for 4 weeks from the 15th day after starting carrageenan treatment. The body weights and the bleeding scores of occult blood in faeces were measured during the experiment. The number of ulcers in the caecum and the colon were counted after killing the guinea-pigs at the end of the experiment. Rapid onset of efficacy was shown by a significant reduction in bleeding scores within a week after administration of the conjugates. Treatment with the lower dose of 5-ASA-CDCA showed a recovery of body weight and a significantly decreased number of ulcers in the caecum, and the ulcers in the colon had completely disappeared by the end of the experiment. There was a good correlation found between the number of ulcers in the caecum and the bleeding scores of occult blood in faeces. The findings indicate that both conjugates were sufficiently delivered to the large intestine without deconjugation and that the lower dose of 5-ASA-CDCA is enough for treatment of ulcerative colitis in colonic inflammatory bowel diseases.
In-vitro and in-vivo evaluation of a matrix-controlled bromocriptine mesilate-releasing vaginal ring
Authors: Acartürk Füsun , Altug Nesrin 
Published: July 2003

Abstract
The aim of this study was to evaluate the in-vitro release rates and in-vivo effectiveness of a controlled release, intravaginal dosage form of bromocriptine mesilate. The dimeticone (poly(dimethylsiloxane)) elastomer vaginal ring contained 3 mg bromocriptine mesilate and low molecular weight gelatin in a ratio of 1:3, and 10% propylene glycol. The daily release rate of the drug was designed to be 10% of the total administered dose and was confirmed with release experiments under sink conditions. The effect of the vaginal ring preparation on plasma prolactin level in the rabbit was investigated over a 10-day period. The results showed that the vaginal ring of bromocriptine mesilate significantly decreased the plasma prolactin level of the test group (P &lt; 0.001–0.05) compared with the control and placebo groups. It was concluded that bromocriptine mesilate was effectively absorbed from rabbit vagina and that this controlled release intravaginal ring preparation of bromocriptine mesilate was effective in decreasing the plasma prolactin level in rabbits for ten days.
Identification of bacterial genes required for in-vivo survival
Authors: Tang C M , Bakshi S , Sun Y-H 
Published: July 2003

Abstract
Genetic approaches used for in-vivo studies of bacterial pathogenesis are providing insights into how bacteria disrupt host defences and exploit host molecules for their own advantage. Signature tagged mutagenesis (STM) provides a means of identifying the genes involved in the process of infection, particularly those genes that are important for bacterial proliferation in-vivo. In this review, the application of STM to the understanding of bacterial pathogenesis and findings from work on three human pathogens, Salmonella typhimurium, Mycobacterium tuberculosis and Neisseria meningitidis, are discussed. The next challenge is to understand how these and other genes influence the infective process at the molecular and cellular levels and to design novel interventions to block the progression of disease.
Investigation of the penetration behaviour of mycophenolate mofetil from a semisolid formulation into human skin ex-vivo
Authors: Jahn Konstanze , Fischer Anja , Neubert Reinhard H H , Wohlrab Johannes 
Published: July 2003

Abstract
Mycophenolate mofetil, the morpholinoethylester of mycophenolic acid, is an immuno-suppressant used in combination with ciclosporin (cyclosporin) and corticosteroids to prevent organ rejection after heart and kidney transplantations. The drug seems also to be effective in dermal diseases after systemic administration. However, up to date mycophenolate mofetil can be only systemically administered and this is associated with several side effects such as nausea, leucopenia, sepsis, and diarrhoea. The aim of this study was to develop a topical formulation containing mycophenolate mofetil and to investigate in-vitro release and penetration into human skin ex-vivo. HPLC was applied to quantify mycophenolate mofetil after release studies from semisolid formulations using a dodecanol-collodion membrane as a lipophilic acceptor. Penetration studies with an amphiphilic cream using excised human breast skin were carried out in Franz-type diffusion cells. Mycophenolate mofetil and its active metabolite mycophenolic acid were detected by HPLC-MS after microsectioning in different skin layers. In this study the penetration of mycophenolate mofetil from an amphiphilic cream into excised human skin was shown. Additionally, the enzymatic hydrolysis of penetrated mycophenolate mofetil into mycophenolic acid was proven even under ex-vivo conditions. In-vivo a higher extent of metabolism ofmycophenolate mofetil to mycophenolic acid would be expected because of the complete enzyme activity. This topical formulation might be a promising alternative to the usual systemic administration of mycophenolate mofetil in the treatment of skin diseases such as psoriasis.