bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics and Pharmacodynamics of Azosemide after Intravenous and Oral Administration to Rats with Alloxan-induced Diabetes Mellitus
Authors: Park Kwang J , Yoon Woo H , Shin Wan G , Lee Myung G
Published: April 2011

Because physiological changes occurring in diabetes mellitus patients could alter the pharmacokinetics and pharmacodynamics of the drugs used to treat the disease, the pharmacokinetics and pharmacodynamics of azosemide were investigated after intravenous and oral administration of the drug (10 mg kg−1) to control and alloxan-induced diabetes mellitus rats (AIDRs).

After intravenous administration of azosemide to the AIDRs, the area under the plasma concentration-time curve (AUC) increased considerably (3120 compared with 2520 μg min mL−1; P < 0.135) and the total body clearance decreased considerably (3.20 compared with 3.96 mL min−1 kg−1; P < 0.0593). The considerable reduction in time-averaged total body clearance in the AIDRs was a result of the significant decrease in renal clearance (1.01 compared with 1.55 mL min−1 kg−1) in the AIDRs, the non-renal clearance being comparable between the two groups of rats. After intravenous administration, the 8-h urinary excretion of azosemide (29.5 compared with 40% of intravenous dose; P < 0.0883) and one of its metabolites, M1 (2.15 compared with 2.60% of intravenous dose, expressed in terms of azosemide; P < 0.05) decreased in the AIDRs because of the impaired kidney function. The diuretic, natriuretic, kaliuretic and chloruretic efficiencies increased significantly in the AIDRs. After oral administration of azosemide, AUC decreased significantly in the AIDRs (115 compared with 215 μg min mL−1) possibly because of the reduced gastrointestinal absorption of azosemide in the AIDRs. After oral administration of azosemide, the 8-h urine output decreased significantly in the AIDRs (9.32 compared with 16.1 mL per 100 g body weight) because of the significantly reduced 8-h urinary excretion of azosemide (3.00 compared with 9.14% of oral dose).

After both intravenous and oral administration some pharmacokinetic and pharmacodynamic parameters of azosemide were significantly different in AIDRs.
Toxicological Effects of Teucrium stocksianum after Acute and Chronic Administration in Rats
Authors: Tanira M O M , Wasfi I A , Homsi M Al , Bashir A K
Published: April 2011

Because of the widespread use of T. stocksianum (Boiss) in herbal medicine and reports of the toxicity of Teucrium chamaedrys to man, the effects of acute (2 and 4 g kg−1, single dose) and chronic (4% in lieu of drinking water for 48 days) administration of an aqueous extract of T. stocksianum has been studied in rats.

After acute administration no change was found in reduced liver glutathione content, plasma total protein concentration or the enzyme activities of aminotransferase or gamma glutamyl transferase. After chronic administration, no change was noticed in the plasma concentrations of total protein, total bilirubin, creatinine, urea, glucose, triglycerides, calcium or phosphorus or the enzyme activities of aminotransferase, alanine aminotransferase, creatinine kinase, gamma glutamyl transferase or lactate dehydrogenase. There was no change in food or water intake or output of urine or faeces; the body weight of the treated animals was, however, slightly reduced. No change was observed in the weight of vital body tissues. Histological examination revealed occasional hepatic ‘apoptosis’ and cerebral neuronal loss in the cortex and hippocampus in treated animals; focal loss of Purkinje cells in the cerebellum was particularly noticed.

The results did not indicate a major hepatotoxic effect of acute or chronic administration of T. stocksianum, unlike other Teucrium spp. We report a neurotoxic effect, however, which warrants monitoring of neurological function in people taking this plant.
Sucrose Laurate Gels as a Percutaneous Delivery System for Oestradiol in Rabbits
Authors: Vermeire An , De Muynck Christian , Vandenbossche Geert , Eechaute Willy , Geerts Marie-Louise , Remon Jean Paul
Published: April 2011

In this study sucrose laurate was formulated in hydrogels and investigated as a suitable transdermal penetration enhancer for oestradiol. Using rabbits as an animal model, the absolute bioavailability and the skin irritation were evaluated after single and multiple application. Three hydrogels containing 60 mg% oestradiol were evaluated: Oestrogel, and two hypromellose gels containing 5 and 15% sucrose laurate (w/w), respectively.

No stability problem of the sucrose laurate was detected during a storage period of four months at 7 ± 2°C. After single application no significant difference (P < 005) was observed between the bioavailability parameters of Oestrogel and the 5% sucrose laurate gel. The values obtained for the 15% sucrose laurate gel were significantly higher than for the other gels. When applied on day 7 after a 6-day treatment, twice daily with the respective placebo gel, no significant difference was seen amongst the three formulations for any of the parameters evaluated. When the results after multiple application were compared with those after single application, a significant increase in oestradiol bioavailability was seen for the gel containing 30% ethanol and a significant decrease in oestradiol bioavailability was seen for the 5 and 15% sucrose laurate gels. Histological evaluation of the untreated and treated skin biopsies, showed a significantly higher incidence of infiltrate for all treated skin biopsies in comparison with the untreated ones. A significant increase in skinfold thickness was seen for the skin biopsies treated with gel containing 15% sucrose laurate.

It can be concluded that sucrose laurate shows a potential as an absorption enhancer for percutaneous drug delivery.
Differential Binding of Warfarin to Maternal, Foetal and Non-pregnant Sera and its Clinical Implications
Authors: Bajoria Rekha , Sooranna Suren R , Contractor Soli F
Published: April 2011

The object of this study was to determine whether differential binding of sodium warfarin in paired maternal and cord sera accounts for its adverse effects on the foetus.

In-vitro binding of sodium warfarin to human serum albumin in maternal, foetal, and non-pregnant (control) subjects was determined by equilibrium dialysis at 37°C. Our data suggest that at therapeutic concentrations, sodium warfarin has a single high affinity binding site on human serum albumin with an association constant of 1–65 × 10-3 M. Serum albumin concentration in the control sera (4.42 ± 0.08 g dL−1) was comparable with that in the cord sera (4.54 ± 0.26 g dL−1) but was significantly higher (P < 0.01) than the maternal levels (4.03 ± 0.21 g dL−1). Binding data indicate that the fraction of unbound warfarin in the foetal sera (6.8 ± 1.9 g dL−1) was significantly higher than in the maternal (3.60 ± 1.3 g dL−1; P < 0.01) and non-pregnant sera (1.96 ± 0.6 g dL−1; P < 0.001). The maternal and foetal fractions of free warfarin were directly proportional to the concentrations of free fatty acids (y = 1268 − 110 x; r = 0.93; P < 0.001), and bilirubin (y = 8.7 + 1.4x; r = 0.91; P < 0.001), respectively.

This study indicates that warfarin was more strongly bound in the maternal sera than in the foetal sera; this was probably because of the competitive and allosteric effect of free fatty acid and bilirubin in the maternal and foetal sera, respectively. The clinical significance of this observation is discussed in this paper.
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

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

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

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

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 < 001) and Bmax (0.56 ± 008 nmol mL−1, P < 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

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

(±)-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

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

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

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

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

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

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

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.
Effects of Two N-arylpiperazinylmethylpyrazolo [1,5-d][1,2,4]triazine Derivatives in Pain and Antidepressant Tests in Mice
Authors: Rubat C , Coudert P , Mavel S , Fialip J , Couquelet J
Published: April 2011

The antinociceptive and antidepressant effects of two pyrazolotriazine derivatives, 2-phenyl-3,3α-dihydro-4-oxo-5-(4-phenylpiperazin-1-yl)methyl-pyrazolo[1,5-d][1,2,4]-triazine (SMI) and 2-phenyl-3,3α-dihydro-4-oxo-5-[4-(4-fluorophenyl)piperazin-1-yl]methylpyrazolo[1,5-d][1,2,4] triazine (SM3) have been investigated in mice using classical pharmacological tests.

The intraperitoneal LD50 values of SMI and SM3 were 253.4 and 218.8 mg kg− respectively. SMI and SM3 showed analgesic properties in the phenylbenzoquinone-induced abdominal constriction test (ED50 ≅ 10–15 mgkg−, i.p.) and in the hot-plate test. The antinociceptive effects of the triazines were significantly reduced by administration of naloxone (1 and 3.2 mgkg−, s.c.) and yohimbine (1 mgkg−, p.o.). Acute intraperitoneal administration of both compounds (1 mgkg− SMI or 1.5 mgkg− SM3) potentiated morphine (0.15 mgkg−, s.c.) analgesia in the phenylbenzoquinone test. Although this synergistic activity was not reversed by methysergide (0.5 mgkg−, i.p.), the analgesic activity of both compounds was enhanced by administration of 5-hydroxytryptophan (50 mgkg−, i.p.) in conjunction with carbidopa (25 mgkg−, i.p.). Furthermore, neither compound (at 100 mgkg−, i.p.) significantly reduced the duration of immobility of mice in the forced swimming test, and both (at 75 mgkg−, i.p.) were ineffective at enhancing the toxic effects of yohimbine (30 mgkg−, s.c). Only SM3 (ED50 = 74.5 mgkg−, i.p.) significantly antagonized reserpine (2.5 mgkg−, i.p.)-induced ptosis.

Thus, the results suggest that SMI and SM3 have antinociceptive properties related to co-involvement of opioidergic and α2-adrenoceptor mechanisms without associated antidepressant properties.
Interaction between Pefloxacin and Aminophylline in Genetically Epilepsy-prone Rats
Authors: Imperatore C , Trimarchi G R , De Sarro A
Published: April 2011

The effects of a chronic treatment with pefloxacin on aminophylline-induced seizures in genetically epilepsyprone rat have been investigated. Two series of experiments were performed. In the first, animals received pefloxacin orally twice a day for five days, then were administered aminophylline intraperitoneally and the occurrence of seizures was evaluated. In the second series of experiments, theophylline serum concentration was evaluated in rats subject to the same experimental protocol.

Pefloxacin significantly, and in a dose-dependent manner, increased the occurrence of seizure phases induced by aminophylline, but did not influence theophylline serum levels measured at different times after the injection of aminophylline.

We suggest that additive neurotoxic effects of both pefloxacin and aminophylline might contribute to the increased severity of seizure score. The possible role of GABA-benzodiazepine, excitatory amino acid and purinergic mechanism, and the role of pharmacokinetic factors are discussed.
Beneficial Effects of Clonidine in Streptozotocin-induced Diabetes and DOCA-hypertensive Rats
Authors: Satia Milan C , Damani Rushabh R , Goyal Ramesh K
Published: April 2011

This investigation was undertaken to study the effects of chronic treatment with clonidine on cardiovascular complications in streptozotocin-induced diabetes and DOCA-hypertensive rats.

Injection of streptozotocin induced glucosuria, hyperglycaemia, hypoinsulinaemia, hypothyroidism, hypercholesterolaemia, hypertriglyceridaemia, bradycardia and a decrease in left ventricular developed pressure (LVDP). DOCA by itself did not induce any change in blood-glucose levels in non-diabetic animals. However, in diabetic animals DOCA significantly reduced blood-glucose levels. Treatment of diabetic and diabetic hypertensive animals with clonidine (25 μg kg− every day for six weeks) significantly prevented diabetes-induced loss of body weight, bradycardia, cardiac hypertrophy and hypothyroidism. It also partially, but significantly, prevented diabetes-induced hyperglycaemia and hypoinsulinaemia in both diabetic and diabetic-hypertensive animals. There was a significant reduction in diabetes-induced elevation of cholesterol and triglyceride levels and an improvement in LVDP at higher filling pressure in diabetic and diabetic hypertensive animals.

This investigation shows that chronic treatment with clonidine produces a number of beneficial effects such as prevention of hyperlipidaemia and hypothyroidism and improvement in cardiomyopathy and glycaemic control in diabetic and diabetic hypertensive rats.
Assessment of the Antitussive Efficacy of Codeine in Cough Associated with Common Cold
Authors: Freestone C , Eccles R
Published: April 2011

Codeine is generally accepted as the standard antitussive against which new antitussive medications are compared. This presents a problem because the support for codeine's antitussive activity comes from studies on cough in animals, and chronic and induced cough models in man, whereas antitussives are almost exclusively used for the treatment of cough associated with acute upper respiratory tract infection (URTI). The aims of this study were twofold. Firstly, to study the antitussive efficacy of codeine in cough associated with URTI and, secondly, to validate a sound meter as tool for quantifying cough.

The efficacy of codeine was assessed in a double-blind, stratified, placebo-controlled, parallel-group, clinical trial using three different measures of cough: cough sound-pressure levels (CSPLs) measured on a sound meter; subjective scores of cough severity; and cough frequency recorded by means of a microphone connected to an ink-pen recorder. A group of 82 subjects (51 females and 31 males; mean age 23.5 years, range 18–46 years) with cough owing to acute URTI were included in the study. The study took place on two separate study days. On study day 1 cough measurements were made before and 90 min after treatment with a single dose of either 50 mg codeine or matched placebo in capsule form. The same three measures of cough were repeated 2–5 days later (study day 2). On study day 1 a highly significant (P < 0.0001) decrease in all three measures of cough was found after treatment with both placebo and codeine yet there was no significant difference between the treatment groups. A highly significant (P < 0·0001) decrease in the three measures of cough was also found between days 1 and 2.

The results demonstrate that codeine is no more effective than placebo in reducing cough associated with acute URTI, as measured by CSPLs, cough frequency or subjective symptom scores. This result might be explained on the basis of two central pathways for cough; a reflex pathway via the brain-stem which is sensitive to codeine and a voluntary pathway via the cortex which is unaffected by codeine. The results also demonstrate that the sound-level meter appears to be a potentially useful investigative tool for the assessment of cough and antitussive efficacy.
Bioadhesive Microspheres for Ophthalmic Administration of Acyclovir
Authors: Genta I , Conti B , Perugini P , Pavanetto F , Spadaro A , Puglisi G
Published: April 2011

The bioavailability of acyclovir to the ophthalmic epithelium is low and when the drug is administered in ophthalmic ointment it must be applied every four hours. An emulsification technique has been used to prepare acyclovir-loaded chitosan microspheres with the aim of promoting the prolonged release of drug and increasing its ocular bioavailability.

The microparticulate drug-delivery systems obtained have been characterized for their morphology and physicochemical characteristics by in-vitro dissolution tests and in-vivo ocular administration to rabbits. The results show that the microspheres obtained are always quite small—the diameters of 90% of the particles are ≤ 25 μm (i.e. d90% never exceeds 25 μm) and physicochemical characterization shows that the drug is homogeneously dispersed in an amorphous state inside the microspheres. The in-vitro dissolution profile of acyclovir from chitosan microspheres is slower than that for the raw drug. Results from in-vivo ocular administration of acyclovir-loaded microspheres to the rabbit eye show prolonged high concentrations of acyclovir and increased AUC values.

The microparticulate drug-carrier seems a promising means of topical administration of acyclovir to the eye.
Study of the Effective Dose of a Topical Antifungal Agent, Omoconazole Nitrate, on the Basis of Percutaneous Pharmacokinetics in Guinea-pigs and Mice
Authors: Hashiguchi Terushi , Ryu Akie , Itoyama Toshio , Uchida Katsuhisa , Yamaguchi Hideyo
Published: April 2011

The clinically useful optimum dose of omoconazole nitrate, a topical antifungal agent, has been examined by analysing the percutaneous pharmacokinetics of the drug to assess its pharmacological activity in an in-vivo study. Creams containing omoconazole nitrate were prepared on a pilot basis.

The therapeutic effect of the omoconazole nitrate creams was examined in an in-vivo pharmacological dermatophytosis infection model in guinea-pigs. Creams containing 0.25% or higher concentrations of omoconazole nitrate resulted in significant inhibition compared with no treatment and with vehicle-treated controls. In the mycological examination no growth of dermatophytes was observed for creams containing 1% or higher concentrations. In an in-vitro hairless mouse skin-permeability test a non-linear least squares program based on a fast inverse Laplace transform algorithm was used to calculate the partition and diffusion parameters of omoconazole nitrate in the stratum corneum and viable epidermis. The time-course of drug concentrations in the skin of the guinea-pig, estimated on the basis of these parameters, led to predictions that percutaneous drug concentrations on the guinea-pig would require 10 or more days to reach equilibrium in the skin; that drug concentrations in the corneum-viable epidermis border, where dermatophytes are considered to grow, would exceed the minimum effective concentration when 0.1% or higher concentration creams were used; and that for binding to keratin drug concentrations would reach the practical minimum effective concentration when creams containing 0.5% or more omoconazole nitrate were used.

These results show that partition and diffusion parameters obtained from in-vitro skin permeation studies can be used to predict in-vivo percutaneous pharmacokinetics and to estimate therapeutically effective concentrations.
Gastroprotective Effect of MX1 (a Novel Salt of the Active Metabolite of Roxatidine with a Complex of Bismuth and Citric Acid) Against Stress Ulcers in Rats
Authors: Marazova K , Klouchek E , Popov A , Ivanov Ch , Krushkov I
Published: April 2011

We have studied the effect of the newly synthesized agent MX1, a salt of the active metabolite of the H2-blocker roxatidine with a complex of bismuth and citric acid (N-[3-(3-(1-piperidinylmethyl)phenoxy)propyl]-hydroxyacetamide-2-hydroxypropane-1,2,3-tricarboxilate-bismuth(3+) complex), against restraint stress ulcers in rats (24 h immobilization).

The effects of MX1 (12.5, 50, 125, 184 and 250 mg kg−) were compared with the effects of equimolar doses of roxatidine (6.5, 25, 70, 100 and 140 mg kg−) and bismuth subcitrate (6.5, 25, 70, 100 and 140 mg kg−). The results show that MX1-pre-treatment, at all the doses used, significantly reduces the mean number and size of ulcers. Even at the lowest dose the number of ulcers was reduced by 64.3% and the size of the ulcer by 55.9%. Roxatidine (25, 70, 100 and 140 mg kg−) dose-dependently reduces ulcer size and number by 24.6, 55.6, 85.3 and 890% and by (+ 7.2), 14.3, 571 and 67.9%, respectively. Bismuth subcitrate significantly reduces ulcer size and number only at the highest dose employed (−28.5 and −44.8%, respectively). The morphometric results have been confirmed histomorphologically.

The results suggest that MX1 has a gastroprotective effect against stress-induced ulcers which is similar to that of the parent compound and more pronounced than that of bismuth subcitrate.
Chronic Treatment with Prazosin Causes a Subtype-specific Increase in the α1-Adrenoceptor Density of the Stressed Rat Cerebral Cortex
Authors: Takita Manabu , Taniguchi Takanobu , Zhu Jun , Muramatsu Ikunobu
Published: April 2011

The effects of chronic treatment with prazosin and of immobilization stress on the α1-adrenoceptor subtypes in rat cerebral cortex have been examined.

Prazosin-treated rats were allowed free access to tap water containing two different concentrations of prazosin (16 or 156 mg L−) for 5 weeks. The mean plasma concentrations of prazosin were 5 ng mL− in groups treated with a low dose and 8 or 14 ng mL− in those treated with a high dose. Immobilization stress (2 h day−, 2 weeks) or chronic treatment with a low dose of prazosin caused no significant change in the affinity for [3H]prazosin or in the maximum number of α1-adrenoceptor sites (Bmax). However, treatment with prazosin (low dose) combined with stress increased the density of α1-adrenoceptors with low affinity for prazosin. Treatment with a high dose of prazosin increased the density of α1L-adrenoceptors, irrespective of stress loading. The densities of α1A- and α1B-adrenoceptors with high affinity for prazosin were increased only after treatment with a high dose of prazosin in combination with stress.

These results indicate that three distinct α1-adrenoceptor subtypes, α1A, α1B and α1L, might be affected differently by treatment with prazosin and by stress.
Antinociceptive Effect of some Amaryllidaceae Plants in Mice
Authors: Çakici Iclal , Ulug Hediye Y , Inci Sibel , Tunçtan Bahar , Abacioglu Nurettin , Kanzik Ilker , Sener Bilge
Published: April 2011

The antinociceptive effects of ethanolic extracts of Pancratium maritimum L., Narcissus tazetta subspecies tazetta and Leucojum aestivum L. bulbs have been investigated in mice using the p-benzoquinone-induced abdominal constriction and hot-plate tests.

In the p-benzoquinone-induced abdominal constriction test the ethanolic extracts of P. maritimum (300, 600 or 1200 mg lg−, s.c.) and N. tazetta subsp. tazetta (5, 50, 100 or 200 mg kg−, s.c.) caused dose-dependent inhibition of abdominal constrictions whereas a fluctuating response was obtained from ethanolic extracts of L. aestivum (2.5–500 mg kg−, s.c). In the hot-plate test P. maritimum and L. aestivum caused a significant increase of latency only at the highest concentrations used (1200 mg kg− and 500 mg kg−, i.p., respectively). However, at these concentrations they also caused significant toxic effects. In contrast with P. maritimum and L aestivum, N. tazetta subsp. tazetta (5–500 mg kg−, i.p.) extracts had no antinociceptive effect in this test.

These findings indicate that the antinociceptive effect of Amaryllidaceae plants differs depending on the model of nociception investigated.
Pharmacological Studies on Puerariae flos III: Protective Effects of Kakkalide on Ethanol-induced Lethality and Acute Hepatic Injury in Mice
Authors: Yamazaki Takashi , Nakajima Yoshijiro , Niiho Yujiro , Hosono Tsuyoshi , Kurashige Tatsuo , Kinjo Junei , Nohara Toshihiro
Published: April 2011

Kakkalide, one of the major isoflavonoid components of Puerariae flos, has been investigated for its effect on ethanol-induced intoxication and on hepatic injury, including hyperglycaemia, in mice.

Kakkalide reduced mortality associated with administration of ethanol. At doses of 100 and 200 mg kg− the effect of kakkalide was significant. The same dose of kakkalide prevented increased serum glutamic oxaloacetic transaminase and glutamic pyruvic transaminase activity. At a dose of 200 mg kg− it also counteracted ethanol-induced elevation of glucose levels.

These results suggest that kakkalide might be useful for counteracting the effects of alcohol and might be effective for treating hepatic injury.
Synthesis and Structure-Opioid Activity Relationships of trans-(±)-3,4-Dichloro-N-methyl-N-[4- or 5-hydroxy-2-(1-pyrrolidiny)cyclohexyl]benzeneacetamides
Authors: Cheng Chen-Yu , Chen Chin-Yuan , Tao Pao-Luh
Published: April 2011

To explore the effects of attaching a hydroxy function to the cyclohexane ring of κ-selective opioid N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamides, trans-(±)-3,4-dichloro-N-methyl-N-[4- or 5-hydroxy-2-(1-pyrrolidiny)cyclohexyl]benzeneacetamides (1–4) and their benzoates (5–8) have been synthesized in a divergent and stereoselective manner.

When compared with the parent compound U-50488, hydroxy derivatives 1–4 maintained high selectivity towards the κ-opioid receptor (μ/κ ratio = 24 to >91); while displaying significant reduction in binding affinity (Ki,κ = 75–218 nm). The lowest κ-affinity was observed with compound 4, where the hydroxy group is attached at the 5-axial or 5-β position. Further reduction in κ-affinity was observed when the hydroxy function was benzoylated. However, the 4β, 5α, and 5β isomers (6–8) maintained varying degrees of κ-selectivity; the 4α-isomer compound 5, with its benzoate moiety situated at the 4-axial position is now a moderately potent μ-selective opioid (Ki/μ= 168 nm, μ/κ = 0.076).

The results suggest the importance of lipophilicity in binding to opioid receptors and the presence of a specific lipophilic binding site on the μ-opioid receptor.