bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacological and Pharmacokinetic Evaluation of EXP3312, an Orally-active Non-peptide Angiotensin II-Receptor Antagonist
Authors: Wong Y Nancy , Wong Pancras C 
Published: April 2011

Abstract
EXP3312, 2-n-propyl-4-chloro-l-[(2′-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]imidazole-5-carboxylaldehyde, is a non-peptide angiotensin II (AII) AT1-receptor antagonist.
In the rabbit isolated aorta EXP3312 inhibited the contractile response to AII competitively with a pA2 value of 8.24. In renal hypertensive rats EXP3312 reduced blood pressure with intravenous and oral ED30 values of 0.19 and 0.14 mg kg−1, respectively. It also reduced blood pressure in frusemide-treated dogs when administered orally at 1 and 3 mg kg−1. In rats and dogs, the absolute oral bioavailability of EXP3312 averaged 60 and 28%, respectively. When EXP3312 was administered intravenously to rats and dogs the plasma elimination half-lives were 1.20 and 2.52 h, respectively. In rats and dogs EXP3312 was metabolized to an active metabolite M1, 2-n-propyl-4-chloro-1-[(2′-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]imidazole-5-carboxylic acid. M1 is about ten times more potent than EXP3312 in renal hypertensive rats; the intravenous ED30 value was 0.02 mg kg−1. Because high plasma levels of M1 were found in rats after oral administration of EXP3312, it is likely that M1 contributes to the long duration of the antihypertensive effects of EXP3312 in renal hypertensive rats.
The results show that EXP3312 is a potent, orally active, competitive and selective AT1-receptor antagonist and a potent antihypertensive agent; it is likely to be therapeutically useful in the treatment of hypertension and congestive heart failure.
Detection of Platinum in the Brain of Mice Treated with Cisplatin and Subjected to Short-term Hypoxia
Authors: Minami T , Ichii M , Okazaki Y 
Published: April 2011

Abstract
Cisplatin is widely used for cancer treatment but has strong side-effects, including nephrotoxicity. Neurotoxicity has been thought to be limited to peripheral damage because the blood-brain barrier is thought to be impervious to hydrophilic substances such as cisplatin. Because anoxic ischaemia has been associated with lesions of the barrier, inductively coupled plasma mass spectrometry has been used to monitor the accumulation of platinum in the brains of mice treated with cisplatin and exposed to oxygen-deficient atmospheres.
Platinum was detected in the cerebral cortex of mice 24 h after the administration of cisplatin (3 mg kg−1) followed by exposure for 60 s to an atmosphere containing 7% oxygen, but not in the cerebral cortex of mice exposed to normal atmospheres. Platinum was also observed in the cerebral cortex after exposure for 120 s to an atmosphere containing 14% oxygen, and platinum levels increased as the concentration of oxygen was reduced. The highest platinum levels were obtained 10 h after administration of cisplatin and exposure for 120 s to an atmosphere containing 7% oxygen. Platinum was still retained in the cerebral cortex one week after administration. In contrast, platinum levels in the blood and kidney decreased with time. Platinum levels were measured in seven regions of the brain: the right and left cerebral cortices, the basal ganglia, the thalamus and hypothalamus, the bulbus olfactorius, the cerebellum, and the mesencephalon. When cisplatin was administered to mice not subjected to hypoxia, platinum was not detected in the right and left cerebral cortices, basal ganglia or the thalamus and hypothalamus, but was detected in the bulbus olfactorius, cerebellum and mesencephalon. When such mice were exposed to low levels of oxygen, however, platinum was detected in the right and left cerebral cortices, the basal ganglia and the thalamus and hypothalamus. Platinum levels in the cerebellum and mesencephalon of mice exposed to low levels of oxygen were higher than those of mice exposed to normal air. In addition, platinum levels in the bulbus olfactorius were significantly higher than those in the other regions, although the platinum content of the bulbus olfactorius was not affected by hypoxia.
From these observations, it is concluded that platinum is easily accumulated in the bulbus olfactorius after the administration of cisplatin, and that after exposure to atmospheres containing low levels of oxygen, platinum easily passes through the blood-brain barrier and accumulates in all parts of the brain.
Xanthone Derivatives as Potential Anti-cancer Drugs
Authors: Lin Chun-Nan , Liou Shiou-Jyh , Lee Tai-Hua , Chuang Yin-Ching , Won Shen-Jeu 
Published: April 2011

Abstract
Xanthone derivatives have been shown to be potent inhibitors of tumour growth. Oxygenated xanthones and [3-(dialkylamino)-2-hydroxypropoxy]xanthones have been prepared and tested for in-vitro inhibition of human PLC/PRF/5, KB and 212 cells.
Structure-activity analysis indicated epoxidation of the hydroxyxanthone increased cytotoxicity against tumour cells but ring-opening of the epoxide group with dialkylamine did not enhance the anti-tumour activity. Further evaluation of three of the most active compounds 2, 6-, 3, 6-, and 3, 5-di(2,3-epoxypropoxy)xanthone (compounds 10a, 11a, and 12a, respectively) in DNA, RNA and protein synthesis of tumour cells showed potent inhibitory activity. The 3,5-di(2,3-epoxypropoxy)xanthone also showed potent inhibitory activity against 212 cells, a Ha-ras oncogene-transformed NIH 3T3 cell line.
The results indicated that compounds 10a and 12a are potent anti-tumour agents which not only suppressed cellular DNA, RNA and protein synthesis but also specifically inhibited the Ha-ras oncogene in 212 cells.
In-vivo Distribution and Erythrocyte Binding Characteristics of Cyclosporin in Renal Transplant Patients
Authors: Kurokawa N , Kadobayashi M , Yamamoto K , Arakawa Y , Sawada M , Takahara S , Okuyama A , Yanaihara C 
Published: April 2011

Abstract
The pharmacokinetic parameters of cyclosporin, a potent immunosuppressive agent, show large intra-and inter-individual variability, possibly because of the different analytical methods used. A recently developed cyclosporin-specific radioimmunoassay has been used to study the in-vivo distribution and binding characteristics of cyclosporin in whole blood, plasma and erythrocytes of fifteen renal transplant patients.
The profiles of cyclosporin concentration-time curves after an oral dose of cyclosporin had either one peak (ten patients, group A) or two (five patients, group B). Essentially no difference was observed between the two groups in the relationship between equilibrium cyclosporin concentrations in erythrocyte and plasma as a function of whole-blood concentration. The equilibrium in-vivo cyclosporin concentrations in erythrocytes and plasma were, however, markedly lower than those previously observed under in-vitro conditions. The ratio of cyclosporin concentration in erythrocytes (CE) to that in plasma (CP) changed with time, in inverse proportion to the change in cyclosporin concentration in blood, over the range 0.63-2.80 in individual patients with an average of 1.36 ± 007 (mean ± s.e.m.) for group A and 1.42 ± 0.23 for group B. The apparent cyclosporin binding affinity (Kd) to erythrocytes under in-vivo conditions averaged 452.2 ± 47.6 nm (543.5 ± 57.2 ng mL−1) for group A and 419.4 ± 41.2 nm (504.1 ± 49.5 ng mL−1) for group B, whereas apparent cyclosporin binding capacity (Bmax) of the blood cell averaged 0.83 ± 0.07 nmol mL−1 for group A and 0.78 ± 0.07 nmol mL−1 for group B. Significantly reduced average Kd (262.7 ± 40.2 nm or 315.8 ± 48.9 ng mL−1, P &lt; 001) and Bmax (0.56 ± 008 nmol mL−1, P &lt; 005) values were observed during the period after Tmax (4–12 h after the drug ingestion) in group A patients. Apparent Kd and Bmax, determined by a nonlinear regression technique, were 131.6 ± 29.4 and 1088.0 ± 114.7 nm (158.2 ± 35.4 and 1307.8 ± 137.9 ng mL−1) and 0.178 ± 0.024 and 0.814 ± 0.078 nmol mL−1, respectively, during the 4–12 h period in group A patients.
These findings reveal distinct differences in in-vivo distribution of cyclosporin and the binding characteristics of the compound to erythrocytes from those previously observed under in-vitro conditions. The significantly lower Kd of cyclosporin binding to erythrocytes during the elimination phase suggests a potential effect of cyclosporin-containing erythrocytes or of cyclosporin contained in erythrocytes during cyclosporin treatment.
Neuropharmacological Effects of Extracts from Sickingia williamsii
Authors: Capasso A , Aquino R , De Simone F , Sorrentino L 
Published: April 2011

Abstract
Sickingia williamsii Standl. (Rubiaceae) is used in Peruvian folk medicine for its analgesic and anti-inflammatory activity. In this study we have examined the pharmacological profiles of petroleum ether, chloroform, chloroform-methanol (9:1) and methanol extracts of the tree.
Both chloroform-methanol (250, 500 or 750 mg kg−1, p.o.) and methanol (125, 250 or 500 mg kg−1, p.o.) extracts significantly reduced both the locomotor activity and motor co-ordination of mice; they also prolonged sleep induced by pentobarbital, although no significant cataleptic response was observed. These extracts did not have a significant impact on the nociceptive threshold in the hot-plate and tail-flick tests. Petroleum ether and chloroform extracts did not, furthermore, induce any significant pharmacological effects.
The results of the study suggest that these extracts possess neurosedative-like properties.
(±)-Govadine and (±)-THP, Two Tetrahydroprotoberberine Alkaloids, as Selective α1-Adrenoceptor Antagonists in Vascular Smooth Muscle Cells
Authors: Ko Feng-Nien , Chang Ya-Ling , Chen Chi-Ming , Teng Che-Ming 
Published: April 2011

Abstract
(±)-Govadine and (±)-THP ((±)-2,3,10,11-tetrahydroxytetrahydroprotoberberine HBr) have been shown to inhibit noradrenaline-induced contraction of rat thoracic aortae. The pharmacological activity of the compounds was determined in thoracic aortae and cardiac tissue isolated from the rat and in trachea isolated from the guinea-pig to determine the selectivity of the compounds towards different types of receptor.
(±)-Govadine and (±)-THP were found to be α1-adrenoceptor blocking agents in rat thoracic aorta as revealed by their competitive antagonism of vasoconstriction induced by noradrenaline (pA2 = 6.57 ± 0.07 and 5.93 ± 0.06, respectively) or phenylephrine (pA2 = 6.74 ± 0.08 and 6.06 ± 0.10, respectively). Removal of endothelium did not affect the antagonistic potencies of (±)-govadine (pA2 = 6.83 ± 0.09) and (±)-THP (pA2 = 6.25 ± 0.06) on phenylephrine-induced vasoconstriction. They were more potent than yohimbine (pA2 = 6.05 ± 0.05), but less so than phentolamine (pA2 = 7.54 ± 0.11) and prazosin (pA2 = 9.27 ± 0.12). (±)-Govadine and (±)-THP, furthermore, inhibited [3H]inositol monophosphate formation caused by noradrenaline (3 μm) in rat thoracic aorta. (±)-Govadine and (±)-THP were also α2-adrenoceptor blocking agents with pA2 values 5.50 ± 0.13 and 5.41 ± 0.11, respectively. A high concentration of (±)-govadine (30 μm) or (±)-THP (30 μm) did not, however, affect the contraction induced by the thromboxane receptor agonist U46619, prostaglandin F2α (PGF2α), 5-hydroxytryptamine (5-HT), angiotensin II, endothelin or high K+ in rat aorta denuded of endothelium. Neither the cyclic AMP nor cyclic GMP content of rat thoracic aorta was, furthermore, changed by (±)-govadine or (±)-THP. Contraction of guinea-pig trachea caused by carbachol, histamine, leukotriene C4 or neurokinin A was not affected by (±)-govadine or (±)-THP. (±)-Govadine or (±)-THP also did not block β1- or β2-adrenoceptor-mediated responses induced by isoprenaline in rat right atria and guinea-pig trachea.
It is concluded that (±)-govadine and (±)-THP are selective α1-adrenoceptor antagonists in vascular smooth muscle.
Synthesis and Physicochemical Properties of the Furan Dicarboxylic Acid, 3-Carboxy-4-methyl-5-propyl-2-furanpropanoic Acid, an Inhibitor of Plasma Protein Binding in Uraemia
Authors: Costigan M G , Gilchrist T L , Lindup W E 
Published: April 2011

Abstract
The furan dicarboxylic acid, 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (5-propyl FPA) accumulates in the plasma of patients with chronic renal failure and is a major contributor to the drug binding defect of uraemic plasma. This acid has also been implicated in several other aspects of the uraemic syndrome: anaemia, irregularities of thyroid function, neurological symptoms and inhibition of active tubular secretion.
The acid is not commercially available and its synthesis, starting with Meldrum's acid and methyl succinyl chloride, is described. The pKa values were measured by titration and values of 3.2 and 3.6 respectively were assigned to the carboxylic acid groups attached directly to the ring at position 3 and at position 2 (on the side-chain). The partition coefficient (log P) between hydrochloric acid and octanol was 1.2 and the distribution coefficient (log D; octanol-phosphate buffer pH 7.4) was −0.59.
The pKa values and the degree of hydrophobic character of 5-propyl FPA are consistent with those of other protein-bound acids which undergo active tubular secretion by the kidney and this substance may serve as an endogenous marker for the effects of drugs and disease on this process.
The Influence of 2-Hydroxypropyl-β-cyclodextrin on the Haemolysis Induced by Bile Acids
Authors: Panini R , Vandelli M A , Leo E , Salvioli G , Cameroni R 
Published: April 2011

Abstract
Cyclodextrins improve the water-solubility of drugs and can mask their haemolytic effect in parenteral use. Because the mechanism by which bile acids induce haemolysis is poorly understood, it has been investigated in the presence of 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD).
The haemolytic effect of 1.8 mm solutions of cholic acid, chenodeoxycholic acid (CDCA), deoxycholic acid and ursodeoxycholic acid (UDCA) in isotonic buffer at pH 7.4 was investigated at 37°C in the presence of HP-β-CyD at concentrations from 0.18 to 32 mm. No haemolytic effect was evident for cholic acid and UDCA. The haemolytic effect of the other bile acids was reduced by addition of HP-β-CyD and was prevented at a molar ratio of 1:1 owing to complex formation. An HP-β-CyD:bile acid molar ratio greater than 5:1 had a different effect on the erythrocyte membrane, irrespective of the identity of the bile acid; the effect was in accordance with the complexion affinities.
In the absence of HP-β-CyD, the haemolytic effect of CDCA and deoxycholic acid appeared related to their capacity to form a surface monolayer and to solubilize the components of the erythrocyte membrane. The haemolytic effect observed after complexation of the bile acids appeared to be solely the effect of HP-β-CyD, which was able to form a reversible inclusion complex with lipophilic components of the erythrocyte membranes at concentrations higher than 12 mm.
The Measurement of Caffeine Concentration in Scalp Hair as an Indicator of Liver Function
Authors: Mizuno Atsuhiro , Uematsu Toshihiko , Gotoh Seiichi , Katoh Eiichi , Nakashima Mitsuyoshi 
Published: April 2011

Abstract
Caffeine concentration in plasma and scalp hair has been determined for subjects consuming normal daily amounts of caffeine and the results used as an indicator of individual hepatic metabolic capacity. Daily exposure to caffeine was assessed in six healthy Japanese volunteers by direct HPLC measurement of the concentrations of caffeine in aliquots of all caffeine-containing beverages consumed by the subjects. The measurements were repeated on three different occasions for each subject and caffeine consumption (mean ± s.d.) was calculated as 178.0 ± 84.3 mg day−1 with an intra-individual variability of 23.8 ± 6.3% as coefficient of variation. A survey of daily caffeine consumption in 121 adult Japanese by means of a questionnaire revealed a similar value (231.8 ± 177.8 mg day−1). Caffeine concentration in the plasma sampled during an overnight caffeine-free interval was measured by HPLC and a comparison made between healthy subjects and patients with liver disease (0.71 ± 0.32, 0.77 ± 0.45 and 3.92 ± 1.91 μg mL−1 for healthy volunteers (n = 6), patients with hepatitis (n = 11) and those with liver cirrhosis (n = 4), respectively). Strands of scalp hair were collected from six healthy subjects and six patients with liver cirrhosis. Caffeine in hair was identified and measured by gas chromatography-mass spectrometry after digestion of the hair matrix with protease and extraction of the caffeine with chloroform. Caffeine concentration in hair collected from patients with liver cirrhosis (26.5 ± 5.04 ng mg−1 hair) was significantly higher than that in hair sampled from healthy subjects (7.21 ± 3.11 ng mg−1).
These findings suggest that the determination of caffeine concentration in the plasma and hair of subjects consuming normal daily amounts of caffeine-containing beverages provides a practical assessment of individual liver metabolic capacity.
Effects of Penetration Enhancers on the In-vitro Percutaneous Absorption of Progesterone
Authors: Valenta Claudia , Wedenig Sabine 
Published: April 2011

Abstract
Because progesterone seems suitable for treatment of premenstrual syndrome, the influence of penetration enhancers such as propylene glycol, urea and laurocapram (Azone) on the percutaneous absorption of progesterone from carbopol hydroalcoholic gels and from poly(ethylene glycol) ointments has been investigated.
Skin experiments were performed using excized abdominal rat and porcine skin. Addition of 10% laurocapram was found to be the most efficient enhancer for progesterone from carbopol hydroalcoholic gels, for both rat and porcine skin; the next most efficient enhancer was urea in poly(ethylene glycol) bases. This enhanced the diffusion rates 2.5 fold, compared with pure poly(ethylene glycol) alone.
The results show that hydroalcoholic gels and poly(ethylene glycol) ointments are both suitable vehicles for progesterone and that premenstrual syndrome might be treated effectively by use of hydroalcoholic gels containing 10% laurocapram.
Enhanced Anticancer Therapy Mediated by Specialized Liposomes
Authors: Dass Crispin R , Walker Todd L , Burton M A , Decruz Exmond E 
Published: April 2011

Abstract
It has been a central aim of experimental and clinical therapeutics to deliver therapeutic agents as close as possible to, or if possible within, a diseased cell. Such targeting achieves two major aims of drug delivery, the maximum dose of therapeutic agent to the diseased cell and avoidance of uptake by and, usually, accompanying side-effects to normal, healthy cells.
Conventional liposomes, originally used for studies in membrane biophysics and biochemistry, have been used in therapy for the past two decades. However, when applied to deliver drugs into cells, conventional liposomes proved inefficient and so novel unconventional or specialized liposomes are constantly being prepared to enhance cell-specific delivery in-vivo. One possible way of achieving better targeting is combination of the positive attributes of more than one specialized type of liposome into one vesicle. Although a limited number of studies has examined the combined effect of such dual-speciality liposomes, more studies are warranted using appropriate models.
Liposomes are composed of one, a few, or many concentric bilayer membranes which alternate with aqueous spaces. The drugs are encapsulated within the aqueous internal volume if they are hydrophilic or in the lipid bilayers if they are hydrophobic (Kim 1993). Liposomes range in size from 25 nm to more than 20 μm (Sugarman & Perez-Soler 1992). Depending on their solubility and method of formulation antimicrobial, cytotoxic and other conventional drugs, hormones, antigens, enzymes, genetic material, viruses and bacteria can be incorporated in either the aqueous or hydrophobic phase.
This review discusses the types and characteristics of non-conventional liposomes used in various modes of cancer therapy, mainly chemotherapy and gene therapy. It concludes with suggestions on improving these novel liposomal to effect better targeting to cancer cells.
Regional Differences in Calcium Sensitivity in the Guinea-pig Intestine
Authors: Okamoto Hiroki , Inoue Kimihiro , Kamisaki Toshiaki , Takahashi Kazuyoshi , Sato Makoto 
Published: April 2011

Abstract
The effect of the Ca2+-channel antagonist nicardipine on the basal tone of six segments (duodenum, jejunum, ileum, proximal colon, distal colon and rectum) of the guinea-pig intestine has been investigated in muscle preparations.
Nicardipine reduced the basal tone of the proximal and distal colon but not of the duodenum, jejunum, ileum and rectum. Similarly, when each segment was incubated in Ca2+-free medium, the basal tone of the proximal and distal colon, but not that of the other four segments, was reduced. The reduced basal tone recovered after cumulative addition of Ca2+ in both colon preparations. The basal tone of the distal colon was partly reduced by tetrodotoxin, atropine and clonidine. Conversely, l-typeCa2+-channel antagonists (Cd2+, verapamil and nicardipine), but not the T-type Ca2+-channel antagonist Ni2+, completely reduced the basal tone of the distal colon.
These results indicate that in the regulation of basal tone there are additional regional differences in the effect of Ca2+ influx into the cells from the extracellular fluid which might involve l-type-like Ca2+ channels and might partly be because of neuronal factors.
The Effect on Plasma Glucose, Insulin and Glucagon Levels of Treatment of Diabetic Rats with the Medicinal Plant Rhazya stricta and with Glibenclamide, Alone and in Combination
Authors: Ali B H 
Published: April 2011

Abstract
Because many diabetic patients in the United Arab Emirates use medicinal plants as a supplement to treatment with insulin or oral hypoglycaemic agents, the effect on plasma glucose, insulin and glucagon concentrations of simultaneous treatment of streptozotocin-diabetic rats with Rhazya stricta extract and glibenclamide has been examined.
Treatment of control rats with the extract at oral doses of 0.5, 20 and 4.0 g kg− did not significantly affect the concentration of glucose, insulin or glucagon for up to 4 h after administration of the extract. The same doses in diabetic rats reduced the glucose level 1 h (2 and 4 gkg−) and 2h (4 gkg−) after administration of the extract. This was accompanied by significant increases in insulin concentration 1, 2 and 4 h after administration of the extract at doses of 2 and 4 gkg−. Glibenclamide (2.5, 5.0 and 10.0 mgkg−) dose-dependently reduced glucose and glucagon levels, and increased that of insulin in normal and diabetic rats. Simultaneous treatment of normal and diabetic rats with the plant extract (0.5, 20 and 5.0 gkg−) and glibenclamide (5.0 mg kg−) significantly exacerbated the effects on glucose, insulin and glucagon induced by the extract or by glibenclamide when given separately. When the plant extract was given at doses of 0.5, 2 and 4 g kg− per day for 6 consecutive days the glucose level was reduced by approximately 6, 8 and 30%, respectively. No significant effect was seen on the levels of cholesterol or protein.
These results imply that co-administration of the extract with glibenclamide might adversely interfere with glycaemic control in diabetic patients.